Optimizing drug therapy for older adults: shifting away from problematic polypharmacy.

INTRODUCTION: The accelerated discovery and production of pharmaceutical products has resulted in many positive outcomes. However, this progress has also contributed to problematic polypharmacy, one of the rapidly growing threats to public health in this century. Problematic polypharmacy results in adverse patient outcomes and imposes increased strain and financial burden on healthcare systems. AREAS COVERED: A review was conducted on the current body of evidence concerning factors contributing to and consequences of problematic polypharmacy. Recent trials investigating interventions that target polypharmacy and emerging solutions, including incorporation of artificial intelligence, are also examined in this article. EXPERT OPINION: To shift away from problematic polypharmacy, a multifaceted interdisciplinary approach is necessary. Any potentially successful strategy must be adapted to suit various healthcare settings and must utilize all available resources, including artificial intelligence.

STOPP/START criteria for potentially inappropriate medications/potential prescribing omissions in older people: uptake and clinical impact.

INTRODUCTION: STOPP/START criteria for potentially inappropriate medications (PIMs, STOPP) and potential prescribing omissions (PPOs, START) have gained considerable interest and traction since they were first published in 2008. This review focuses on their uptake and impact in various clinical settings. AREAS COVERED: STOPP/START criteria, now in their third iteration, are explicit criteria designed to facilitate detection of common and clinically important PIMs and PPOs during routine medication review in any clinical setting. We examine the influence of the criteria, particularly in clinical trials that focused on their impact on clinically relevant endpoints. EXPERT OPINION: STOPP/START criteria are widely used in several countries within Europe and beyond for medication review and audit. As a discreet intervention, the criteria have been tested in several single-center and two large-scale multi-center clinical trials. The single-center trials indicate that STOPP/START criteria reduce polypharmacy, inappropriate prescribing, ADRs (adverse drug reactions), medication cost and falls. In contrast, the SENATOR and OPERAM multicentre trials did not demonstrate significant reduction in ADRs, all-cause mortality, drug-related hospital readmissions, nor any improvement in quality-of-life. Further clinical trials are required to examine whether STOPP/START criteria as an intervention can deliver significant clinical benefit in a reproducible manner in various clinical settings.

STOPP/START criteria for potentially inappropriate prescribing in older people: version 3.

PURPOSE: STOPP/START is a physiological systems-based explicit set of criteria that attempts to define the clinically important prescribing problems relating to potentially inappropriate medications (PIMs-STOPP criteria) and potential prescribing omissions (PPOs-START criteria). The previous two versions of STOPP/START criteria were published in 2008 and 2015. The present study describes the revised and updated third version of the criteria. METHODS: A detailed system-by-system review of the published literature from April 2014 to March 2022 was undertaken with the aim of including clinically important new explicit PIM and PPO criteria and removing any criteria considered to be no longer correct or outdated. A panel of 11 academic physicians with recognized expertise in geriatric pharmacotherapy from 8 European countries participated in a Delphi panel with the task of validating the draft criteria. The panel was presented with the draft new criteria using the SurveyMonkey® on-line platform in which panelists were asked to indicate their level of agreement on a five-point Likert scale. RESULTS: Two hundred and four evidence-based draft criteria (one hundred and forty-five STOPP criteria, fifty-nine START criteria) were presented to panelists for assessment using the Delphi validation method. Over the course of four rounds of Delphi validation, the panel achieved consensus on 133 STOPP criteria and 57 START criteria, i.e., 190 STOPP/START criteria in total representing a 66.7% increase in the number of criteria compared to STOPP/START version 2 published in 2015. CONCLUSION: A fully revised and updated version of STOPP/START criteria has been validated by a European expert panel using the Delphi consensus process.

Polypharmacy stewardship: a novel approach to tackle a major public health crisis.

