Psychostimulant prescribing trends in a paediatric population in Ireland: a national cohort study.

BACKGROUND: Psychotropic paediatric prescribing trends are increasing internationally. The aim of this study is to examine the prevalence and secular trends in psychotropic prescribing in Irish children and adolescents between 2002 and 2011. METHODS: Data was obtained from the Irish General Medical Services (GMS) scheme pharmacy claims database from the Health Service Executive Primary Care Reimbursement Services (HSE-PCRS). Prescribing rates per 1000 eligible population and associated 95% confidence intervals (CIs) were calculated across years (2002-2011), age groups (0-4, 5-11, 12-15 years) and gender. Rates of concomitant prescriptions for psycholeptics and antidepressants were also examined. The total expenditure costs were calculated and expressed as a percentage of the cost of all prescriptions for this age group (≤ 15 years). RESULTS: In 2002, 3.77/1000 GMS population (95% CI: 3.53-4.01) received at least one psychostimulant prescription and this rate increased to 8.63/1000 GMS population (95% CI: 8.34-8.92) in 2011. Methylphenidate was the most frequently prescribed psychostimulant. For both males and females the prevalence of medication use was highest among the 12-15 year old group. On average, a psycholeptic medication was prescribed to 8% of all psychostimulant users and an antidepressant was concomitantly prescribed on average to 2%. Total expenditure rose from €89,254 in 2002 to €1,532,016 in 2011. CONCLUSIONS: The rate and cost of psychostimulant prescribing among GMS children and adolescents in Ireland increased significantly between 2002 and 2011. Further research is necessary to assess the safety, efficacy and economic impact of concomitant psychotropic prescribing in this population.

A simplified approach to the pooled analysis of calibration of clinical prediction rules for systematic reviews of validation studies.

OBJECTIVE: Estimating calibration performance of clinical prediction rules (CPRs) in systematic reviews of validation studies is not possible when predicted values are neither published nor accessible or sufficient or no individual participant or patient data are available. Our aims were to describe a simplified approach for outcomes prediction and calibration assessment and evaluate its functionality and validity. STUDY DESIGN AND METHODS: Methodological study of systematic reviews of validation studies of CPRs: a) ABCD(2) rule for prediction of 7 day stroke; and b) CRB-65 rule for prediction of 30 day mortality. Predicted outcomes in a sample validation study were computed by CPR distribution patterns ("derivation model"). As confirmation, a logistic regression model (with derivation study coefficients) was applied to CPR-based dummy variables in the validation study. Meta-analysis of validation studies provided pooled estimates of "predicted:observed" risk ratios (RRs), 95% confidence intervals (CIs), and indexes of heterogeneity (I(2) ) on forest plots (fixed and random effects models), with and without adjustment of intercepts. The above approach was also applied to the CRB-65 rule. RESULTS: Our simplified method, applied to ABCD(2) rule in three risk strata (low, 0-3; intermediate, 4-5; high, 6-7 points), indicated that predictions are identical to those computed by univariate, CPR-based logistic regression model. Discrimination was good (c-statistics =0.61-0.82), however, calibration in some studies was low. In such cases with miscalibration, the under-prediction (RRs =0.73-0.91, 95% CIs 0.41-1.48) could be further corrected by intercept adjustment to account for incidence differences. An improvement of both heterogeneities and P-values (Hosmer-Lemeshow goodness-of-fit test) was observed. Better calibration and improved pooled RRs (0.90-1.06), with narrower 95% CIs (0.57-1.41) were achieved. CONCLUSION: Our results have an immediate clinical implication in situations when predicted outcomes in CPR validation studies are lacking or deficient by describing how such predictions can be obtained by everyone using the derivation study alone, without any need for highly specialized knowledge or sophisticated statistics.

Potentially inappropriate prescribing among older people in the United Kingdom.

