Cardiovascular and Renal Treatment in Heart Failure Patients with Hyperkalemia or High Risk of Hyperkalemia: Rationale and Design of the CARE-HK in HF Registry.

BACKGROUND: Despite guideline recommendations, many patients with heart failure (HF) do not receive target doses of renin-angiotensin-aldosterone system inhibitors (RAASis) in clinical practice due, in part, to concerns about hyperkalemia (HK). METHODS AND RESULTS: This non-interventional, multinational, multicenter registry (NCT04864795; 111 sites in Europe and the USA) enrolled 2,558 eligible adults with chronic HF (mostly with reduced ejection fraction [HFrEF]). Eligibility criteria included use of angiotensin-converting-enzyme inhibitor / angiotensin-II receptor blocker / angiotensin-receptor-neprilysin inhibitor, candidate for or treatment with mineralocorticoid receptor antagonist, and increased risk of HK (eg, current serum potassium >5.0 mmol/L], history of HK in the previous 24 months, or estimated glomerular filtration rate <45 mL/min/1.73 m2). Information on RAASi and other guideline-recommended therapies was collected retrospectively and prospectively (≥6 months). Patients were followed according to local clinical practice, without study-specific visits or interventions. The main objectives were to characterize RAASi treatment patterns compared with guideline recommendations, describe RAASi modifications following episodes of HK, and describe RAASi treatment in patients treated with patiromer. Baseline characteristics for the first 1,000 patients are presented. CONCLUSIONS: CARE-HK is a multinational prospective HF registry designed to report on the management and outcomes of patients with HF at high risk for HK in routine clinical practice.

Patiromer for Heart Failure Medication Optimization in Patients With Current or Past Hyperkalemia: DIAMOND Subanalysis.

BACKGROUND: For heart failure with reduced ejection fraction (HFrEF), suboptimal use of renin-angiotensin-aldosterone system inhibitors (RAASis), including mineralocorticoid receptor antagonists (MRAs), due to hyperkalemia, may be improved by potassium binders. OBJECTIVES: This prespecified analysis of the phase 3 DIAMOND (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure) trial assessed the effect of patiromer in patients with HFrEF and either current or past hyperkalemia. METHODS: Patients with HFrEF and current or past (within 1 year before enrollment) hyperkalemia (serum potassium [sK+] >5.0 mmol/L) entered a single-blind, run-in phase to optimize RAASis while receiving patiromer. They were subsequently randomized, double-blind, to continue patiromer or change to placebo. RESULTS: Of the 1,038 patients who completed run-in, 354 (83.9%) of 422 with current hyperkalemia and 524 (85.1%) of 616 with past hyperkalemia achieved RAASi optimization and were randomized to treatment. During the double-blind phase, patiromer lowered sK+ levels compared with placebo in both the current and past hyperkalemia subgroups: difference in adjusted mean change from baseline: -0.12 (95% CI: -0.17 to -0.07) and -0.08 (95% CI: -0.12 to -0.05), respectively; Pinteraction = 0.166. Patiromer was more effective than placebo in maintaining MRA at target dose in patients with current vs past hyperkalemia (HR: 0.45 [95% CI: 0.26-0.76] vs HR: 0.85 [95% CI: 0.54-1.32]; Pinteraction = 0.031). Adverse events were similar between subgroups. CONCLUSIONS: The use of patiromer facilitates achieving target doses of RAASis in patients with HFrEF with either current or past hyperkalemia. For those with current hyperkalemia before RAASi optimization, use of patiromer may be more beneficial in helping to maintain sK+ control and achieve MRA target dose. (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure [DIAMOND]; NCT03888066).

Patiromer Facilitates Angiotensin Inhibitor and Mineralocorticoid Antagonist Therapies in Patients With Heart Failure and Hyperkalemia.

