The Role of a Composite Fitness Score in the Association Between Low-Density Cholesterol and All-Cause Mortality in Older Adults: An Individual Patient Data Meta-Analysis.

BACKGROUND: In the general population, an increase in low-density lipoprotein cholesterol (LDL-C) predicts higher cardiovascular disease risk, and lowering LDL-C can prevent cardiovascular disease and reduces mortality risk. Interestingly, in cohort studies that include very old populations, no or inverse associations between LDL-C and mortality have been observed. This study aims to investigate whether the association between LDL-C and mortality in the very old is modified by a composite fitness score. METHODS: A 2-stage meta-analysis of individual participant data from the 5 observational cohort studies. The composite fitness score was operationalized by performance on a combination of 4 markers: functional ability, cognitive function, grip strength, and morbidity. We pooled hazard ratios (HR) from Cox proportional-hazards models for 5-year mortality risk for a 1 mmol/L increase in LDL-C. Models were stratified by high/low composite fitness score. RESULTS: Composite fitness scores were calculated for 2 317 participants (median 85 years, 60% females participants), of which 994 (42.9%) had a high composite fitness score, and 694 (30.0%) had a low-composite fitness score. There was an inverse association between LDL-C and 5-year mortality risk (HR 0.87 [95% CI: 0.80-0.94]; p < .01), most pronounced in participants with a low-composite fitness score (HR 0.85 [95% CI: 0.75-0.96]; p = .01), compared to those with a high composite fitness score (HR = 0.98 [95% CI: 0.83-1.15]; p = .78), the test for subgroups differences was not significant. CONCLUSIONS: In this very old population, there was an inverse association between LDL-C and all-cause mortality, which was most pronounced in participants with a low-composite fitness scores.

Assessment of the appropriateness of cardiovascular preventive medication in older people: using the RAND/UCLA Appropriateness Method.

BACKGROUND: In clinical practice and science, there is debate for which older adults the benefits of cardiovascular preventive medications (CPM) still outweigh the risks in older age. Therefore, we aimed to assess how various clinical characteristics influence the judgement of appropriateness of CPM in older adults. METHOD: We assessed the appropriateness of CPM for adults ≥75 years with regard to clinical characteristics (cardiovascular variables, complexity of health problems, age, side effects and life expectancy) using the RAND/ University of California at Los Angeles Appropriateness Method. A multidisciplinary panel, including 11 medical professionals and 3 older representatives of the target population, received an up-to-date overview of the literature. Using 9-point Likert scales (1 = extremely inappropriate; 9 = extremely appropriate), they assessed the appropriateness of starting and stopping cholesterol lowering medication, antihypertensives and platelet aggregation inhibitors, for various theoretical clinical scenarios. There were two rating rounds, with one face-to-face discussion in between. The overall appropriateness judgments were based on the median panel ratings of the second round and level of disagreement. RESULTS: The panelists emphasized the importance of the individual context of the patient for appropriateness of CPM. They judged that in general, a history of atherosclerotic cardiovascular disease strongly adds to the appropriateness of CPM, while increasing complexity of health problems, presence of hindering or severe side effects, and life expectancy < 1 year all contribute to the inappropriateness of CPM. Age had only minor influence on the appropriateness judgments. The appropriateness judgments were different for the three types of CPM. The literature, time-to-benefit, remaining life expectancy, number needed to treat, and quality of life, were major themes in the panel discussions. The considerations to stop CPM were different from the considerations not to start CPM. CONCLUSION: Next to the patients' individual context, which was considered decisive in the final decision to start or stop CPM, there were general trends of how clinical characteristics influenced the appropriateness, according to the multidisciplinary panel. The decision to stop, and not start CPM, appeared to be two distinct concepts. Results of this study may be used in efforts to support clinical decision making about CPM in older adults.

Do we AGREE on the targets of antihypertensive drug treatment in older adults: a systematic review of guidelines on primary prevention of cardiovascular diseases.

