Mortality Outcomes in a Large Population with and without Covert Cerebrovascular Disease.

Covert cerebrovascular disease (CCD) is frequently reported on neuroimaging and associates with increased dementia and stroke risk. We aimed to determine how incidentally-discovered CCD during clinical neuroimaging in a large population associates with mortality. We screened CT and MRI reports of adults aged ≥50 in the Kaiser Permanente Southern California health system who underwent neuroimaging for a non-stroke clinical indication from 2009-2019. Natural language processing identified incidental covert brain infarcts (CBI) and/or white matter hyperintensities (WMH), grading WMH as mild/moderate/severe. Models adjusted for age, sex, ethnicity, multimorbidity, vascular risks, depression, exercise, and imaging modality. Of n=241,028, the mean age was 64.9 (SD=10.4); mean follow-up 4.46 years; 178,554 (74.1%) had CT; 62,474 (25.9%) had MRI; 11,328 (4.7%) had CBI; and 69,927 (29.0%) had WMH. The mortality rate per 1,000 person-years with CBI was 59.0 (95%CI 57.0-61.1); with WMH=46.5 (45.7-47.2); with neither=17.4 (17.1-17.7). In adjusted models, mortality risk associated with CBI was modified by age, e.g. HR 1.34 [1.21-1.48] at age 56.1 years vs HR 1.22 [1.17-1.28] at age 72 years. Mortality associated with WMH was modified by both age and imaging modality e.g., WMH on MRI at age 56.1 HR = 1.26 [1.18-1.35]; WMH on MRI at age 72 HR 1.15 [1.09-1.21]; WMH on CT at age 56.1 HR 1.41 [1.33-1.50]; WMH on CT at age 72 HR 1.28 [1.24-1.32], vs. patients without CBI or without WMH, respectively. Increasing WMH severity associated with higher mortality, e.g. mild WMH on MRI had adjusted HR=1.13 [1.06-1.20] while severe WMH on CT had HR=1.45 [1.33-1.59]. Incidentally-detected CBI and WMH on population-based clinical neuroimaging can predict higher mortality rates. We need treatments and healthcare planning for individuals with CCD.

Effect of vitamin D on regression to normal glucose regulation and individual glycemic measures: A secondary analysis among participants adherent to the trial protocol in the randomized clinical trial vitamin D and type 2 diabetes (D2d) study.

AIMS: To examine the effect of vitamin D on regression to normal glucose regulation (NGR) and individual glycemic measures in the D2d study. METHODS: In per-protocol analyses, we examined time to new-onset diabetes; time to new-onset NGR defined as first occurrence of: 2-or-3 glycemic criteria in the normal range (NGR-1) or fasting plasma glucose (FPG) and 2-hour post-load-glucose (2hPG) in the normal range (NGR-2); proportion meeting NGR at the last study visit; and change in FPG, 2hPG, and HbA1c. RESULTS: Among 2423 participants, hazard ratio [HR] for diabetes was 0.84 [95%CI, 0.71, 0.99]). HR (95%CI) was 1.16 (0.99, 1.36) for new-onset NGR-1 and 1.06 (0.87, 1.30) for NGR-2. At the last visit, NGR-1 occurred in 12.4% vs. 9.5% participants in the vitamin D vs. placebo group (rate ratio for vitamin D 1.31 [1.02, 1.70]); whereas, NGR-2 occurred in 8.7% vs. 6.0% (rate ratio for vitamin D 1.45 [1.05, 2.00]). During follow-up, FPG, HbA1c, and 2hPG increased in both groups. Mean difference in FPG favored vitamin D (-0.80 mg/dL; 95%CI, -1.26, -0.33). CONCLUSIONS: In secondary analyses among participants adherent to the trial protocol, vitamin D lowered risk of developing diabetes and increased likelihood of NGR at the end of the study.

Indices of hepatic steatosis and fibrosis in prediabetes and association with diabetes development in the vitamin D and type 2 diabetes study.

