Long-term low-dose acetylsalicylic use shows protective potential for the development of both vascular dementia and Alzheimer's disease in patients with coronary heart disease but not in other individuals from the general population: results from two large cohort studies.

BACKGROUND: No population-based cohort study investigated a potential inverse association between long-term low-dose acetylsalicylic acid (ASA) use and all-cause dementia and its two most common sub-types Alzheimer's disease (AD) and vascular dementia (VD) so far. METHODS: Cox regression models with inverse probability of treatment weighting to model the underlying cardiovascular risk were used to assess the associations of low-dose ASA use with all-cause dementia, AD, and VD incidence in community-dwelling older adults from the German ESTHER study (N = 5258) and the UK Biobank (N = 305,394). Inclusion criteria were age of 55 years or older and completed drug assessment. Meta-analyses of the individual participant data from the two prospective cohort studies were performed. RESULTS: Four hundred seventy-six cases of all-cause dementia, 157 cases of AD, and 183 cases of VD were diagnosed over a median of 14.3 years of follow-up in ESTHER. In the UK Biobank, 5584 participants were diagnosed with all-cause dementia, 2029 with AD, and 1437 with VD over a median of 11.6 years. The meta-analysis of both cohorts revealed a weak reduction in hazards for all-cause dementia (hazard ratio (HR) [95% confidence interval (CI)]: 0.96 [0.93 to 0.99]). The strongest protective effect of low-dose ASA was observed in participants with coronary heart disease (CHD) in both cohorts, and a significant interaction was detected. In particular, in meta-analysis, a 31% reduction in hazard for AD, 69% for VD and 34% for all-cause dementia were observed (HR [95% CI]: 0.69 [0.59 to 0.80], 0.31 [0.27 to 0.35], 0.46 [0.42 to 0.50], respectively). Furthermore, compared to non-users, users of low-dose ASA for 10 years or longer (who likely use it because they have CHD or a related diagnosis putting them at an increased risk for cardiovascular events) demonstrated a strong protective effect on all dementia outcomes, especially for VD (HR [95% CI]: 0.48 [0.42 to 0.56]) whereas no protective associations were observed with shorter low-dose ASA use. CONCLUSIONS: The protective potential of low-dose ASA for all-cause dementia, AD, and VD seems to strongly depend on pre-existing CHD and the willingness of patients to take it for a minimum of ten years.

Strongly increased risk of gastric and duodenal ulcers among new users of low-dose aspirin: results from two large cohorts with new-user design.

BACKGROUND: Low-dose aspirin is a risk factor for peptic ulcer disease but previous, population-based cohort studies may have underestimated the low-dose aspirin risk because they did not use a new-user design. Gastrointestinal bleeding occurs more frequently early after initiation of low-dose aspirin therapy than in later years. AIM: To assess the associations of low-dose aspirin with gastric and duodenal ulcer incidence in prevalent- and new-user design. METHODS: Multivariate Cox regression models in the German ESTHER study (N = 7737) and the UK Biobank (N = 213,598) with more than 10 years of follow-up. RESULTS: In the prevalent-user design, there was no significant association between low-dose aspirin and gastric ulcer observed in both cohorts. Furthermore, low-dose aspirin was weakly, statistically significantly associated with prevalent duodenal ulcer in the UK Biobank (hazard ratio [95% confidence interval]: 1.27 [1.07-1.51]) but not in the ESTHER study (1.33 [0.54-3.29]). When restricting the exposure to only new users, the hazard ratios for incident gastric and duodenal ulcer disease were 1.82 [1.58-2.11] and 1.66 [1.36-2.04] in the UK Biobank, respectively, and 2.83 [1.40-5.71] and 3.89 [1.46-10.42] in the ESTHER study, respectively. CONCLUSIONS: This study shows that low-dose aspirin is an independent risk factor for both gastric and duodenal ulcers. The associations were not significant or weak in the prevalent-user design and strong and statistically significant in the new-user design in both cohorts. Thus, it is important to weigh risks against benefits when low-dose aspirin treatment shall be initiated and to monitor adverse gastrointestinal symptoms after the start of low-dose aspirin therapy.

