Effects of Intensive Blood Pressure Treatment on Acute Kidney Injury Events in the Systolic Blood Pressure Intervention Trial (SPRINT).

BACKGROUND: Treating to a lower blood pressure (BP) may increase acute kidney injury (AKI) events. STUDY DESIGN: Data for AKI resulting in or during hospitalization or emergency department visits were collected as part of the serious adverse events reporting process of the Systolic Blood Pressure Intervention Trial (SPRINT). SETTING & PARTICIPANTS: 9,361 participants 50 years or older with 1 or more risk factors for cardiovascular disease. INTERVENTIONS: Participants were randomly assigned to a systolic BP target of <120 (intensive arm) or <140mmHg (standard arm). OUTCOMES & MEASUREMENTS: Primary outcome was the number of adjudicated AKI events. Secondary outcomes included severity of AKI and degree of recovery of kidney function after an AKI event. Baseline creatinine concentration was defined as the most recent SPRINT outpatient creatinine value before the date of the AKI event. RESULTS: There were 179 participants with AKI events in the intensive arm and 109 in the standard arm (3.8% vs 2.3%; HR, 1.64; 95% CI, 1.30-2.10; P<0.001). Of 288 participants with an AKI event, 248 (86.1%) had a single AKI event during the trial. Based on modified KDIGO (Kidney Disease: Improving Global Outcomes) criteria for severity of AKI, the number of AKI events in the intensive versus standard arm by KDIGO stage was 128 (58.5%) versus 81 (62.8%) for AKI stage 1, 42 (19.2%) versus 18 (14.0%) for AKI stage 2, and 42 (19.2%) versus 25 (19.4%) for AKI stage 3 (P=0.5). For participants with sufficient data, complete or partial resolution of AKI was seen for 169 (90.4%) and 9 (4.8%) of 187 AKI events in the intensive arm and 86 (86.9%) and 4 (4.0%) of 99 AKI events in the standard arm, respectively. LIMITATIONS: Trial results are not generalizable to patients with diabetes mellitus or without risk factors for cardiovascular disease. CONCLUSIONS: More intensive BP lowering resulted in more frequent episodes of AKI. Most cases were mild and most participants had complete recovery of kidney function. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01206062.

Associations of Early Kidney Disease With Brain Magnetic Resonance Imaging and Cognitive Function in African Americans With Type 2 Diabetes Mellitus.

BACKGROUND: Relationships between early kidney disease, neurocognitive function, and brain anatomy are poorly defined in African Americans with type 2 diabetes mellitus (T2DM). STUDY DESIGN: Cross-sectional associations were assessed between cerebral anatomy and cognitive performance with estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) in African Americans with T2DM. SETTING & PARTICIPANTS: African Americans with cognitive testing and cerebral magnetic resonance imaging (MRI) in the African American-Diabetes Heart Study Memory in Diabetes (AA-DHS MIND; n=512; 480 with MRI) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) MIND (n=484; 104 with MRI) studies. PREDICTORS: eGFR (CKD-EPI creatinine equation), spot UACR. MEASUREMENTS: MRI-based cerebral white matter volume (WMV), gray matter volume (GMV), and white matter lesion volume; cognitive performance (Mini-Mental State Examination, Digit Symbol Coding, Stroop Test, and Rey Auditory Verbal Learning Test). Multivariable models adjusted for age, sex, body mass index, scanner, intracranial volume, education, diabetes duration, hemoglobin A1c concentration, low-density lipoprotein cholesterol concentration, smoking, hypertension, and cardiovascular disease were used to test for associations between kidney phenotypes and the brain in each study; a meta-analysis was performed. RESULTS: Mean participant age was 60.1±7.9 (SD) years; diabetes duration, 12.1±7.7 years; hemoglobin A1c concentration, 8.3%±1.7%; eGFR, 88.7±21.6mL/min/1.73m2; and UACR, 119.2±336.4mg/g. In the fully adjusted meta-analysis, higher GMV associated with lower UACR (P<0.05), with a trend toward association with higher eGFR. Higher white matter lesion volume was associated with higher UACR (P<0.05) and lower eGFR (P<0.001). WMV was not associated with either kidney parameter. Higher UACR was associated with lower Digit Symbol Coding performance (P<0.001) and a trend toward association with higher Stroop interference; eGFR was not associated with cognitive tests. LIMITATIONS: Cross-sectional; single UACR measurement. CONCLUSIONS: In African Americans with T2DM, mildly high UACR and mildly low eGFR were associated with smaller GMV and increased white matter lesion volume. UACR was associated with poorer processing speed and working memory.

