Angiotensin Receptor Blockers and Cognition: a Scoping Review.

PURPOSE OF REVIEW: To provide an overview of the association between angiotensin II receptor blocker (ARB) use and cognitive outcomes. RECENT FINDINGS: ARBs have previously shown greater neuroprotection compared to other anti-hypertensive classes. The benefits are primarily attributed to the ARB's effect on modulating the renin-angiotensin system via inhibiting the Ang II/AT1R pathway and activating the Ang II/AT2R, Ang IV/AT4R, and Ang-(1-7)/MasR pathways. These interactions are associated with pleiotropic neurocognitive benefits, including reduced ß-amyloid accumulation and abnormal hyperphosphorylation of tau, ameliorated brain hypo-fusion, reduced neuroinflammation and synaptic dysfunction, better neurotoxin clearing, and blood-brain barrier function restoration. While ACEis also inhibit AT1R, they simultaneously lower Ang II and block the Ang II/AT2R and Ang IV/AT4R pathways that counterbalance the potential benefits. ARBs may be considered an adjunctive approach for neuroprotection. This preliminary evidence, coupled with their underlying mechanistic pathways, emphasizes the need for future long-term randomized trials to yield more definitive results.

Management of Hyperkalemia in Patients with Chronic Kidney Disease Using Renin Angiotensin Aldosterone System Inhibitors.

PURPOSE OF REVIEW: Use of renin-angiotensin-aldosterone system (RAAS) inhibiting medications is critical in the prevention of cardiovascular disease and kidney function decline in patients with chronic kidney disease (CKD); however, these agents can lead to hyperkalemia, an electrolyte disorder associated with risk of arrythmia, conduction disorders, and increased overall mortality. Discontinuation, or reduction of dose, of RAAS inhibitor therapy in hyperkalemic patients with CKD can lead to loss of kidney and cardiovascular protection afforded by these medications. Given the high prevalence of hyperkalemia among patients with CKD utilizing RAAS inhibitors, clear management principles are critical to minimize risk and maximize benefit when facing this clinical dilemma. RECENT FINDINGS: Strategies to mitigate hyperkalemia that do not interfere with optimal RAAS inhibitor therapy should be prioritized when managing potassium elevation in patients with CKD. These strategies include discontinuing non-RAAS inhibitor medications known to cause hyperkalemia, correction of metabolic acidosis, and maximization of medication therapies that lower serum potassium, including diuretics and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Initiation of potassium exchange resins should also be considered to allow for sustained RAAS inhibitor utilization. An approach which employs multiple strategies concurrently is important to mitigate hyperkalemia and maintain long-term use of RAAS-inhibitors. Persistence of RAAS inhibitor use in patients with CKD is important to slow kidney function decline, delay onset of dialysis or the need for kidney transplant, and prevent adverse cardiovascular outcomes. When hyperkalemia develops among patients with CKD utilizing a RAAS inhibitor, a deliberate effort to reduce serum potassium levels using an approach that allows for continuation of maximally dosed RAAS inhibitor therapy is important. Patient education and engagement in the potassium management process is important for sustained success.

Drug Interactions with Antihypertensives.

PURPOSE OF REVIEW: Hypertension is remarkably prevalent, affecting an estimated 1.13 billion people worldwide. It often requires the use of multi-drug regimens and is commonly associated with a myriad of other comorbidities which increase medication use. The pervasive use of antihypertensive medications combined with the presence of polypharmacy in many hypertensive patients results in significant risk of drug interactions. This review will summarize the relevant literature to assist clinicians in mitigating drug interaction risks when prescribing antihypertensives. RECENT FINDINGS: Pharmacokinetic interactions affect drug disposition in the body and can occur at the steps of absorption, distribution, metabolism, or elimination of involved medications. Data has established the calcium channel blockers, namely, diltiazem and verapamil, as potent inhibitors of CYP3A4, and the majority of significant drug interactions involving antihypertensives are attributable to these two agents. Although less common, pharmacokinetic drug interactions with other antihypertensive classes have also been identified. Pharmacodynamic drug interactions with antihypertensives lead to synergy or antagonism of blood pressure lowering effects and can increase or mitigate adverse effects depending on the agents involved. Knowledge is emerging about drug-induced phenoconversion, a phenomenon whereby a drug interaction results in a drug metabolizing phenotype that is different than that predicted by an individual's genotype. Antihypertensive use in patients with comorbidities and polypharmacy increases the likelihood of encountering important drug-drug interactions. Dedicated efforts to better understand the relationship between pharmacokinetic drug interactions and pharmacogenomic information is important to advance efforts related to personalized medicine.