With growing global concern regarding medication-related harm, WHO launched a global patient safety challenge, Medication Without Harm, in March, 2017. Multimorbidity, polypharmacy, and fragmented health care (ie, patients attending appointments with multiple physicians in various health-care settings) are key drivers of medication-related harm, which can result in negative functional outcomes, high rates of hospitalisation, and excess morbidity and mortality, particularly in patients with frailty older than 75 years. Some studies have examined the effect of medication stewardship interventions in older patient cohorts, but focused on a narrow spectrum of potentially adverse medication practices, with mixed results. In response to the WHO challenge, we propose the novel concept of broad-spectrum polypharmacy stewardship, a coordinated intervention designed to improve the management of multimorbidities, taking into account potentially inappropriate medications, potential prescribing omissions, drug-drug and drug-disease interactions, and prescribing cascades, aligning treatment regimens with the condition, prognosis, and preferences of the individual patient. Although the safety and efficacy of polypharmacy stewardship need to be tested with well designed clinical trials, we propose that this approach could minimise medication-related harm in older people with multimorbidities exposed to polypharmacy.

Comparison of 6 Mortality Risk Scores for Prediction of 1-Year Mortality Risk in Older Adults With Multimorbidity.

Importance: The most appropriate therapy for older adults with multimorbidity may depend on life expectancy (ie, mortality risk), and several scores have been developed to predict 1-year mortality risk. However, often, these mortality risk scores have not been externally validated in large sample sizes, and a head-to-head comparison in a prospective contemporary cohort is lacking. Objective: To prospectively compare the performance of 6 scores in predicting the 1-year mortality risk in hospitalized older adults with multimorbidity. Design, Setting, and Participants: This prognostic study analyzed data of participants in the OPERAM (Optimising Therapy to Prevent Avoidable Hospital Admissions in Multimorbid Older People) trial, which was conducted between December 1, 2016, and October 31, 2018, in surgical and nonsurgical departments of 4 university-based hospitals in Louvain, Belgium; Utrecht, the Netherlands; Cork, Republic of Ireland; and Bern, Switzerland. Eligible participants in the OPERAM trial had multimorbidity (≥3 coexisting chronic diseases), were aged 70 years or older, had polypharmacy (≥5 long-term medications), and were admitted to a participating ward. Data were analyzed from April 1 to September 30, 2020. Main Outcomes and Measures: The outcome of interest was any-cause death occurring in the first year of inclusion in the OPERAM trial. Overall performance, discrimination, and calibration of the following 6 scores were assessed: Burden of Illness Score for Elderly Persons, CARING (Cancer, Admissions ≥2, Residence in a nursing home, Intensive care unit admit with multiorgan failure, ≥2 Noncancer hospice guidelines) Criteria, Charlson Comorbidity Index, Gagné Index, Levine Index, and Walter Index. These scores were assessed using the following measures: Brier score (0 indicates perfect overall performance and 0.25 indicates a noninformative model); C-statistic and 95% CI; Hosmer-Lemeshow goodness-of-fit test and calibration plots; and sensitivity, specificity, and positive and negative predictive values. Results: The 1879 patients in the study had a median (IQR) age of 79 (74-84) years and 835 were women (44.4%). The median (IQR) number of chronic diseases was 11 (8-16). Within 1 year, 375 participants (20.0%) died. Brier scores ranged from 0.16 (Gagné Index) to 0.24 (Burden of Illness Score for Elderly Persons). C-statistic values ranged from 0.62 (95% CI, 0.59-0.65) for Charlson Comorbidity Index to 0.69 (95% CI, 0.66-0.72) for the Walter Index. Calibration was good for the Gagné Index and moderate for other mortality risk scores. Conclusions and Relevance: Results of this prognostic study suggest that all 6 of the 1-year mortality risk scores examined had moderate prognostic performance, discriminatory power, and calibration in a large cohort of hospitalized older adults with multimorbidity. Overall, none of these mortality risk scores outperformed the others, and thus none could be recommended for use in daily clinical practice.

Full inversion tillage during pasture renewal to increase soil carbon storage: New Zealand as a case study.