Recruitment strategies and challenges in a large intervention trial: Systolic Blood Pressure Intervention Trial.

BACKGROUND: The Systolic Blood Pressure Intervention Trial is a multicenter, randomized clinical trial of 9361 participants with hypertension who are ≥50 years old. The trial is designed to evaluate the effect of intensive systolic blood pressure control (systolic blood pressure goal <120 mm Hg) compared to standard control (systolic blood pressure goal <140 mm Hg) on cardiovascular events using commonly prescribed antihypertensive medications and lifestyle modification. OBJECTIVE: To describe the recruitment strategies and lessons learned during recruitment of the Systolic Blood Pressure Intervention Trial cohort and five targeted participant subgroups: pre-existing cardiovascular disease, pre-existing chronic kidney disease, age ≥75 years, women, and minorities. METHODS: In collaboration with the National Institutes of Health Project Office and Systolic Blood Pressure Intervention Trial Coordinating Center, five Clinical Center Networks oversaw clinical site selection, recruitment, and trial activities. Recruitment began on 8 November 2010 and ended on 15 March 2013 (about 28 months). Various recruitment strategies were used, including mass mailing, brochures, referrals from healthcare providers or friends, posters, newspaper ads, radio ads, and electronic medical record searches. RESULTS: Recruitment was scheduled to last 24 months to enroll a target of 9250 participants; in just over 28 months, the trial enrolled 9361 participants. The trial screened 14,692 volunteers, with 33% of initial screens originating from the use of mass mailing lists. Screening results show that participants also responded to recruitment efforts through referral by Systolic Blood Pressure Intervention Trial staff, healthcare providers, or friends (45%); brochures or posters placed in clinic waiting areas (15%); and television, radio, newspaper, Internet ads, or toll-free numbers (8%). The overall recruitment yield (number randomized/number screened) was 64% (9361 randomized/14,692 screened), 77% for those with cardiovascular disease, 79% for those with chronic kidney disease, 70% for those aged ≥75 years, 55% for women, and 61% for minorities. As recruitment was observed to lag behind expectations, additional clinics were included and inclusion criteria were broadened, keeping event rates and trial power in mind. As overall recruitment improved, a greater focus on subgroup recruitment was implemented. CONCLUSION: Systolic Blood Pressure Intervention Trial met its overall projected recruitment goal using diverse, locally adapted enrollment strategies to specifically target persons with cardiovascular disease, chronic kidney disease, ≥75 years old, women, and minority subgroups. The trial exceeded its recruitment goal for minorities but found it a challenge to meet the competing demands of the targeted goals for recruiting into the remaining four subgroups. Important lessons include the imperative to monitor the recruitment process carefully, decide early to add new clinics or modify inclusion and exclusion criteria if recruitment lags, and consider limiting enrollment to subgroups only. We found benefit in using multiple recruitment sources simultaneously; mass mailing produced the largest number of participants, but referrals resulted in the greater randomization yield.

Sleep duration, cognitive decline, and dementia risk in older women.

INTRODUCTION: Consistent evidence linking habitual sleep duration with risks of mild cognitive impairment (MCI) and dementia is lacking. METHODS: We conducted a prospective study on 7444 community-dwelling women (aged 65-80 y) with self-reported sleep duration, within the Women's Health Initiative Memory Study in 1995-2008. Incident MCI/dementia cases were ascertained by validated protocols. Cox models were used to adjust for multiple sociodemographic and lifestyle factors, depression, cardiovascular disease (CVD), and other clinical characteristics. RESULTS: We found a statistically significant (P = .03) V-shaped association with a higher MCI/dementia risk in women with either short (≤6 hours/night) or long (≥8 hours/night) sleep duration (vs. 7 hours/night). The multicovariate-adjusted hazard for MCI/dementia was increased by 36% in short sleepers irrespective of CVD, and by 35% in long sleepers without CVD. A similar V-shaped association was found with cognitive decline. DISCUSSION: In older women, habitual sleep duration predicts the future risk for cognitive impairments including dementia, independent of vascular risk factors.

Effects of combination lipid therapy in type 2 diabetes mellitus.

BACKGROUND: We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease. METHODS: We randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS: The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P=0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P=0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P=0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol (P=0.057 for interaction). CONCLUSIONS: The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)

Lipid-modifying therapies and risk of pancreatitis: a meta-analysis.