Antihypertensive Agents in the Dialysis Patient.

PURPOSE OF REVIEW: Hypertension and antihypertensive drug utilization are remarkably prevalent in ESRD patients. Management of blood pressure elevation in this population is complicated by many factors, including a multidimensional etiology, challenges in obtaining accurate and appropriately timed blood pressure measurements, highly specific drug dosing requirements, and a paucity of outcomes-based evidence to guide management decisions. The purpose of this review is to summarize and apply knowledge from existing clinical trials to enhance safe and effective use of antihypertensive agents in dialysis patients. RECENT FINDINGS: Two meta-analyses have established the benefit of antihypertensive therapy in ESRD. Data supporting the use of one antihypertensive class over another is less robust; however, beta-blockers have more clearly demonstrated improved cardiovascular outcomes in prospective randomized trials. Interdialytic home blood pressure monitoring has been demonstrated to be better associated with cardiovascular outcomes than clinic pre- or post-dialysis readings and should ideally be considered as a routine part of blood pressure management in this population. As data from small trials provides limited guidance for the management of hypertension in ESRD, more research is needed to guide medication selection and utilization. Specifically, large prospective randomized trails comparing cardiovascular outcomes of various medication classes and differing blood pressure targets are needed.

Long-term blood pressure variability and frailty risk in older adults.

INTRODUCTION: In healthy older adults, the relationship between long-term, visit-to-visit variability in blood pressure (BP) and frailty is uncertain. METHODS: Secondary analysis of blood pressure variability (BPV) and incident frailty in >13 000 participants ≥65-70 years enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial and its observational follow-up (ASPREE-XT). Participants were without dementia, physical disability, or cardiovascular disease at baseline. BPV was estimated using standard deviation of mean BP from three annual visits (baseline through the second annual follow-up). Frailty was defined using Fried phenotype and a frailty deficit accumulation index (FDAI). Participants with frailty during the BPV estimation period were excluded from the main analysis. Adjusted Cox proportional hazards regression evaluated the association between BPV and incident frailty, and linear mixed models for change in frailty scores, through a maximum of 9 years of follow-up. RESULTS: Participants in the highest systolic BPV tertile were at higher risk of frailty compared to those in the lowest (referent) tertile of systolic BPV [Fried hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.04-1.31; FDAI HR 1.18, 95% CI 1.07-1.30]. Findings were consistent when adjusted for multiple covariates and when stratified by antihypertensive use. Linear mixed models showed that higher systolic BPV was associated with increasing frailty score over time. Diastolic BPV was not consistently associated. CONCLUSIONS: High systolic BPV, independent of mean BP, is associated with increased risk of frailty in healthy older adults. Variability of BP across visits, even in healthy older adults, can convey important risk information beyond mean BP. TRIAL REGISTRATION: ClinicalTrials.gov NCT01038583 and ISRCTN83772183.

Daily low-dose aspirin and blood pressure in community-dwelling older adults.

