Do FDA label changes work? Assessment of the 2010 class label change for proton pump inhibitors using the Sentinel System's analytic tools.

PURPOSE: To pilot use of the US Food and Drug Administration's (FDA's) Sentinel System data and analytic tools by a non-FDA stakeholder through the Innovation in Medical Evidence Development and Surveillance system of the Reagan Udall Foundation. We evaluated the US FDA 2010 proton pump inhibitor (PPI) class label change that warned of increased risk of bone fracture, to use PPIs for the lowest dose and shortest duration, and to manage bone status for those at risk for osteoporosis. METHODS: The cohort consisted of adults aged 18 years or older prescribed PPIs without fracture risk factors. We evaluated incident and prevalent uses of the 8 PPIs noted in the label change. Outcomes evaluated before and after label change were PPI dispensing patterns, incident fractures, and osteoporosis screening or interventions. Consistent with FDA use of descriptive tools, we did not include direct comparisons or statistical testing. RESULTS: There were 1 488 869 and 2 224 420 incident PPI users in the before [PRE] and after [POST] periods, respectively. Users with 1 year or more of exposure decreased (8.4% vs 7.5%), as did mean days supplied/user (130.4 to 113.7 d among all users and 830.8 to 645.4 d among users with 1 y or more of exposure). Osteoporosis screening and interventions did not appear to increase, but the proportion of patients with fractures decreased (4.4% vs 3.1%). Prevalent user results were similar. CONCLUSIONS: This analysis demonstrated the ability to use Sentinel tools to assess the effectiveness of a label change and accompanying communication at the population level and suggests an influence on subsequent dispensing behavior.

Quantification of the risk of liver injury associated with flucloxacillin: a UK population-based cohort study.

Background: Flucloxacillin is an established cause of liver injury. Despite this, there are a lack of published data on both the strength of association after adjusting for potential confounders, and the absolute incidence among different subgroups of patients. Objectives: To assess the relative and absolute risks of liver injury following exposure to flucloxacillin and identify subgroups at potentially increased risk. Methods: A cohort study between 1 January 2000 and 1 January 2012 using the UK Clinical Practice Research Datalink, including 1 046 699 people with a first prescription for flucloxacillin (861 962) or oxytetracycline (184 737). Absolute risks of experiencing both symptom-defined (jaundice) and laboratory-confirmed liver injury within 1-45 and 46-90 days of antibiotic initiation were estimated. Multivariable logistic regression was used to estimate 1-45 day relative effects. Results: There were 183 symptom-defined cases (160 prescribed flucloxacillin) and 108 laboratory-confirmed cases (102 flucloxacillin). The 1-45 day adjusted risk ratio for laboratory-confirmed injury was 5.22 (95% CI 1.64-16.62) comparing flucloxacillin with oxytetracycline use. The 1-45 day risk of laboratory-confirmed liver injury was 8.47 per 100 000 people prescribed flucloxacillin (95% CI 6.64-10.65). People who received consecutive flucloxacillin prescriptions had a 1-45 day risk of jaundice of 39.00 per 100 000 (95% CI 26.85-54.77), while those aged >70 receiving consecutive prescriptions had a risk of 110.57 per 100 000 (95% CI 70.86-164.48). Conclusions: The short-term risk of laboratory-confirmed liver injury was >5-fold higher after a flucloxacillin prescription than an oxytetracycline prescription. The risk of flucloxacillin-induced liver injury is particularly high within those aged >70 and those who receive multiple flucloxacillin prescriptions. The stratified risk estimates from this study could help guide clinical care.

The IMI PROTECT project: purpose, organizational structure, and procedures.

The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) initiative was a collaborative European project that sought to address limitations of current methods in the field of pharmacoepidemiology and pharmacovigilance. Initiated in 2009 and ending in 2015, PROTECT was part of the Innovative Medicines Initiative, a joint undertaking by the European Union and pharmaceutical industry. Thirty-five partners including academics, regulators, small and medium enterprises, and European Federation of Pharmaceuticals Industries and Associations companies contributed to PROTECT. Two work packages within PROTECT implemented research examining the extent to which differences in the study design, methodology, and choice of data source can contribute to producing discrepant results from observational studies on drug safety. To evaluate the effect of these differences, the project applied different designs and analytic methodology for six drug-adverse event pairs across several electronic healthcare databases and registries. This papers introduces the organizational structure and procedures of PROTECT, including how drug-adverse event and data sources were selected, study design and analyses documents were developed, and results managed centrally.