BACKGROUND: Potentially inappropriate prescribing (PIP) in older people is associated with increases in morbidity, hospitalisation and mortality. The objective of this study was to estimate the prevalence of and factors associated with PIP, among those aged ≥70 years, in the United Kingdom, using a comprehensive set of prescribing indicators and comparing these to estimates obtained from a truncated set of the same indicators. METHODS: A retrospective cross-sectional study was carried out in the UK Clinical Practice Research Datalink (CPRD), in 2007. Participants included those aged ≥ 70 years, in CPRD. Fifty-two PIP indicators from the Screening Tool of Older Persons Potentially Inappropriate Prescriptions (STOPP) criteria were applied to data on prescribed drugs and clinical diagnoses. Overall prevalence of PIP and prevalence according to individual STOPP criteria were estimated. The relationship between PIP and polypharmacy (≥4 medications), comorbidity, age, and gender was examined. A truncated, subset of 28 STOPP criteria that were used in two previous studies, were further applied to the data to facilitate comparison. RESULTS: Using 52 indicators, the overall prevalence of PIP in the study population (n = 1,019,491) was 29%. The most common examples of PIP were therapeutic duplication (11.9%), followed by use of aspirin with no indication (11.3%) and inappropriate use of proton pump inhibitors (PPIs) (3.7%). PIP was strongly associated with polypharmacy (Odds Ratio 18.2, 95% Confidence Intervals, 18.0-18.4, P < 0.05). PIP was more common in those aged 70-74 years vs. 85 years or more and in males. Application of the smaller subset of the STOPP criteria resulted in a lower PIP prevalence at 14.9% (95% CIs 14.8-14.9%) (n = 151,598). The most common PIP issues identified with this subset were use of PPIs at maximum dose for > 8 weeks, NSAIDs for > 3 months, and use of long-term neuroleptics. CONCLUSIONS: PIP was prevalent in the UK and increased with polypharmacy. Application of the comprehensive set of STOPP criteria allowed more accurate estimation of PIP compared to the subset of criteria used in previous studies. These findings may provide a focus for targeted interventions to reduce PIP.

Long-term risk of stroke after transient ischaemic attack: a hospital-based validation of the ABCD² rule.

BACKGROUND: The ABCD2 clinical prediction rule is a seven point summation of clinical factors independently predictive of stroke risk. The purpose of this cohort study is to validate the ABCD2 rule in a Bulgarian hospital up to three years after TIA. METHODS: All consecutive admissions to an emergency department with symptoms of a first TIA were included. Baseline data and clinical examinations including the ABCD2 scores were documented by neurologists. Discrimination and calibration performance was examined using ABCD2 cut-off scores of ≥3, ≥4 and ≥5 points, consistent with the international guidelines. The Hosmer-Lemeshow test was used to examine calibration between the observed and expected outcomes as predicted by ABCD2 score within the logistic regression analysis. RESULTS: Eighty-nine patients were enrolled to the study with a mean age of 63 years (+/- 12 years). Fifty-nine percent (n = 53) of the study population was male. Seven strokes (7.8%) occurred within the first year and six further strokes within the three-year follow-up period. There was no incident of stroke within the first 90 days after TIA. The rule demonstrated good predictive (OR = 1.58, 95% CI 1.09-2.29) and discriminative performance (AUCROC = 0.72, 95% CI 0.58-0.86), as well as a moderate calibration performance at three years. CONCLUSION: This validation of the ABCD2 rule in a Bulgarian hospital demonstrates that the rule has good predictive and discriminative performance at three years. The ABCD2 is quick to administer and may serve as a useful tool to assist clinicians in the long-term management of individuals with TIA.

Potential for alcohol and drug interactions in older adults: evidence from the Irish longitudinal study on ageing.

BACKGROUND: Older adults are susceptible to adverse effects from the concomitant use of prescription medications and alcohol. This study estimates the prevalence of exposure to alcohol interactive (AI) medications and concomitant alcohol use by therapeutic class in a large, nationally representative sample of older adults. METHODS: Cross-sectional analysis of a population based sample of older Irish adults aged ≥60 years using data from The Irish Longitudinal Study on Ageing (TILDA) (N = 3,815). AI medications were identified using Stockley's Drug Interactions, the British National Formulary and the Irish Medicines Formulary. An in-home inventory of medications was used to characterise AI drug exposure by therapeutic class. Self-reported alcohol use was classified as non-drinker, light/moderate and heavy drinking. Comorbidities known to be exacerbated by alcohol were also recorded (diabetes mellitus, hypertension, peptic ulcer disease, liver disease, depression, gout or breast cancer), as well as sociodemographic and health factors. RESULTS: Seventy-two per cent of participants were exposed to AI medications, with greatest exposure to cardiovascular and CNS agents. Overall, 60% of participants exposed to AI medications reported concomitant alcohol use, compared with 69.5% of non-AI exposed people (p < 0.001). Almost 28% of those reporting anti-histamine use were identified as heavy drinkers. Similarly almost one in five, combined heavy drinking with anti-coagulants/anti-platelets and cardiovascular agents, with 16% combining heavy drinking with CNS agents. Multinomial logistic regression showed that being male, younger, urban dwelling, with higher levels of education and a history of smoking, were associated with an increased risk for concomitant exposure to alcohol consumption (both light/moderate and heavier) and AI medications. Current smokers and people with increasing co-morbidities were also at greatest risk for heavy drinking in combination with AI medications. CONCLUSIONS: The concurrent use of alcohol with AI medications, or with conditions known to be exacerbated by alcohol, is common among older Irish adults. Prescribers should be aware of potential interactions, and screen patients for alcohol use and provide warnings to minimize patient risk.