AIMS: Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity that leads to poor outcomes in people at high risk for development of type 2 diabetes (T2D). Vitamin D is a possible mediator. In the vitamin D and type 2 diabetes study (D2d), we investigated the relationship of baseline indices of NAFLD with incident T2D and whether the effect of vitamin D on diabetes was modified by NAFLD. METHODS: Cross-sectional associations of indices of NAFLD with glycemia and vitamin D status were assessed in 3972 individuals screened for the D2d study. In those with prediabetes randomized to vitamin D or placebo (n = 2423), we examined longitudinal associations of NAFLD indices with incident T2D. We used validated non-invasive scores to assess steatosis [(hepatic steatosis index (HSI); NAFLD-liver fat score (NAFLD-LFS)] and advanced fibrosis [fibrosis-4 (FIB-4) index; AST to Platelet Ratio Index (APRI)]. RESULTS: Eighty-five percent of screened participants had likely steatosis by HSI and 71 % by NAFLD-LFS; 3 % were likely to have advanced fibrosis by FIB-4 and 1.2 % by APRI. FIB-4 indicated that 20.4 % of individuals require further follow up to assess liver health. Steatosis and fibrosis scores were higher among participants with worse glycemia. The NAFLD-LFS and APRI predicted development of diabetes (hazard ratios [95%CI] 1.35 [1.07, 1.70]; P = 0.012) and 2.36 (1.23, 4.54; P = 0.010), respectively). The effect of vitamin D on diabetes risk was not modified by baseline NAFLD indices. Individuals with likely steatosis had a smaller increase in serum 25-hydroxyvitamin D level in response to vitamin D than those without steatosis. CONCLUSIONS: The predicted high prevalence of steatosis, the need for further fibrosis workup, and the relationship between liver health and incident T2D suggest that routine screening with clinically accessible scores may be an important strategy to reduce disease burden.

Effect of intratrial mean 25(OH)D concentration on diabetes risk, by race and weight: an ancillary analysis in the D2d study.

BACKGROUND: Higher serum 25-hydroxyvitamin D [25(OH)D] is associated with lower type 2 diabetes risk. 25(OH)D varies due to skin pigmentation and weight. OBJECTIVES: This analysis aims to determine whether the effect of vitamin D differs among people of color and those with overweight/obesity (who have higher diabetes risk) compared with individuals who are White or have normal weight. METHODS: The D2d study is a randomized clinical trial in people with prediabetes that tested the effects of daily vitamin D3 4000 IU vs. placebo on diabetes risk (median followup 2.5 y). We compared baseline and intratrial mean 25(OH)D concentrations, defined as the mean of all available annual 25(OH)D values, among groups defined by self-reported race and body mass index (BMI). We used Cox proportional hazards models to assess the associations between intratrial mean 25(OH)D and diabetes risk by race- and BMI-based groups. RESULTS: Asian (n=130), Black (n=616), and White (n=1616) participants were included. Both baseline and intratrial mean 25(OH)D concentrations differed significantly by race groups (both P < 0.001) and were lower in Asian and Black vs. White participants, and in those with higher vs. lower BMI adjusted for race (both P < 0.001). Compared with those with lower concentrations, Black and White participants with intratrial mean 25(OH)D ≥ 40 ng/mL had significantly reduced diabetes risk [HR (95% CI): Black: 0.51 (0.29, 0.92); White: 0.42 (0.30, 0.60)] and with a similar reduction in diabetes risk among Asian participants: 0.39 (0.14, 1.11). Compared with those with lower concentrations, participants with baseline BMI < 40 kg/m2 who achieved intratrial mean 25(OH)D concentrations ≥ 40 ng/mL had a significantly reduced diabetes risk. There was no statistically significant interaction between intratrial 25(OH)D and race or between intratrial 25(OH)D and BMI on diabetes risk. CONCLUSIONS: Among people with prediabetes, particularly for Black and White race groups and those with BMI < 40 kg/m2, the optimal 25(OH)D concentration may be ≥ 40 ng/mL to optimize diabetes-prevention efforts. This trial was registered at clinicaltrials.gov as NCT01942694.

Vitamin D and Risk for Type 2 Diabetes in People With Prediabetes : A Systematic Review and Meta-analysis of Individual Participant Data From 3 Randomized Clinical Trials.