As soils under permanent pasture and grasslands have large topsoil carbon (C) stocks, the scope to sequester additional C may be limited. However, because C in pasture/grassland soils declines with depth, there may be potential to sequester additional C in the subsoil. Data from 247 continuous pasture sites in New Zealand (representing five major soil Orders and ~80% of the grassland area) showed that, on average, the 0.15-0.30 m layer contained 25-34 t ha-1 less C than the top 0.15 m. High-production grazed pastures require periodic renewal (re-seeding) every 7-14 years to maintain productivity. Our objective was to assess whether a one-time pasture renewal, involving full inversion tillage (FIT) to a depth of 0.30 m, has potential to increase C storage by burying C-rich topsoil and bringing low-C subsoil to the surface where C inputs from pasture production are greatest. Data from the 247 pasture sites were used to model changes in C stocks following FIT pasture renewal by predicting (1) the C accumulation in the new 0-0.15 m layer and (2) the decomposition of buried-C in the new 0.15-0.30 m layer. In the 20 years following FIT pasture renewal, soil C was predicted to increase by an average of 7.3-10.3 (Sedimentary soils) and 9.6-12.7 t C ha-1 (Allophanic soils), depending on the assumptions applied. Adoption of FIT for pasture renewal across all suitable soils (2.0-2.6 M ha) in New Zealand was predicted to sequester ~20-36 Mt C, sufficient to offset 9.6-17.5% of the country's cumulative greenhouse gas emissions from agriculture over 20 years at the current rate of emissions. Given that grasslands account for ~70% of global agricultural land, FIT renewal of pastures or grassland could offer a significant opportunity to sequester soil C and offset greenhouse gas emissions.

Deprescribing in older people approaching end-of-life: development and validation of STOPPFrail version 2.

BACKGROUND: Screening Tool of Older Persons Prescriptions in Frail adults with limited life expectancy (STOPPFrail) criteria were developed in 2017 to assist physicians with deprescribing decisions in older people approaching end-of-life. Updating was required to make the tool more practical, patient-centred and complete. METHODS: a thorough literature review was conducted to, first, devise a practical method for identifying older people who are likely to be approaching end-of-life, and second, reassess and update the existing deprescribing criteria. An eight-member panel with a wide-ranging experience in geriatric pharmacotherapy reviewed a new draft of STOPPFrail and were invited to propose new deprescribing criteria. STOPPFrail version 2 was then validated using Delphi consensus methodology. RESULTS: STOPPFrail version 2 emphasises the importance of shared decision-making in the deprescribing process. A new method for identifying older people who are likely to be approaching end-of-life is included along with 25 deprescribing criteria. Guidance relating to the deprescribing of antihypertensive therapies, anti-anginal medications and vitamin D preparations comprises the new criteria. CONCLUSIONS: STOPPFrail criteria have been updated to assist physicians in efforts to reduce drug-related morbidity and burden for their frailest older patients. Version 2 is based on an up-to-date literature review and consensus validation by a panel of experts.

Prevention of adverse drug reactions in hospitalized older patients with multi-morbidity and polypharmacy: the SENATOR* randomized controlled clinical trial.

BACKGROUND: Multi-morbidity and polypharmacy increase the risk of non-trivial adverse drug reactions (ADRs) in older people during hospitalization. Despite this, there are no established interventions for hospital-acquired ADR prevention. METHODS: We undertook a pragmatic, multi-national, parallel arm prospective randomized open-label, blinded endpoint (PROBE) controlled trial enrolling patients at six European medical centres. We randomized 1,537 older medical and surgical patients with multi-morbidity and polypharmacy on admission in a 1:1 ratio to SENATOR software-guided medication optimization plus standard care (intervention, n = 772, mean number of daily medications = 9.34) or standard care alone (control, n = 765, mean number of daily medications = 9.23) using block randomization stratified by site and admission type. Attending clinicians in the intervention arm received SENATOR-generated advice at a single time point with recommendations they could choose to adopt or not. The primary endpoint was occurrence of probable or certain ADRs within 14 days of randomization. Secondary endpoints were primary endpoint derivatives; tertiary endpoints included all-cause mortality, re-hospitalization, composite healthcare utilization and health-related quality of life. RESULTS: For the primary endpoint, there was no difference between the intervention and control groups (24.5 vs. 24.8%; OR 0.98; 95% CI 0.77-1.24; P = 0.88). Similarly, with secondary and tertiary endpoints, there were no significant differences. Among attending clinicians in the intervention group, implementation of SENATOR software-generated medication advice points was poor (~15%). CONCLUSIONS: In this trial, uptake of software-generated medication advice to minimize ADRs was poor and did not reduce ADR incidence during index hospitalization.