CONTEXT: Statin therapy has been associated with pancreatitis in observational studies. Although lipid guidelines recommend fibrate therapy to reduce pancreatitis risk in persons with hypertriglyceridemia, fibrates may lead to the development of gallstones, a risk factor for pancreatitis. OBJECTIVE: To investigate associations between statin or fibrate therapy and incident pancreatitis in large randomized trials. DATA SOURCES: Relevant trials were identified in literature searches of MEDLINE, EMBASE, and Web of Science (January 1, 1994, for statin trials and January 1, 1972, for fibrate trials, through June 9, 2012). Published pancreatitis data were tabulated where available (6 trials). Unpublished data were obtained from investigators (22 trials). STUDY SELECTION: We included randomized controlled cardiovascular end-point trials investigating effects of statin therapy or fibrate therapy. Studies with more than 1000 participants followed up for more than 1 year were included. DATA EXTRACTION: Trial-specific data described numbers of participants developing pancreatitis and change in triglyceride levels at 1 year. Trial-specific risk ratios (RRs) were calculated and combined using random-effects model meta-analysis. Between-study heterogeneity was assessed using the I2 statistic. RESULTS: In 16 placebo- and standard care-controlled statin trials with 113,800 participants conducted over a weighted mean follow-up of 4.1 (SD, 1.5) years, 309 participants developed pancreatitis (134 assigned to statin, 175 assigned to control) (RR, 0.77 [95% CI, 0.62-0.97; P = .03; I2 = 0%]). In 5 dose-comparison statin trials with 39,614 participants conducted over 4.8 (SD, 1.7) years, 156 participants developed pancreatitis (70 assigned to intensive dose, 86 assigned to moderate dose) (RR, 0.82 [95% CI, 0.59-1.12; P = .21; I2 = 0%]). Combined results for all 21 statin trials provided RR 0.79 (95% CI, 0.65-0.95; P = .01; I2 = 0%). In 7 fibrate trials with 40,162 participants conducted over 5.3 (SD, 0.5) years, 144 participants developed pancreatitis (84 assigned to fibrate therapy, 60 assigned to placebo) (RR, 1.39 [95% CI, 1.00-1.95; P = .053; I2 = 0%]). CONCLUSION: In a pooled analysis of randomized trial data, use of statin therapy was associated with a lower risk of pancreatitis in patients with normal or mildly elevated triglyceride levels.

Role of fibrates in cardiovascular disease prevention, the ACCORD-Lipid perspective.

PURPOSE OF REVIEW: To examine the results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Lipid trial, particularly the subgroup analyses. It is important, when a study fails to meet its overall primary endpoint, to ensure that interpretation of the results include analyses of subgroups that might benefit from the treatment tested. The goal of this review, therefore, is to provide insight and advice to physicians and healthcare workers treating patients similar to those enrolled in ACCORD. RECENT FINDINGS: The recently published results of ACCORD-Lipid trial will be presented upon the background of previous trials that have tested the ability of fibrates to lower cardiovascular risk. SUMMARY: Although ACCORD-Lipid trial did not provide support for the general addition of fenofibrate to statin-treated patients with type 2 diabetes mellitus (T2DM), it added significantly to the results from fibrate monotherapy trials indicative of benefit from such treatment in subgroups of patients who present with significant dyslipidemia. In particular, ACCORD-Lipid trial, in our view, supports the addition of fenofibrate to statin therapy in patients with T2DM and optimal low-density lipoprotein cholesterol levels but persistent, significant hypertriglyceridemia (>200 mg/dl) and low high-density lipoprotein cholesterol levels (<35-40 mg/dl).

Incidence and Outcomes of Acute Heart Failure With Preserved Versus Reduced Ejection Fraction in SPRINT.

BACKGROUND: In the SPRINT (Systolic Blood Pressure Intervention Trial), intensive BP treatment reduced acute decompensated heart failure (ADHF) events. Here, we report the effect on HF with preserved ejection fraction (HFpEF) and HF with reduced EF (HFrEF) and their subsequent outcomes. METHODS: Incident ADHF was defined as hospitalization or emergency department visit, confirmed, and formally adjudicated by a blinded events committee using standardized protocols. HFpEF was defined as EF ≥45%, and HFrEF was EF <45%. RESULTS: Among the 133 participants with incident ADHF who had EF assessment, 69 (52%) had HFpEF and 64 (48%) had HFrEF (P value: 0.73). During average 3.3 years follow-up in those who developed incident ADHF, rates of subsequent all-cause and HF hospital readmission and mortality were high, but there were no significant differences between those who developed HFpEF versus HFrEF. Randomization to the intensive arm had no effect on subsequent mortality or readmissions after the initial ADHF event, irrespective of EF subtype. During follow-up among participants who developed HFpEF, although relatively modest number of events limited statistical power, age was an independent predictor of all-cause mortality, and Black race independently predicted all-cause and HF hospital readmission. CONCLUSIONS: In SPRINT, intensive BP reduction decreased both acute decompensated HFpEF and HFrEF events. After initial incident ADHF, rates of subsequent hospital admission and mortality were high and were similar for those who developed HFpEF or HFrEF. Randomization to the intensive arm did not alter the risks for subsequent all-cause, or HF events in either HFpEF or HFrEF. Among those who developed HFpEF, age and Black race were independent predictors of clinical outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.