Incorporation of functional status, frailty, comorbidities and comedication in prediction models for colorectal cancer survival.

Limitations in functional status, frailty, multiple comorbidities and comedications are common among older colorectal cancer (CRC) patients. We investigated whether adding these factors could improve the predictive value of a reference model containing age, sex, tumor stage and location for prediction of 5-year overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), recurrence-free survival (RFS) and nondisease-specific survival (nDSS) for all CRC patients as well as for younger (<65 years) and older patients (≥65 years). Overall, 3410 CRC patients from the DACHS study were analyzed and area under receiver operating characteristic curves (AUC) and net reclassification improvements (NRI) were assessed. In prediction of OS, the reference model plus functional status was identified as the best model among all CRC patients (AUC: 0.762) and younger CRC patients (AUC: 0.820). In older CRC patients, comorbidity should additionally be added (AUC: 0.747). For nDSS, the reference model plus comorbidity and frailty had the best predictive performance in all CRC patients (AUC: 0.776). For the outcomes DFS (AUC: 0.727), DSS (AUC: 0.838) and RFS (AUC: 0.784), the reference model was already the best model in all CRC patients because no significant NRIs were observed. The pattern "The less CRC-specific the survival outcome and the older the CRC patients, the more relevant the inclusion of functional status, comorbidity, and frailty in CRC prognostic scores is" was observed. Thus, different nomograms for younger and older CRC patients for 1-, 3- and 5-year OS prognosis estimation are being suggested.

Association of Comedication Quality With Chemotherapy-Related Adverse Drug Reactions and Survival in Older Colorectal Cancer Patients.

BACKGROUND: Evidence about the clinical relevance of appropriate comedication among older colorectal cancer (CRC) patients is sparse. METHODS: A cohort study was conducted with 3239 CRC patients aged 65 years and older. To assess comedication quality, we calculated the total Fit fOR The Aged (FORTA) score and its subscores for medication overuse, underuse, and potentially inappropriate medication use. Multivariable Cox proportional hazards or logistic regression models were performed to evaluate the association of comedication quality with up to 5-year overall survival, CRC-specific survival, and chemotherapy-related adverse drug reactions. RESULTS: Overall, 3239 and 1209 participants were included in analyses on survival and adverse drug reactions, respectively. The hazard ratios [95% confidence intervals] for the total FORTA score ≥ 7 versus 0-1 points were 1.83 [1.40-2.40] and 1.76 [1.22-2.52] for up to 5-year overall and CRC-specific survival, respectively. Worse up to 5-year overall survival and CRC-specific survival was also evident for FORTA subscores for potentially inappropriate medication use and overuse, whereas no association was observed for underuse. Although results for the total FORTA and potentially inappropriate medication score were much stronger among patients receiving chemotherapy, no significant associations with chemotherapy-related adverse drug reactions were observed. Moreover, associations were particularly strong among men and rectal cancer patients as compared to women and colon cancer patients. CONCLUSIONS: Poor total comedication quality was significantly associated with worse up to 5-year overall and CRC-specific survival. Randomized controlled trials are needed to test whether improved cancer comedication management in older CRC patients prolongs survival.

Association of renin-angiotensin-aldosterone system inhibition with Covid-19 hospitalization and all-cause mortality in the UK biobank.