BACKGROUND: The role of vitamin D in people who are at risk for type 2 diabetes remains unclear. PURPOSE: To evaluate whether administration of vitamin D decreases risk for diabetes among people with prediabetes. DATA SOURCES: PubMed, Embase, and ClinicalTrials.gov from database inception through 9 December 2022. STUDY SELECTION: Eligible trials that were specifically designed and conducted to test the effects of oral vitamin D versus placebo on new-onset diabetes in adults with prediabetes. DATA EXTRACTION: The primary outcome was time to event for new-onset diabetes. Secondary outcomes were regression to normal glucose regulation and adverse events. Prespecified analyses (both unadjusted and adjusted for key baseline variables) were conducted according to the intention-to-treat principle. DATA SYNTHESIS: Three randomized trials were included, which tested cholecalciferol, 20 000 IU (500 mcg) weekly; cholecalciferol, 4000 IU (100 mcg) daily; or eldecalcitol, 0.75 mcg daily, versus matching placebos. Trials were at low risk of bias. Vitamin D reduced risk for diabetes by 15% (hazard ratio, 0.85 [95% CI, 0.75 to 0.96]) in adjusted analyses, with a 3-year absolute risk reduction of 3.3% (CI, 0.6% to 6.0%). The effect of vitamin D did not differ in prespecified subgroups. Among participants assigned to the vitamin D group who maintained an intratrial mean serum 25-hydroxyvitamin D level of at least 125 nmol/L (≥50 ng/mL) compared with 50 to 74 nmol/L (20 to 29 ng/mL) during follow-up, cholecalciferol reduced risk for diabetes by 76% (hazard ratio, 0.24 [CI, 0.16 to 0.36]), with a 3-year absolute risk reduction of 18.1% (CI, 11.7% to 24.6%). Vitamin D increased the likelihood of regression to normal glucose regulation by 30% (rate ratio, 1.30 [CI, 1.16 to 1.46]). There was no evidence of difference in the rate ratios for adverse events (kidney stones: 1.17 [CI, 0.69 to 1.99]; hypercalcemia: 2.34 [CI, 0.83 to 6.66]; hypercalciuria: 1.65 [CI, 0.83 to 3.28]; death: 0.85 [CI, 0.31 to 2.36]). LIMITATIONS: Studies of people with prediabetes do not apply to the general population. Trials may not have been powered for safety outcomes. CONCLUSION: In adults with prediabetes, vitamin D was effective in decreasing risk for diabetes. PRIMARY FUNDING SOURCE: None. (PROSPERO: CRD42020163522).

Development of Parkinson Disease and Its Relationship with Incidentally Discovered White Matter Disease and Covert Brain Infarction in a Real-World Cohort.

OBJECTIVE: This study aimed to examine the relationship between covert cerebrovascular disease, comprised of covert brain infarction and white matter disease, discovered incidentally in routine care, and subsequent Parkinson disease. METHODS: Patients were ≥50 years and received neuroimaging for non-stroke indications in the Kaiser Permanente Southern California system from 2009 to 2019. Natural language processing identified incidentally discovered covert brain infarction and white matter disease and classified white matter disease severity. The Parkinson disease outcome was defined as 2 ICD diagnosis codes. RESULTS: 230,062 patients were included (median follow-up 3.72 years). A total of 1,941 Parkinson disease cases were identified (median time-to-event 2.35 years). Natural language processing identified covert cerebrovascular disease in 70,592 (30.7%) patients, 10,622 (4.6%) with covert brain infarction and 65,814 (28.6%) with white matter disease. After adjustment for known risk factors, white matter disease was associated with Parkinson disease (hazard ratio 1.67 [95%CI, 1.44, 1.93] for patients <70 years and 1.33 [1.18, 1.50] for those ≥70 years). Greater severity of white matter disease was associated with increased incidence of Parkinson disease(/1,000 person-years), from 1.52 (1.43, 1.61) in patients without white matter disease to 4.90 (3.86, 6.13) in those with severe disease. Findings were robust when more specific definitions of Parkinson disease were used. Covert brain infarction was not associated with Parkinson disease (adjusted hazard ratio = 1.05 [0.88, 1.24]). INTERPRETATION: Incidentally discovered white matter disease was associated with subsequent Parkinson disease, an association strengthened with younger age and increased white matter disease severity. Incidentally discovered covert brain infarction did not appear to be associated with subsequent Parkinson disease. ANN NEUROL 2022;92:620-630.

