Becca S. Feldman

Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies

Objective To evaluate the extent to which circulating biomarker and supplements of vitamin D are associated with mortality from cardiovascular, cancer, or other conditions, under various circumstances. Design Systematic review and meta-analysis of observational studies and randomised controlled trials. Data sources Medline, Embase, Cochrane Library, and reference lists of relevant studies to August 2013; correspondance with investigators. Study selection Observational cohort studies and randomised controlled trials in adults, which reported associations between vitamin D (measured as circulating 25-hydroxyvitamin D concentration or vitamin D supplement given singly) and cause specific mortality outcomes. Data extraction Data were extracted by two independent investigators, and a consensus was reached with involvement of a third. Study specific relative risks from 73 cohort studies (849 412 participants) and 22 randomised controlled trials (vitamin D given alone versus placebo or no treatment; 30 716 participants) were meta-analysed using random effects models and were grouped by study and population characteristics. Results In the primary prevention observational studies, comparing bottom versus top thirds of baseline circulating 25-hydroxyvitamin D distribution, pooled relative risks were 1.35 (95% confidence interval 1.13 to 1.61) for death from cardiovascular disease, 1.14 (1.01 to 1.29) for death from cancer, 1.30 (1.07 to 1.59) for non-vascular, non-cancer death, and 1.35 (1.22 to 1.49) for all cause mortality. Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements. In randomised controlled trials, relative risks for all cause mortality were 0.89 (0.80 to 0.99) for vitamin D3 supplementation and 1.04 (0.97 to 1.11) for vitamin D2 supplementation. The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics. However, for vitamin D2 supplementation, increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods. Conclusions Evidence from observational studies indicates inverse associations of circulating 25-hydroxyvitamin D with risks of death due to cardiovascular disease, cancer, and other causes. Supplementation with vitamin D3 significantly reduces overall mortality among older adults; however, before any widespread supplementation, further investigations will be required to establish the optimal dose and duration and whether vitamin D3 and D2 have different effects on mortality risk.

Decreased Serum Concentrations of 25-Hydroxycholecalciferol Are Associated With Increased Risk of Progression to Impaired Fasting Glucose and Diabetes

OBJECTIVE To study the association between vitamin D status and the risk of incident impaired fasting glucose (IFG) and diabetes in a population-based cohort of diabetes-free subjects. RESEARCH DESIGN AND METHODS In a historical prospective cohort study of subjects from the Clalit Health Services database, which includes information on nearly 4 million people, diabetes-free subjects aged 40–70 years with serum 25-hydroxycholecalciferol (25-OHD) measurements available were followed for 2 years to assess the development of IFG and diabetes in five 25-OHD subgroups: ≥25, 25.1–37.5, 37.6–50, 50.1–75, and >75 nmol/L. RESULTS The baseline cohort included 117,960 adults: 83,526 normoglycemic subjects and 34,434 subjects with IFG. During follow-up, 8,629 subjects (10.3% of the normoglycemic group) developed IFG, and 2,162 subjects (1.8% of the total cohort) progressed to diabetes. A multivariable model adjusted for age, sex, population group, immigrant status, BMI, season of vitamin D measurement, LDL and HDL cholesterol, triglycerides, estimated glomerular filtration rate, history of hypertension or cardiovascular disease, Charlson comorbidity index, smoking, and socioeconomic status revealed an inverse association between 25-OHD and the risk of progression to IFG and diabetes. The odds of transitioning from normoglycemia to IFG, from normoglycemia to diabetes, and from IFG to diabetes in subjects with a 25-OHD level ≤25 nmol/L were greater than those of subjects with a 25-OHD level >75 nmol/L [odds ratio 1.13 (95% CI 1.03–1.24), 1.77 (1.11–2.83), and 1.43 (1.16–1.76), respectively]. CONCLUSIONS Vitamin D deficiency appears to be an independent risk factor for the development of IFG and diabetes.

Effectiveness of 23-Valent Pneumococcal Polysaccharide Vaccine Against Invasive Disease and Hospital-Treated Pneumonia Among People Aged ≥65 Years: A Retrospective Case-Control Study