Prevalence of potentially inappropriate prescribing and prescribing omissions in older Irish adults: findings from The Irish LongituDinal Study on Ageing study (TILDA).

PURPOSE: We sought to estimate the prevalence of potentially inappropriate prescriptions (PIP) and potential prescribing omissions (PPOs) using a subset of the STOPP/START criteria in a population based sample of Irish adults aged ≥ 65 years using data from The Irish LongituDinal Study on Ageing (TILDA). METHODS: A subset of 26 PIP indicators and 10 PPO indicators from the STOPP/START criteria were applied to the TILDA dataset. PIP/PPO prevalence according to individual STOPP/START criteria and the overall prevalence of PIP/PPO were estimated. The relationship between PIP and PPOs and polypharmacy, age, gender and multimorbidity was examined using logistic regression. RESULTS: The overall prevalence of PIP in the study population (n=3,454) was 14.6 %. The most common examples of PIP identified were NSAID with moderate-severe hypertension (200 participants; 5.8 %) and aspirin with no history of coronary, cerebral, or peripheral vascular symptoms or occlusive event (112 participants; 3.2 %). The overall prevalence of PPOs was 30 % (n=1,035). The most frequent PPO was antihypertensive therapy where systolic blood pressure consistently >160 mmHg (n=341, 9.9 %), There was a significant association between PIP and PPO and polypharmacy when adjusting for age, sex and multimorbidity (adjusted OR 2.62, 95 % CI 2.05-3.33 for PIP and adjusted OR 1.46, 95 % CI 1.23-1.75 for prescribing omissions). CONCLUSION: Our findings indicate prescribing omissions are twice as prevalent as PIP in the elderly using a subset of the STOPP/START criteria as an explicit process measure of potentially inappropriate prescribing and prescribing omissions. Polypharmacy was independently associated with both PPO and PIP. Application of such screening tools to prescribing decisions may reduce unnecessary medication, related adverse events, healthcare utilisation and cost.

Prescribing patterns of glucosamine in an older population: a national cohort study.

BACKGROUND: Glucosamine is commonly prescribed as a disease modulating agent in osteoarthritis. However, the evidence to date suggests that it has a limited impact on the clinical symptoms of the disease including joint pain, radiological progression, function and quality of life. The aim of this study was to examine the prescribing patterns of glucosamine from 2002-2011 in an elderly Irish national population cohort using data from the Health Service Executive Primary Care Reimbursement (HSE-PCRS) General medical services (GMS) Scheme. METHODS: Patients aged ≥ 70 years on the HSE-PCRS pharmacy claims database between January 2002 and December 2011 were included. ATC code M01AX05 (glucosamine) was extracted. Prevalence rates per 1000 eligible population with 95% confidence intervals were calculated for all years and age groups (70-74 years, ≥75 years). A negative binomial regression analysis was used to determine longitudinal usage trends and compare prevalence rates across years, sex and age groups. RESULTS: The annual patient rate of glucosamine prescribing increased significantly from 13.0/1000 eligible population (95% CI 12.6-13.4) in 2002 to 68.7/1000 population (95% CI 67.8-69.5) in 2009 before decreasing to 62.4/1000 population (95% CI 61.6-63.2) in 2011. The rate of prescribing of glucosamine varied with sex, with women receiving significantly more prescriptions than men. The cost of glucosamine also increased from 2002-2008. In 2008 total expenditure reached a high of €4.6 million before decreasing to €2.6 million in 2011. CONCLUSION: The national trend in prescribing of glucosamine increased significantly from 2002 to 2009 before decreasing in 2010 and 2011, in keeping with current international guidelines. There is a need for awareness among healthcare professionals and patients alike of the best available evidence to inform decision making relating to the prescription and consumption of such supplements.