The effect of vitamin D supplementation on cardiovascular risk in patients with prediabetes: A secondary analysis of the D2d study.

AIMS: Low blood 25(OH)D level is associated with increased cardiovascular disease (CVD) risk. Additionally, individuals with prediabetes are at higher risk for CVD than individuals with normoglycemia. We investigated the effects of vitamin D supplementation on CVD outcomes in the vitamin D and type 2 diabetes (D2d) study, a large trial among adults with prediabetes. METHODS: 2423 participants were randomized to 4000 IU/day of vitamin D3 or placebo and followed for median 3.0 years for new-onset diabetes. In pre-specified secondary analyses, we examined the effect of vitamin D supplementation on composite Major Adverse Cardiovascular Events (MACE); expanded MACE (MACE + revascularization); atherosclerotic CVD (ASCVD) risk score; and individual CVD risk factors (blood pressure, lipids, high-sensitivity C-reactive protein). Cox models compared hazard ratios (HR) between the two groups on MACE and expanded MACE. RESULTS: Mean age was 60 years, 45 % were women, 13 % had history of CVD. Twenty-one participants assigned to vitamin D and 12 participants assigned to placebo met the MACE outcome (HR 1.81, 95%CI 0.89 to 3.69). There were 27 expanded MACE outcomes in each group (HR 1.02, 95%CI, 0.59 to 1.76). There were no significant differences between vitamin D and placebo in individual CVD risk factors, but change in ASCVD risk score favored the vitamin D group (-0.45 %, 95%CI -0.75 to -0.15). CONCLUSIONS: In people with prediabetes not selected for vitamin D insufficiency and with intermediate CVD risk, vitamin D supplementation did not decrease MACE but had a small favorable effect on ASCVD risk score. TRIAL REGISTRATION: D2d ClinicalTrials.gov number, NCT01942694, prospectively registered September 16, 2013.

Safety and tolerability of high-dose daily vitamin D3 supplementation in the vitamin D and type 2 diabetes (D2d) study-a randomized trial in persons with prediabetes.

BACKGROUND/OBJECTIVES: Routine use of vitamin D supplements has increased substantially in the United States. However, the safety and tolerability of long-term use of high-dose vitamin D are not known. We assessed the safety and tolerability of high-dose, daily vitamin D3 in the vitamin D and type 2 diabetes (D2d) study. SUBJECTS/METHODS: In total, 2423 overweight/obese persons with prediabetes were randomized in a double-blind manner to either 4000 IU of vitamin D3 (the tolerable upper intake level for adults by the National Academy of Medicine) taken daily or matching placebo. All participants were included in this analysis. Incident adverse events (AE) were ascertained 4 times a year at in-person visits (twice a year) and interim remote encounters (twice a year) and were defined as untoward or unfavorable medical occurrences. Serious adverse events (SAE) included death, life-threatening events, and hospitalizations. RESULTS: A total of 8304 AEs occurred during 3 years of follow-up and were less frequent in the vitamin D group compared to placebo (Incidence Rate Ratio [IRR] = 0.94; 95% Confidence Interval (CI) 0.90, 0.98). The overall frequency of protocol-specified AEs of interest, which included nephrolithiasis, hypercalcemia, hypercalciuria, or low estimated glomerular filtration rate, was low and did not differ by group. There were no significant between-group differences in total SAEs (IRR = 0.96 (0.81, 1.14)). CONCLUSION: Vitamin D3 supplementation at 4000 IU per day was safe and well tolerated among overweight/obese participants at high risk for diabetes who were appropriately monitored for safety. In this population, this dose of vitamin D3 did not increase risk of AEs or SAEs, including those previously associated with vitamin D such as hypercalcemia, hypercalciuria, or nephrolithiasis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01942694, prospectively registered September 16, 2013.