BACKGROUND Streptococcus pneumoniae contributes considerably to the burden of pneumonia and invasive pneumococcal disease (IPD), with the effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) for preventing all-cause pneumonia still undetermined. The aim of this study was to control for common biases and confounders associated with previous observational studies and to assess PPSV23 vaccine effectiveness in preventing IPD and the most resource-intensive type of community-acquired pneumonia, hospital-treated pneumonia (HTP). METHODS This was a retrospective case-control study nested in a population-based cohort, with age-, sex-, and risk-matched controls as the base case. Demographic information, laboratory data, and diagnoses were extracted from the chronic disease registry and from inpatient and outpatient records in the Clalit Health Services database. Vaccine effectiveness for PPSV23 was assessed using multivariable conditional logistic regression. Subgroup, sensitivity, and secondary analyses were conducted to validate findings. RESULTS A total of 470 070 individuals aged ≥65 years were members of Clalit Health Services during the study period (1 January 2007 through 31 December 2010). The case cohort consisted of 212 participants with IPD and 23 441 with HTP. The adjusted association between vaccination and IPD was protective (odds ratio [OR], 0.58; 95% confidence interval [CI], .41-.81), whereas there was no demonstrated protective effect between vaccination and HTP (OR, 1.01; 95% CI, .97-1.04). The sensitivity analysis and all but 1 subgroup analysis provided consistent results to the base case. CONCLUSIONS The PPSV23 vaccine is effective against the most severe invasive forms of pneumococcal disease, but the lack of effectiveness of PPSV23 in protecting against all-cause HTP should be considered for future vaccine policies.

Defining the Role of Medication Adherence in Poor Glycemic Control among a General Adult Population with Diabetes

Aims This study assesses the attributable impact of adherence to oral glucose medications as a risk factor for poor glycemic control in population subgroups of a large general population, using an objective medication adherence measure. Methods Using electronic health records data, adherence to diabetes medications over a two-year period was calculated by prescription-based Medication Possession Ratios for adults with diabetes diagnosed before January 1, 2010. Glycemic control was determined by the HbA1c test closest to the last drug prescription during 2010–2012. Poor control was defined as HbA1c>75 mmol/mol (9.0%). Medication adherence was categorized as “good” (>80%), “moderate” (50–80%), or “poor” (<50%). Logistic regression models assessed the role medication adherence plays in the association between disease duration, age, and poor glycemic control. We calculated the change in the attributable fraction of glucose control if the non-adherent diabetic medication population would become adherent by age-groups. Results Among 228,846 diabetes patients treated by oral antiglycemic medication, 46.4% had good, 28.8% had moderate, and 24.8% had poor adherence. Good adherence rates increased with increasing disease duration, while glycemic control became worse. There was a strong inverse association between adherence level and poor control (OR = 2.50; CI = 2.43–2.58), and adherence was a significant mediator between age and poor control. Conclusions A large portion of the diabetes population is reported to have poor adherence to oral diabetes medications, which is strongly associated with poor glycemic control in all disease durations. While poor adherence does not mediate the poorer glycemic control seen in patients with longer-standing disease, it is a significant mediator of poor glycemic control among younger diabetes patients. A greater fraction of poorly controlled younger patients, compared to older patients, could be prevented if at least 80% adherence to their medications was achieved. Therefore, our results suggest that interventions to improve adherence should focus on this younger sub-group.

Association Between Achieved Low-Density Lipoprotein Levels and Major Adverse Cardiac Events in Patients With Stable Ischemic Heart Disease Taking Statin Treatment

IMPORTANCE International guidelines recommend treatment with statins for patients with preexisting ischemic heart disease to prevent additional cardiovascular events but differ regarding target levels of low-density lipoprotein cholesterol (LDL-C). Trial data on this question are inconclusive and observational data are lacking. OBJECTIVE To assess the relationship between levels of LDL-C achieved with statin treatment and cardiovascular events in adherent patients with preexisting ischemic heart disease. DESIGN, SETTING, AND PARTICIPANTS Population-based observational cohort study from 2009 to 2013 using data from a health care organization in Israel covering more than 4.3 million members. Included patients had ischemic heart disease, were aged 30 to 84 years, were treated with statins, and were at least 80% adherent to treatment or, in a sensitivity analysis, at least 50% adherent. Patients with active cancer or metabolic abnormalities were excluded. EXPOSURES Index LDL-C was defined as the first achieved serum LDL-C measure after at least 1 year of statin treatment, grouped as low (≤70.0 mg/dL), moderate (70.1-100.0 mg/dL), or high (100.1-130.0 mg/dL). MAIN OUTCOMES AND MEASURES Major adverse cardiac events included acute myocardial infarction, unstable angina, stroke, angioplasty, bypass surgery, or all-cause mortality. The hazard ratio of adverse outcomes was estimated using 2 Cox proportional hazards models with low vs moderate and moderate vs high LDL-C, adjusted for confounders and further tested using propensity score matching analysis. RESULTS The cohort with at least 80% adherence included 31 619 patients, for whom the mean (SD) age was 67.3 (9.8) years. Of this population, 27% were female and 29% had low, 53% moderate, and 18% high LDL-C when taking statin treatment. Overall, there were 9035 patients who had an adverse outcome during a mean 1.6 years of follow-up (6.7 per 1000 persons per year). The adjusted incidence of adverse outcomes was not different between low and moderate LDL-C (hazard ratio [HR], 1.02; 95% CI, 0.97-1.07; P = .54), but it was lower with moderate vs high LDL-C (HR, 0.89; 95% CI, 0.84-0.94; P < .001). Among 54 884 patients with at least 50% statin adherence, the adjusted HR was 1.06 (95% CI, 1.02-1.10; P = .001) in the low vs moderate groups and 0.87 (95% CI, 0.84-0.91; P = .001) in the moderate vs high groups. CONCLUSIONS AND RELEVANCE Patients with LDL-C levels of 70 to 100 mg/dL taking statins had lower risk of adverse cardiac outcomes compared with those with LDL-C levels between 100 and 130 mg/dL, but no additional benefit was gained by achieving LDL-C of 70 mg/dL or less. These population-based data do not support treatment guidelines recommending very low target LDL-C levels for all patients with preexisting heart disease.