AIMS: With growing evidence on the protective effect of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in coronavirus disease 2019 (Covid-19), we aimed to thoroughly investigate the association between the use of major classes of antihypertensive medications and Covid-19 outcomes in comparison with the use of ACEIs and ARBs. METHODS: We conducted a population-based study in patients with pre-existing hypertension in the UK Biobank with data from the first 2 SARS-CoV-2 waves prior population-based vaccination. Multivariable logistic regression analysis was performed adjusting for a wide range of confounders. RESULTS: The use of either ß-blockers (BBs), calcium-channel blockers (CCBs) or diuretics was associated with a higher risk of Covid-19 hospitalization compared to ACEI use (adjusted OR (95%CI): 1.66 [1.43-1.93]) and ARB use (1.53 [1.30-1.81]). The risk of 28-day mortality among Covid-19 patients was also increased among users of BBs, CCBs or diuretics when compared to ACEI users (1.74 [1.30-2.33]) but not when compared to ARB users (1.26 [0.93-1.71]). The association between BB, CCB or diuretic use (compared to ACEI use) and 28-day mortality among hospitalized Covid-19 patients narrowly missed statistical significance (1.47 [0.99-2.18]) but it was statistically significant when the analysis was restricted to patients hospitalized during the second SARS-CoV-2 wave (1.80 [1.15-2.83]). CONCLUSION: Our results suggest protective effects of inhibition of the renin-angiotensin-aldosterone system on Covid-19 hospitalization and mortality, particularly with ACEI, among patients with pharmaceutically treated hypertension. If confirmed by randomized controlled trials, this finding could have high clinical relevance for treating hypertension during the SARS-CoV-2 pandemic.

Association of Polypharmacy with Colorectal Cancer Survival Among Older Patients.

BACKGROUND: In geriatric oncology, polypharmacy is often assessed during a comprehensive geriatric assessment. Previous studies about its association with survival among patients with colorectal cancer (CRC) were inconclusive and had high risk for indication bias. PATIENTS AND METHODS: A cohort study was conducted with 3,239 patients with CRC, aged ≥65 years, who were recruited in Germany between 2003 and 2016, while being hospitalized for CRC surgery. We defined polypharmacy as the concurrent use of five or more drugs, and excessive polypharmacy (EPP) as concurrent use of eight or more drugs. Cox proportional hazards regression models were performed to assess the associations of polypharmacy with 5-year overall (OS), CRC-specific (CSS), and non-cancer-specific survival (NCS) with rigorous adjustment for morbidity to minimize indication bias (e.g., for cancer stage, functional status, and 13 common diseases/conditions). RESULTS: The prevalence of polypharmacy was 54.7% and that of EPP was 24.2%. During up to 5 years of follow-up, 1,070 participants died, among whom 615 died of CRC and 296 died of other causes than cancer. EPP was statistically significantly associated with poorer up-to-5-year OS (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.02-1.47) and CSS (HR, 1.31; 95% CI, 1.03-1.68). HR point estimate for NCS was higher than 1 (1.22) but not statistically significant. CONCLUSION: Polypharmacy was very common and EPP was a weak risk factor for mortality in this large cohort of older patients with CRC. Clinical trials are needed to address the causality of this relationship because older patients with CRC might benefit from deprescribing drugs without an indication. IMPLICATIONS FOR PRACTICE: The results of this study support the hypothesis that excessive polypharmacy, defined as use of eight or more concurrently used active substances, has a negative impact on the prognosis of older patients with colorectal cancer (CRC). This study suggests to oncologists that performing a medication review for older patients with CRC with eight drugs or more is indicated (especially when a broader comprehensive geriatric assessment is being performed). Such a medication review should not only focus on reducing the number of medications (by deprescribing drugs without an indication) but also check the appropriateness of indicated drugs for older patients with cancer.

Comparison of Five Lists to Identify Potentially Inappropriate Use of Non-Steroidal Anti-Inflammatory Drugs in Older Adults.