Multi-centre, multi-database studies with common protocols: lessons learnt from the IMI PROTECT project.

PURPOSE: To assess the impact of a variety of methodological parameters on the association between six drug classes and five key adverse events in multiple databases. METHODS: The selection of Drug-Adverse Event pairs was based on public health impact, regulatory relevance, and the possibility to study a broad range of methodological issues. Common protocols and data analytical specifications were jointly developed and independently and blindly executed in different databases in Europe with replications in the same and different databases. RESULTS: The association between antibiotics and acute liver injury, benzodiazepines and hip fracture, antidepressants and hip fracture, inhaled long-acting beta2-agonists and acute myocardial infarction was consistent in direction across multiple designs, databases and methods to control for confounding. Some variation in magnitude of the associations was observed depending on design, exposure and outcome definitions, but none of the differences were statistically significant. The association between anti-epileptics and suicidality was inconsistent across the UK CPRD, Danish National registries and the French PGRx system. Calcium channel blockers were not associated with the risk of cancer in the UK CPRD, and this was consistent across different classes of calcium channel blockers, cumulative durations of use up to >10 years and different types of cancer. CONCLUSIONS: A network for observational drug effect studies allowing the execution of common protocols in multiple databases was created. Increased consistency of findings across multiple designs and databases in different countries will increase confidence in findings from observational drug research and benefit/risk assessment of medicines.

Exposure to benzodiazepines (anxiolytics, hypnotics and related drugs) in seven European electronic healthcare databases: a cross-national descriptive study from the PROTECT-EU Project.

PURPOSE: Studies on drug utilization usually do not allow direct cross-national comparisons because of differences in the respective applied methods. This study aimed to compare time trends in BZDs prescribing by applying a common protocol and analyses plan in seven European electronic healthcare databases. METHODS: Crude and standardized prevalence rates of drug prescribing from 2001-2009 were calculated in databases from Spain, United Kingdon (UK), The Netherlands, Germany and Denmark. Prevalence was stratified by age, sex, BZD type [(using ATC codes), i.e. BZD-anxiolytics BZD-hypnotics, BZD-related drugs and clomethiazole], indication and number of prescription. RESULTS: Crude prevalence rates of BZDs prescribing ranged from 570 to 1700 per 10,000 person-years over the study period. Standardization by age and sex did not substantially change the differences. Standardized prevalence rates increased in the Spanish (+13%) and UK databases (+2% and +8%) over the study period, while they decreased in the Dutch databases (-4% and -22%), the German (-12%) and Danish (-26%) database. Prevalence of anxiolytics outweighed that of hypnotics in the Spanish, Dutch and Bavarian databases, but the reverse was shown in the UK and Danish databases. Prevalence rates consistently increased with age and were two-fold higher in women than in men in all databases. A median of 18% of users received 10 or more prescriptions in 2008. CONCLUSION: Although similar methods were applied, the prevalence of BZD prescribing varied considerably across different populations. Clinical factors related to BZDs and characteristics of the databases may explain these differences.

Acute nonarteritic anterior ischemic optic neuropathy and exposure to phosphodiesterase type 5 inhibitors.