High-quality randomized trial evidence is lacking on whether low-dose aspirin exerts significant effects on blood pressure (BP) in older adults. The authors assessed longitudinal BP changes in participants enrolled in ASPirin in Reducing Events in the Elderly (ASPREE), a randomized, placebo-controlled trial of 100 mg daily aspirin in 19 114 community-dwelling Australian and U.S. adults without cardiovascular disease (CVD), dementia, or independence-limiting physical disability. Participants' BP was recorded at baseline and annual study visits, and managed by their usual care provider. BP trajectories for aspirin versus placebo during 4.7 years of follow-up were examined for systolic and diastolic BP separately, using linear mixed models to account for between and within-individual variability in BP. Analyses by subgroups were also explored with inclusion of interaction terms in the models. The difference in mean change in systolic BP between aspirin and placebo during study follow-up was -0.03 mm Hg (95% confidence interval [CI]: -0.13, 0.07; p = .541) (aspirin minus placebo), while the mean difference for change in diastolic BP was -0.05 mm Hg (95% CI: -0.11, 0.01; p = .094). These small, non-significant differences in BP change between the aspirin and placebo groups were consistent across baseline levels of BP and antihypertensive treatment status (treated/untreated). Likewise, subgroups of age, sex, chronic kidney disease, diabetes, and frailty revealed no interaction effect between the subgroup, aspirin treatment, and time. Interval-censored Cox proportional hazards regression showed no difference in rates of incident treated hypertension between aspirin and placebo-treated participants. The authors conclude that daily low-dose aspirin does not significantly affect BP in older adults when managed by usual care.

Dietary supplement and complementary and alternative medicine use among older adults in Australia and the United States.

BACKGROUND: Dietary supplement and complementary and alternative medication (CAM) use can contribute to drug interactions, polypharmacy, nonadherence with prescription medications, and healthcare expenses, whereas evidence supporting benefits of using these products is sparse. There is a lack of current published literature describing the patterns or predictors of their use in community-dwelling older adults. MATERIALS AND METHODS: We performed a cross-sectional analysis of community-dwelling adults from Australia and the US, aged 70 years and older (65 years for US minorities), enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) study. At study enrollment, eligible participants were required to be without concurrent 5-year life-limiting illness and free of documented evidence of cardiovascular disease, dementia, or significant physical disability. During the final study visit, a questionnaire was administered to collect information about supplement/CAM use. Data from 15,729 participants who completed this questionnaire between January 2017 and January 2018 were analyzed. Descriptive statistics were used to report the prevalence and types of products used. Factors associated with use were determined using multivariate regression. RESULTS: Mean age of respondents was 79.6 years; 56.4% were female, 88.8% were from Australia, 56.5% reported 12 years of education or less, and 98.7% were living at home. Two-thirds (66.2%) of participants reported use of one or more supplement/CAM in the previous month. Products most commonly used included vitamin D (33.8% of participants), fish oil (22.7%), calcium (20.6%), glucosamine (14.8%), and multivitamin (12.9%). Female sex, US residency, higher education, polypharmacy (prescription medications), and frailty (in women) were significantly associated with higher use of supplements/CAMs. CONCLUSIONS: Dietary supplement and CAM use is common among community-dwelling older adults in the United States and Australia. Given the high prevalence of use, collaboration between healthcare providers and older adult patients is important to insure safe and optimal use of these products.

GFR Variability, Survival, and Cardiovascular Events in Older Adults.

Rationale & Objective: Variability in estimated glomerular filtration rate (eGFR) over time is often observed, but it is unknown whether this variation is clinically important. We investigated the association between eGFR variability and survival free of dementia or persistent physical disability (disability-free survival) and cardiovascular disease (CVD) events (myocardial infarction, stroke, hospitalization for heart failure, or CVD death). Study Design: Post hoc analysis. Setting & Participants: 12,549 participants of the ASPirin in Reducing Events in the Elderly trial. Participants were without documented dementia, major physical disability, previous CVD, and major life-limiting illness at enrollment. Predictors: eGFR variability. Outcomes: Disability-free survival and CVD events. Analytical Approach: eGFR variability was estimated using the standard deviation of eGFR measurements obtained from participants' baseline, first, and second annual visits. Associations between tertiles of eGFR variability with disability-free survival and CVD events occurring after the eGFR variability estimation period were examined. Results: During median follow-up of 2.7 years after the second annual visit, 838 participants died, developed dementia, or acquired a persistent physical disability; 379 had a CVD event. The highest tertile of eGFR variability had an increased risk of death/dementia/disability (HR, 1.35; 95% CI, 1.14-1.59) and CVD events (HR, 1.37; 95% CI, 1.06-1.77) compared with the lowest tertile after covariate adjustment. These associations were present in patients with and without chronic kidney disease at baseline. Limitations: Limited representation of diverse demographics. Conclusions: In older, generally healthy adults, higher variability in eGFR over time predicts increased risk of future death/dementia/disability and CVD events.

