Medical care and biomarker-based assessment of mortality in two cohorts of patients with chronic coronary syndrome 10 years apart.

BACKGROUND: This study aimed to describe the characteristics and mortality of two cohorts of patients with chronic coronary syndrome (CCS) recruited with identical study designs in the same rehabilitation clinics but approximately 10 years apart. METHODS: The KAROLA cohorts included patients with CCS participating in an inpatient cardiac rehabilitation programme in Germany (KAROLA-I: years 1999/2000, KAROLA-II: 2009-2011). Blood samples and information on sociodemographic factors, lifestyle, and medical treatment were collected at baseline, at the end of rehabilitation, and after one year of follow-up. A biomarker-based risk model (ABC-CHD model) and Cox regression analysis were used to evaluate cardiovascular (CV) and non-CV mortality risk. RESULTS: We included 1130 patients from KAROLA-I (mean age 58.7 years, 84.4% men) and 860 from KAROLA-II (mean age 60.4 years, 83.4% men). Patients in the KAROLA-I cohort had significantly higher concentrations of CV biomarkers and fewer patients were taking CV medications, except for statins. The biomarker-based ABC-CHD model provided a higher estimate of CV death risk for patients in the KAROLA-I cohort (median 3-year risk, 3.8%) than for patients in the KAROLA-II cohort (median 3-year risk, 2.7%, p-value for difference < 0.001). After 10 years of follow-up, 91 (8.1%) patients in KAROLA-I and 45 (5.2%) in KAROLA-II had died from a CV event. CONCLUSIONS: Advances in disease management over the past 20 years may have led to modest improvements in pharmacological treatment during cardiac rehabilitation and long-term outpatient care for patients with CCS. However, modifiable risk factors such as obesity have increased in the more recent cohort and should be targeted to further improve the prognosis of these patients.

Potential of Vitamin D Food Fortification in Prevention of Cancer Deaths-A Modeling Study.

Meta-analyses of randomized controlled trials (RCTs) have estimated a 13% reduction of cancer mortality by vitamin D supplementation among older adults. We evaluated if and to what extent similar effects might be expected from vitamin D fortification of foods. We reviewed the literature on RCTs assessing the impact of vitamin D supplementation on cancer mortality, on increases of vitamin D levels by either supplementation or food fortification, and on costs of supplementation or fortification. Then, we derived expected effects on total cancer mortality and related costs and savings from potential implementation of vitamin D food fortification in Germany and compared the results to those for supplementation. In RCTs with vitamin D supplementation in average doses of 820-2000 IU per day, serum concentrations of 25-hydroxy-vitamin D increased by 15-30 nmol/L, respectively. Studies on food fortification found increases by 10-42 nmol/L, thus largely in the range of increases previously demonstrated by supplementation. Fortification is estimated to be considerably less expensive than supplementation. It might be similarly effective as supplementation in reducing cancer mortality and might even achieve such reduction at substantially larger net savings. Although vitamin D overdoses are unlikely in food fortification programs, implementation should be accompanied by a study monitoring the frequency of potentially occurring adverse effects by overdoses, such as hypercalcemia. Future studies on effectiveness of vitamin D supplementation and fortification are warranted.

Association of glycated hemoglobin A1c levels with cardiovascular outcomes in the general population: results from the BiomarCaRE (Biomarker for Cardiovascular Risk Assessment in Europe) consortium.

