Establishing clinically meaningful within-individual improvement thresholds for eight patient-reported outcome measures in people with relapsing-remitting multiple sclerosis.

BACKGROUND: As disease-modifying therapies do not reverse the course of multiple sclerosis (MS), assessment of therapeutic success involves documenting patient-reported outcomes (PROs) concerning health-related quality of life, disease and treatment-related symptoms, and the impact of symptoms on function. Interpreting PRO data involves going beyond statistical significance to calculate within-patient meaningful change scores. These thresholds are needed for each PRO in order to fully interpret the PRO data. This analysis of PRO data from the PROMiS AUBAGIO study, which utilized 8 PRO instruments in teriflunomide-treated relapsing-remitting MS (RRMS) patients, was designed to estimate clinically meaningful within-individual improvement thresholds in the same manner, for 8 PRO instruments. RESULTS: The analytical approach followed a triangulation exercise that considered results from anchor- and distribution-based methods and graphical representations of empirical cumulative distribution functions in PRO scores in groups defined by anchor variables. Data from 8 PRO instruments (MSIS-29 v2, FSMC, MSPS, MSNQ, TSQM v1.4, PDDS, HRPQ-MS v2, and HADS) were assessed from 434 RRMS patients. For MSIS-29 v2, FSMC, MSPS, and MSNQ total scores, available anchor variables enabled both anchor- and distribution-based methods to be applied. For instruments with no appropriate anchor available, distribution-based methods were applied. A recommended value for meaningful within-individual improvement was defined by comparing mean change in PRO scores between participants showing improvement of one or two categories in the anchor variable or those showing no change. A "lower bound" estimate was calculated using distribution-based methods. An improvement greater than the lower-bound estimate was considered "clinically meaningful". CONCLUSION: This analysis produced estimates for assessing meaningful within-individual improvements for 8 PRO instruments used in MS studies. These estimates should be useful for interpreting scores and communicating study results and should facilitate decision-making by regulatory and healthcare authorities where these 8 PROs are commonly employed.

A toolbox of different approaches to analyze and present PRO-CTCAE data in oncology studies.

BACKGROUND: The patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) is used to assess symptomatic adverse events in oncology trials. Currently, no standard for PRO-CTCAE analysis exists. METHODS: Key methods of descriptive analysis and longitudinal modeling using PRO-CTCAE data from an oncology clinical trial, DRiving Excellence in Approaches to Multiple Myeloma-2 (DREAMM-2), a phase II trial of belantamab mafodotin in multiple myeloma (NCT03525678), were explored. Descriptive methods included maximum postbaseline ratings, mean change over time, ratings above a predefined cutoff, line graphs, and stacked bar charts to illustrate patient-reported adverse events at one timepoint or dynamics over time. Analysis methods involving modeling over time included toxicity over time (ToxT) (repeated measurement model, time-to-event, area under the curve analyses), generalized estimating equations (GEE), and ordinal log-linear models (OLLMs). RESULTS: Visualizations of PRO-CTCAE data highlighted different aspects of the data. Selection of the appropriate visualization will depend on the audience and message to be conveyed. Consistent results were obtained by all modeling approaches; no difference was found between dose groups of the DREAMM-2 study in any PRO-CTCAE item by the ToxT approach or the more sophisticated GEE and OLLM methods. Interpretation of GEE results was the most challenging. OLLM supported the interval nature of the PRO-CTCAE response scale in the DREAMM-2 study. All modeling approaches account for multiple testing (driven by the number of items). CONCLUSIONS: Descriptive analyses and longitudinal modeling approaches are complementary approaches to presenting PRO-CTCAE data. In modeling, the ToxT approach may be a good compromise compared with more sophisticated analyses.

Blood pressure and proteinuria control remains a challenge in patients with type 2 diabetes mellitus and chronic kidney disease: experience from the prospective observational ALICE-PROTECT study.

