The Associations of Diuretics and Laxatives Use with Cardiovascular Mortality. An Individual Patient-Data Meta-analysis of Two Large Cohort Studies.

PURPOSE: To investigate the associations of diuretics overall, non-potassium-sparing diuretics in specific, and laxative use with cardiovascular mortality (CVM) in subjects with antihypertensive treatment. METHODS: Analyses included 4253 participants, aged 50 to 75 years, from the German ESTHER cohort and 105,359 participants, aged 50 to 69 years, from the UK Biobank. Cox proportional hazard regression models were applied in both studies, and then results were pooled using random-effects model meta-analyses. RESULTS: During 14 and 7 years of follow-up, 476 and 1616 CVM cases were observed in the ESTHER study and the UK Biobank, respectively. Compared to non-users, a 1.6-fold (hazard ratio [95% confidence interval] 1.57 [1.29; 1.90]), a 1.4-fold (1.39 [1.26; 1.53]), and no statistically significantly increased (1.13 [0.94; 1.36]) CVM were observed in users of diuretics overall, non-potassium-sparing diuretics in specific, and laxatives, respectively. Concurrent use of non-potassium-sparing diuretics and laxatives was associated with a 2-fold increased CVM (2.05 [1.55; 2.71]) when compared to users of neither diuretics nor laxatives. However, a test for interaction slightly missed statistical significance (p = 0.075). CONCLUSIONS: These consistent results from two large cohort studies imply that more research is needed on the safety of diuretics in routine care. Although not statistically significant in this study, a drug-drug interaction of non-potassium-sparing diuretics and laxatives appears plausible. Physicians and pharmacists are advised to clarify additional laxative use in users of non-potassium-sparing diuretics and inform about the risk of concurrent use. Moreover, closer potassium monitoring intervals (e.g., every 3 months) might be indicated in concurrent users to prevent fatal cardiovascular events.

Investigation of a possible association of potentially inappropriate medication for older adults and frailty in a prospective cohort study from Germany.

OBJECTIVE: potentially inappropriate medications (PIMs) are commonly defined as drugs that should be avoided in older adults because they are considered to have a negative risk-benefit ratio. PIMs are suspected to increase the risk for frailty, but this has yet to be examined. DESIGN: prospective population-based cohort study. SETTING AND PARTICIPANTS: a German cohort of community-dwelling older adults (≥60 years) was followed from October 2008 to September 2016. METHODS: in propensity score-adjusted logistic and Cox regression models, associations between baseline PIM use and prevalent/incident frailty were investigated. Frailty was assessed using the definition by Fried and co-workers, PIM were defined with the 2015 BEERS criteria, the BEERS criteria to avoid in cognitively impaired patients (BEERS dementia PIM), the EU(7)-PIM and the PRISCUS list. RESULTS: of 2,865 participants, 261 were frail at baseline and 423 became frail during follow-up. Only BEERS dementia PIM use was statistically significantly associated with prevalent frailty (odds ratio (95% confidence interval), 1.51 (1.04-2.17)). The strength of the association was comparable for all frailty components. Similarly, in longitudinal analyses, only BEERS dementia PIM use was associated with incident frailty albeit not statistically significant (hazard ratio, 1.19 (0.84-1.68)). CONCLUSIONS: the association of PIM use and frailty seems to be restricted to drug classes, which can induce frailty symptoms (anticholinergics, benzodiazepines, z-substances and antipsychotics). Physicians are advised to perform frailty assessments before and after prescribing these drug classes to older patients and to reconsider treatment decisions in case of negative performance changes.

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.

Polypharmacy and mortality: new insights from a large cohort of older adults by detection of effect modification by multi-morbidity and comprehensive correction of confounding by indication.

PURPOSE: The objective was to investigate whether the association of polypharmacy with non-cancer mortality is independent from comorbidity and is not a result of confounding by indication. METHODS: Analyses were conducted in 2687 participants of a German, population-based cohort of older adults with data collection 2008-2010. Polypharmacy was defined as ≥5 drugs and hyperpolypharmacy as ≥10 drugs. Drugs without relevant propensity of causing adverse drug reactions or drug-drug interactions were not counted. Confounding by indication was addressed by model adjustment for a propensity score for polypharmacy. RESULTS: The median age of study participants was 70 years, 10.7% had multi-morbidity, and 47.4% took five drugs or more (8.6% took ≥10 drugs). During 4.4 years of follow-up, 87 participants died of a cause other than cancer. Statistically significant, more than twofold increased non-cancer mortality was observed for subjects with polypharmacy or hyperpolypharmacy in a model adjusted for age, sex, education, lifestyle variables, and comorbidity, but associations lost statistical significance after additional adjustment for a propensity score for polypharmacy. However, a significant interaction of hyperpolypharmacy and multi-morbidity was detected (p = 0.019). The hazard ratio for the association of hyperpolypharmacy with non-cancer mortality was 1.42 (95%CI 0.57; 3.57) in subjects without multi-morbidity and 0.51 (95%CI 0.11; 2.27) in subjects with multi-morbidity. CONCLUSIONS: Polypharmacy was not independently associated with non-cancer mortality. This study highlights the importance to adjust for confounding by indication in studies on polypharmacy by a propensity score. The detected interaction suggests that hyperpolypharmacy can be indicated in subjects with multi-morbidity and may only be harmful in subjects without multi-morbidity.

The Association of Potentially Inappropriate Medication at Older Age With Cardiovascular Events and Overall Mortality: A Systematic Review and Meta-Analysis of Cohort Studies.

OBJECTIVE: The aim of this systematic review was to identify, evaluate, and meta-analyze cohort studies reporting the association of potentially inappropriate medication (PIM) intake with mortality and cardiovascular events. DESIGN: A systematic review and meta-analysis of prospective and retrospective cohort studies were conducted. Study appraisal included a thorough risk of bias assessment. Data synthesis followed a random-effects model. DATA SOURCES: The included studies were retrieved from the databases MEDLINE and ISI Web of Knowledge. Additionally, the authors checked the references of the included studies for further relevant literature. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: For inclusion in a study, the population needed to be older than 60 years of age and not restricted to having one specific disease. The outcome had to address all-cause mortality or cardiovascular events. Studies that examined polypharmacy or specific drugs were excluded. RESULTS: At first, 13 studies were included in a meta-analysis. The association of PIM with overall mortality was not statistically significant (risk ratio; 95% confidence interval, 1.13; 0.95-1.35). However, the majority of studies showed a high risk of specific forms of bias. These biases can be excluded by applying a new user design. It ascertains that adverse events occurring early in therapy are recorded. After restricting the meta-analysis to three studies with a new user design, the association of PIM use and mortality was statistically significant (risk ratio; 95% confidence interval, 1.59; 1.45-1.75). Only one study focused on cardiovascular events and found no statistically significant association. However, the study was not conducted with a new user design. CONCLUSION: In studies with adequate methods (new user design), PIM use, defined by Beers criteria or the HEDIS-DAE list, was associated with a 1.6-fold increased mortality in older adults. Physicians should therefore avoid prescribing PIM for older adults whenever feasible. Further new user design studies are required for cardiovascular outcomes and to compare the predictive value of different PIM criteria for mortality.