Cemented versus uncemented fixation in total hip replacement: a systematic review and meta-analysis of randomized controlled trials.

The optimal method of fixation for primary total hip replacements (THR), particularly fixation with or without the use of cement is still controversial. In a systematic review and metaanalysis of all randomized controlled trials comparing cemented versus uncemented THRS available in the published literature, we found that there is no significant difference between cemented and uncemented THRs in terms of implant survival as measured by the revision rate. Better short-term clinical outcome, particularly an improved pain score can be obtained with cemented fixation. However, the results are unclear for the long-term clinical and functional outcome between the two groups. No difference was evident in the mortality and the post operative complication rate. On the other hand, the radiographic findings were variable and do not seem to correlate with clinical findings as differences in the surgical technique and prosthesis design might be associated with the incidence of osteolysis. We concluded in our review that cemented THR is similar if not superior to uncemented THR, and provides better short term clinical outcomes. Further research, improved methodology and longer follow up are necessary to better define specific subgroups of patients in whom the relative benefits of cemented and uncemented implant fixation can be clearly demonstrated.

The GFR and GFR decline cannot be accurately estimated in type 2 diabetics.

There are no adequate studies that have formally tested the performance of different estimating formulas in patients with type 2 diabetes both with and without overt nephropathy. Here we evaluated the agreement between baseline GFRs, GFR changes at month 6, and long-term GFR decline measured by iohexol plasma clearance or estimated by 15 creatinine-based formulas in 600 type 2 diabetics followed for a median of 4.0 years. Ninety patients were hyperfiltering. The number of those identified by estimation formulas ranged from 0 to 24:58 were not identified by any formula. Baseline GFR was significantly underestimated and a 6-month GFR reduction was missed in hyperfiltering patients. Long-term GFR decline was also underestimated by all formulas in the whole study group and in hyper-, normo-, and hypofiltering patients considered separately. Five formulas generated positive slopes in hyperfiltering patients. Baseline concordance correlation coefficients and total deviation indexes ranged from 32.1% to 92.6% and from 0.21 to 0.53, respectively. Concordance correlation coefficients between estimated and measured long-term GFR decline ranged from -0.21 to 0.35. The agreement between estimated and measured values was also poor within each subgroup considered separately. Thus, our study questions the use of any estimation formula to identify hyperfiltering patients and monitor renal disease progression and response to treatment in type 2 diabetics without overt nephropathy.

Effectiveness of medicines review with web-based pharmaceutical treatment algorithms in reducing potentially inappropriate prescribing in older people in primary care: a cluster randomized trial (OPTI-SCRIPT study protocol).

BACKGROUND: Potentially inappropriate prescribing in older people is common in primary care and can result in increased morbidity, adverse drug events, hospitalizations and mortality. In Ireland, 36% of those aged 70 years or over received at least one potentially inappropriate medication, with an associated expenditure of over €45 million.The main objective of this study is to determine the effectiveness and acceptability of a complex, multifaceted intervention in reducing the level of potentially inappropriate prescribing in primary care. METHODS/DESIGN: This study is a pragmatic cluster randomized controlled trial, conducted in primary care (OPTI-SCRIPT trial), involving 22 practices (clusters) and 220 patients. Practices will be allocated to intervention or control arms using minimization, with intervention participants receiving a complex multifaceted intervention incorporating academic detailing, medicines review with web-based pharmaceutical treatment algorithms that provide recommended alternative treatment options, and tailored patient information leaflets. Control practices will deliver usual care and receive simple patient-level feedback on potentially inappropriate prescribing. Routinely collected national prescribing data will also be analyzed for nonparticipating practices, acting as a contemporary national control. The primary outcomes are the proportion of participant patients with potentially inappropriate prescribing and the mean number of potentially inappropriate prescriptions per patient. In addition, economic and qualitative evaluations will be conducted. DISCUSSION: This study will establish the effectiveness of a multifaceted intervention in reducing potentially inappropriate prescribing in older people in Irish primary care that is generalizable to countries with similar prescribing challenges. TRIAL REGISTRATION: Current controlled trials ISRCTN41694007.