BACKGROUND: translation of the available evidence concerning primary cardiovascular prevention into clinical guidance for the heterogeneous population of older adults is challenging. With this review, we aimed to give an overview of the thresholds and targets of antihypertensive drug therapy for older adults in currently used guidelines on primary cardiovascular prevention. Secondly, we evaluated the relationship between the advised targets and guideline characteristics, including guideline quality. METHODS: we systematically searched PubMed, Embase, Emcare and five guideline databases. We selected guidelines with (i) numerical thresholds for the initiation or target values of antihypertensive drug therapy in context of primary prevention (January 2008-July 2020) and (ii) specific advice concerning antihypertensive drug therapy in older adults. We extracted the recommendations and appraised the quality of included guidelines with the AGREE II instrument. RESULTS: thirty-four guidelines provided recommendations concerning antihypertensive drug therapy in older adults. Twenty advised a higher target of systolic blood pressure (SBP) for octogenarians in comparison with the general population and three advised a lower target. Over half of the guidelines (n = 18) recommended to target a SBP <150 mmHg in the oldest old, while four endorsed targets of SBP lower than 130 or 120 mmHg. Although many guidelines acknowledged frailty, only three gave specific thresholds and targets. Guideline characteristics, including methodological quality, were not related with the recommended targets. CONCLUSION: the ongoing debate concerning targets of antihypertensive treatment in older adults, is reflected in an inconsistency of recommendations across guidelines. Recommended targets are largely set on chronological rather than biological age.

Correction: Statin Use and Self-Reported Hindering Muscle Complaints in Older Persons: A Population Based Study.

[This corrects the article DOI: 10.1371/journal.pone.0166857.].

General practitioners' deprescribing decisions in older adults with polypharmacy: a case vignette study in 31 countries.

BACKGROUND: General practitioners (GPs) should regularly review patients' medications and, if necessary, deprescribe, as inappropriate polypharmacy may harm patients' health. However, deprescribing can be challenging for physicians. This study investigates GPs' deprescribing decisions in 31 countries. METHODS: In this case vignette study, GPs were invited to participate in an online survey containing three clinical cases of oldest-old multimorbid patients with potentially inappropriate polypharmacy. Patients differed in terms of dependency in activities of daily living (ADL) and were presented with and without history of cardiovascular disease (CVD). For each case, we asked GPs if they would deprescribe in their usual practice. We calculated proportions of GPs who reported they would deprescribe and performed a multilevel logistic regression to examine the association between history of CVD and level of dependency on GPs' deprescribing decisions. RESULTS: Of 3,175 invited GPs, 54% responded (N = 1,706). The mean age was 50 years and 60% of respondents were female. Despite differences across GP characteristics, such as age (with older GPs being more likely to take deprescribing decisions), and across countries, overall more than 80% of GPs reported they would deprescribe the dosage of at least one medication in oldest-old patients (> 80 years) with polypharmacy irrespective of history of CVD. The odds of deprescribing was higher in patients with a higher level of dependency in ADL (OR =1.5, 95%CI 1.25 to 1.80) and absence of CVD (OR =3.04, 95%CI 2.58 to 3.57). INTERPRETATION: The majority of GPs in this study were willing to deprescribe one or more medications in oldest-old multimorbid patients with polypharmacy. Willingness was higher in patients with increased dependency in ADL and lower in patients with CVD.

Managing hypertension in frail oldest-old-The role of guideline use by general practitioners from 29 countries.

BACKGROUND: The best management of hypertension in frail oldest-old (≥80 years of age) remains unclear and we still lack guidelines that provide specific recommendations. Our study aims to investigate guideline use in general practitioners (GPs) and to examine if guideline use relates to different decisions when managing hypertension in frail oldest-old. DESIGN/SETTING: Cross-sectional study among currently active GPs from 29 countries using a case-vignettes survey. METHODS: GPs participated in a survey with case-vignettes of frail oldest-olds varying in systolic blood pressure (SBP) levels and cardiovascular disease (CVD). GPs from 26 European countries and from Brazil, Israel and New Zealand were invited. We compared the percentage of GPs reporting using guidelines per country and further stratified on the most frequently mentioned guidelines. To adjust for patient characteristics (SBP, CVD and GPs' sex, years of experience, prevalence of oldest-old and location of their practice), we used a mixed-effects regression model accounting for clustering within countries. RESULTS: Overall, 2,543 GPs from 29 countries were included. 59.4% of them reported to use guidelines. Higher guideline use was found in female (p = 0.031) and less-experienced GPs (p<0.001). Across countries, we found a large variation in self-reported guideline use, ranging from 25% to 90% of the GPs, but there was no difference in hypertension treatment decisions in frail oldest-old patients between GPs that did not use and GPs that used guidelines, irrespective of the guidelines they used. CONCLUSION: Many GPs reported using guidelines to manage hypertension in frail oldest-old patients, however guideline users did not decide differently from non-users concerning hypertension treatment decisions. Instead of focusing on the fact if GPs use guidelines or not, we as a scientific community should put an emphasis on what guidelines suggest in frail and oldest-old patients.