BACKGROUND: Biomarkers may contribute to improved cardiovascular risk estimation. Glycated hemoglobin A1c (HbA1c) is used to monitor the quality of diabetes treatment. Its strength of association with cardiovascular outcomes in the general population remains uncertain. This study aims to assess the association of HbA1c with cardiovascular outcomes in the general population. METHODS: Data from six prospective population-based cohort studies across Europe comprising 36,180 participants were analyzed. HbA1c was evaluated in conjunction with classical cardiovascular risk factors (CVRFs) for association with cardiovascular mortality, cardiovascular disease (CVD) incidence, and overall mortality in subjects without diabetes (N = 32,496) and with diabetes (N = 3684). RESULTS: Kaplan-Meier curves showed higher event rates with increasing HbA1c levels (log-rank-test: p < 0.001). Cox regression analysis revealed significant associations between HbA1c (in mmol/mol) in the total study population and the examined outcomes. Thus, a hazard ratio (HR) of 1.16 (95% confidence interval (CI) 1.02-1.31, p = 0.02) for cardiovascular mortality, 1.13 (95% CI 1.03-1.24, p = 0.01) for CVD incidence, and 1.09 (95% CI 1.02-1.17, p = 0.01) for overall mortality was observed per 10 mmol/mol increase in HbA1c. The association with CVD incidence and overall mortality was also observed in study participants without diabetes with increased HbA1c levels (HR 1.12; 95% CI 1.01-1.25, p = 0.04) and HR 1.10; 95% CI 1.01-1.20, p = 0.02) respectively. HbA1c cut-off values of 39.9 mmol/mol (5.8%), 36.6 mmol/mol (5.5%), and 38.8 mmol/mol (5.7%) for cardiovascular mortality, CVD incidence, and overall mortality, showed also an increased risk. CONCLUSIONS: HbA1c is independently associated with cardiovascular mortality, overall mortality and cardiovascular disease in the general European population. A mostly monotonically increasing relationship was observed between HbA1c levels and outcomes. Elevated HbA1c levels were associated with cardiovascular disease incidence and overall mortality in participants without diabetes underlining the importance of HbA1c levels in the overall population.

Vitamin D supplementation to the older adult population in Germany has the cost-saving potential of preventing almost 30 000 cancer deaths per year.

Recent meta-analyses of randomized controlled trials (RCTs) have demonstrated significant reduction in cancer mortality by vitamin D supplementation. We estimated costs and savings for preventing cancer deaths by vitamin D supplementation of the population aged 50+ years in Germany. Our analysis is based on national data on cancer mortality in 2016. The number of preventable cancer deaths was estimated by multiplying cancer deaths above age 50 with the estimated proportionate reduction in cancer mortality derived by vitamin D supplementation according to meta-analyses of RCTs (13%). Saved costs were estimated by multiplying this number by estimated end-of-life cancer care costs (€40 000). Annual costs of vitamin D supplementation were estimated at 25€ per person above age 50. Comprehensive sensitivity analyses were conducted. In the main analysis, vitamin D supplementation was estimated to prevent almost 30 000 cancer deaths per year at approximate costs of €900 million and savings of €1.154 billion, suggesting net savings of €254 million. Our results support promotion of supplementation of vitamin D among older adults as a cost-saving approach to substantially reduce cancer mortality.

Caring for the elderly: A person-centered segmentation approach for exploring the association between health care needs, mental health care use, and costs in Germany.

BACKGROUND: Person-centered care demands the evaluation of needs and preferences of the patients. In this study, we conducted a segmentation analysis of a large sample of older people based on their bio-psycho-social-needs and functioning. The aim of this study was to clarify differences in health care use and costs of the elderly in Germany. METHODS: Data was derived from the 8-year follow-up of the ESTHER study-a German epidemiological study of the elderly population. Trained medical doctors visited n = 3124 participants aged 57 to 84 years in their home. Bio-psycho-social health care needs were assessed using the INTERMED for the Elderly (IM-E) interview. Further information was measured using questionnaires or assessment scales (Barthel index, Patients Health Questionnaire (PHQ) etc.). The segmentation analysis applied a factor mixture model (FMM) that combined both a confirmatory factor analysis and a latent class analysis. RESULTS: In total, n = 3017 persons were included in the study. Results of the latent class analysis indicated that a five-cluster-model best fit the data. The largest cluster (48%) can be described as healthy, one cluster (13.9%) shows minor physical complaints and higher social support, while the third cluster (24.3%) includes persons with only a few physical and psychological difficulties ("minor physical and psychological complaints"). One of the profiles (10.5%) showed high and complex bio-psycho-social health care needs ("complex needs") while another profile (2.5%) can be labelled as "frail". Mean values of all psychosomatic variables-including the variable health care costs-gradually increased over the five clusters. Use of mental health care was comparatively low in the more burdened clusters. In the profiles "minor physical and psychological complaints" and "complex needs", only half of the persons suffering from a mental disorder were treated by a mental health professional; in the frail cluster, only a third of those with a depression or anxiety disorder received mental health care. CONCLUSIONS: The segmentation of the older people of this study sample led to five different clusters that vary profoundly regarding their bio-psycho-social needs. Results indicate that elderly persons with complex bio-psycho-social needs do not receive appropriate mental health care.