Effect of Vitamin D Supplementation on Kidney Function in Adults with Prediabetes: A Secondary Analysis of a Randomized Trial.

BACKGROUND AND OBJECTIVES: Low serum 25-hydroxyvitamin D (25[OH]D) concentration has been associated with higher levels of proteinuria and lower levels of eGFR in observational studies. In the Vitamin D and Type 2 Diabetes (D2d) study, we investigated the effect of vitamin D supplementation on kidney outcomes in a population with prediabetes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Overweight/obese adults with high risk for type 2 diabetes (defined by meeting two of three glycemic criteria for prediabetes) were randomized to vitamin D3 4000 IU per day versus placebo. Median duration of treatment was 2.9 years (interquartile range 2.0-3.5 years). Kidney outcomes included (1) worsening in Kidney Disease: Improving Global Outcomes (KDIGO ) risk score (low, moderate, high, very high) on two consecutive follow-up visits after the baseline visit and (2) mean changes in eGFR and urine albumin-to-creatinine ratio (UACR). RESULTS: Among 2166 participants (mean age 60 years, body mass index 32 kg/m2, serum 25(OH)D 28 ng/ml, eGFR 87 ml/min per 1.73 m2, UACR 11 mg/g, 79% with hypertension), 10% had moderate, high, or very high KDIGO risk score. Over a median follow-up of 2.9 years, there were 28 cases of KDIGO worsening in the vitamin D group and 30 in the placebo group (hazard ratio, 0.89; 95% confidence interval [95% CI], 0.52 to 1.52]). Mean difference in eGFR from baseline was -1.0 ml/min per 1.73 m2 (95% CI, -1.3 to -0.7) in the vitamin D group and -0.1 ml/min per 1.73 m2 (95% CI, -0.4 to 0.2) in the placebo group; between-group difference was -1.0 ml/min per 1.73 m2 (95% CI, -1.4 to -0.6). Mean difference in UACR was 2.7 mg/g (95% CI, 1.2 to 4.3) in the vitamin D group and 2.0 (95% CI, 0.5 to 3.6) in the placebo group; between-group difference was 0.7 mg/g (95% CI, -1.5 to 2.9). CONCLUSIONS: Among persons with prediabetes, who were not preselected on the basis of serum 25(OH)D concentration, vitamin D supplementation did not affect progression of KDIGO risk scores and did not have a meaningful effect on change in UACR or eGFR.

Vitamin D Supplementation for Prevention of Cancer: The D2d Cancer Outcomes (D2dCA) Ancillary Study.

CONTEXT: Observational studies suggest that low vitamin D status may be a risk factor for cancer. OBJECTIVE: In a population with prediabetes and overweight/obesity that is at higher risk of cancer than the general population, we sought to determine if vitamin D supplementation lowers the risk of cancer and precancers. METHODS: The Vitamin D and type 2 diabetes (D2d) cancer outcomes study (D2dCA) is an ancillary study to the D2d study, which was conducted at 22 academic medical centers in the United States. Participants had prediabetes and overweight/obesity and were free of cancer for the previous 5 years. Participants were randomized to receive vitamin D3 4000 IU daily or placebo. At scheduled study visits (4 times/year), cancer and precancer events were identified by questionnaires. Clinical data were collected and adjudicated for all reported events. Cox proportional hazard models compared the hazard ratio (HR) of incident cancers and precancers between groups. RESULTS: Over a median follow-up period of 2.9 years, among 2385 participants (mean age 60 years and 25-hydroxyvitamin D 28 ng/mL), there were 89 cases of cancer. The HR of incident cancer for vitamin D vs placebo was 1.07 (95% CI 0.70, 1.62). Of 241 participants with incident precancers, 239 had colorectal adenomatous polyps. The HR for colorectal polyps for vitamin D vs placebo was 0.83 (95% CI 0.64, 1.07). CONCLUSION: In the D2d population of participants with prediabetes and overweight/obesity, not selected for vitamin D insufficiency, vitamin D supplementation did not have a significant effect on risk of incident cancer or colorectal polyps.