Recommendations for (Discontinuation of) Statin Treatment in Older Adults: Review of Guidelines.

OBJECTIVES: As a person's age increases and his/her health status declines, new challenges arise that may lead physicians to consider deprescribing statins. We aimed to provide insight into recommendations available in international cardiovascular disease prevention guidelines regarding discontinuation of statin treatment applicable to older adults. DESIGN: We systematically searched PubMed, EMBASE, EMCARE, and the websites of guideline development organizations and online guideline repositories for cardiovascular disease prevention guidelines aimed at the general population. We selected all guidelines with recommendations (instructions and suggestions) on discontinuation of statin treatment applicable to older adults, published between January 2009 and April 2019. In addition, we performed a synthesis of information from all other recommendations for older adults regarding statin treatment. Methodological quality of the included guidelines was appraised using the appraisal of guidelines for research & evaluation II (AGREE II) instrument. RESULTS: Eighteen international guidelines for cardiovascular disease prevention in the general adult population provided recommendations for statin discontinuation that were applicable to older adults. We identified three groups of instructions for statin discontinuation related to statin intolerance, and none was specifically aimed at older adults. Three guidelines also included suggestions to consider statin discontinuation in patients with poor health status. Of the 18 guidelines included, 16 made recommendations regarding statin treatment in older adults, although details on how to implement these recommendations in practice were not provided. CONCLUSION: Current international cardiovascular disease prevention guidelines provide little specific guidance for physicians who are considering statin discontinuation in older adults in the context of declining health status and short life expectancy. J Am Geriatr Soc 68:417-425, 2020.

Patient Characteristics and General Practitioners' Advice to Stop Statins in Oldest-Old Patients: a Survey Study Across 30 Countries.

BACKGROUND: Statins are widely used to prevent cardiovascular disease (CVD). With advancing age, the risks of statins might outweigh the potential benefits. It is unclear which factors influence general practitioners' (GPs) advice to stop statins in oldest-old patients. OBJECTIVE: To investigate the influence of a history of CVD, statin-related side effects, frailty and short life expectancy, on GPs' advice to stop statins in oldest-old patients. DESIGN: We invited GPs to participate in this case-based survey. GPs were presented with 8 case vignettes describing patients > 80 years using a statin, and asked whether they would advise stopping statin treatment. MAIN MEASURES: Cases varied in history of CVD, statin-related side effects and frailty, with and without shortened life expectancy (< 1 year) in the context of metastatic, non-curable cancer. Odds ratios adjusted for GP characteristics (ORadj) were calculated for GPs' advice to stop. KEY RESULTS: Two thousand two hundred fifty GPs from 30 countries participated (median response rate 36%). Overall, GPs advised stopping statin treatment in 46% (95%CI 45-47) of the case vignettes; with shortened life expectancy, this proportion increased to 90% (95CI% 89-90). Advice to stop was more frequent in case vignettes without CVD compared to those with CVD (ORadj 13.8, 95%CI 12.6-15.1), with side effects compared to without ORadj 1.62 (95%CI 1.5-1.7) and with frailty (ORadj 4.1, 95%CI 3.8-4.4) compared to without. Shortened life expectancy increased advice to stop (ORadj 50.7, 95%CI 45.5-56.4) and was the strongest predictor for GP advice to stop, ranging across countries from 30% (95%CI 19-42) to 98% (95% CI 96-99). CONCLUSIONS: The absence of CVD, the presence of statin-related side effects, and frailty were all independently associated with GPs' advice to stop statins in patients aged > 80 years. Overall, and within all countries, cancer-related short life expectancy was the strongest independent predictor of GPs' advice to stop statins.

Statin Use and Self-Reported Hindering Muscle Complaints in Older Persons: A Population Based Study.