Longitudinal association between panic disorder and health care costs in older adults.

BACKGROUND: To analyze whether probable panic disorder (PD) is associated with health care costs in older age over time. METHODS: Data regarding individuals aged 65 and over were derived from two waves of the ESTHER cohort study (nt1 = 2,348, nt2 = 2,090). Probable PD was assessed using the panic screening module from the Patient Health Questionnaire. Health care costs were obtained through monetary valuation of self-reported health care use data. Fixed effects regressions analyzed the association between transitions in probable PD status and change in health care costs, while adjusting for potential confounders. RESULTS: On a descriptive level, study participants with a positive PD screening displayed higher three-month health care costs compared to those without (incremental costs: € 259 for t1 , € 1,544 for t2 ). Transitions in probable PD were associated with an approximate increase of 65% in outpatient health care costs (ß = 0.50, p < .05). There was no significant association between probable PD transition and change in any other cost category. CONCLUSIONS: Using longitudinal data, our results highlight the economic consequences of probable PD in older adults. Future research should address whether reducing PD in older adults may reduce the associated economic burden and analyze underlying mechanisms.

A novel superior medication-based chronic disease score predicted all-cause mortality in independent geriatric cohorts.

OBJECTIVES: On the basis of current treatment guidelines, we developed and validated a medication-based chronic disease score (medCDS) and tested its association with all-cause mortality of older outpatients. STUDY DESIGN AND SETTING: Considering the most prevalent chronic diseases in the elderly German population, we compiled a list of evidence-based medicines used to treat these disorders. Based on this list, a score (medCDS) was developed to predict mortality using data of a large longitudinal cohort of older outpatients (training sample; MultiCare Cohort Study). By assessing receiver-operating characteristics (ROC) curves, the performance of medCDS was then confirmed in independent cohorts (ESTHER, KORA-Age) of community-dwelling older patients and compared with already existing medication-based scores and a score using selected anatomical-therapeutic-chemical (ATC) codes. RESULTS: The final medCDS score had an ROC area under the curve (AUC) of 0.73 (95% CI 0.70-0.76). In the validation cohorts, its ROC AUCs were 0.79 (0.76-0.82, KORA-Age) and 0.74 (0.71-0.78, ESTHER), which were superior to already existing medication-based scores (RxRisk, CDS) and scores based on pharmacological ATC code subgroups (ATC3) or age and sex alone (Age&Sex). CONCLUSIONS: A new medCDS, which is based on actual treatment standards, predicts mortality of older outpatients significantly better than already existing scores.

The associations of geriatric syndromes and other patient characteristics with the current and future use of potentially inappropriate medications in a large cohort study.