The association of allopurinol with persistent physical disability and frailty in a large community based older cohort.

BACKGROUND: The protective effects of allopurinol on physical function in older adults are not well understood, despite its potential to improve functional gains and reduce sarcopenia. This study aims to determine the association between allopurinol, persistent physical disability, and frailty in older gout patients. METHODS: This analysis used data from a randomized trial in an older cohort, ASPirin in Reducing Events in the Elderly (ASPREE). ASPREE recruited 19,114 participants aged ≥65 years without prior cardiovascular events, dementia, or independence-limiting physical disability at trial enrolment. This analysis examined the association of baseline and time-varying allopurinol use with persistent physical disability and new-onset frailty in participants with gout at baseline (self-report or use of any anti-gout medications). Frailty was measured using the Fried frailty phenotype (score ≥3/5) and a deficit accumulation frailty index (FI) (score >0.21/1.0). Multivariable Cox proportional-hazards models were used for main analyses. RESULTS: This analysis included 1155 gout participants, with 630 taking allopurinol at baseline and 525 not. During a median follow-up of 5.7 years, 113 new allopurinol users were identified. Compared with nonusers, baseline allopurinol use was associated with a significant risk reduction of persistent physical disability (Adjusted HR 0.46, 95% CI 0.23-0.92, p = 0.03). The strength of the association was modestly attenuated in the time-varying analysis (Adjusted HR 0.56, 0.29-1.08, p = 0.08). No significant associations with frailty measures were observed for either baseline allopurinol use (Fried frailty: Adjusted HR 0.83, 0.62-1.12; FI: Adjusted HR 0.96, 0.74-1.24) or time-varying allopurinol use (Fried frailty: Adjusted HR 0.92, 0.69-1.24; FI: Adjusted HR 1.02, 0.78-1.33). CONCLUSIONS: Allopurinol use in older adults with gout is associated with a reduced risk of persistent physical disability but not associated with risk of frailty.

Thiazide and the Thiazide-Like Diuretics: Review of Hydrochlorothiazide, Chlorthalidone, and Indapamide.

The term thiazide is universally understood to refer to diuretics that exert their principal action in the distal tubule. The thiazide class is heterogenous and can be further subdivided into compounds containing the benzothiadiazine ring structure-the thiazide-type (e.g., hydrochlorothiazide)-and those lacking the benzothiadiazine ring-the thiazide-like (e.g., chlorthalidone and indapamide) drugs. Thiazide-like agents are longer acting and constitute the diuretics used in most of the cardiovascular outcome trials that established benefits of treatment with diuretics, but pragmatic aspects, such as lack of availability in convenient formulations, limit their use. Regardless of class heterogeneity, thiazides have retained importance in the management of hypertension for over 60 years. They are reliably effective as monotherapy in a majority of hypertensive patients, and augment the efficacy of other classes of antihypertensives when used in combination. Importantly, a thiazide-based treatment regimen lowers cardiovascular events, and their sturdy effect reinforces their place among the recommended first-line agents to treat hypertension in major domestic and international hypertension guidelines. There are few head-to-head comparisons within the class, but potential differences have been explored indirectly as well as in non-blood pressure mechanisms and potential pleiotropic properties. Until proven otherwise, the importance of these differences remains speculative, and clinicians should assume that cardiovascular events will be lowered similarly across agents when equivalent blood pressure reduction occurs. Thiazides remain underutilized, with only about one-third of hypertensive patients receiving them. For many patients, however, a thiazide is an indispensable component of their regimen to achieve adequate blood pressure control.

An Exploratory Mixed Methods Study of Standardized Patient Comments on Empathy and Student Communication Scores.