BACKGROUND: Hyperkalemia (HK) is associated with suboptimal renin-angiotensin system (RAS) inhibitor and mineralocorticoid receptor antagonist (MRA) use in heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: This study sought to assess characteristics and RAS inhibitor/MRA use in patients receiving patiromer during the DIAMOND (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure) run-in phase. METHODS: Patients with HFrEF and HK or past HK entered a run-in phase of ≤12 weeks with patiromer-facilitated RAS inhibitor/MRA optimization to achieve ≥50% recommended RAS inhibitor dose, 50 mg/d MRA, and normokalemia. Patients achieving these criteria (randomized group) were compared with the run-in failure group (patients not meeting the randomization criteria). RESULTS: Of 1,038 patients completing the run-in, 878 (84.6%) were randomized and 160 (15.4%) were run-in failures. Overall, 422 (40.7%) had HK entering run-in with a similar frequency in the randomized and run-in failure groups (40.3% vs 42.5%; P = 0.605). From start to the end of run-in, in the randomized group, an increase was observed in target RAS inhibitor and MRA use in patients with HK (RAS inhibitor: 76.8% to 98.6%; MRA: 35.9% to 98.6%) and past HK (RAS inhibitor: 60.5% to 98.1%; MRA: 15.6% to 98.7%). Despite not meeting the randomization criteria, an increase after run-in was observed in the run-in failure group in target RAS inhibitor (52.5% to 70.6%) and MRA use (15.0% to 48.1%). This increase was observed in patients with HK (RAS inhibitor: 51.5% to 64.7%; MRA: 19.1% to 39.7%) and past HK (RAS inhibitor: 53.3% to 75.0%; MRA: 12.0% to 54.3%). CONCLUSIONS: In patients with HFrEF and HK or past HK receiving suboptimal RAS inhibitor/MRA therapy, RAS inhibitor/MRA optimization increased during patiromer-facilitated run-in.

Patiromer-Facilitated Renin-Angiotensin-Aldosterone System Inhibitor Utilization in Patients with Heart Failure with or without Comorbid Chronic Kidney Disease: Subgroup Analysis of DIAMOND Randomized Trial.

INTRODUCTION: Renin-angiotensin-aldosterone system inhibitor (RAASi; including mineralocorticoid receptor antagonists [MRAs]) benefits are greatest in patients with heart failure with reduced ejection fraction (HFrEF) and chronic kidney disease (CKD); however, the risk of hyperkalemia (HK) is high. METHODS: The DIAMOND trial (NCT03888066) assessed the ability of patiromer to control serum potassium (sK+) in patients with HFrEF with/without CKD. Prior to randomization (double-blind withdrawal, 1:1), patients on patiromer had to achieve ≥50% recommended doses of RAASi and 50 mg/day of MRA with normokalemia during a run-in period. The present analysis assessed the effect of baseline estimated glomerular filtration rate (eGFR) in subgroups of ≥/<60, ≥/<45 (prespecified), and ≥/<30 mL/min/1.73 m2 (added post hoc). RESULTS: In total, 81.3, 78.9, and 81.1% of patients with eGFR <60, <45, and <30 mL/min/1.73 m2 at screening achieved RAASi/MRA targets. A greater efficacy of patiromer versus placebo to control sK+ in patients with more advanced CKD was reported (p-interaction ≤ 0.027 for all eGFR subgroups). Greater effects on secondary endpoints were observed with patiromer versus placebo in patients with eGFR <60 and <45 mL/min/1.73 m2. Adverse effects were similar between patiromer and placebo across subgroups. CONCLUSION: Patiromer enabled use of RAASi, controlled sK+, and minimized HK risk in patients with HFrEF, with greater effect sizes for most endpoints noted in patient subgroups with lower eGFR. Patiromer was well tolerated by patients in all eGFR subgroups.

Iron deficiency and the effectiveness of the BNT162b2 vaccine for SARS-CoV-2 infection: A retrospective, longitudinal analysis of real-world data.