PURPOSE: To assess the changes in use of potentially inappropriate medication (PIM) as defined by the 2015 Beers criteria, the EU(7)-PIM, and the PRISCUS list over a 6-year period and to identify determinants for current and future PIM use with a particular focus on geriatric syndromes. METHODS: In a German cohort of 2878 community-dwelling adults aged ≥ 60 years, determinants of the use of ≥ 1 PIM were identified in multivariable logistic regression (cross-sectional analysis) and weighted generalized estimating equation models (longitudinal analysis). RESULTS: Prevalences for Beers, EU(7), and PRISCUS PIM were 26.4, 37.4, and 13.7% at baseline and decreased to 23.1, 36.5, and 12.3%, respectively, 6 years later. Unadjusted prevalences in participants with any geriatric syndrome (frailty, co-morbidity, functional, or cognitive impairment) were approximately twice as high as in robust older adults. In multivariable analyses, cognitive impairment was statistically significantly associated with the use of PIM of all three criteria in the cross-sectional (odds ratio (OR) point estimates 1.90-2.21) but not in the longitudinal models. In contrast, frailty, co-morbidity, and functional impairment were statistically significantly associated with the use of PIM of at least one of the three criteria in both models. However, the associations varied for the PIM criteria, and in the longitudinal analysis, associations were only statistically significant for Beers PIM (ORs [95% confidence intervals]: frailty (2.23 [1.15, 4.31]), co-morbidity by five total co-morbidity score points (1.21 [1.05, 1.38]), and functional impairment (1.51 [1.00, 2.27]). Other statistically significant determinants of the incidence of PIM (any definition) were female sex, age, coronary heart disease, heart failure, biomarkers of the metabolic syndrome, and history of ulcer, depressive episodes, hip fracture, or any cancer. CONCLUSIONS: Older adults with frailty, co-morbidity, cognitive, and functional impairment had higher odds of taking PIM or getting a PIM prescription in the future (exception: cognitive impairment). Physicians should be especially cautious when prescribing drugs for these patients who are particularly susceptible to adverse reactions.

Burden of hip fracture using disability-adjusted life-years: a pooled analysis of prospective cohorts in the CHANCES consortium.

BACKGROUND: No studies have estimated disability-adjusted life-years (DALYs) lost due to hip fractures using real-life follow-up cohort data. We aimed to quantify the burden of disease due to incident hip fracture using DALYs in prospective cohorts in the CHANCES consortium, and to calculate population attributable fractions based on DALYs for specific risk factors. METHODS: We used data from six cohorts of participants aged 50 years or older at recruitment to calculate DALYs. We applied disability weights proposed by the National Osteoporosis Foundation and did a series of sensitivity analyses to examine the robustness of DALY estimates. We calculated population attributable fractions for smoking, body-mass index (BMI), physical activity, alcohol intake, type 2 diabetes and parity, use of hormone replacement therapy, and oral contraceptives in women. We calculated summary risk estimates across cohorts with pooled analysis and random-effects meta-analysis methods. FINDINGS: 223 880 men and women were followed up for a mean of 13 years (SD 6). 7724 (3·5%) participants developed an incident hip fracture, of whom 413 (5·3%) died as a result. 5964 DALYs (27 per 1000 individuals) were lost due to hip fractures, 1230 (20·6%) of which were in the group aged 75-79 years. 4150 (69·6%) DALYs were attributed to disability. Current smoking was the risk factor responsible for the greatest hip fracture burden (7·5%, 95% CI 5·2-9·7) followed by physical inactivity (5·5%, 2·1-8·5), history of diabetes (2·8%, 2·1-4·0), and low to average BMI (2·0%, 1·4-2·7), whereas low alcohol consumption (0·01-2·5 g per day) and high BMI had a protective effect. INTERPRETATION: Hip fracture can lead to a substantial loss of healthy life-years in elderly people. National public health policies should be strengthened to reduce hip fracture incidence and mortality. Primary prevention measures should be strengthened to prevent falls, and reduce smoking and a sedentary lifestyle. FUNDING: European Community's Seventh Framework Programme.

A Longitudinal Investigation of Willingness to Pay for Health Insurance in Germany.

OBJECTIVE: To investigate factors affecting willingness to pay (WTP) for health insurance of older adults in a longitudinal setting in Germany. DATA SOURCES: Survey data from a cohort study in Saarland, Germany, from 2008-2010 and 2011-2014 (n1  = 3,124; n2  = 2,761) were used. STUDY DESIGN: Panel data were taken at two points from an observational, prospective cohort study. DATA COLLECTION: WTP estimates were derived using a contingent valuation method with a payment card. Participants provided data on sociodemographics, lifestyle factors, morbidity, and health care utilization. PRINCIPAL FINDINGS: Fixed effects regression models showed higher individual health care costs to increase WTP, which in particular could be found for members of private health insurance. Changes in income and morbidity did not affect WTP among members of social health insurance, whereas these predictors affected WTP among members of private health insurance. CONCLUSIONS: The fact that individual health care costs affected WTP positively might indicate that demanding (expensive) health care services raises the awareness of the benefits of health insurance. Thus, measures to increase WTP in old age should target at improving transparency of the value of health insurances at the moment when individual health care utilization and corresponding costs are still relatively low.