Towards a subsiding diabetes epidemic: trends from a large population-based study in Israel

BackgroundWith increasing diabetes prevalence worldwide, an impending diabetes “pandemic” has been reported. However, definitions of incident cases and the population at risk remain varied and ambiguous. This study analyzed trends in mortality and screening that contribute to diabetes prevalence and incidence, distinguishing between new incident cases and newly detected cases.MethodsIn an integrated provider-and-payer-system covering 53% of Israel’s population, a composite diabetes case-finding algorithm was built using diagnoses, lab tests, and antidiabetic medication purchases from the organization’s electronic medical record database. Data were extracted on adult members aged 26+ each year from January 1, 2004 through December 31, 2012. Rates of diabetes prevalence, incidence, screening, and mortality were reported, with incidence rates evaluated among the total, “previously-screened,” and “previously-unscreened” at-risk populations.ResultsThere were 343,554 diabetes cases in 2012 (14.4%) out of 2,379,712 members aged 26+. A consistent but decelerating upward trend in diabetes prevalence was observed from 2004-2012. Annual mortality rates among diabetics decreased from 13.8/1000 to 10.7/1000 (p = 0.0002). Total population incidence rates declined from 13.3/1000 in 2006 to 10.8/1000 in 2012 (p < 0.0001), with similar incidence trends (13.2/1000 to 10.2/1000; p = 0.0007) among previously-screened at-risk members, and a rise in testing rates from 53.0% to 66.7% (p = 0.0004). The previously-unscreened group decreased 28.6%, and the incidence rates within this group remained stable.ConclusionsThe increase in diabetes prevalence is decelerating despite declining mortality and increasing testing rates. A decline in previously-screened incident cases and a shrinking pool of previously-unscreened members suggests that diabetes trends in Israel are moving toward equilibrium, rather than a growing epidemic.

Obesity or smoking: Which factor contributes more to the incidence of myocardial infarction?

OBJECTIVE Comparing the contributions of smoking and obesity to the risk of myocardial infarction (MI) can help prioritize behavioral modifications. The objective of this study was to determine the relative risk of smoking, obesity and the joint burden on the risk of MI. METHODS This is a retrospective cohort study of data accessed from electronic medical records of the largest health care organization in Israel. The study population included all 738,380 members of Clalit Health Services, with at least one smoking status and one BMI assessment recorded in 2009 or 2010, aged 40-74years, who were MI-free before 2009. Obesity was defined as BMI >30kg/m(2). New and primary MI between January 1 and December 31, 2011 were recorded. RESULTS Rates of MI were: 0.18% for non-obese never smokers, 0.25% for obese never smokers, 0.40% for non-obese past smokers, 0.50% for obese past smokers, 0.53% for non-obese current smokers and 0.66% for obese current smokers. Among non-obese individuals, past smokers and current smokers had a greater risk of MI than did never smokers, after adjusting for age, gender and socioeconomic position (OR, 1.45; 95% CI, 1.23-1.70 and OR, 2.35; 95% CI, 2.10-2.63, respectively). The burden of obesity increased the risk of MI for never smokers but the burden of obesity did not elevate the risk of MI when combined with current or past smoking groups, after adjusting for comorbidities. CONCLUSIONS Past and, more so, current smoking confers greater risk for MI than obesity.

Pneumococcal vaccine targeting strategy for older adults: customized risk profiling.