INTRODUCTION: Nonarteritic anterior ischemic optic neuropathy (NAION), a rare visual disorder, has been reported in men using phosphodiesterase type 5 inhibitors (PDE5i) for erectile dysfunction. AIM: We examined whether intermittent use of PDE5i is associated with acute NAION onset within approximately five half-lives following drug ingestion. METHODS: One hundred two ophthalmology centers in the United States and Europe identified potential cases of NAION. An expert adjudication committee conducted a blind review of the records of those with recent PDE5i use to classify cases as Definite, Possible, or not NAION. Subjects provided information on PDEi use via telephone interview. Each NAION case's PDE5i exposure immediately prior to onset was compared against his recent patterns of use in an observational case-crossover design. A sample size of 40 cases with intermittent PDE5i exposure in the 30 days prior to NAION onset was needed to detect an odds ratio (OR) of 3.0 with 80% power. MAIN OUTCOME MEASURES: The daily relative risk for acute NAION on days within five half-lives of PDE5i use vs. other days was estimated via an OR obtained from conditional logistic regression. RESULTS: Among 43 Definite NAION cases with PDE5i exposure in the prior 30 days, the OR was 2.15 (95% confidence interval [CI]: 1.06, 4.34). When 21 Possible NAION cases were included (n = 64), the OR was 2.36 (95% CI: 1.33, 4.19). CONCLUSIONS: We found an approximately twofold increased risk of acute NAION within five half-lives of PDE5i use compared with use in a more prior time period. Bias from inaccurate recall of exposure was unlikely to have substantially affected the results. Based on our results, we estimate that weekly use of PDE5i adds three NAION cases per 100,000 men 50 years and older annually.

Photoperiodic regulation of the seasonal pattern of photosynthetic capacity and the implications for carbon cycling.

Although temperature is an important driver of seasonal changes in photosynthetic physiology, photoperiod also regulates leaf activity. Climate change will extend growing seasons if temperature cues predominate, but photoperiod-controlled species will show limited responsiveness to warming. We show that photoperiod explains more seasonal variation in photosynthetic activity across 23 tree species than temperature. Although leaves remain green, photosynthetic capacity peaks just after summer solstice and declines with decreasing photoperiod, before air temperatures peak. In support of these findings, saplings grown at constant temperature but exposed to an extended photoperiod maintained high photosynthetic capacity, but photosynthetic activity declined in saplings experiencing a naturally shortening photoperiod; leaves remained equally green in both treatments. Incorporating a photoperiodic correction of photosynthetic physiology into a global-scale terrestrial carbon-cycle model significantly improves predictions of seasonal atmospheric CO(2) cycling, demonstrating the benefit of such a function in coupled climate system models. Accounting for photoperiod-induced seasonality in photosynthetic parameters reduces modeled global gross primary production 2.5% (∼4 PgC y(-1)), resulting in a >3% (∼2 PgC y(-1)) decrease of net primary production. Such a correction is also needed in models estimating current carbon uptake based on remotely sensed greenness. Photoperiod-associated declines in photosynthetic capacity could limit autumn carbon gain in forests, even if warming delays leaf senescence.

A Structured Process to Identify Fit-for-Purpose Study Design and Data to Generate Valid and Transparent Real-World Evidence for Regulatory Uses.

Generating evidence from real-world data requires fit-for-purpose study design and data. In addition to validity, decision makers require transparency in the reasoning that underlies study design and data source decisions. The 2019 Structured Preapproval and Postapproval Comparative Study Design Framework to Generate Valid and Transparent Real-World Evidence (SPACE) and the 2021 Structured Process to Identify Fit-For-Purpose Data (SPIFD)-intended to be used together-provide a step-by-step guide to identify decision grade, fit-for-purpose study design and data. In this update (referred to as "SPIFD2" to encompass both the design and data aspects) we provide an update to these frameworks that combines the templates into one, more explicitly calls for articulation of the hypothetical target trial and sources of bias that may arise in the real-world emulation, and provides explicit references to the Structured Template and Reporting Tool for Real-World Evidence (STaRT-RWE) tables that we suggest using immediately after invoking the SPIFD2 framework. Following the steps recommended in the SPIFD2 process requires due diligence on the part of the researcher to ensure that every aspect of study design and data selection is rationalized and supported by evidence. The resulting stepwise documentation enables reproducibility and clear communication with decision makers, and it increases the likelihood that the evidence generated is valid, fit-for-purpose, and sufficient to support healthcare and regulatory decisions.

Integration of Real-World Data and Genetics to Support Target Identification and Validation.