BACKGROUND: Iron plays a key role in human immune responses; however, the influence of iron deficiency on the coronavirus disease 2019 (COVID-19) vaccine effectiveness is unclear. AIM: To assess the effectiveness of the BNT162b2 messenger RNA COVID-19 vaccine in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19-related hospitalization and death in individuals with or without iron deficiency. METHODS: This large retrospective, longitudinal cohort study analyzed real-world data from the Maccabi Healthcare Services database (covering 25% of Israeli residents). Eligible adults (aged ≥16 years) received a first BNT162b2 vaccine dose between December 19, 2020, and February 28, 2021, followed by a second dose as per approved vaccine label. Individuals were excluded if they had SARS-CoV-2 infection before vaccination, had hemoglobinopathy, received a cancer diagnosis since January 2020, had been treated with immunosuppressants, or were pregnant at the time of vaccination. Vaccine effectiveness was assessed in terms of incidence rates of SARS-CoV-2 infection confirmed by real-time polymerase chain reaction assay, relative risks of COVID-19-related hospitalization, and mortality in individuals with iron deficiency (ferritin <30 ng/mL or transferrin saturation <20%). The two-dose protection period was Days 7 to 28 after the second vaccination. RESULTS: Data from 184,171 individuals with (mean [standard deviation; SD] age 46.2 [19.6] years; 81.2% female) versus 1,072,019 without (mean [SD] age 46.9 [18.0] years; 46.2% female) known iron deficiency were analyzed. Vaccine effectiveness in the two-dose protection period was 91.9% (95% confidence interval [CI] 83.7-96.0%) and 92.1% (95% CI 84.2-96.1%) for those with versus without iron deficiency (P = 0.96). Of patients with versus without iron deficiency, hospitalizations occurred in 28 and 19 per 100,000 during the reference period (Days 1-7 after the first dose), and in 19 and 7 per 100,000 during the two-dose protection period, respectively. Mortality rates were comparable between study groups: 2.2 per 100,000 (4/181,012) in the population with iron deficiency and 1.8 per 100,000 (19/1,055,298) in those without known iron deficiency. CONCLUSIONS: Results suggest that the BNT162b2 COVID-19 vaccine is >90% effective in preventing SARS-CoV-2 infection in the 3 weeks after the second vaccination, irrespective of iron-deficiency status. These findings support the use of the vaccine in populations with iron deficiency.

Sex differences in the generalizability of randomized clinical trials in heart failure with reduced ejection fraction.

AIMS: In order to understand how sex differences impact the generalizability of randomized clinical trials (RCTs) in patients with heart failure (HF) and reduced ejection fraction (HFrEF), we sought to compare clinical characteristics and clinical outcomes between RCTs and HF observational registries stratified by sex. METHODS AND RESULTS: Data from two HF registries and five HFrEF RCTs were used to create three subpopulations: one RCT population (n = 16 917; 21.7% females), registry patients eligible for RCT inclusion (n = 26 104; 31.8% females), and registry patients ineligible for RCT inclusion (n = 20 810; 30.2% females). Clinical endpoints included all-cause mortality, cardiovascular mortality, and first HF hospitalization at 1 year. Males and females were equally eligible for trial enrolment (56.9% of females and 55.1% of males in the registries). One-year mortality rates were 5.6%, 14.0%, and 28.6% for females and 6.9%, 10.7%, and 24.6% for males in the RCT, RCT-eligible, and RCT-ineligible groups, respectively. After adjusting for 11 HF prognostic variables, RCT females showed higher survival compared to RCT-eligible females (standardized mortality ratio [SMR] 0.72; 95% confidence interval [CI] 0.62-0.83), while RCT males showed higher adjusted mortality rates compared to RCT-eligible males (SMR 1.16; 95% CI 1.09-1.24). Similar results were also found for cardiovascular mortality (SMR 0.89; 95% CI 0.76-1.03 for females, SMR 1.43; 95% CI 1.33-1.53 for males). CONCLUSION: Generalizability of HFrEF RCTs differed substantially between the sexes, with females having lower trial participation and female trial participants having lower mortality rates compared to similar females in the registries, while males had higher than expected cardiovascular mortality rates in RCTs compared to similar males in registries.

Generalizability of randomized controlled trials in heart failure with reduced ejection fraction.

BACKGROUND: Heart failure (HF) trials have stringent inclusion and exclusion criteria, but limited data exist regarding generalizability of trials. We compared patient characteristics and outcomes between patients with HF and reduced ejection fraction (HFrEF) in trials and observational registries. METHODS AND RESULTS: Individual patient data for 16 922 patients from five randomized clinical trials and 46 914 patients from two HF registries were included. The registry patients were categorized into trial-eligible and non-eligible groups using the most commonly used inclusion and exclusion criteria. A total of 26 104 (56%) registry patients fulfilled the eligibility criteria. Unadjusted all-cause mortality rates at 1 year were lowest in the trial population (7%), followed by trial-eligible patients (12%) and trial-non-eligible registry patients (26%). After adjustment for age and sex, all-cause mortality rates were similar between trial participants and trial-eligible registry patients [standardized mortality ratio (SMR) 0.97; 95% confidence interval (CI) 0.92-1.03] but cardiovascular mortality was higher in trial participants (SMR 1.19; 1.12-1.27). After full case-mix adjustment, the SMR for cardiovascular mortality remained higher in the trials at 1.28 (1.20-1.37) compared to RCT-eligible registry patients. CONCLUSION: In contemporary HF registries, over half of HFrEF patients would have been eligible for trial enrolment. Crude clinical event rates were lower in the trials, but, after adjustment for case-mix, trial participants had similar rates of survival as registries. Despite this, they had about 30% higher cardiovascular mortality rates. Age and sex were the main drivers of differences in clinical outcomes between HF trials and observational HF registries.