OBJECTIVE: To compare the prevalence of potentially inappropriate non-steroidal anti-inflammatory drugs (NSAIDs) among NSAIDs users defined with frequently used potentially inappropriate medication (PIM) lists and to identify the determinants of their use. DESIGN AND SETTING: Cross-sectional survey among community-dwelling older adults from Germany. SUBJECTS: N = 284 NSAIDs users aged 65-89 years. METHODS: All currently regularly or as-needed used drugs were recorded during a home visit. Multivariate logistic regression models were applied to assess the potential determinants of potentially inappropriate NSAIDs use. RESULTS: Prevalence of potentially inappropriate NSAIDs use was 54.2%, 45.4%, 29.9%, 20.4%, and 3.5% when applying the STOPP, 2019 Beers, EU(7)-PIM, FORTA, and PRISCUS list, respectively. No study participant was identified as a potentially inappropriate NSAIDs user by all five lists simultaneously. The majority (68%) were identified only by one or two lists. Merely the STOPP and Beers criteria had a moderate inter-instrument agreement. Lower pain severity, gout, peptic ulcer (PU), cardiovascular disease (CVD), and chronic kidney disease (CKD) were statistically significantly associated with potentially inappropriate NSAIDs use defined by the STOPP criteria and the latter three conditions also with the 2019 Beers criteria. CONCLUSIONS: The STOPP and Beers criteria may be superior to the other lists because they more frequently identify potentially inappropriate NSAIDs use in conditions implying a high risk for NSAIDs' adverse events (i.e., PUD, CKD and CVD). We developed a harmonized, country-independent PIM list for NSAIDs with the same advantages as observed for the STOOP and 2019 Beers criteria and recommended its use.

Systematic Review and Meta-Analysis on the Associations of Polypharmacy and Potentially Inappropriate Medication With Adverse Outcomes in Older Cancer Patients.

BACKGROUND: Both polypharmacy and potentially inappropriate medication (PIM) intake are highly prevailing in older cancer patients. However, only studies on the association of polypharmacy and postoperative complications have been meta-analyzed previously. METHODS: A systematic review and a meta-analysis of prospective/retrospective observational studies reporting associations of polypharmacy or PIM with at least one out of five predefined adverse health outcomes in a population of older cancer patients (≥60 years) were carried out. PubMed and Web of Science were used to search for relevant studies published between January 1991 and March 2020. Data were pooled by adopting a random-effects model. RESULTS: Overall, 42 publications were included in the systematic review. Meta-analyses could be performed on 39 studies about polypharmacy and 13 studies about PIM. Polypharmacy was found to be statistically significantly associated with all-cause mortality (risk ratio [95% confidence interval]: 1.37 [1.25-1.50]), hospitalization (1.53 [1.37-1.71]), treatment-related toxicity (1.22 [1.01-1.47]), and postoperative complications (1.73 [1.36-2.20]). The association of polypharmacy with prolongation of hospitalization was not statistically significant at the p < .05 significance level (1.62 [0.98-2.66]). With respect to PIM, a statistically significant association with all-cause mortality (1.43 [1.08-1.88]) was observed but not with other adverse outcomes. CONCLUSIONS: Polypharmacy was found to be associated with several adverse outcomes and PIM use with all-cause mortality in older cancer patients. However, these results should be interpreted with caution because about three-quarters of the studies identified did not adjust for comorbidity and are prone to confounding by indication.

Pain severity and analgesics use in the community-dwelling older population: a drug utilization study from Germany.

PURPOSE: Chronic pain is common in the older population and a significant public health concern. However, comprehensive studies on analgesics use in this age group from Germany are scarce. This study aims to give a comprehensive overview on the use of the most common therapeutic groups of analgesics in community-dwelling older adults from Germany. METHODS: A cross-sectional study was carried out using data from a German cohort of 2038 community-dwelling adults aged 63-89 years. Descriptive statistics and logistic regression models were applied to assess the utilization of analgesics by age, sex, pain severity, pain duration, and locations. RESULTS: One out of four study participants was suffering from high-intensity or disabling pain. Approximately half of those taking analgesics still reported to suffer from high-intensity or disabling pain. Among analgesics users, occasional non-steroidal anti-inflammatory drugs (NSAIDs) use was the most frequent pain therapy (in 43.6% of users), followed by metamizole (dipyrone) use (16.1%), regular NSAIDs use (12.9%), strong opioids use (12.7%), and weak opioids use (12.0%). In multivariate logistic regression models, higher age, higher pain severity, longer pain duration, abdominal pain, and back pain were statistically significantly associated with opioids use. Metamizole use was also statistically significantly associated with higher pain severity but inversely associated with pain duration. CONCLUSIONS: A significant number of older German adults are affected by high-intensity and disabling chronic pain despite receiving analgesics. Long-term studies are needed to compare the effectiveness and safety of different treatments for chronic pain in older adults.