Even modest improvements in the probability of success of selecting drug targets which are ultimately approved can substantially reduce the costs of research and development. Drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs. A key enabler of identifying and validating these genetically validated targets is access to association results from genome-wide genotyping, whole-exome sequencing, and whole-genome sequencing studies with observable traits (often diseases) across large numbers of individuals. Today, linkage between genotype and real-world data (RWD) provides significant opportunities to not only increase the statistical power of genome-wide association studies by ascertaining additional cases for diseases of interest, but also to improve diversity and coverage of association studies across the disease phenome. As RWD-genetics linked resources continue to grow in diversity of participants, breadth of data captured, length of observation, and number of participants, there is a greater need to leverage the experience of RWD experts, clinicians, and highly experienced geneticists together to understand which lessons and frameworks from general research using RWD sources are relevant to improve genetics-driven drug discovery and development. This paper describes new challenges and opportunities for phenotypes enabled by diverse RWD sources, considerations in the use of RWD phenotypes for disease gene identification across the disease phenome, and challenges and opportunities in leveraging RWD phenotypes in target validation. The paper concludes with views on the future directions for phenotype development using RWD, and key questions requiring further research and development to advance this nascent field.

The Structured Process to Identify Fit-For-Purpose Data: A Data Feasibility Assessment Framework.

To complement real-world evidence (RWE) guidelines, the 2019 Structured Preapproval and Postapproval Comparative study design framework to generate valid and transparent real-world Evidence (SPACE) framework elucidated a process for designing valid and transparent real-world studies. As an extension to SPACE, here, we provide a structured framework for conducting feasibility assessments-a step-by-step guide to identify decision grade, fit-for-purpose data, which complements the United States Food and Drug Administration (FDA)'s framework for a RWE program. The process was informed by our collective experience conducting systematic feasibility assessments of existing data sources for pharmacoepidemiology studies to support regulatory decisions. Used with the SPACE framework, the Structured Process to Identify Fit-For-Purpose Data (SPIFD) provides a systematic process for conducting feasibility assessments to determine if a data source is fit for decision making, helping ensure justification and transparency throughout study development, from articulation of a specific and meaningful research question to identification of fit-for-purpose data and study design.

Simulating carbon dioxide exchange rates of deciduous tree species: evidence for a general pattern in biochemical changes and water stress response.

BACKGROUND AND AIMS: Deciduous trees have a seasonal carbon dioxide exchange pattern that is attributed to changes in leaf biochemical properties. However, it is not known if the pattern in leaf biochemical properties - maximum Rubisco carboxylation (V(cmax)) and electron transport (J(max)) - differ between species. This study explored whether a general pattern of changes in V(cmax), J(max), and a standardized soil moisture response accounted for carbon dioxide exchange of deciduous trees throughout the growing season. METHODS: The model MAESTRA was used to examine V(cmax) and J(max) of leaves of five deciduous trees, Acer rubrum 'Summer Red', Betula nigra, Quercus nuttallii, Quercus phellos and Paulownia elongata, and their response to soil moisture. MAESTRA was parameterized using data from in situ measurements on organs. Linking the changes in biochemical properties of leaves to the whole tree, MAESTRA integrated the general pattern in V(cmax) and J(max) from gas exchange parameters of leaves with a standardized soil moisture response to describe carbon dioxide exchange throughout the growing season. The model estimates were tested against measurements made on the five species under both irrigated and water-stressed conditions. KEY RESULTS: Measurements and modelling demonstrate that the seasonal pattern of biochemical activity in leaves and soil moisture response can be parameterized with straightforward general relationships. Over the course of the season, differences in carbon exchange between measured and modelled values were within 6-12 % under well-watered conditions and 2-25 % under water stress conditions. Hence, a generalized seasonal pattern in the leaf-level physiological change of V(cmax) and J(max), and a standardized response to soil moisture was sufficient to parameterize carbon dioxide exchange for large-scale evaluations. CONCLUSIONS: Simplification in parameterization of the seasonal pattern of leaf biochemical activity and soil moisture response of deciduous forest species is demonstrated. This allows reliable modelling of carbon exchange for deciduous trees, thus circumventing the need for extensive gas exchange experiments on different species.

A Structured Preapproval and Postapproval Comparative Study Design Framework to Generate Valid and Transparent Real-World Evidence for Regulatory Decisions.