Burden of Cancer in a Large Consortium of Prospective Cohorts in Europe.

BACKGROUND: Disability-adjusted life-years (DALYs) are an indicator of mortality, morbidity, and disability. We calculated DALYs for cancer in middle-aged and older adults participating in the Consortium on Health and Ageing Network of Cohorts in Europe and the United States (CHANCES) consortium. METHODS: A total of 90 199 participants from five European cohorts with 10 455 incident cancers and 4399 deaths were included in this study. DALYs were calculated as the sum of the years of life lost because of premature mortality (YLLs) and the years lost because of disability (YLDs). Population-attributable fractions (PAFs) were also estimated for five cancer risk factors, ie, smoking, adiposity, physical inactivity, alcohol intake, and type II diabetes. RESULTS: After a median follow-up of 12 years, the total number of DALYs lost from cancer was 34 474 (382 per 1000 individuals) with a similar distribution by sex. Lung cancer was responsible for the largest number of lost DALYs (22.9%), followed by colorectal (15.3%), prostate (10.2%), and breast cancer (8.7%). Mortality (81.6% of DALYs) predominated over disability. Ever cigarette smoking was the risk factor responsible for the greatest total cancer burden (24.0%, 95% confidence interval [CI] = 22.2% to 26.0%), followed by physical inactivity (4.9%, 95% CI = 0.8% to 8.1%) and adiposity (1.8%, 95% CI = 0.2% to 2.8%). CONCLUSIONS: DALYs lost from cancer were substantial in this large European sample of middle-aged and older adults. Even if the burden of disease because of cancer is predominantly caused by mortality, some cancers have sizeable consequences for disability. Smoking remained the predominant risk factor for total cancer burden.

Associations of frailty with health care costs--results of the ESTHER cohort study.

BACKGROUND: The concept of frailty is rapidly gaining attention as an independent syndrome with high prevalence in older adults. Thereby, frailty is often related to certain adverse outcomes like mortality or disability. Another adverse outcome discussed is increased health care utilization. However, only few studies examined the impact of frailty on health care utilization and corresponding costs. The aim of this study was therefore to investigate comprehensively the relationship between frailty, health care utilization and costs. METHODS: Cross sectional data from 2598 older participants (57-84 years) recruited in the Saarland, Germany, between 2008 and 2010 was used. Participants passed geriatric assessments that included Fried's five frailty criteria: weakness, slowness, exhaustion, unintentional weight loss, and physical inactivity. Health care utilization was recorded in the sectors of inpatient treatment, outpatient treatment, pharmaceuticals, and nursing care. RESULTS: Prevalence of frailty (≥3 symptoms) was 8.0%. Mean total 3-month costs of frail participants were €3659 (4 or 5 symptoms) and €1616 (3 symptoms) as compared to €642 of nonfrail participants (no symptom). Controlling for comorbidity and general socio-demographic characteristics in multiple regression models, the difference in total costs between frail and non-frail participants still amounted to €1917; p < .05 (4 or 5 symptoms) and €680; p < .05 (3 symptoms). Among the 5 symptoms of frailty, weight loss and exhaustion were significantly associated with total costs after controlling for comorbidity. CONCLUSIONS: The study provides evidence that frailty is associated with increased health care costs. The analyses furthermore indicate that frailty is an important factor for health care costs independent from pure age and comorbidity. Costs were rather attributable to frailty (and comorbidity) than to age. This stresses that the overlapping concepts of multimorbidity and frailty are both necessary to explain health care use and corresponding costs among older adults.

Health service use and costs associated with excess weight in older adults in Germany.