Impact of Baseline Fatigue on a Physical Activity Intervention to Prevent Mobility Disability.

OBJECTIVES: Our aim was to examine the impacts of baseline fatigue on the effectiveness of a physical activity (PA) intervention to prevent major mobility disability (MMD) and persistent major mobility disability (PMMD) in participants from the Lifestyle Interventions and Independence for Elders (LIFE) study. DESIGN: Prospective cohort of individuals aged 65 years or older undergoing structured PA intervention or health education (HE) for a mean of 2.6 years. SETTING: LIFE was a multicenter eight-site randomized trial that compared the efficacy of a structured PA intervention with an HE program in reducing the incidence of MMD. PARTICIPANTS: Study participants (N = 1591) at baseline were 78.9 ± 5.2 years of age, with low PA and at risk for mobility impairment. MEASUREMENTS: Self-reported fatigue was assessed using the modified trait version of the Exercise-Induced Feelings Inventory, a six-question scale rating energy levels in the past week. Responses ranged from 0 (none of the time) to 5 (all of the time). Total score was calculated by averaging across questions; baseline fatigue was based on the median split: 2 or higher = more fatigue (N = 856) and lower than 2 = less fatigue (N = 735). Participants performed a usual-paced 400-m walk every 6 months. We defined incident MMD as the inability to walk 400-m at follow-up visits; PMMD was defined as two consecutive walk failures. Cox proportional hazard models quantified the risk of MMD and PMMD in PA vs HE stratified by baseline fatigue adjusted for covariates. RESULTS: Among those with higher baseline fatigue, PA participants had a 29% and 40% lower risk of MMD and PMMD, respectively, over the trial compared with HE (hazard ratio [HR] for MMD = .71; 95% confidence interval [CI] = .57-.90; P = .004) and PMMD (HR = .60; 95% CI = .44-.82; P = .001). For those with lower baseline fatigue, no group differences in MMD (P = .36) or PMMD (P = .82) were found. Results of baseline fatigue by intervention interaction was MMD (P = .18) and PMMD (P = .05). CONCLUSION: A long-term moderate intensity PA intervention was particularly effective at preserving mobility in older adults with higher levels of baseline fatigue. J Am Geriatr Soc 68:619-624, 2020.

The Moderate Alcohol and Cardiovascular Health Trial (MACH15): Design and methods for a randomized trial of moderate alcohol consumption and cardiometabolic risk.

BACKGROUND: Observational studies have documented lower risks of coronary heart disease and diabetes among moderate alcohol consumers relative to abstainers, but only a randomized clinical trial can provide conclusive evidence for or against these associations. AIM: The purpose of this study was to describe the rationale and design of the Moderate Alcohol and Cardiovascular Health Trial, aimed to assess the cardiometabolic effects of one alcoholic drink daily over an average of six years among adults 50 years or older. METHODS: This multicenter, parallel-arm randomized trial was designed to compare the effects of one standard serving (∼11-15 g) daily of a preferred alcoholic beverage to abstention. The trial aimed to enroll 7800 people at high risk of cardiovascular disease. The primary composite endpoint comprised time to the first occurrence of non-fatal myocardial infarction, non-fatal ischemic stroke, hospitalized angina, coronary/carotid revascularization, or total mortality. The trial was designed to provide >80% power to detect a 15% reduction in the risk of the primary outcome. Secondary outcomes included diabetes. Adverse effects of special interest included injuries, congestive heart failure, alcohol use disorders, and cancer. RESULTS: We describe the design, governance, masking issues, and data handling. In three months of field center activity until termination by the funder, the trial randomized 32 participants, successfully screened another 70, and identified ∼400 additional interested individuals. CONCLUSIONS: We describe a feasible design for a long-term randomized trial of moderate alcohol consumption. Such a study will provide the highest level of evidence for the effects of moderate alcohol consumption on cardiovascular disease and diabetes, and will directly inform clinical and public health guidelines.

Heart Failure Prevention in Older Patients Using Intensive Blood Pressure Reduction: Potential Role of Diuretics.