Intratrial Exposure to Vitamin D and New-Onset Diabetes Among Adults With Prediabetes: A Secondary Analysis From the Vitamin D and Type 2 Diabetes (D2d) Study.

OBJECTIVE: Postrandomization biases may influence the estimate of efficacy of supplemental vitamin D in diabetes prevention trials. In the Vitamin D and Type 2 Diabetes (D2d) study, repeated measures of serum 25-hydroxyvitamin D [25(OH)D] level provided an opportunity to test whether intratrial vitamin D exposure affected diabetes risk and whether the effect was modified by trial assignment (vitamin D vs. placebo). RESEARCH DESIGN AND METHODS: The D2d study compared the effect of daily supplementation with 100 µg (4,000 units) of vitamin D3 versus placebo on new-onset diabetes in adults with prediabetes. Intratrial vitamin D exposure was calculated as the cumulative rolling mean of annual serum 25(OH)D measurements. Hazard ratios for diabetes among participants who had intratrial 25(OH)D levels of <50, 75-99, 100-124, and ≥125 nmol/L were compared with those with levels of 50-74 nmol/L (the range considered adequate by the National Academy of Medicine) in the entire cohort and by trial assignment. RESULTS: There was an interaction of trial assignment with intratrial 25(OH)D level in predicting diabetes risk (interaction P = 0.018). The hazard ratio for diabetes for an increase of 25 nmol/L in intratrial 25(OH)D level was 0.75 (95% CI 0.68-0.82) among those assigned to vitamin D and 0.90 (0.80-1.02) among those assigned to placebo. The hazard ratios for diabetes among participants treated with vitamin D who maintained intratrial 25(OH)D levels of 100-124 and ≥125 nmol/L were 0.48 (0.29-0.80) and 0.29 (0.17-0.50), respectively, compared with those who maintained a level of 50-74 nmol/L. CONCLUSIONS: Daily vitamin D supplementation to maintain a serum 25(OH)D level ≥100 nmol/L is a promising approach to reducing the risk of diabetes in adults with prediabetes.

Vitamin D Supplementation and Prevention of Type 2 Diabetes.

BACKGROUND: Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS: We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS: A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS: Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.).

Establishing an electronic health record-supported approach for outreach to and recruitment of persons at high risk of type 2 diabetes in clinical trials: The vitamin D and type 2 diabetes (D2d) study experience.

AIMS: To establish recruitment approaches that leverage electronic health records in multicenter prediabetes/diabetes clinical trials and compare recruitment outcomes between electronic health record-supported and conventional recruitment methods. METHODS: Observational analysis of recruitment approaches in the vitamin D and type 2 diabetes (D2d) study, a multicenter trial in participants with prediabetes. Outcomes were adoption of electronic health record-supported recruitment approaches by sites, number of participants screened, recruitment performance (proportion screened who were randomized), and characteristics of participants from electronic health record-supported versus non-electronic health record methods. RESULTS: In total, 2423 participants were randomized: 1920 from electronic health record (mean age of 60 years, 41% women, 68% White) and 503 from non-electronic health record sources (mean age of 56.9 years, 58% women, 61% White). Electronic health record-supported recruitment was adopted by 21 of 22 sites. Electronic health record-supported recruitment was associated with more participants screened versus non-electronic health record methods (4969 vs 2166 participants screened), higher performance (38.6% vs 22.7%), and more randomizations (1918 vs 505). Participants recruited via electronic health record were older, included fewer women and minorities, and reported higher use of dietary supplements. Electronic health record-supported recruitment was incorporated in diverse clinical environments, engaging clinicians either at the individual or the healthcare system level. CONCLUSION: Establishing electronic health record-supported recruitment approaches across a multicenter prediabetes/diabetes trial is feasible and can be adopted by diverse clinical environments.

One-year outcomes of out-of-hospital administration of intravenous glucose, insulin, and potassium (GIK) in patients with suspected acute coronary syndromes (from the IMMEDIATE [Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care] Trial).

The Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care Trial of very early intravenous glucose-insulin-potassium (GIK) for acute coronary syndromes (ACS) in out-of-hospital emergency medical service (EMS) settings showed 80% reduction in infarct size at 30 days, suggesting potential longer-term benefits. Here we report 1-year outcomes. Prespecified 1-year end points of this randomized, placebo-controlled, double-blind, effectiveness trial included all-cause mortality and composites including cardiac arrest, mortality, or hospitalization for heart failure (HF). Of 871 participants randomized to GIK versus placebo, death occurred within 1 year in 11.6% versus 13.5%, respectively (unadjusted hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.57 to 1.23, p = 0.36). The composite of cardiac arrest or 1-year mortality was 12.8% versus 17.0% (HR 0.71, 95% CI 0.50 to 1.02, p = 0.06). The composite of hospitalization for HF or mortality within 1 year was 17.2% versus 17.2% (HR 0.98, 95% CI 0.70 to 1.37, p = 0.92). The composite of mortality, cardiac arrest, or HF hospitalization within 1 year was 18.1% versus 20.4% (HR 0.85, 95% CI 0.62 to 1.16, p = 0.30). In patients presenting with suspected ST elevation myocardial infarction, HRs for 1-year mortality and the 3 composites were, respectively, 0.65 (95% CI 0.33 to 1.27, p = 0.21), 0.52 (95% CI 0.30 to 0.92, p = 0.03), 0.63 (95% CI 0.35 to 1.16, p = 0.14), and 0.51 (95% CI 0.30 to 0.87, p = 0.01). In patients with suspected acute coronary syndromes, serious end points generally were lower with GIK than placebo, but the differences were not statistically significant. However, in those with ST elevation myocardial infarction, the composites of cardiac arrest or 1-year mortality, and of cardiac arrest, mortality, or HF hospitalization within 1 year, were significantly reduced.

A community consultation survey to evaluate support for and success of the IMMEDIATE trial.

BACKGROUND: The IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care) Trial, a randomized controlled double-blind clinical effectiveness trial of glucose-insulin-potassium (GIK) administered in ambulances in the out-of-hospital setting, used the Exception from Informed Consent Requirements (EFIC) for Emergency Research under Title 21 of the Code of Federal Regulations. EFIC requirements include community consultation that typically involves using a variety of communication methods and venues to inform the public of the research and to receive their feedback. Although not the primary purpose of the community consultation process, a common concern to research sponsors, staff, and institutional review boards (IRBs) is whether there will be a sufficient number of participants to justify mounting a study in their community. Information from community consultation regarding the community acceptance might inform this question. PURPOSE: We evaluated the utility of telephone survey data done as part of the EFIC process as a way to project the ultimate rate of trial participant enrollment. METHODS: A telephone survey community consultation process was undertaken in nine communities planning to be IMMEDIATE Trial sites using a representative sampling of the target population in the areas covered by participating emergency medical service (EMS) agencies. Survey respondents were read a description of the planned study and its informed consent approach that included the option for patients to decline participation in the trial while being transported for acute care in an ambulance. Survey respondents were then asked whether they would object to participating in the study. At the conclusion of actual trial enrollment, the Coordinating Center compared the survey results with the actual rates of enrollment at each site. RESULTS: Approximately 200 (range = 200-271) respondents completed the survey in each of the study communities. Of 2079 survey respondents, 68% (range = 61%-75%) said that they would not object to participating in the trial if experiencing a heart attack, and 85% (range = 79%-89%) said that they would allow the study to be done in their community. During actual trial enrollment in the communities, 79% (range = 63%-91%) of the 828 potential participants agreed in the ambulance to have the study drug started and provided informed consent at the hospital, an average of 13 percentage-points higher than projected by the survey (95% confidence interval (CI): 9%-17%), 19% higher on a relative scale (CI: 14%-25%). CONCLUSIONS: The survey-based approach to community consultation proved to be an efficient way to obtain representative input from potential clinical trial participants. The survey data generated a relatively good and conservative estimate of the ultimate rate of trial enrollment. This information could be useful to investigators and IRBs in projecting enrollment for clinical trials using EFIC.