Computer-generated STOPP/START recommendations for hospitalised older adults: evaluation of the relationship between clinical relevance and rate of implementation in the SENATOR trial.

BACKGROUND: findings from a recent qualitative study indicate that the perceived clinical relevance of computer-generated STOPP/START recommendations was a key factor affecting their implementation by physician prescribers caring for hospitalised older adults in the SENATOR trial. AIM: to systematically evaluate the clinical relevance of these recommendations and to establish if clinical relevance significantly affected the implementation rate. METHODS: a pharmacist-physician pair retrospectively reviewed the case records for all SENATOR trial intervention patients at Cork University Hospital and assigned a degree of clinical relevance for each STOPP/START recommendation based on a previously validated six-point scale. The chi-square test was used to quantify the differences in prescriber implementation rates between recommendations of varying clinical relevance, with statistical significance set at P < 0.05. RESULTS: in 204 intervention patients, the SENATOR software produced 925 STOPP/START recommendations. Nearly three quarters of recommendations were judged to be clinically relevant (73.6%); however, nearly half of these were deemed of 'possibly low relevance' (320/681; 47%). Recommendations deemed of higher clinical relevance were significantly more likely to be implemented than those of lower clinical relevance (P < 0.05). CONCLUSIONS: a large proportion (61%) of the computer-generated STOPP/START recommendations provided were of potential 'adverse significance', of 'no clinical relevance' or of 'possibly low relevance'. The adjudicated clinical relevance of computer-generated medication recommendations significantly affects their implementation. Meticulous software refinement is required for future interventions of this type to increase the proportion of recommendations that are of high clinical relevance. This should facilitate their implementation, resulting in prescribing optimisation and improved clinical outcomes for multimorbid older adults.

Deprescribing in Older People Approaching End of Life: A Randomized Controlled Trial Using STOPPFrail Criteria.

OBJECTIVES: Older people approaching end of life are commonly prescribed multiple medications, many of which may be inappropriate or futile. Our objective was to examine the effect of applying the STOPPFrail, a recently developed deprescribing tool, to the medication regimens of older patients with advanced frailty. DESIGN: Randomized controlled trial. SETTING: Two acute hospitals in Ireland. PARTICIPANTS: Adults 75 years or older (n = 130) with advanced frailty and polypharmacy (five or more drugs), transferring to long-term nursing home care. INTERVENTION: A STOPPFrail-guided deprescribing plan was presented to attending physicians who judged whether or not to implement recommended medication changes. MEASUREMENTS: The primary outcome was the change in the number of regular medications at 3 months. Secondary outcomes included unscheduled hospital presentations, falls, quality of life, monthly medication costs, and mortality. RESULTS: Intervention (n = 65) and control group (n = 65) participants were prescribed a mean (plus or minus standard deviation [SD]) of 11.5 (±3.0) and 10.9 (±3.5) medications, respectively, at baseline. The mean (SD) change in the number of medications at 3 months was -2.6 (±2.73) in the intervention group and -.36 (±2.60) in the control group (mean difference = 2.25 ± .54; 95% confidence interval [CI] = 1.18-3.32; P < .001). The mean change in monthly medication cost was -$74.97 (±$148.32) in the intervention group and -$13.22 (±$110.40) in the control group (mean difference $61.74 ± $26.60; 95% CI = 8.95-114.53; P = .02). No significant differences were found between groups for any of the other secondary outcomes. CONCLUSION: STOPPFrail-guided deprescribing significantly reduced polypharmacy and medication costs in frail older people. No significant differences between groups were observed with regard to falls, hospital presentations, quality of life, and mortality, although the trial was likely underpowered to detect differences in these outcomes. J Am Geriatr Soc 68:762-769, 2020.

Predicting 1-Year Mortality in Older Hospitalized Patients: External Validation of the HOMR Model.