OBJECTIVES: This study assessed the potential role of differential diuretic drugs in preventing incident acute decompensated heart failure (ADHF) in the SPRINT (Systolic Blood Pressure Intervention Trial) study. BACKGROUND: SPRINT showed that intensive blood pressure reduction in older patients (50 to 97 years of age) resulted in 36% fewer incident cases of ADHF. However, some investigators have questioned whether this was due merely to intergroup differences in diuretic medications. METHODS: Detailed use of medication data prospectively collected throughout the trial were examined. RESULTS: ADHF events occurred in 173 of 9,361 participants. Diuretic medication increased in both arms from screening to baseline visit (from 45% to 50% in the standard arm; and from 43% to 63% in the intensive arm) and then remained steady. The lowest use of diuretic agents was among participants in the standard arm who never had an ADHF event. Withdrawal of diuretic agents at the baseline visit occurred in 6.1% (n = 284) of participants in the standard arm and 2.3% (n = 107) of participants in the intensive arm. Of these, only 11 developed ADHF during the trial (10 in the standard arm, 1 in the intensive arm), and only 1 occurred ≤1 month after diuretic withdrawal. The benefit of ADHF reduction remained significant even after excluding those 11 participants (hazard ratio [HR]: 0.69; 95% confidence interval [CI]: 0.5 to 0.94; p = 0.02). Most ADHF events occurred in participants who were taking prescribed diuretic therapy at the last visit, prior to the ADHF event. There was limited use of loop (<6%) and potassium-sparing diuretic agents (2%). Diuretic use was not a predictor of ADHF (HR: 0.96; 95% CI: 0.66 to 1.40; p = 0.83). CONCLUSIONS: No evidence was found to suggest that the reduction in new ADHF events in SPRINT was due to differential diuretic use. (Systolic Blood Pressure Intervention Trial [SPRINT]; NCT01206062).

Serum Sodium and Pulse Pressure in SPRINT.

BACKGROUND: High dietary sodium intake may induce a small, yet physiologically relevant rise in serum sodium concentration, which associates with increased systolic blood pressure. Cellular data suggest that this association is mediated by increased endothelial cell stiffness. We hypothesized that higher serum sodium levels were associated with greater arterial stiffness in participants in the Systolic Blood Pressure Intervention Trial (SPRINT). METHODS: Multivariable linear regression was used to examine the association between baseline serum sodium level and (i) pulse pressure (PP; n = 8,813; a surrogate measure of arterial stiffness) and (ii) carotid-femoral pulse wave velocity (CFPWV; n = 591 in an ancillary study to SPRINT). RESULTS: Baseline mean ± SD age was 68 ± 9 years and serum sodium level was 140 ± 2 mmol/L. In the PP analysis, higher serum sodium was associated with increased baseline PP in the fully adjusted model (tertile 3 [≥141 mmol] vs. tertile 2 [139-140 mmol]; ß = 0.87, 95% CI = 0.32 to 1.43). Results were similar in those with and without chronic kidney disease. In the ancillary study, higher baseline serum sodium was not associated with increased baseline CFPWV in the fully adjusted model (ß = 0.35, 95% CI = -0.14 to 0.84). CONCLUSIONS: Among adults at high risk for cardiovascular events but free from diabetes, higher serum sodium was independently associated with baseline arterial stiffness in SPRINT, as measured by PP, but not by CFPWV. These results suggest that high serum sodium may be a marker of risk for increased PP, a surrogate index of arterial stiffness.

Effect of Losartan and Fish Oil on Plasma IL-6 and Mobility in Older Persons. The ENRGISE Pilot Randomized Clinical Trial.

BACKGROUND: Low-grade chronic inflammation, characterized by elevations in plasma Interleukin-6 (IL-6), is an independent risk factor of impaired mobility in older persons. Angiotensin receptor blockers and omega-3 polyunsaturated fatty acids (ω-3) may reduce IL-6 and may potentially improve physical function. To assess the main effects of the angiotensin receptor blocker losartan and ω-3 as fish oil on IL-6 and 400 m walking speed, we conducted the ENRGISE Pilot multicenter randomized clinical trial. METHODS: The ENRGISE Pilot enrolled participants between April 2016 and June 2017, who participated for 12 months. Participants were aged ≥70 years with mobility impairment, had IL-6 between 2.5 and 30 pg/mL, and were able to walk 400 m at baseline. Participants were randomized in three strata 2 × 2 factorial to: (i) losartan 50-100 mg/d or placebo (n = 43), (ii) fish oil 1,400-2,800 mg/d or placebo (n = 180), and (iii) with both (n = 66). RESULTS: Two hundred eighty-nine participants were randomized (mean age 78.3 years, 47.4% women, 17.0% black). There was no effect of losartan (difference of means = -0.065 ± 0.116 [SE], 95% confidence interval [CI]: -0.293-0.163, p = .58) or fish oil (-0.020 ± 0.077, 95% CI: -0.171-0.132, p = .80) on the log of IL-6. Similarly, there was no effect of losartan (-0.025 ± 0.026, 95% CI: -0.076-0.026, p = .34) or fish oil (0.010 ± 0.017, 95% CI: -0.025-0.044, p = .58) on walking speed (m/s). CONCLUSIONS: These results do not support the use of these interventions to prevent mobility loss in older adults at risk of disability with low-grade chronic inflammation. REGISTRATION: Clinicaltrials.gov NCT02676466.