Objective. To quantify student pharmacists' communication ability based on scores from standardized patient (SP) communication rubrics, describe and categorize SP comments about student empathy, and test the relationship between students' communication scores and empathy.Methods. A concurrent mixed methods research design was used to assess a graded performance-based assessment (PBA) of student pharmacists that had been conducted at one college of pharmacy. The PBA rubrics (n=218) completed by SPs contained 20 assessment items and space for open-ended feedback. Scoring categories for communication assessment included: yes, inconsistent, no, and not applicable (N/A). Descriptive statistics were calculated for rubric scores. Feedback from standardized patients was analyzed and used to categorize student interactions during the encounter as reflecting high empathy, mixed empathy, or low empathy. Kruskal-Wallis ANOVA was used to test the relationship between empathy category and communication score.Results. Standardized patients had written comments on 141 of the 218 rubrics (64.7%). The mean communication score was 39.0±1.6 (range, 31-40) out of a maximum 40 points. The total scores for the low, mixed, and high empathy category transformations were 6 (4.3%), 95 (67.4%), and 40 (28.4%), respectively. The results of the Kruskal-Wallis ANOVA were significant, suggesting that communication scores were different between empathy categories.Conclusion. There was a positive association between students' scores on communication rubrics and student empathy categorization, with student pharmacists exhibiting different levels of clinical empathy. While the PBA of interest was not specifically focused on empathy, SPs frequently provided feedback about empathy to students, suggesting that showing empathy during the encounter was important.

Long-Term Blood Pressure Variability and Kidney Function in Participants of the ASPREE Trial.

BACKGROUND: Whether long-term blood pressure variability (BPV) predicts kidney function decline in generally healthy older adults is unknown. We investigated this association in ASPirin in Reducing Events in the Elderly (ASPREE) trial participants. METHODS: Between 2010 and 2014, Australian and US individuals aged ≥70 years (≥65 if US minority) were recruited and followed with annual study visits for a median of 4.7 years. Time-to-event analyses and linear mixed effects models were used to examine associations between incident chronic kidney disease (CKD), and trajectories of estimated glomerular filtration rate (eGFR) and log albumin-creatinine ratio (log ACR) with systolic BPV as a continuous measure, and, by tertile of SD of systolic blood pressure (BP). BPV was estimated using systolic BP measures from baseline through the second annual visit, and kidney outcomes were assessed following this period. RESULTS: Incident CKD occurred in 1,829 of 6,759 participants (27.2%), and more commonly in BPV tertiles 2 (27.4%) and 3 (28.3%) than tertile 1 (25.5%); however, the risk was not significantly increased after covariate adjustment (tertile 3 hazard ratio = 1.02; 95% confidence interval: 0.91-1.14). Analysis of eGFR (n = 16,193) and log ACR trajectories (n = 15,213) showed individuals in the highest BPV tertile having the lowest eGFR and highest log ACR, cross-sectionally. However, the trajectories of eGFR and log ACR did not differ across BPV tertiles. CONCLUSIONS: CKD and markers of reduced kidney function occur more commonly in individuals with higher BPV; however, BPV does not influence trajectory of decline in kidney function over time in older adults who are in generally good health. CLINICAL TRIALS REGISTRATION: Trial Number NCT01038583 and ISRCTN83772183.

Anticholinergic medication burden and cognitive function in participants of the ASPREE study.

STUDY OBJECTIVE: What is the association between anticholinergic burden and specific domains of cognitive function in older adults who are initially without major cognitive impairment? DESIGN: Post-hoc analysis of longitudinal observational data from the ASPirin in Reducing Events in the Elderly (ASPREE) study. PATIENTS: 19,114 participants from Australia and the United States aged 70 years and older (65 years and older for US minorities) were recruited and followed for a median of 4.7 years. At enrollment, participants were free of known cardiovascular disease, major physical disability, or dementia. MEASUREMENTS: Cognitive assessments administered at baseline and biennially at follow-up visits included the Modified Mini-Mental State examination (3MS), Hopkins Verbal Learning Test-Revised (HVLT-R) delayed recall, Controlled Oral Word Association Test (COWAT), and Symbol Digit Modalities Test (SDMT). Anticholinergic burden was calculated at baseline using the Anticholinergic Cognitive Burden (ACB) scale and grouped as scores of 0 (no burden), 1-2 (low to moderate), or 3+ (high). MAIN RESULTS: Linear mixed effects models were used to assess the relationship between ACB score and cognition over time. After adjusting for sex, age, education, minority status, smoking status, hypertension, diabetes, depression, chronic kidney disease, country, and frailty, participants with a high ACB score had worse performance over time for 3MS (Adjusted [Adj] B=-0.092, P=0.034), HVLT-R delayed recall (Adj B=-0.104, P<0.001), COWAT (Adj B=-0.151, P<0.001), and SDMT (Adj B=-0.129, P=0.026), than participants with an ACB score of 0. A low to moderate ACB score was also associated with worse performance over time for HVLT-R delayed recall (Adj B=-0.037, P=0.007) and COWAT (Adj B=-0.065, P=0.003), compared to those with no ACB. CONCLUSIONS: Anticholinergic burden predicts worse cognitive function over time in initially dementia-free older adults, particularly for executive function (COWAT) and episodic memory (HVLT-R).