OBJECTIVES: Accurate prognostic information can enable patients and physicians to make better healthcare decisions. The Hospital-patient One-year Mortality Risk (HOMR) model accurately predicted mortality risk (concordance [C] statistic = .92) in adult hospitalized patients in a recent study in North America. We evaluated the performance of the HOMR model in a population of older inpatients in a large teaching hospital in Ireland. DESIGN: Retrospective cohort study. SETTING: Acute hospital. PARTICIPANTS: Patients aged 65 years or older cared for by inpatient geriatric medicine services from January 1, 2013, to March 6, 2015 (n = 1654). After excluding those who died during the index hospitalization (n = 206) and those with missing data (n = 39), the analytical sample included 1409 patients. MEASUREMENTS: Administrative data and information abstracted from hospital discharge reports were used to determine covariate values for each patient. One-year mortality was determined from the hospital information system, local registries, or by contacting the patient's general practitioner. The linear predictor for each patient was calculated, and performance of the model was evaluated in terms of its overall performance, discrimination, and calibration. Recalibrated and revised models were also estimated and evaluated. RESULTS: One-year mortality rate after hospital discharge in this patient cohort was 18.6%. The unadjusted HOMR model had good discrimination (C statistic = .78; 95% confidence interval = .76-.81) but was poorly calibrated and consistently overestimated mortality prediction. The model's performance was modestly improved by recalibration and revision (optimism corrected C statistic = .8). CONCLUSION: The superior discriminative performance of the HOMR model reported previously was substantially attenuated in its application to our cohort of older hospitalized patients, who represent a specific subset of the original derivation cohort. Updating methods improved its performance in our cohort, but further validation, refinement, and clinical impact studies are required before use in routine clinical practice. J Am Geriatr Soc 1-6, 2019.

Explicit criteria as clinical tools to minimize inappropriate medication use and its consequences.

Polypharmacy and prescribing of potentially inappropriate medications (PIMs) are the key elements of inappropriate medication use (IMU) in older multimorbid people. IMU is associated with a range of negative healthcare consequences including adverse drug events and unplanned hospitalizations. Furthermore, prescribing guidelines are commonly derived from randomized controlled clinical trials which have specifically excluded older adults with multimorbidity. Consequently, indiscriminate application of single disease pharmacotherapy guidelines to older multimorbid patients can lead to increased risk of drug-drug interactions, drug-disease interactions and poor drug adherence. Both polypharmacy and PIMs are highly prevalent in older people and strategies to improve the quality and safety of prescribing, largely through avoidance of IMU, are needed. In the last 30 years, numerous explicit PIM criteria-based tools have been developed to assist physicians with medication management in clinically complex multimorbid older people. Very few of these PIM criteria sets have been tested as an intervention compared with standard pharmaceutical care in well-designed clinical trials. In this review, we describe the most widely used sets of explicit PIM criteria to address inappropriate polypharmacy with particular focus on STOPP/START criteria and FORTA criteria which have been associated with positive patient-related outcomes when used as interventions in recent randomized controlled trials.

Association of polypharmacy and hyperpolypharmacy with frailty states: a systematic review and meta-analysis.

PURPOSE: To investigate: (1) the cross-sectional association between polypharmacy, hyperpolypharmacy and presence of prefrailty or frailty; (2) the risk of incident prefrailty or frailty in persons with polypharmacy, and vice versa. METHODS: A systematic review and meta-analysis was performed according to PRISMA guidelines. We searched PubMed, Web of Science, and Embase from 01/01/1998 to 5/2/2018. Pooled estimates were obtained through random effect models and Mantel-Haenszel weighting. Homogeneity was assessed with the I2 statistic and publication bias with Egger's and Begg's tests. RESULTS: Thirty-seven studies were included. The pooled proportion of polypharmacy in persons with prefrailty and frailty was 47% (95% CI 33-61) and 59% (95% CI 42-76), respectively. Increased odds ratio of polypharmacy were seen for prefrail (pooled OR = 1.52; 95% CI 1.32-1.79) and frail persons (pooled OR = 2.62, 95% CI 1.81-3.79). Hyperpolypharmacy was also increased in prefrail (OR = 1.95; 95% CI 1.41-2.70) and frail (OR = 6.57; 95% CI 9.57-10.48) persons compared to robust persons. Only seven longitudinal studies reported data on the risk of either incident prefrailty or frailty in persons with baseline polypharmacy. A significant higher odds of developing prefrailty was found in robust persons with polypharmacy (pooled OR = 1.30; 95% CI 1.12-1.51). We found no papers investigating polypharmacy incidence in persons with prefrailty/frailty. CONCLUSIONS: Polypharmacy is common in prefrail and frail persons, and these individuals are also more likely to be on extreme drug regimens, i.e. hyperpolypharmacy, than robust older persons. More research is needed to investigate the causal relationship between polypharmacy and frailty syndromes, thereby identifying ways to jointly reduce drug burden and prefrailty/frailty in these individuals. PROSPERO REGISTRATION NUMBER: CRD42018104756.