Serum Biomarkers of Iron Stores Are Associated with Increased Risk of All-Cause Mortality and Cardiovascular Events in Nondialysis CKD Patients, with or without Anemia.

BACKGROUND: Approximately 30%-45% of patients with nondialysis CKD have iron deficiency. Iron therapy in CKD has focused primarily on supporting erythropoiesis. In patients with or without anemia, there has not been a comprehensive approach to estimating the association between serum biomarkers of iron stores, and mortality and cardiovascular event risks. METHODS: The study included 5145 patients from Brazil, France, the United States, and Germany enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study, with first available transferrin saturation (TSAT) and ferritin levels as exposure variables. We used Cox models to estimate hazard ratios (HRs) for all-cause mortality and major adverse cardiovascular events (MACE), with progressive adjustment for potentially confounding variables. We also used linear spline models to further evaluate functional forms of the exposure-outcome associations. RESULTS: Compared with patients with a TSAT of 26%-35%, those with a TSAT ≤15% had the highest adjusted risks for all-cause mortality and MACE. Spline analysis found the lowest risk at TSAT 40% for all-cause mortality and MACE. Risk of all-cause mortality, but not MACE, was also elevated at TSAT ≥46%. Effect estimates were similar after adjustment for hemoglobin. For ferritin, no directional associations were apparent, except for elevated all-cause mortality at ferritin ≥300 ng/ml. CONCLUSIONS: Iron deficiency, as captured by TSAT, is associated with higher risk of all-cause mortality and MACE in patients with nondialysis CKD, with or without anemia. Interventional studies evaluating the effect on clinical outcomes of iron supplementation and therapies for alternative targets are needed to better inform strategies for administering exogenous iron.

Serum biomarkers of iron stores are associated with worse physical health-related quality of life in nondialysis-dependent chronic kidney disease patients with or without anemia.

BACKGROUND: Iron deficiency (ID) is a common condition in nondialysis-dependent chronic kidney disease (NDD-CKD) patients that is associated with poorer clinical outcomes. However, the effect of ID on health-related quality of life (HRQoL) in this population is unknown. We analyzed data from a multinational cohort of NDD-CKD Stages 3-5 patients to test the association between transferrin saturation (TSAT) index and ferritin with HRQoL. METHODS: Patients from Brazil (n = 205), France (n = 2015) and the USA (n = 293) in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps, 2013-2019) were included. We evaluated the association of TSAT and ferritin (and functional and absolute ID, defined as TSAT ≤20% and ferritin ≥300 or <50 ng/mL) on pre-specified HRQoL measures, including the 36-item Kidney Disease Quality of Life physical component summary (PCS) and mental component summary (MCS) as the primary outcomes. Models were adjusted for confounders including hemoglobin (Hb). RESULTS: TSAT ≤15% and ferritin <50 ng/mL and ≥300 ng/mL were associated with worse PCS scores, but not with MCS. Patients with composite TSAT ≤20% and ferritin <50 or ≥300 ng/mL had lower functional status and worse PCS scores than those with a TSAT of 20-30% and ferritin 50-299 ng/mL. Patients with a lower TSAT were less likely to perform intense physical activity. Adjustment for Hb only slightly attenuated the observed effects. CONCLUSIONS: Low TSAT levels, as well as both low TSAT with low ferritin and low TSAT with high ferritin, are associated with worse physical HRQoL in NDD-CKD patients, even after accounting for Hb level. Interventional studies of iron therapy on HRQoL among NDD-CKD individuals are needed to confirm these findings.

A real-world longitudinal study of anemia management in non-dialysis-dependent chronic kidney disease patients: a multinational analysis of CKDopps.