BACKGROUND: excess weight is a risk factor for numerous co-morbidities that predominantly occur in later life. This study's purpose was to analyse the association between excess weight and health service use/costs in the older population in Germany. METHODS: this cross-sectional analysis used data of n = 3,108 individuals aged 58-82 from a population-based prospective cohort study. Body mass index (BMI) and waist-to-height ratio (WHtR) were calculated based on clinical examinations. Health service use was measured by a questionnaire for a 3-month period. Corresponding costs were calculated applying a societal perspective. RESULTS: 21.8% of the sample were normal weight, 43.0% overweight, 25.5% obese class 1 and 9.6% obese class ≥2 according to BMI. In 42.6%, WHtR was ≥0.6. For normal weight, overweight, obese class 1 and obese class ≥2 individuals, mean costs (3-month period) of outpatient care were 384€, 435€, 475€ and 525€ (P < 0.001), mean costs of inpatient care were 284€, 408€, 333€ and 652€ (P = 0.070) and mean total costs 716€, 891€, 852€ and 1,244€ (P = 0.013). For individuals with WHtR <0.6 versus ≥0.6, outpatient costs were 401€ versus 499€ (P < 0.001), inpatient costs 315€ versus 480€ (P = 0.016) and total costs 755€ versus 1,041€ (P < 0.001). Multiple regression analyses controlling for sociodemographic variables showed a significant effect of obesity on costs of outpatient care (class 1: +72€; class ≥2: +153€) and total costs (class ≥2: +361€) while the effect of overweight was not significant. WHtR ≥0.6 significantly increased outpatient costs by +79€ and total costs by +189€. CONCLUSIONS: excess weight is associated with increased service use and cost in elderly individuals, in particular in obese class ≥2 individuals.

Is vitamin D deficiency a cause of increased morbidity and mortality at older age or simply an indicator of poor health?

To assess whether vitamin D deficiency is a cause of increased morbidity and mortality or simply an indicator of poor health, we assessed (1) the cross-sectional and longitudinal association of vitamin D deficiency with self-rated health (SRH) and frailty and (2) the association of vitamin D deficiency with mortality, with and without control for SRH and frailty. Analyses were performed in 9,579 participants of the German, population-based ESTHER cohort (age-range at baseline: 50-74 years), with follow-ups after 2, 5 and 8 years (mortality: 12 years). During follow-up, 129 subjects newly reported poor SRH, 510 developed frailty and 1,450 died. In cross-sectional analyses, subjects with vitamin D deficiency had higher odds of a poor SRH and frailty but no association with SRH or frailty was observed in longitudinal analyses. The association of vitamin D deficiency with all-cause and several cause-specific mortalities was strong and unaltered by time-dependent adjustment for classic mortality risk factors, SRH and frailty. In conclusion, vitamin D deficiency may not cause frailty or poor general health but may nevertheless be a prognostic marker for mortality, independent of the individual's morbidity.

Gender differences in healthcare utilization of patients with diabetes.

OBJECTIVES: To examine gender differences in healthcare utilization including outpatient and inpatient medical care for patients with type 2 diabetes mellitus (T2DM), despite participation in T2DM-specific disease management programs (DMP-DM). STUDY DESIGN: Baseline data from a cohort study in southwest Germany including 1146 patients with T2DM recruited between October 2008 and March 2010 were used. METHODS: After bivariate analyses, multivariate Poisson and logistic regression models were used to estimate the effect of sex on the number of general practitioner (GP) and medical specialist appointments, prescribed medications, hospitalizations, and inpatient rehabilitations, with additional consideration of glycemic control levels. Poor glycemic control (PGC) was defined as glycated hemoglobin ≥7.5%. RESULTS: In total, 905 participants had acceptable glycemic control and 237 participants had poor glycemic control. PGC was more prevalent in men than in women (23% vs 18%). Bivariate analyses among participants with PGC showed significantly fewer GP and medical specialist appointments, a lower number of medications, and longer rehabilitation stays in men than in women. Multivariate regression analyses among participants with PGC confirmed statistically significant gender differences for GP appointments and number of prescribed medications (P <.05) for men compared with women. Gender differences regarding inpatient care were less evident. CONCLUSIONS: Our data disclosed major gender differences in healthcare utilization of diabetes patients in Germany despite a high DMP-DM rate. Future research should focus attention on gender-specific approaches to healthcare delivery to improve quality and access to care.