Measurable urinary albumin predicts cardiovascular risk among normoalbuminuric patients with type 2 diabetes.

Micro- or macroalbuminuria is associated with increased cardiovascular risk factors among patients with type 2 diabetes, but whether albuminuria within the normal range predicts long-term cardiovascular risk is unknown. We evaluated the relationships between albuminuria and cardiovascular events in 1208 hypertensive, normoalbuminuric patients with type 2 diabetes from the BErgamo NEphrologic Diabetes Complication Trial (BENEDICT), all of whom received angiotensin-converting enzyme inhibitor (ACEI) therapy at the end of the trial and were followed for a median of 9.2 years. The main outcome was time to the first of fatal or nonfatal myocardial infarction; stroke; coronary, carotid, or peripheral artery revascularization; or hospitalization for heart failure. Overall, 189 (15.6%) of the patients experienced a main outcome event (2.14 events/100 patient-years); 24 events were fatal. Albuminuria independently predicted events (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.02-1.08). Second-degree polynomial multivariable analysis showed a continuous nonlinear relationship between albuminuria and events without thresholds. Considering the entire study population, even albuminuria at 1-2 µg/min was significantly associated with increased risk compared with albuminuria <1 µg/min (HR, 1.04; 95% CI, 1.02-1.07). This relationship was similar in the subgroup originally randomly assigned to non-ACEI therapy. Among those originally receiving ACEI therapy, however, the event rate was uniformly low and was not significantly associated with albuminuria. Taken together, among normoalbuminuric patients with type 2 diabetes, any degree of measurable albuminuria bears significant cardiovascular risk. The association with risk is continuous but is lost with early ACEI therapy.

Glomerular hyperfiltration and renal disease progression in type 2 diabetes.

OBJECTIVE: To describe the prevalence and determinants of hyperfiltration (glomerular filtration rate [GFR] ≥120 mL/min/1.73 m(2)), GFR decline, and nephropathy onset or progression in type 2 diabetic patients with normo- or microalbuminuria. RESEARCH DESIGN AND METHODS: We longitudinally studied 600 hypertensive type 2 diabetic patients with albuminuria <200 µg/min and who were retrieved from two randomized trials testing the renal effect of trandolapril and delapril. Target blood pressure (BP) was <120/80 mmHg, and HbA(1c) was <7%. GFR, albuminuria, and glucose disposal rate (GDR) were centrally measured by iohexol plasma clearance, nephelometry in three consecutive overnight urine collections, and hyperinsulinemic euglycemic clamp, respectively. RESULTS: Over a median (range) follow-up of 4.0 (1.7-8.1) years, GFR declined by 3.37 (5.71-1.31) mL/min/1.73 m(2) per year. GFR change was bimodal over time: a larger reduction at 6 months significantly predicted slower subsequent decline (coefficient: -0.0054; SE: 0.0009), particularly among hyperfiltering patients. A total of 90 subjects (15%) were hyperfiltering at inclusion, and 11 of 47 (23.4%) patients with persistent hyperfiltration progressed to micro- or macroalbuminuria versus 53 (10.6%) of the 502 who had their hyperfiltration ameliorated at 6 months or were nonhyperfiltering since inclusion (hazard ratio 2.16 [95% CI 1.13-4.14]). Amelioration of hyperfiltration was independent of baseline characteristics or ACE inhibition. It was significantly associated with improved BP and metabolic control, amelioration of GDR, and slower long-term GFR decline on follow-up. CONCLUSIONS: Despite intensified treatment, patients with type 2 diabetes have a fast GFR decline. Hyperfiltration affects a subgroup of patients and may contribute to renal function loss and nephropathy onset or progression. Whether amelioration of hyperfiltration is renoprotective is worth investigating.

Effects of manidipine and delapril in hypertensive patients with type 2 diabetes mellitus: the delapril and manidipine for nephroprotection in diabetes (DEMAND) randomized clinical trial.