PURPOSE: Statins are widely used by older persons in primary and secondary prevention of cardiovascular disease. Although serious adverse events are rare, many statin users report mild muscle pain and/or muscle weakness. It's unclear what impact statins exert on a patient's daily life. Research on statin related side effects in older persons is relatively scarce. We therefore investigated the relation between statin use and self-reported hindering muscle complaints in older persons in the general population. METHODS: The present research was performed within the Integrated Systematic Care for Older Persons (ISCOPE) study in the Netherlands (Netherlands trial register, NTR1946). All registered adults aged ≥ 75 years from 59 participating practices (n = 12,066) were targeted. Information about the medical history and statin use at baseline and after 9 months was available for 4355 participants from the Electronic Patient Records of the general practitioners. In the screening questionnaire at baseline we asked participants: 'At the moment, which health complaints limit you the most in your day-to-day life?' Answers indicating muscle or musculoskeletal complaints were coded as such. No specific questions about muscle complaints were asked. RESULTS: The participants had a median age of 80.3 (IQR 77.6-84.4) years, 60.8% were female and 28.5% had a history of CVD. At baseline 29% used a statin. At follow-up, no difference was found in the prevalence of self-reported hindering muscle complaints in statin users compared to non-statin users (3.3% vs. 2.5%, OR 1.39, 95% CI 0.94-2.05; P = 0.98). Discontinuation of statin use during follow-up was independent of self-reported hindering muscle complaints. CONCLUSION: Based on the present findings, prevalent statin use in this community-dwelling older population is not associated with self-reported hindering muscle complaints; however, the results might be different for incident users.

Disturbed Serotonergic Neurotransmission and Oxidative Stress in Elderly Patients with Delirium.

BACKGROUND: Oxidative stress and disturbances in serotonergic and dopaminergic neurotransmission may play a role in the pathophysiology of delirium. AIMS: In this study, we investigated levels of amino acids, amino acid ratios and levels of homovanillic acid (HVA) as indicators for oxidative stress and disturbances in neurotransmission. METHODS: Plasma levels of amino acids, amino acid ratios and HVA were determined in acutely ill patients aged ≥65 years admitted to the wards of Internal Medicine and Geriatrics of the Erasmus University Medical Center and the ward of Geriatrics of the Havenziekenhuis, Rotterdam, The Netherlands. Differences in the biochemical parameters between patients with and without delirium were investigated by analysis of variance in models adjusted for age, gender and comorbidities. RESULTS: Of the 86 patients included, 23 had delirium. In adjusted models, higher mean phenylalanine/tyrosine ratios (1.34 vs. 1.14, p = 0.028), lower mean tryptophan/large neutral amino acids ratios (4.90 vs. 6.12, p = 0.021) and lower mean arginine levels (34.8 vs. 45.2 µmol/l, p = 0.022) were found in patients with delirium when compared to those without. No differences were found in HVA levels between patients with and without delirium. CONCLUSION: The findings of this study suggest disturbed serotonergic neurotransmission and an increased status of oxidative stress in patients with delirium.

Neopterin: a potential biomarker for delirium in elderly patients.

BACKGROUND/AIMS: The diagnosis of delirium is not supported by specific biomarkers. In a previous study, high neopterin levels were found in patients with a postoperative delirium. In the present study, we investigated levels of neopterin, interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1) in acutely ill admitted elderly patients with and without a delirium. METHODS: Plasma/serum levels of neopterin, IL-6 and IGF-1 were determined in patients aged ≥65 years admitted to the wards of Internal Medicine and Geriatrics. Differences in biomarker levels between patients with and without a delirium were investigated by the analysis of variance in models adjusted for age, gender, comorbidities and eGFR (when appropriate). RESULTS: Eighty-six patients were included; 23 of them with a delirium. In adjusted models, higher mean levels of neopterin (70.5 vs. 45.9 nmol/l, p = 0.009) and IL-6 (43.1 vs. 18.5 pg/ml, p = 0.034) and lower mean levels of IGF-1 (6.3 vs. 9.3 nmol/l, p = 0.007) were found in patients with a delirium compared to those without. CONCLUSIONS: The findings of this study suggest that neopterin might be a potential biomarker for delirium which, through oxidative stress and activation of the immune system, may play a role in the pathophysiology of delirium.