BACKGROUND Current pneumococcal vaccine campaigns take a broad, primarily age-based approach to immunization targeting, overlooking many clinical and administrative considerations necessary in disease prevention and resource planning for specific patient populations. We aim to demonstrate the utility of a population-specific predictive model for hospital-treated pneumonia to direct effective vaccine targeting. METHODS Data was extracted for 1,053,435 members of an Israeli HMO, age 50 and older, during the study period 2008-2010. We developed and validated a logistic regression model to predict hospital-treated pneumonia using training and test samples, including a set of standard and population-specific risk factors. The models predictive value was tested for prospectively identifying cases of pneumonia and invasive pneumococcal disease (IPD), and was compared to the existing international paradigm for patient immunization targeting. RESULTS In a multivariate regression, age, co-morbidity burden and previous pneumonia events were most strongly positively associated with hospital-treated pneumonia. The model predicting hospital-treated pneumonia yielded a c-statistic of 0.80. Utilizing the predictive model, the top 17% highest-risk within the study validation population were targeted to detect 54% of those members who were subsequently treated for hospitalized pneumonia in the follow up period. The high-risk population identified through this model included 46% of the follow-up years IPD cases, and 27% of community-treated pneumonia cases. These outcomes were compared with international guidelines for risk for pneumococcal diseases that accurately identified only 35% of hospitalized pneumonia, 41% of IPD cases and 21% of community-treated pneumonia. CONCLUSIONS We demonstrate that a customized model for vaccine targeting performs better than international guidelines, and therefore, risk modeling may allow for more precise vaccine targeting and resource allocation than current national and international guidelines. Health care managers and policy-makers may consider the strategic potential of utilizing clinical and administrative databases for creating population-specific risk prediction models to inform vaccination campaigns.

Low adherence to antidepressants is associated with increased mortality following stroke: A large nationally representative cohort study

Post stroke depression is common and pervasive. In the general population, there has been some controversy that antidepressant (AD) medication is associated with premature mortality. Data is still lacking regarding the association between adherence to antidepressants (AD) and all-cause mortality. In this retrospective analysis of a population-based cohort of patients, 32,361 post-stroke patients who purchased at least one AD were followed for all-cause mortality over 4-years. Adherence to AD was measured as a ratio between dispensed and prescribed durations and was modeled as: non-adherence (<20%, n=8619), poor (20-50%, n=5108), moderate (50-80%, n=5656), and good (>80%, n=12,978) adherence. Multivariable survival analyses, adjusted for demographic and clinical variables including physical comorbidities known to influence mortality, were conducted. Unadjusted mortality rates were 16.5%, 20.2%, 22.2% and 23.7% in those classified as non-adherent, poor, moderate and good adherence respectively (χ2=174.6, p<0.0001). In the adjusted model, the non-adherent and poor adherence groups had significantly increased mortality Hazard Ratios (HR) of 1.25 (95% CI: 1.17-1.33) and 1.17 (95% CI: 1.09-1.26) respectively compared to the good adherence group. This nationally representative data suggests that poor adherence to AD is associated with increased all-cause mortality among people who had a stroke. Given our findings and the high prevalence of anxiety and depression along with AD effectiveness, efforts to promote AD adherence in this population may be warranted in clinical practice.

Maternal age and cardiovascular and metabolic disease outcomes: A retrospective cohort study using data from population-based electronic medical records

Abstract Objective: To evaluate whether a woman’s age at first birth is associated with cardiovascular risk and metabolic health outcomes (cardiometabolic outcomes) by age 45. Methods: This is a retrospective, population-based cohort study that uses electronic health record data from the largest health fund in Israel. Women aged 34–39 at baseline (2004–2006) free of chronic diseases were identified as nulliparous at baseline and were followed up to 10 years (through 2016). The cohort was divided into three groups based on their age at first birth: younger parturients (ages 35–39), older parturients (ages 40–44), and never had children. The percentage of adverse pregnancy events and cardiometabolic outcomes at age 45 were compared across these three groups as well as to women in the general population. Cardiovascular risk and metabolic health outcomes were defined as: Type 2 diabetes, obesity, hypertension, cardiovascular disease, and Framingham risk score. Methods and results: Out of a group of 126,121 women aged 34–39 at baseline, 9979 were nulliparous and free of comorbidities. Over the course of the follow-up, there were 952 younger parturients and 673 older parturients who had their first birth, and 8354 women who remained persistent nulliparous. While older parturients had more adverse pregnancy events, there was no difference in rates of cardiometabolic outcomes between the two parturient groups, and they both had lower rates than the persistent nulliparous and the general population. Conclusions: Parturients free of major chronic diseases who give birth at a later age do not have increased cardiometabolic outcomes in midlife as compared to a general population of women in a large retrospective cohort. Our results may support clinicians when counseling healthy women who are seeking advice regarding delaying their first pregnancy without a tradeoff on health outcomes.