Previously lacking in the literature, we describe longitudinal patterns of anemia prescriptions for non-dialysis-dependent chronic kidney disease (NDD-CKD) patients under nephrologist care. We analyzed data from 2818 Stage 3-5 NDD-CKD patients from Brazil, Germany, and the US, naïve to anemia medications (oral iron, intravenous [IV] iron, or erythropoiesis stimulating agent [ESA]) at enrollment in the CKDopps. We report the cumulative incidence function (CIF) of medication initiation stratified by baseline characteristics. Even in patients with hemoglobin (Hb) < 10 g/dL, the CIF at 12 months for any anemia medication was 40%, and 28% for ESAs. Patients with TSAT < 20% had a CIF of 26% and 6% for oral and IV iron, respectively. Heart failure was associated with earlier initiation of anemia medications. IV iron was prescribed to < 10% of patients with iron deficiency. Only 40% of patients with Hb < 10 g/dL received any anemia medication within a year. Discontinuation of anemia treatment was very common. Anemia treatment is initiated in a limited number of NDD-CKD patients, even in those with guideline-based indications to treat. Hemoglobin trajectory and a history of heart failure appear to guide treatment start. These results support the concept that anemia is sub-optimally managed among NDD-CKD patients in the real-world setting.

Low hemoglobin at hemodialysis initiation: an international study of anemia management and mortality in the early dialysis period.

BACKGROUND: Anemia at hemodialysis (HD) initiation is common. Correcting low hemoglobin (Hgb) before HD initiation may improve survival by avoiding potential harms of chronic anemia, high doses of erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron in the early HD period, and/or rapid Hgb rise. METHODS: We included 4604 incident HD patients from 21 countries in the Dialysis Outcomes and Practice Patterns Study Phases 4-5 (2009-15). Because low Hgb at HD start may reflect comorbidity or ESA hyporesponse, we restricted our analysis to the 80% of patients who achieved Hgb ≥10 g/dL 91-120 days after HD start (Month 4). RESULTS: About 53% of these patients had Hgb <10 g/dL in Month 1 (<30 days after HD start); they were younger with a similar comorbidity profile (versus Hgb ≥10 g/dL). Month 1 Hgb was associated with first-year HD mortality (adjusted hazard ratio for 1 g/dL higher Hgb was 0.89; 95% confidence interval: 0.81-0.97), despite minimal differences in Month 4 Hgb. Patients with lower Hgb in Month 1 received higher doses of ESA, but not IV iron, over the first 3 months of HD. Results were consistent when excluding catheter users or adjusting for IV iron and ESA dose over the first 3 months. CONCLUSIONS: Even among patients with Hgb ≥10 g/dL 3 months later, anemia at HD initiation was common and associated with elevated mortality. A more proactive approach to anemia management in advanced chronic kidney disease (CKD) may thus improve survival on HD, though long-term prospective studies of non-dialysis CKD patients are needed.

On-demand proton pump inhibitory treatment in overweight/obese patients with gastroesophageal reflux disease: are there pharmacodynamic arguments for using higher doses?

BACKGROUND: Increased body mass index (BMI) is associated with a higher risk of gastroesophageal reflux disease (GORD). AIM: To investigate whether overweight/obesity affects proton pump inhibitor pharmacodynamics when used in a single dose in patients with GORD. METHODS: Post hoc analyses by patient BMI were performed on data from two single-center, double-blind, single-dose, crossover studies comparing the pharmacodynamics of rabeprazole 20 mg and pantoprazole 40 mg in GORD patients with a history of nocturnal heartburn. The primary endpoint was the mean percentage of time with intragastric pH >4 between lean and overweight/obese patients (BMI <25 and ≥25). RESULTS: 24 h baseline intragastric pH values were not different between BMI groups. The pharmacodynamic effects of both proton pump inhibitors were not significantly different between BMI groups, and no evidence was found for an interaction between BMI and treatment. As compared with pantoprazole, rabeprazole showed a significantly greater effect on the antisecretory response for both BMI groups. CONCLUSIONS: Overweight/obesity in GORD patients does not appear to affect the antisecretory efficacy of a single dose of rabeprazole and pantoprazole. These data do not support adapting the dosage of rabeprazole and pantoprazole according to BMI in GORD patients when administered as an on-demand therapy schedule.