To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria <200 mg/min included in a multicenter, double-blind, placebo-controlled trial (DEMAND [Delapril and Manidipine for Nephroprotection in Diabetes]) and randomized to 3-year treatment with manidipine/delapril combination (10/30 mg/d; n=126), delapril (30 mg/d; n=127), or placebo (n=127). GFR was centrally measured by iohexol plasma clearance. Median monthly GFR decline (interquartile range [IQR]) was 0.32 mL/min per 1.73 m(2) (IQR: 0.16-0.50 mL/min per 1.73 m(2)) on combined therapy, 0.36 mL/min per 1.73 m(2) (IQR: 0.18-0.53 mL/min per 1.73 m(2)) on delapril, and 0.30 mL/min per 1.73 m(2) (IQR: 0.12-0.50 mL/min per 1.73 m(2)) on placebo (P=0.87 and P=0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 (0.04-0.78; P=0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0.07-0.99; P=0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24-0.87; P=0.017) and 0.52 (0.27-0.99; P=0.048), respectively. Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo (P=0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity.

Risk of drug-related mortality during periods of transition in methadone maintenance treatment: a cohort study.

This study aims to identify periods of elevated risk of drug-related mortality during methadone maintenance treatment (MMT) in primary care using a cohort of 3,162 Scottish drug users between January 1993 and February 2004. Deaths occurring during treatment or within 3 days after last methadone prescription expired were considered as cases "on treatment." Fatalities occurring 4 days or more after leaving treatment were cases "off treatment." Sixty-four drug-related deaths were identified. The greatest risk of drug-related death was in the first 2 weeks of treatment (adjusted hazard ratio 2.60, 95% confidence interval 1.03-6.56). Risk of drug-related death was lower after the first 30 days following treatment cessation, relative to the first 30 days off treatment. History of psychiatric admission was associated with increased risk of drug-related death in treatment. Increasing numbers of treatment episodes and urine testing were protective. History of psychiatric admission, increasing numbers of urine tests, and coprescriptions of benzodiazepines increased the risk of mortality out of treatment. The risk of drug-related mortality in MMT is elevated during periods of treatment transition, specifically treatment initiation and the first 30 days following treatment dropout or discharge.

Depressive vulnerabilities predict depression status and trajectories of depression over 1 year in persons with acute coronary syndrome.

OBJECTIVE: Depression is prevalent in patients hospitalized with acute coronary syndrome (ACS). We determined whether theoretical vulnerabilities for depression (interpersonal life events, reinforcing events, cognitive distortions, Type D personality) predicted depression, or depression trajectories, post-hospitalization. METHODS: We followed 375 ACS patients who completed depression scales during hospital admission and at least once during three follow-up intervals over 1 year (949 observations). Questionnaires assessing vulnerabilities were completed at baseline. Logistic regression for panel/longitudinal data predicted depression status during follow-up. Latent class analysis determined depression trajectories. Multinomial logistic regression modeled the relationship between vulnerabilities and trajectories. RESULTS: Vulnerabilities predicted depression status over time in univariate and multivariate analysis, even when controlling for baseline depression. Proportions in each depression trajectory category were as follows: persistent (15%), subthreshold (37%), never depressed (48%). Vulnerabilities independently predicted each of these trajectories, with effect sizes significantly highest for the persistent depression group. CONCLUSIONS: Self-reported vulnerabilities - stressful life events, reduced reinforcing events, cognitive distortions, personality - measured during hospitalization can identify those at risk for depression post-ACS and especially those with persistent depressive episodes. Interventions should focus on these vulnerabilities.

Prognostic value of the ABCD² clinical prediction rule: a systematic review and meta-analysis.

OBJECTIVE: The purpose of this systematic review with meta-analysis is to determine the predictive value of the ABCD ²at 7 and 90 days across three strata of risk. Background. The risk of stroke after transient ischaemic attack (TIA) is significant. The ABCD ²clinical prediction rule is designed to predict early risk of stroke after TIA. A number of independent validation studies have been conducted since the rule was derived. METHODS: A systematic literature search was conducted to identify studies that validated the ABCD². The derived rule was used as a predictive model and applied to subsequent validation studies. Comparisons were made between observed and predicted number of strokes stratified by risk group: low (0-3 points), moderate (4-5 points) and high (6-7 points). Pooled results are presented as risk ratios (RRs) with 95% confidence intervals (CIs), in terms of over-prediction (RR > 1) or under-prediction (RR < 1) of stroke at 7 and 90 days. RESULTS: We include 16 validation studies. Fourteen studies report 7-day stroke risk (n = 6282, 388 strokes). The ABCD² rule correctly predicts occurrence of stroke at 7 days across all three risk strata: low [RR 0.86, 95% CI (0.47-1.58), I² = 16%], moderate [RR 0.99, 95% CI (0.67-1.47), I² = 68%] and high [RR 0.84, 95% CI (0.6-1.19), I² = 46%]. Eleven studies report 90-day stroke risk (n = 6304). There is a non-significant trend towards over-prediction of stroke in all risk categories at 90 days. There are 426 strokes observed in contrast to a predicted 626 strokes. As the trichotomized ABCD² score increases, the risk of stroke increases (P < 0.01). There is no evidence of publication bias in these studies (P > 0.05). CONCLUSION: The ABCD² is a useful CPR, particularly in relation to 7-day risk of stroke.