Gender, blood pressure, and cardiovascular and renal outcomes in adults with hypertension from the Systolic Blood Pressure Intervention Trial.

BACKGROUND: To determine if the effects of intensive lowering of systolic blood pressure (goal of less than 120 mmHg) versus standard lowering (goal of less than 140 mmHg) upon cardiovascular, renal, and safety outcomes differed by gender. METHODS: Nine thousand three hundred and sixty-one men and women aged 50 years or older with systolic blood pressure of 130 mmHg or greater, taking 0-4 antihypertensive medications, and with increased risk of cardiovascular disease, but free of diabetes, were randomly assigned to either a systolic blood pressure target of less than 120 mmHg (intensive treatment) or a target of less than 140 mmHg (standard treatment). The primary composite outcome encompassed incident myocardial infarction, heart failure, other acute coronary syndromes, stroke, or cardiovascular-related death. All-cause mortality, renal outcomes, and serious adverse events were also assessed. RESULTS: Compared with the standard treatment group, the primary composite outcome in the intensive treatment group was reduced by 16% [hazard ratio 0.84 (0.61-1.13)] in women, and by 27% in men [hazard ratio 0.73 (0.59-0.89), P value for interaction between treatment and gender is 0.45]. Similarly, the effect of the intensive treatment on individual components of the primary composite outcome, renal outcomes, and overall serious adverse events was not significantly different according to gender. CONCLUSION: In adults with hypertension but not with diabetes, treatment to a systolic blood pressure goal of less than 120 mmHg, compared with a goal of less than 140 mmHg, resulted in no heterogeneity of effect between men and women on cardiovascular or renal outcomes, or on rates of serious adverse events.ClinicalTrials.gov number, NCT01206062.

Evolution of the lipid trial protocol of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial aims to test whether a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) plus a fibrate is more efficacious in reducing cardiovascular events than a statin plus placebo in patients with type 2 diabetes mellitus with defined glycemic control. This is a blinded component in a 5,518-patient subset of the ACCORD cohort. These participants were randomized to either be (1) treated with simvastatin (titrated to 40 mg/day if necessary to achieve a goal low-density lipoprotein [LDL] cholesterol level of <2.59 mmol/L [100 mg/dL]) plus placebo or (2) treated to the same goal LDL cholesterol level with the statin plus active fenofibrate 160 mg/day or its bioequivalent (or 54 mg/day if the estimated glomerular filtration rate ranges from 30 to <50 mL/min per 1.73 m2). Setting an upper limit of LDL cholesterol qualifying for randomization excluded patients who would not likely achieve the LDL cholesterol goal. Recruitment for ACCORD began in January 2001, and follow-up is scheduled to end in June 2009. Since recruitment began, several clinical trials and consensus statements have been published that led to changes in the details of the lipid treatment algorithm and protocol. This report describes the design of the lipid protocol and modifications to the protocol during the course of the study in response to and in anticipation of these developments. The current protocol is designed to provide an ethically justifiable test of combined statin plus fibrate treatment consistent with the highest level of safety and lipid treatment standards of care.

Recruitment strategies in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is a randomized, multicenter clinical trial using a double 2 x 2 factorial design in 10,251 participants with type 2 diabetes mellitus at high risk for cardiovascular disease (CVD) events. ACCORD is testing 3 complementary medical treatment strategies that may reduce high rates of major CVD morbidity and mortality in patients with type 2 diabetes. The ACCORD vanguard phase, conducted at 59 clinics in the United States and Canada, recruited 1,174 participants in 20 weeks from January through June 1, 2001, with a recruitment efficiency (R-factor) of 0.65. The recruitment strategies used in this vanguard phase were almost exclusively chart and database review within clinical practices and institutions. Recruitment for the main trial began in February 2003, involved 77 clinics, and resulted in an additional 9,077 participants by October 29, 2005 (total, 10,251). The R-factor during main trial recruitment was 0.96. Although new and refined recruitment strategies were formulated from the vanguard experience, the most powerful determinant of improved recruitment efficiency was the immediate start of enrollment by most clinics at the beginning of the main trial. Recruitment in the main trial required only a brief extension of 3 months and facilitated the nearly complete capture of the expected number of person-years of observation. Described herein are vanguard and main trial recruitment activities, including strategy implementation, screening procedures, randomization results, problems encountered, and lessons learned.