The association between polypharmacy, frailty and disability-free survival in community-dwelling healthy older individuals.

OBJECTIVES: Polypharmacy and frailty are two common geriatric conditions. In community-dwelling healthy older adults, we examined whether polypharmacy is associated with frailty and affects disability-free survival (DFS), assessed as a composite of death, dementia, or persistent physical disability. METHODS: We included 19,114 participants (median age 74.0 years, IQR: 6.1 years) from ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial. Frailty was assessed by a modified Fried phenotype and a deficit accumulation Frailty Index (FI). Polypharmacy was defined as concomitant use of five or more prescription medications. Multinomial logistic regression was used to examine the cross-sectional association between polypharmacy and frailty at base line, and Cox regression to determine the effect of polypharmacy and frailty on DFS over five years. RESULTS: Individuals with polypharmacy (vs. <5 medications) were 55% more likely to be pre-frail (Relative Risk Ratio or RRR: 1.55; 95%Confidence Interval or CI:1.44, 1.68) and three times more likely to be frail (RRR: 3.34; 95%CI:2.64, 4.22) according to Fried phenotype. Frailty alone was associated with double risk of the composite outcome (Hazard ratio or HR: 2.16; 95%CI: 1.56, 2.99), but frail individuals using polypharmacy had a four-fold risk (HR: 4.24; 95%CI: 3.28, 5.47). Effect sizes were larger when frailty was assessed using the FI. CONCLUSION: Polypharmacy was significantly associated with pre-frailty and frailty at baseline. Polypharmacy-exposed frailty increased the risk of reducing disability-free survival among older adults. Addressing polypharmacy in older people could ameliorate the impact of frailty on individuals' functional status, cognition and survival.

Influence of patient characteristics on success of ambulatory blood pressure monitoring.

STUDY OBJECTIVE: To examine the influence of specific patient characteristics on the success of ambulatory blood pressure monitoring (ABPM). DESIGN: Retrospective analysis. SETTING: University-affiliated family care center. PATIENTS: Five hundred thirty patients (mean age 52.7 yrs, range 14-90 yrs) who were undergoing ABPM between January 1, 2001, and July 1, 2007. MEASUREMENT AND MAIN RESULTS: Specific patient characteristics were identified through an electronic medical record review and then examined for association with ABPM session success rate. These patient characteristics included age, sex, weight, height, body mass index (BMI), occupation, clinic blood pressure, travel distance to clinic, and presence of diabetes mellitus or renal disease. The percentage of valid readings obtained during an ABPM session was analyzed continuously (0-100%), whereas overall session success was analyzed dichotomously (0-79% or 80-100%). Univariate and multivariate regression analyses were performed to examine the influence of patient characteristics on the percentage of valid readings and the overall likelihood of achieving a successful session. In the 530 patients, the average percentage of valid readings was 90%, and a successful ABPM session (>or= 80% valid readings) was obtained in 84.7% (449 patients). A diagnosis of diabetes was found to negatively predict ABPM session success (continuous variable analysis, p=0.019; dichotomous variable analysis, odds ratio [OR] 0.45, 95% confidence interval [CI] 0.23-0.87, p=0.019), as did renal disease (continuous variable analysis, p=0.006; dichotomous variable analysis, OR 0.39, 95% CI 0.17-0.90, p=0.027) and increasing BMI (continuous variable analysis, p<0.001; dichotomous variable analysis, OR 0.78, 95% CI 0.65-0.93, p=0.005). Renal disease and BMI remained significant predictors in adjusted analyses. CONCLUSION: For most patients, ABPM was successful; however, elevated BMI and renal disease were associated with less complete ABPM session results. Adaptation and individualization of the ABPM process may be necessary to improve results in these patients.

Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers for Geriatric Ischemic Stroke Patients: Are the Rates Right?

BACKGROUND: Our objective is to estimate the effects associated with higher rates of renin-angiotensin system antagonists, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEI/ARBs), in secondary prevention for geriatric (aged >65 years) patients with new ischemic strokes by chronic kidney disease (CKD) status. METHODS AND RESULTS: The effects of ACEI/ARBs on survival and renal risk were estimated by CKD status using an instrumental variable (IV) estimator. Instruments were based on local area variation in ACEI/ARB use. Data abstracted from charts were used to assess the assumptions underlying the instrumental estimator. ACEI/ARBs were used after stroke by 45.9% and 45.2% of CKD and non-CKD patients, respectively. ACEI/ARB rate differences across local areas grouped by practice styles were nearly identical for CKD and non-CKD patients. Higher ACEI/ARB use rates for non-CKD patients were associated with higher 2-year survival rates, whereas higher ACEI/ARB use rates for patients with CKD were associated with lower 2-year survival rates. While the negative survival estimates for patients with CKD were not statistically different from zero, they were statistically lower than the estimates for non-CKD patients. Confounders abstracted from charts were not associated with the instrumental variable used. CONCLUSIONS: Higher ACEI/ARB use rates had different survival implications for older ischemic stroke patients with and without CKD. ACEI/ARBs appear underused in ischemic stroke patients without CKD as higher use rates were associated with higher 2-year survival rates. This conclusion is not generalizable to the ischemic stroke patients with CKD, as higher ACEI/ARBS use rates were associated with lower 2-year survival rates that were statistically lower than the estimates for non-CKD patients.

Management of gout in the older adult.

BACKGROUND: Gout affects 3 million people in the United States, with rates almost 5 times higher in those aged 70 to 79 years compared with those aged < 50 years. Management of gout in elderly subjects can be complicated by comorbidities and polypharmacy. OBJECTIVE: The purpose of this article was to review the unique clinical presentation, treatment, and prevention of gout in the older adult, with attention to the age-related factors that may affect outcomes in this population. METHODS: PubMed and the Iowa Drug Information Service were searched (1944-January 14, 2011) for clinical studies of gout using the following search terms: gout, elderly, colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroid, prednisone, prednisolone, methylprednisolone, triamcinolone, allopurinol, febuxostat, probenecid, sulfinpyrazone, uricosuric, fenofibrate, and losartan. Articles were limited to clinical trials in humans, published in English. Citations of these articles were analyzed for additional relevant studies, and current guidelines were also consulted. RESULTS: Twenty-nine citations were reviewed. Evidence suggests that colchicine, NSAIDs, and corticosteroids are all efficacious in the treatment of acute gout in the older adult. Relevant limitations to colchicine use in the older adult include high cost, dosing restrictions in severe renal and hepatic dysfunction, gastrointestinal intolerance, and potential drug interactions. NSAID therapy is not recommended in older patients with congestive heart failure, renal failure, or gastrointestinal problems. Corticosteroids pose little risk when used in the short-term and may be preferred in patients with contraindications to colchicine or NSAIDs. Urate lowering with allopurinol for prevention of gout is well tolerated and has minimal cost per month; however, dose reduction is recommended in patients with renal impairment, which often results in failure to achieve target serum urate concentrations. Febuxostat does not require dose adjustment in mild to moderate renal disease and may be preferred in older people with this condition. CONCLUSION: Management of gout in the older adult involves careful selection of treatment based on potential benefits and consequences of therapy, considered in tandem with individual patient-specific characteristics. ClinicalTrials.gov identifiers NCT00549549, NCT01101035, NCT00241839, NCT01157936, NCT00997542, NCT00288158, and NCT00987415.