Indirect comparisons of therapeutic interventions.

HEALTH POLITICAL BACKGROUND: The comparison of the effectiveness of health technologies is not only laid down in German law (Social Code Book V, § 139 and § 35b) but also constitutes a central element of clinical guidelines and decision making in health care. Tools supporting decision making (e. g. Health Technology Assessments (HTA)) are therefore in need of a valid methodological repertoire for these comparisons. SCIENTIFIC BACKGROUND: Randomised controlled head-to-head trials which directly compare the effects of different therapies are considered the gold standard methodological approach for the comparison of the efficacy of interventions. Because this type of trial is rarely found, comparisons of efficacy often need to rely on indirect comparisons whose validity is being controversially debated. RESEARCH QUESTIONS: RESEARCH QUESTIONS FOR THE CURRENT ASSESSMENT ARE: Which (statistical) methods for indirect comparisons of therapeutic interventions do exist, how often are they applied and how valid are their results in comparison to the results of head-to-head trials? METHODS: In a systematic literature research all medical databases of the German Institute of Medical Documentation and Information (DIMDI) are searched for methodological papers as well as applications of indirect comparisons in systematic reviews. Results of the literature analysis are summarized qualitatively for the characterisation of methods and quantitatively for the frequency of their application. The validity of the results from indirect comparisons is checked by comparing them to the results from the gold standard - a direct comparison. Data sets from systematic reviews which use both direct and indirect comparisons are tested for consistency by of the z-statistic. RESULTS: 29 methodological papers and 106 applications of indirect methods in systematic reviews are being analysed. Four methods for indirect comparisons can be identified: Unadjusted indirect comparisons include, independent of any comparator, all randomised controlled trials (RCT) that provide a study arm with the intervention of interest. Adjusted indirect comparisons and metaregression analyses include only those studies that provide one study arm with the intervention of interest and another study arm with a common comparator. While the aforementioned methods use conventional metaanalytical techniques, Mixed treatment comparisons (MTC) use Bayesian statistics. They are able to analyse a complex network of RCT with multiple comparators simultaneously. During the period from 1999 to 2008 adjusted indirect comparisons are the most commonly used method for indirect comparisons. Since 2006 an increase in the application of the more methodologically challenging MTC is being observed. For the validity check 248 data sets, which include results of a direct and an indirect comparison, are available. The share of statistically significant discrepant results is greatest in the unadjusted indirect comparisons (25,5% [95% CI: 13,1%; 38%]), followed by metaregression analyses (16,7% [95% CI: -13,2%; 46,5%]), adjusted indirect comparisons (12,1% [95% CI: 6,1%; 18%]) and MTC (1,8% [95% CI: -1,7%; 5,2%]). Discrepant results are mainly detected if the basic assumption for an indirect comparison - between-study homogeneity - does not hold. However a systematic over- or underestimation of the results of direct comparisons by any of the indirectly comparing methods was not observed in this sample. DISCUSSION: The selection of an appropriate method for an indirect comparison has to account for its validity, the number of interventions to be compared and the quality as well as the quantity of available studies. Unadjusted indirect comparisons provide, contrasted with the results of direct comparisons, a low validity. Adjusted indirect comparisons and MTC may, under certain circumstances, give results which are consistent with the results of direct comparisons. The limited number of available reviews utilizing metaregression analyses for indirect comparisons currently prohibits empirical evaluation of this methodology. CONCLUSIONS/RECOMMENDATIONS: Given the main prerequisite - a pool of homogenous and high-quality RCT - the results of head-to-head trials may be pre-estimated by an adjusted indirect comparison or a MTC. In the context of HTA and guideline development they are valuable tools if there is a lack of a direct comparison of the interventions of interest.