Real-world evidence provides important information about the effects of medicines in routine clinical practice. To engender trust that evidence generated for regulatory purposes is sufficiently valid, transparency in the reasoning that underlies study design decisions is critical. Building on existing guidance and frameworks, we developed the Structured Preapproval and Postapproval Comparative study design framework to generate valid and transparent real-world Evidence (SPACE) as a process for identifying design elements and minimal criteria for feasibility and validity concerns, and for documenting decisions. Starting with an articulated research question, we identify key components of the randomized controlled trial needed to maximize validity, and pragmatic choices are considered when required. A causal diagram is used to justify the variables identified for confounding control, and key decisions, assumptions, and evidence are captured in a structured way. In this way, SPACE may improve dialogue and build trust among healthcare providers, patients, regulators, and researchers.

Prevalence of cardiovascular disease risk factor clustering among the adult population of China: results from the International Collaborative Study of Cardiovascular Disease in Asia (InterAsia).

BACKGROUND: The prevalence of cardiovascular disease (CVD) risk factors has been increasing in China. METHODS AND RESULTS: We examined the prevalence of CVD risk factor clustering among Chinese adults aged 35 to 74 years with data from the International Collaborative Study of Cardiovascular Disease in Asia (InterAsia), a cross-sectional survey of a nationally representative sample (n=14 690) conducted during 2000 to 2001 and compared these data with those of US adults from the National Health and Nutrition Examination Survey of 1999 to 2000. Overall, 80.5%, 45.9%, and 17.2% of Chinese adults had > or =1, > or =2, and > or =3 modifiable CVD risk factors (dyslipidemia, hypertension, diabetes, cigarette smoking, and overweight), respectively. By comparison, 93.1%, 73.0%, and 35.9% of US adults had > or =1, > or =2, and > or =3 of these risk factors, respectively. In a multivariate model including age, sex, and area of residence, the odds ratio (95% confidence interval [CI]) of having > or =1, > or =2, and > or =3 CVD risk factors versus none of the studied risk factors was 2.61 (95% CI, 2.09 to 3.27), 3.55 (95% CI, 2.77 to 4.54), and 4.97 (95% CI, 3.67 to 6.74), respectively, for Chinese adults 65 to 74 years old versus 35 to 44 years old; 3.65 (95% CI, 3.21 to 4.15), 4.67 (95% CI, 4.06 to 5.38), and 5.60 (95% CI, 4.70 to 6.67), respectively, for men compared with women; 1.18 (95% CI, 1.07 to 1.30), 1.34 (95% CI, 1.21 to 1.50), and 1.84 (95% CI, 1.60 to 2.12), respectively, for urban compared with rural residents; and 1.98 (95% CI, 1.76 to 2.22), 2.75 (95% CI, 2.42 to 3.13), and 4.36 (95% CI, 3.68 to 5.18), respectively, for residents of northern compared with southern China. CONCLUSIONS: Clustering of CVD risk factors is common in China. Prevention, detection, and treatment of CVD risk factor clustering should be an important component of a national strategy to reduce the increasing burden of CVD in China.

Prevalence of the metabolic syndrome and overweight among adults in China.

BACKGROUND: The metabolic syndrome and obesity are major risk factors for cardiovascular disease. Little information exists on the prevalence of the metabolic syndrome in China. We aimed to provide up-to-date estimates of the prevalence of the metabolic syndrome and overweight in the general adult population in China. METHODS: We did a cross-sectional survey in a nationally representative sample of 15,540 Chinese adults aged 35-74 years in 2000-01. Metabolic syndrome was defined according to guidelines from the US National Cholesterol Education Program. Overweight was defined as body-mass index of 25.0 kg/m2 or greater. FINDINGS: The age-standardised prevalence of metabolic syndrome was 9.8% (95% CI 9.0-10.6) in men and 17.8% (16.6-19.0) in women. The age-standardised prevalence of overweight was 26.9% (25.7-28.1) in men and 31.1% (29.7-32.5) in women. The prevalence of the metabolic syndrome and overweight was higher in northern than in southern China, and higher in urban than rural residents. INTERPRETATION: Our results indicate that a large proportion of Chinese adults have the metabolic syndrome and that overweight has become an important public health problem in China. These findings emphasise the urgent need to develop national strategies for the prevention, detection, and treatment of overweight and the metabolic syndrome, to reduce the societal burden of cardiovascular disease in China.

Computer-assisted expert case definition in electronic health records.