Effect of Physical Activity versus Health Education on Physical Function, Grip Strength and Mobility.

BACKGROUND: Physical activity (PA) reduces the rate of mobility disability, compared with health education (HE), in at risk older adults. It is important to understand aspects of performance contributing to this benefit. OBJECTIVE: To evaluate intervention effects on tertiary physical performance outcomes. DESIGN: The Lifestyle Interventions and Independence for Elders (LIFE) was a multi-centered, single-blind randomized trial of older adults. SETTING: Eight field centers throughout the United States. PARTICIPANTS: 1635 adults aged 78.9 ± 5.2 years, 67.2% women at risk for mobility disability (Short Physical Performance Battery [SPPB] <10). INTERVENTIONS: Moderate PA including walking, resistance and balance training compared with HE consisting of topics relevant to older adults. OUTCOMES: Grip strength, SPPB score and its components (balance, 4 m gait speed, and chair-stands), as well as 400 m walking speed. RESULTS: Total SPPB score was higher in PA versus HE across all follow-up times (overall P = .04) as was the chair-stand component (overall P < .001). No intervention effects were observed for balance (overall P = .12), 4 m gait speed (overall P = .78), or grip strength (overall P = .62). However, 400 m walking speed was faster in PA versus HE group (overall P =<.001). In separate models, 29% of the rate reduction of major mobility disability in the PA versus HE group was explained by change in SPPB score, while 39% was explained by change in the chair stand component. CONCLUSION: Lower extremity performance (SPPB) was significantly higher in the PA compared with HE group. Changes in chair-stand score explained a considerable portion of the effect of PA on the reduction of major mobility disability-consistent with the idea that preserving muscle strength/power may be important for the prevention of major mobility disability.

Effect of Intensive Blood Pressure Treatment on Heart Failure Events in the Systolic Blood Pressure Reduction Intervention Trial.

BACKGROUND: Acute decompensated heart failure (ADHF) was a frequent common outcome in SPRINT (Systolic Blood Pressure Intervention Trial). We examined whether there was differential reduction in ADHF events from intensive blood pressure [BP] treatment among the 6 key, prespecified subgroups in SPRINT: age ≥75 years, prior cardiovascular disease, chronic kidney disease, women, black race, and 3 levels of baseline systolic BP (≤132 versus >132 to <145 versus ≥145 mm Hg). METHODS AND RESULTS: ADHF was defined as hospitalization for ADHF, confirmed and formally adjudicated by a blinded events committee using standardized protocols. At 3.29 years follow-up, there were 103 ADHF events (2.2%) among 4683 standard arm participants and 65 ADHF events (1.4%) among 4678 intensive arm participants (Cox proportional hazards ratio, 0.63; 95% confidence interval, 0.46-0.85; P value =0.003). In multivariable analyses, including treatment arm, baseline covariates that were significant predictors for ADHF included chronic kidney disease, cardiovascular disease, age≥75 years, body mass index, and higher systolic BP. The beneficial effect of the intervention on incident ADHF was consistent across all prespecified subgroups. Participants who had incident ADHF had markedly increased risk of subsequent cardiovascular events, including a 27-fold increase (P<0.001) in cardiovascular death. CONCLUSIONS: Targeting a systolic BP<120 mm Hg, compared with <140 mm Hg, significantly reduced ADHF events, and the benefit was similar across all key, prespecified subgroups. Participants who developed ADHF had markedly increased risk for subsequent cardiovascular events and death, highlighting the importance of strategies aimed at prevention of ADHF, especially intensive BP reduction. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062.

Association of Fenofibrate Therapy With Long-term Cardiovascular Risk in Statin-Treated Patients With Type 2 Diabetes.