Effects of verapamil added-on trandolapril therapy in hypertensive type 2 diabetes patients with microalbuminuria: the BENEDICT-B randomized trial.

OBJECTIVES: To address whether nondihydropyridine calcium-channel blocker added-on angiotensin-converting-enzyme inhibitor therapy ameliorates albuminuria and cardiovascular outcomes in type 2 diabetes patients. DESIGN: The Bergamo Nephrologic Diabetes Complications Trial-B was a multicentre, prospective, double-blind, parallel-group trial comparing renal and cardiovascular outcomes in 281 hypertensive type 2 diabetes patients with microalbuminuria randomized to at least 2-year VeraTran (verapamil/trandolapril 180 mg/2 mg daily) or trandolapril (2 mg daily, identical image) treatment. Main outcome was persistent macroalbuminuria (albuminuria >200 µg/min in two consecutive visits). Treatment targets were SBP/DBP less than 120/80 mmHg and HbA1C less than 7%. RESULTS: Over a median follow-up of 4.5 years, 18 patients (13%) on VeraTran vs. 15 (10.5%) on trandolapril [unadjusted hazard ratio (95% confidence interval [CI]) 1.07 (0.54-2.12), P = 0.852] progressed to macroalbuminuria, respectively; 62 (44.9%) vs. 71 (49.7%) [0.80 (0.57-1.12), P = 0.198] regressed to normoalbuminuria (urinary albumin excretion <20 µg/min), and 20 (14.5%) vs. 21 (14.7%) [hazard ratio 0.93 (0.50-1.72), P = 0.816] had major cardiovascular events. BP and metabolic control were similar between groups. Patients with cardiovascular events were significantly less [13 (9.8%) vs. 28 (18.9%), hazard ratio: 0.37 (0.19-0.71), P = 0.003] among those regressing to normoalbuminuria than those without regression. Difference was independent of treatment allocation and was significant also after adjusting for baseline characteristics [0.40 (0.20-0.79), P = 0.009], follow-up SBP [0.40 (0.20-0.80), P = 0.010] or DBP [0.36 (0.18-0.73), P = 0.004] BP or HbA1C [0.43 (0.21-0.88), P = 0.021]. CONCLUSION: In hypertensive type 2 diabetes patients with microalbuminuria, verapamil added-on trandolapril did not improve renal or cardiovascular outcomes. Independent of verapamil, trandolapril normalized albuminuria in half of patients and this translated into significant cardioprotection.

Effects of add-on fluvastatin therapy in patients with chronic proteinuric nephropathy on dual renin-angiotensin system blockade: the ESPLANADE trial.

BACKGROUND AND OBJECTIVES: This open, prospective, randomized trial aimed to assess the effects of statins in chronic kidney disease patients on optimized antiproteinuric treatment with combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: After 1-month benazepril therapy followed by 1-month benazepril-valsartan combined therapy (run-in), 186 consenting patients with residual proteinuria >0.5 g/24 h were randomized to 6-month benazepril-valsartan therapy alone or combined with fluvastatin. Between-groups changes in proteinuria (primary outcome), serum lipids, and GFR were compared by ANCOVA. Analyses were blinded and by intention to treat. RESULTS: During the run-in, proteinuria decreased more on benazepril-valsartan than on benazepril alone. Proteinuria reduction correlated with concomitant reduction in total, LDL, and HDL cholesterol, and apolipoprotein B and apolipoprotein A levels. After randomization, median proteinuria similarly decreased from 1.2 (0.6 to 2.2) to 1.1 (0.5 to 1.7) g/24 h on fluvastatin and from 1.5 (0.8 to 2.7) to 1.0 (0.5 to 2.4) g/24 h on benazapril-valsartan therapy alone. Fluvastatin further reduced total and LDL cholesterol and apolipoprotein B versus benazepril-valsartan alone, but did not affect serum triglycerides and GFR. Treatment was well tolerated. CONCLUSIONS: In chronic kidney disease patients with residual proteinuria despite combined angiotensin-converting enzyme inhibitor and angiotensin receptor blockade therapy, add-on fluvastatin does not affect urinary proteins, but further reduces serum lipids and is safe. Whether combined angiotensin-converting enzyme inhibitor, angiotensin receptor blockade, and statin therapy may improve cardiovascular outcomes in this high-risk population is worth investigating.