Sustained safety and efficacy of once-daily hydromorphone extended-release (OROS® hydromorphone ER) compared with twice-daily oxycodone controlled-release over 52 weeks in patients with moderate to severe chronic noncancer pain.

Once-daily hydromorphone extended-release (OROS(®) hydromorphone ER) and oxycodone controlled-release (CR) are semisynthetic, ER opioid analgesics with established efficacy. An open-label, randomized, 24-week, parallel group, flexible-dose study demonstrated noninferiority of OROS hydromorphone ER vs. twice-daily oxycodone CR in patients with chronic noncancer pain. In total, 112 patients were enrolled in a 28-week, open-label extension study; 60 patients received OROS hydromorphone ER and 52 received oxycodone CR. The primary efficacy measure was the change from baseline to Weeks 38 and 52 in Brief Pain Inventory item "pain right now." Global assessments of efficacy, dosing convenience, and tolerability were secondary endpoints. Mean change in "pain right now" from baseline to Week 38 was -3.0 (OROS hydromorphone ER) vs. -2.8 (oxycodone CR), and from baseline to Week 52 was -2.9 vs. -2.8; these changes were similar to the changes in the core phase (-2.1 vs. -2.1). Similar improvements were demonstrated for secondary assessments, including pain, pain interference, and quality of life. At Week 52, global assessment of efficacy was rated as "very good" or "good" by the majority of patients (OROS hydromorphone ER, 91.7%; oxycodone CR, 86.5%). More patients in the OROS hydromorphone ER group (35.0% vs. 21.2%) assessed mode of drug intake as "very convenient." The majority of patients receiving OROS hydromorphone ER (88.3%) and oxycodone CR (88.5%) rated tolerability as "good" or "very good" at Week 52; few patients discontinued treatment because of an adverse event (1.6% vs. 0.4%, respectively). The effectiveness of OROS hydromorphone ER and oxycodone CR was maintained through 1 year.

Predictors of placebo response in adults with attention-deficit/hyperactivity disorder: data from 2 randomized trials of osmotic-release oral system methylphenidate.

OBJECTIVE: To find potential correlates of placebo response in adults with attention-deficit/hyperactivity disorder (ADHD) and gain insights into why placebo response may be high in clinical trials. METHOD: Post hoc analysis of placebo data from 2 randomized controlled trials of osmotic-release oral system (OROS) methylphenidate in adults with ADHD defined according to the Diagnostic and Statistical Manual of Mental Diseases, Fourth Edition: the Long-Acting Methylphenidate in Adults with ADHD (LAMDA-I) study (2005-2006, 5 weeks, n = 95) and the LAMDA-II study (2008-2009, 13 weeks, n = 97). The primary efficacy measure was the Conners' Adult ADHD Rating Scale-observer rated, short version (CAARS:O-SV). Predictors of CAARS:O-SV change were assessed using a random-intercepts model with demographic and disease-related parameters as independent variables. Sensitivity analyses were conducted using the CAARS self-report (CAARS:S-S) and a categorical response criterion (improvement of > 30% in CAARS:O-SV), and in subjects who completed the study. RESULTS: In LAMDA-I, mean ± SD change in CAARS:O-SV was -7.6 ± 9.9 with placebo and -11.9 ± 10.6 with OROS methylphenidate. Higher baseline CAARS score (P = .007) and lower educational achievement (P = .014) were significantly associated with greater improvement in placebo-treated subjects. In LAMDA-II, mean ± SD change in CAARS:O-SV was -10.4 ± 11.0 and -14.1 ± 10.7 in subjects receiving placebo and OROS methylphenidate, respectively. Variables significantly associated with greater placebo response were higher baseline CAARS:O-SV (P = .019), shorter time since ADHD diagnosis (P < .045), and younger age (P = .014). None of the sensitivity analyses challenged the outcomes. CONCLUSIONS: Possible predictors of placebo response in adults with ADHD include higher severity of ADHD symptoms, younger age, shorter time since diagnosis, and lower educational level.

Long-term efficacy and safety outcomes with OROS-MPH in adults with ADHD.