Importance: Patients with type 2 diabetes are at high risk of cardiovascular disease (CVD) in part owing to hypertriglyceridemia and low high-density lipoprotein cholesterol. It is unknown whether adding triglyceride-lowering treatment to statin reduces this risk. Objective: To determine whether fenofibrate reduces CVD risk in statin-treated patients with type 2 diabetes. Design, Setting, and Participants: Posttrial follow-up of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Study between July 2009 and October 2014; 5 years of follow-up were completed for a total of 9.7 years at general community and academic outpatient research clinics in the United States and Canada. Of the original 5518 ACCORD Lipid Trial participants, 4644 surviving participants were selected based on the presence of type 2 diabetes and either prevalent CVD or CVD risk factors and high-density lipoprotein levels less than 50 mg/dL (<55 mg/dL for women and African American individuals). Interventions: Passive follow-up of study participants previously treated with fenofibrate or masked placebo. Main Outcomes and Measures: Occurrence of cardiovascular outcomes including primary composite outcome of fatal and nonfatal myocardial infarction and stroke in all participants and in prespecified subgroups. Results: The 4644 follow-on study participants were broadly representative of the original ACCORD study population and included significant numbers of women (n = 1445; 31%), nonwhite individuals (n = 1094; 21%), and those with preexisting cardiovascular events (n = 1620; 35%). Only 4.3% of study participants continued treatment with fenofibrate following completion of ACCORD. High-density lipoprotein and triglyceride values rapidly equalized among participants originally randomized to fenofibrate or placebo. Over a median total postrandomization follow-up of 9.7 years, the hazard ratio (HR) for the primary study outcome among participants originally randomized to fenofibrate vs placebo (HR, 0.93; 95% CI, 0.83-1.05; P = .25) was comparable with that originally observed in ACCORD (HR, 0.92; 95% CI, 0.79-1,08; P = .32). Despite these overall neutral results, we continued to find evidence that fenofibrate therapy effectively reduced CVD in study participants with dyslipidemia, defined as triglyceride levels greater than 204 mg/dL and high-density lipoprotein cholesterol levels less than 34 mg/dL (HR, 0.73; 95% CI, 0.56-0.95). Conclusions and Relevance: Extended follow-up of ACCORD-lipid trial participants confirms the original neutral effect of fenofibrate in the overall study cohort. The continued observation of heterogeneity of treatment response by baseline lipids suggests that fenofibrate therapy may reduce CVD in patients with diabetes with hypertriglyceridemia and low high-density lipoprotein cholesterol. A definitive trial of fibrate therapy in this patient population is needed to confirm these findings. Trial Registration: clinicaltrials.gov Identifier: NCT00000620.

Economic analysis of vinorelbine plus cisplatin versus paclitaxel plus carboplatin for advanced non-small-cell lung cancer.

BACKGROUND: It is increasingly important to have timely information about the economic impact of new cancer therapies in today's cost-conscious environment. Nearly 170 000 people are diagnosed with lung cancer annually in the United States. We performed an economic analysis alongside Southwest Oncology Group Trial S9509 to estimate the cost-effectiveness of cisplatin plus vinorelbine versus carboplatin plus paclitaxel for patients with advanced non-small-cell lung cancer. There were no statistically significant differences in survival or cancer-related quality of life between the treatment arms. METHODS: Use of both protocol and nonprotocol lung cancer-related health care was tracked for 24 months from the initiation of therapy. To determine expenditures, nationally standardized costs were applied to each type of health care service used, and these were summed over time. Lifetime expenditures and 95% confidence intervals (CIs) for each arm of the trial were calculated with the use of a multivariate regression technique that accounts for censoring. Student's t tests were used to compare the difference in costs between the arms. All statistical tests were two-sided. RESULTS: Cancer-related health care costs over the period of observation averaged 40,292 dollars (95% CI = 36,226 dollars to 44,359 dollars) for patients in the cisplatin plus vinorelbine arm versus 48,940 dollars (95% CI = 44,674 dollars to 53,208 dollars) for patients in the carboplatin plus paclitaxel arm (P =.004), with a mean difference of 8648 dollars (95% CI = 2634 dollars to 14,662 dollars). Protocol chemotherapy drugs and medical procedures costs were statistically significantly higher in the paclitaxel arm (P =.0003 and P<.0001, respectively), whereas protocol chemotherapy delivery costs were statistically significantly higher in the vinorelbine arm (P<.0001). There was no difference between the arms in costs for blood products, supportive care medications, nonprotocol-related inpatient or outpatient care, and nonprotocol chemotherapy. CONCLUSIONS: Treatment with carboplatin plus paclitaxel is substantially and statistically significantly more expensive than treatment with cisplatin plus vinorelbine. The majority of the cost difference is due to the additional cost of the protocol chemotherapy (approximately 12,000 dollars). Notable differences in costs of downstream health care were not apparent.