Sirolimus therapy to halt the progression of ADPKD.

Activation of mammalian target of rapamycin (mTOR) pathways may contribute to uncontrolled cell proliferation and secondary cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). To assess the effects of mTOR inhibition on disease progression, we performed a randomized, crossover study (The SIRENA Study) comparing a 6-month treatment with sirolimus or conventional therapy alone on the growth of kidney volume and its compartments in 21 patients with ADPKD and GFR>or=40 ml/min per 1.73 m2. In 10 of the 15 patients who completed the study, aphthous stomatitis complicated sirolimus treatment but was effectively controlled by topical therapy. Compared with pretreatment, posttreatment mean total kidney volume increased less on sirolimus (46+/-81 ml; P=0.047) than on conventional therapy (70+/-72 ml; P=0.002), but we did not detect a difference between the two treatments (P=0.45). Cyst volume was stable on sirolimus and increased by 55+/-75 ml (P=0.013) on conventional therapy, whereas parenchymal volume increased by 26+/-30 ml (P=0.005) on sirolimus and was stable on conventional therapy. Percentage changes in cyst and parenchyma volumes were significantly different between the two treatment periods. Sirolimus had no appreciable effects on intermediate volume and GFR. Albuminuria and proteinuria marginally but significantly increased during sirolimus treatment. In summary, sirolimus halted cyst growth and increased parenchymal volume in patients with ADPKD. Whether these effects translate into improved long-term outcomes requires further investigation.

Impact of the PPAR-gamma2 Pro12Ala polymorphism and ACE inhibitor therapy on new-onset microalbuminuria in type 2 diabetes: evidence from BENEDICT.

OBJECTIVE: Cross-sectional studies found less microalbuminuria in type 2 diabetic patients with the Ala12 allele of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) Pro12Ala polymorphism. We prospectively evaluated the association between Pro12Ala polymorphism (rs1801282) and new-onset microalbuminuria. RESEARCH DESIGN AND METHODS: Pro12Ala polymorphism was genotyped by TaqMan-based assay in genomic DNA of 1,119 consenting patients from BErgamo NEphrologic DIabetic Complications Trial (BENEDICT)-a prospective, randomized trial evaluating ACE inhibition effect on new-onset microalbuminuria (albuminuria 20-200 microg/min in at least two of three consecutive overnight urine collections in two consecutive visits) in hypertensive type 2 diabetes with albuminuria <20 microg/min at inclusion. RESULTS: Baseline characteristics of Ala (Ala/Ala or Ala/Pro) carriers and Pro/Pro homozygotes were similar, with a nonsignificant trend to lower albuminuria (P = 0.1107) in the 177 Ala carriers. Over a median (interquartile range) of 44.0 (17.1-51.9) months, 7 (4%) Ala carriers and 86 (9.1%) Pro/Pro homozygotes developed microalbuminuria (hazard ratio [HR] 0.45 [95% CI 0.21-0.97]; P = 0.042). Final albuminuria was significantly lower in Ala carriers than Pro/Pro homozygotes (7.3 +/- 9.1 vs. 10.5 +/- 24.9 microg/min, respectively), even after adjustment for baseline albuminuria (P = 0.048). Baseline and follow-up blood pressure and metabolic control were similar in both groups. Incidence of microalbuminuria was significantly decreased by ACE versus non-ACE inhibitor therapy in Pro/Pro homozygotes (6.3 vs. 11.9%, respectively, HR 0.46 [0.29-0.72]; P < 0.001). CONCLUSIONS: In type 2 diabetes, the Ala allele protects from worsening albuminuria and new-onset microalbuminuria, and ACE inhibition blunts the excess risk of microalbuminuria associated with the Pro/Pro genotype. Evaluating Pro12Ala polymorphism may help identifying patients at risk who may benefit the most from early renoprotective therapy.