PURPOSE: To describe how computer-assisted presentation of case data can lead experts to infer machine-implementable rules for case definition in electronic health records. As an illustration the technique has been applied to obtain a definition of acute liver dysfunction (ALD) in persons with inflammatory bowel disease (IBD). METHODS: The technique consists of repeatedly sampling new batches of case candidates from an enriched pool of persons meeting presumed minimal inclusion criteria, classifying the candidates by a machine-implementable candidate rule and by a human expert, and then updating the rule so that it captures new distinctions introduced by the expert. Iteration continues until an update results in an acceptably small number of changes to form a final case definition. RESULTS: The technique was applied to structured data and terms derived by natural language processing from text records in 29,336 adults with IBD. Over three rounds the technique led to rules with increasing predictive value, as the experts identified exceptions, and increasing sensitivity, as the experts identified missing inclusion criteria. In the final rule inclusion and exclusion terms were often keyed to an ALD onset date. When compared against clinical review in an independent test round, the derived final case definition had a sensitivity of 92% and a positive predictive value of 79%. CONCLUSION: An iterative technique of machine-supported expert review can yield a case definition that accommodates available data, incorporates pre-existing medical knowledge, is transparent and is open to continuous improvement. The expert updates to rules may be informative in themselves. In this limited setting, the final case definition for ALD performed better than previous, published attempts using expert definitions.

Optimising case detection within UK electronic health records: use of multiple linked databases for detecting liver injury.

OBJECTIVES: We aimed to create a 'multidatabase' algorithm for identification of cholestatic liver injury using multiple linked UK databases, before (1) assessing the improvement in case ascertainment compared to using a single database and (2) developing a new single-database case-definition algorithm, validated against the multidatabase algorithm. DESIGN: Method development for case ascertainment. SETTING: Three UK population-based electronic health record databases: the UK Clinical Practice Research Datalink (CPRD), the UK Hospital Episodes Statistics (HES) database and the UK Office of National Statistics (ONS) mortality database. PARTICIPANTS: 16 040 people over the age of 18 years with linked CPRD-HES records indicating potential cholestatic liver injury between 1 January 2000 and 1 January 2013. PRIMARY OUTCOME MEASURES: (1) The number of cases of cholestatic liver injury detected by the multidatabase algorithm. (2) The relative contribution of each data source to multidatabase case status. (3) The ability of the new single-database algorithm to discriminate multidatabase algorithm case status. RESULTS: Within the multidatabase case identification algorithm, 4033 of 16 040 potential cases (25%) were identified as definite cases based on CPRD data. HES data allowed possible cases to be discriminated from unlikely cases (947 of 16 040, 6%), but only facilitated identification of 1 definite case. ONS data did not contribute to case definition. The new single-database (CPRD-only) algorithm had a very good ability to discriminate multidatabase case status (area under the receiver operator characteristic curve 0.95). CONCLUSIONS: CPRD-HES-ONS linkage confers minimal improvement in cholestatic liver injury case ascertainment compared to using CPRD data alone, and a multidatabase algorithm provides little additional information for validation of a CPRD-only algorithm. The availability of laboratory test results within CPRD but not HES means that algorithms based on CPRD-HES-linked data may not always be merited for studies of liver injury, or for other outcomes relying primarily on laboratory test results.

Therapeutic lifestyle changes and drug treatment for high blood cholesterol in China and application of the Adult Treatment Panel III guidelines.

The prevalence of elevated blood cholesterol in China has increased during the past several decades. We estimated the percentage of the Chinese population for whom therapeutic lifestyle changes and drug therapy to lower blood cholesterol should be considered by applying the United States' National Cholesterol Education Panel's Adult Treatment Panel III guidelines to a nationally representative sample of the Chinese population from the International Collaborative Study of Cardiovascular Disease in Asia. Serum samples were collected for 14,919 Chinese adults, 35 to 74 years old, in 2000 and 2001, after an overnight fast of > or =8 hours and their low-density lipoprotein (LDL) cholesterol level was calculated using the Freidewald equation. Using the Adult Treatment Panel III guidelines, 85.9 million Chinese adults (18.2%) should initiate therapeutic lifestyle changes to lower their LDL cholesterol and 35.0 million (7.4%) should be considered for lifestyle changes and lipid-lowering drug therapy. Of those for whom drug therapy should be considered, 4.7 million (13.4%) reported having been told they had "high cholesterol" by a healthcare provider and 1.6 million (33.7% of those aware of their high cholesterol) were receiving lipid-lowering medication-leaving 33.4 million Chinese adults with untreated elevated LDL cholesterol (95.5% of those with elevated LDL cholesterol). A 10% population-wide reduction in LDL cholesterol would reduce the number of Chinese adults who should be considered for drug therapy by 45% to 19.3 million (4.1% of adults). In conclusion, most adults in China with an elevated LDL cholesterol remain untreated.