Deprescribing in multi-morbid older people with polypharmacy: agreement between STOPPFrail explicit criteria and gold standard deprescribing using 100 standardized clinical cases.

PURPOSE: Older people with advanced frailty are among the highest consumers of medications. When life expectancy is limited, some of these medications are likely to be inappropriate. The aim of this study was to compare STOPPFrail, a concise, easy-to-use, deprescribing tool based on explicit criteria, with gold standard, systematic geriatrician-led deprescribing. METHODS: One hundred standardized clinical cases involving 1024 medications were prepared. Clinical cases were based on anonymized hospitalized patients aged ≥ 65 years, with advanced frailty (Clinical Frailty Scale ≥ 6), receiving ≥ 5 regular medications, who were selected from a recent observational study. Level of agreement between deprescribing methods was measured by Cohen's kappa coefficient. Sensitivity and positive predictive value of STOPPFrail-guided deprescribing relative to gold standard deprescribing was also measured. RESULTS: Overall, 524 medications (51.2%) of medications prescribed to this frail, elderly cohort were potentially inappropriate by gold standard criteria. STOPPFrail-guided deprescribing led to the identification of 70.2% of the potentially inappropriate medications. Cohen's kappa was 0.60 (95% confidence interval 0.55-0.65; p < 0.001) indicating moderate agreement between STOPPFrail-guided and gold standard deprescribing. The positive predictive value of STOPPFrail was 89.3% indicating that the great majority of deprescribing decisions aligned with gold standard care. CONCLUSIONS: STOPPFrail removes an important barrier to deprescribing by explicitly highlighting circumstances where commonly used medications can be safely deprescribed in older people with advanced frailty. Our results suggest that in multi-morbid older patients with advanced frailty, the use of STOPPFrail criteria to address inappropriate polypharmacy may be reasonable alternative to specialist medication review.

Rapid increases in soil pH solubilise organic matter, dramatically increase denitrification potential and strongly stimulate microorganisms from the Firmicutes phylum.

Rapid and transient changes in pH frequently occur in soil, impacting dissolved organic matter (DOM) and other chemical attributes such as redox and oxygen conditions. Although we have detailed knowledge on microbial adaptation to long-term pH changes, little is known about the response of soil microbial communities to rapid pH change, nor how excess DOM might affect key aspects of microbial N processing. We used potassium hydroxide (KOH) to induce a range of soil pH changes likely to be observed after livestock urine or urea fertilizer application to soil. We also focus on nitrate reductive processes by incubating microcosms under anaerobic conditions for up to 48 h. Soil pH was elevated from 4.7 to 6.7, 8.3 or 8.8, and up to 240-fold higher DOM was mobilized by KOH compared to the controls. This increased microbial metabolism but there was no correlation between DOM concentrations and CO2 respiration nor N-metabolism rates. Microbial communities became dominated by Firmicutes bacteria within 16 h, while few changes were observed in the fungal communities. Changes in N-biogeochemistry were rapid and denitrification enzyme activity (DEA) increased up to 25-fold with the highest rates occurring in microcosms at pH 8.3 that had been incubated for 24-hour prior to measuring DEA. Nitrous oxide reductase was inactive in the pH 4.7 controls but at pH 8.3 the reduction rates exceeded 3,000 ng N2-N g-1 h-1 in the presence of native DOM. Evidence for dissimilatory nitrate reduction to ammonium and/or organic matter mineralisation was observed with ammonium increasing to concentrations up to 10 times the original native soil concentrations while significant concentrations of nitrate were utilised. Pure isolates from the microcosms were dominated by Bacillus spp. and exhibited varying nitrate reductive potential.