Special considerations for treatment of type 2 diabetes mellitus in the elderly.

PURPOSE: The intensity and selection of therapy for the treatment of type 2 diabetes mellitus in elderly patients are discussed. SUMMARY: Glycemic control is fundamental in diabetes care; however, as glycemic goals are approached, the risk of hypoglycemia increases. This risk is even greater in the elderly due to many predisposing factors, including renal insufficiency, polypharmacy, drug-drug interactions, comorbidities, irregular meal patterns, and infrequent self-monitoring of blood glucose. When deciding on the desired intensity of diabetes treatment, the risk of hypoglycemic complications must be weighed against the potential benefit of reducing microvascular and macrovascular complications. Three large-scale, randomized controlled trials examining the effects of intensive versus standard glycemic control on microvascular and macrovascular outcomes in patients with type 2 diabetes have been published in recent years. In general, a glycosylated hemoglobin (HbA(1c)) goal of <7% is reasonable for most patients. A less-aggressive goal may be considered for patients at high risk of hypoglycemia or high risk of complications from hypoglycemia, as long as acutely symptomatic hyperglycemia is avoided. Chlorpropamide, glyburide, and rosiglitazone, which pose a great risk for hypoglycemia, should be avoided in the elderly. CONCLUSION: In the absence of clear evidence advocating strict glycemic targets goal of <7% is for elderly patients, an HbA(1c) reasonable for most patients; however, the risk of hypoglycemic complications must be weighed against the potential benefit of reducing microvascular and macrovascular disease. Metformin may be used as first-line therapy, but chlorpropamide and glyburide, which pose a great risk for hypoglycemia, should be avoided in the elderly. Due to increased cardiovascular risk, use of rosiglitazone in the elderly should also be avoided.

Febuxostat: a selective xanthine-oxidase/xanthine-dehydrogenase inhibitor for the management of hyperuricemia in adults with gout.

BACKGROUND: Febuxostat, a nonpurine selective inhibitor of both the oxidized and reduced forms of xanthine oxidase, was approved in February 2009 by the US Food and Drug Administration for the management of hyperuricemia in adults with gout. OBJECTIVE: The purpose of this review was to summarize available information about the clinical use of febuxostat, including its chemistry, pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety profile. METHODS: A search of the medical literature using PubMed (1949-August 2009) and the Iowa Drug Information Service (1966-August 2009) was performed to identify all published articles about febuxostat. Key search terms included febuxostat, hyperuricemia, gout, TMX-67, and TEI-6720. Articles were limited to those published in English. Reference lists of the primary set of articles identified were reviewed for pertinent articles and scientific meeting abstracts not identified in the original search. RESULTS: A total of 88 published articles (including 14 human studies) were identified in the original search. Review of the references of these 88 articles yielded 7 additional trials published in abstract form. Clinical trial data from this review were obtained from these 21 studies. Dose-dependent reductions from baseline in serum urate occur with febuxostat. Clinical trials found that 40 mg/d of febuxostat was noninferior to conventionally dosed allopurinol (300 mg/d) in the percentage of subjects achieving the primary end point of serum urate <6.0 mg/dL (45% for febuxostat vs 42% for allopurinol), whereas 80 mg/d of febuxostat was reported to be superior (67% vs 42%; P < 0.001). Febuxostat 40 and 80 mg/d appeared to be well tolerated in the populations studied, with adverse events mostly limited to liver enzyme elevations (6.6% and 4.6%, respectively), nausea (1.1% and 1.3%), arthralgias (1.1% and 0.7%), and rash (0.5% and 1.6%). Febuxostat does not require dosage adjustment in patients with mild to moderate renal impairment (creatinine clearance, 30-89 mL/min). Because of the risk of acute gout flares occurring when febuxostat treatment is initiated, concomitant therapy with colchicine or an NSAID for >or=8 weeks is recommended. CONCLUSIONS: Febuxostat is the first agent marketed in the United States to treat hyperuricemia of gout since allopurinol was approved in 1964. In English-language published clinical trials, it was found to be noninferior to allopurinol and generally well tolerated.