Therapeutic decisions for menopause: results of the DAMES project in central Massachusetts.

OBJECTIVE: To investigate the factors that influence therapeutic decisions at menopause, particularly those related to the burden of menopause symptoms, in a population of women living in Massachusetts, as part of the multisite DAMES (Decisions At Menopause Study). DESIGN: A survey using face-to-face interviews with a randomly selected sample of 293 women aged 45 to 55 who are members of the Fallon Community Health Plan in Central Massachusetts. The instrument combined closed- and open-ended questions and elicited information about a number of health topics, including the symptoms experienced by respondents over the preceding month and the decisions they made regarding therapies. RESULTS: Symptom reporting was found to be relatively high, with more than half of the sample reporting hot flashes, sleep disturbances, joint pains, and headaches in the month preceding the survey; one third to one half of the women reported palpitations, night sweats, fatigue, and numbness. The highest frequency of symptoms occurred during perimenopause. Nearly four fifths of the women consulted a healthcare provider, and one fifth used hormone therapy. More than half of the respondents said menopause is a difficult phase, and about half found decisionmaking about it to be difficult. CONCLUSIONS: This study documents a relatively heavy burden of symptoms in a relatively healthy population and provides an update on earlier studies in Massachusetts.

The role of treatment intentions and concerns about side effects in women's decision to discontinue postmenopausal hormone therapy.

OBJECTIVES: To investigate the factors that influence women's decisions about hormone therapy use and the duration of use, in particular the effect of women's reasons for initiating hormone therapy, the source of information about hormones, women's symptom experience, and their concerns about side effects from hormone therapy. METHODS: Eight hundred and sixteen women aged 45-59 who began hormone therapy between July 1993 and June 1995 in a Massachusetts health maintenance organization were followed for two years from the day they received a prescription for estrogen. This cohort has been previously studied for health, treatment and demographic determinants of hormone therapy discontinuation. In March 1999, these women were mailed a questionnaire containing closed and open-ended questions. 449 women (55%) completed the survey. Discrete-time hazards models were used to identify determinants of discontinuation, controlling for medical predictors of survey nonresponse. RESULTS: Women's assessment of the difficulty of their decision to use hormone therapy (RR=1.25 for each point on a 7-point scale, 95% CI: 1.16, 1.35) was associated with discontinuation. Women who described their decision as extremely difficult had the greatest likelihood of discontinuing. The importance placed on preventing osteoporosis (RR=0.93 for each point on a 7-point scale, 95% CI: 0.86, 0.99) and cardiovascular disease (RR=0.94 for each point on a 7-point scale, 95% CI: 0.88, 0.99) were also statistically significant predictors of discontinuation. Women for whom the prevention of osteoporosis and cardiovascular disease were extremely important in deciding to use hormone therapy were the most likely to continue using hormones. Concerns about the return of monthly bleeding (RR=3.00, 95% CI: 1.45, 6.17) and weight gain (RR=2.06, 95% CI: 1.16, 3.67) at the time hormone therapy was initiated, but not the actual experience of these side effects while using hormones, were associated with a higher rate of discontinuation. Symptoms around the time of initiating hormone therapy, including the perceived severity of the symptom, were not statistically associated with discontinuation. CONCLUSIONS: Discontinuation of hormone therapy is the result of a complex process of decision-making that is influenced by the value placed on the prevention of osteoporosis and cardiovascular disease at the time of initiation and women's perceptions and interpretations of side effects. Concerns about the potential side effects of hormone therapy, in particular weight gain and monthly bleeding, lead women to discontinue hormone therapy.