Methylphenidate (MPH) is widely prescribed for adults with attention deficit hyperactivity disorder (ADHD), but data on long-term treatment and maintenance of effect are lacking. Osmotic release oral system-methylphenidate (OROS-MPH) was evaluated in a 52-wk open-label study in subjects who had previously completed a short-term placebo-controlled trial and short-term open-label extension. Efficacy was assessed using the investigator- and subject-rated Conners' Adult ADHD Rating Scales (CAARS:O-SV and CAARS:S-S), and the Clinical Global Impression - Severity (CGI-S), Sheehan Disability Scale (SDS) and Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Subjects completing ≥52 wk of treatment were eligible for a 4-wk randomized, placebo-controlled withdrawal phase in which loss of treatment effect was assessed using CAARS:O-SV and CGI-S. In the open-label phase (n=156), mean CAARS:O-SV score decreased from baseline by 1.9±7.8 (p<0.01), and small, statistically significant improvements from baseline were observed for CAARS:S-S, CGI-S and SDS. In the double-blind phase (OROS-MPH, n=23; placebo, n=22), CAARS:O-SV increased from double-blind baseline in the OROS-MPH and placebo arms (4.0±7.6 vs. 6.5±7.8, not statistically significant). Long-term OROS-MPH treatment was well tolerated, and there was no evidence of withdrawal or rebound after discontinuation. In conclusion, the short-term benefits of OROS-MPH continue during long-term open-label treatment. Maintenance of efficacy in a placebo-controlled withdrawal design remains to be confirmed in larger patient populations.

A Phase IIIb, Multicentre, Randomised, Parallel-Group, Placebo-Controlled, Double-Blind Study to Investigate the Efficacy and Safety of OROS Hydromorphone in Subjects with Moderate-to-Severe Chronic Pain Induced by Osteoarthritis of the Hip or the Knee.

Background. Opioid analgesics are included in treatment guidelines for the symptomatic management of osteoarthritis (OA). Starting with a low dose of opioid and slowly titrating to a higher dose may help avoid intolerable side effects. Methods. Subjects aged ≥40 years, with moderate to severe pain induced by OA of the hip or knee not adequately controlled by previous non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol treatment, were enrolled. Subjects received OROS hydromorphone 4 mg or placebo once-daily. The dose was titrated every 3-4 days in case of unsatisfactory pain control during the 4-week titration phase. A 12 week maintenance phase followed. The primary efficacy endpoint was the change in "pain on average" measured on the Brief Pain Inventory (BPI) scale from baseline to the end of the maintenance phase. Results. 139 subjects received OROS hydromorphone and 149 subjects received placebo. All efficacy endpoints showed similar improvements from baseline to end of study in the 2 groups. The safety results were consistent with the safety profile of OROS hydromorphone. Conclusion.The study did not meet the primary endpoint; although many subjects' pain was not adequately controlled at inclusion, their pain may have improved with continued paracetamol or NSAID treatment.

A randomized study to demonstrate noninferiority of once-daily OROS(®) hydromorphone with twice-daily sustained-release oxycodone for moderate to severe chronic noncancer pain.

This was a randomized, open-label, comparative, parallel group study designed to demonstrate the noninferiority of once-daily OROS(®) hydromorphone compared with twice-daily sustained-release (SR) oxycodone in subjects with chronic noncancer pain severe enough to require continuous opioid therapy. The core phase (24 weeks) consisted of titration and maintenance periods. This was followed by an optional extension phase (28 weeks), which collected data used to assess long-term safety and efficacy outcomes. Five hundred four subjects were randomized between the 2 treatment groups. The primary efficacy analysis showed that OROS hydromorphone was noninferior to SR oxycodone (P = 0.011) as measured by change in Brief Pain Inventory (BPI) pain severity subscore "pain right now." The treatment difference with respect to change in BPI pain severity subscore "pain right now" was 0.29 (95% confidence interval: -0.27 to 0.84). The equianalgesic doses were 16 mg OROS hydromorphone and 40 mg SR oxycodone (median values). Secondary outcomes included other BPI scale items, the Medical Outcomes Study (MOS) Sleep Indices, and quality of life measured by the Short Form 36 (SF-36) questionnaire. Both treatment groups showed improvements in the main secondary efficacy endpoints. No statistically significant differences were shown between the treatment groups, except for the scores for somnolence (MOS sleep subscale) and physical functioning (SF-36), which both had a statistically significant difference between treatments groups in favor of OROS hydromorphone. Both study medications had equivalent and acceptable safety profiles. The results of this open-label study showed that once-daily OROS hydromorphone is a safe and well-tolerated treatment for chronic pain and as efficacious as twice-daily SR oxycodone.