BACKGROUND: Type 2 diabetes (T2DM) is the leading cause of chronic kidney disease (CKD) in western countries. The combination of both increases the risk of end stage renal disease (ESRD), cardiovascular events and all-cause mortality. Early control of blood pressure (BP) and proteinuria (Pu) is crucial to slow down the progression of the CKD and prevent cardiovascular events and mortality. The primary objective of the study was to assess BP and Pu control after a 2-year follow-up in T2DM patients with CKD. METHODS: Prospective, multicenter, observational study. Overall, 153 French nephrologists included 986 T2DM patients with Pu (≥0.5 g/day) and an eGFR >15 ml/min/1.73 m2. Data from 729 patients were available after a 2-year follow-up. BP and Pu control were respectively defined as less than 140/90 mmHg and 0.5 g/day. We also looked at renal and cardiovascular events. RESULTS: At baseline, 74 % of the patients were male, mean age was 70 years. The mean T2DM duration was 17 years with a mean HbA1c of 7.4 %. All were treated for hypertension and 33 % had a controlled BP; 81 % had dyslipidemia and LDLc was <1 g/L for 54 %; 44 % had retinopathy, 40 % macrovascular complications and 12 % heart failure. Mean Pu was 2 g/day and eGFR 40 ± 20 mL/min/1.73 m2, with 13, 18, 32 and 37 % of the patients in respectively stage 2, 3a, 3b and 4 CKD. After two years, 21 % reached the Pu target and 39 % the BP target. The mean eGFR of 40 ± 20.3 ml/min/1.73 m2 at baseline dropped to 33.9 ± 22.6 ml/min/1.73 m2 by year two (p < 0.001). This corresponded to a mean annual eGFR reduction of 3.2 ml/min/1.73 m2. 118 patients presented a renal event (16.2 %): doubling of serum creatinine for 86 patients (11.8 %) and start of dialysis for 72 (9.9 %); 176 patients (24.1 %) developed at least one cardiovascular complication (mainly coronary events and acute heart failure) during the follow-up period, and among these, 50 had also developed renal complications. Sixty patients died, i.e., 8.2 %, 26 patients from cardiovascular causes. CONCLUSION: Our study highlights that achieving BP and Pu targets remains a major challenge in patients with T2DM and nephropathy. Renal failure emerges as a more frequent event than death.

Physical activity in patients with type 2 diabetes and hypertension--insights into motivations and barriers from the MOBILE study.

BACKGROUND: Although physical activity (PA) is key in the management of type 2 diabetes (T2DM) and hypertension, it is difficult to implement in practice. METHODS: Cross-sectional, observational study. Participating physicians were asked to recruit two active and four inactive patients, screened with the Ricci-Gagnon (RG) self-questionnaire (active if score ≥16). Patients subsequently completed the International Physical Activity Questionnaire. The objective was to assess the achievement of individualized glycated hemoglobin and blood pressure goals (<140/90 mmHg) in the active vs inactive cohort, to explore the correlates for meeting both targets by multivariate analysis, and to examine the barriers and motivations to engage in PA. RESULTS: About 1,766 patients were analyzed. Active (n=628) vs. inactive (n=1,138) patients were more often male, younger, less obese, had shorter durations of diabetes, fewer complications and other health issues, such as osteoarticular disorders (P<0.001 for all). Their diabetes and hypertension control was better and obtained despite a lower treatment burden. The biggest difference in PA between the active vs inactive patients was the percentage who declared engaging in regular leisure-type PA (97.9% vs. 9.6%), also reflected in the percentage with vigorous activities in International Physical Activity Questionnaire (59.5% vs. 9.6%). Target control was achieved by 33% of active and 19% of inactive patients (P<0.001). Active patients, those with fewer barriers to PA, with lower treatment burden, and with an active physician, were more likely to reach targets. The physician's role emerged in the motivations (reassurance on health issues, training on hypoglycemia risk, and prescription/monitoring of the PA by the physician). A negative self-image was the highest ranked barrier for the inactive patients, followed by lack of support and medical concerns. CONCLUSION: Physicians should consider PA prescription as seriously as any drug prescription, and take into account motivations and barriers to PA to tailor advice to patients' specific needs and reduce their perceived constraints.

CHANGES IN VISUAL ACUITY IN PATIENTS WITH WET AGE-RELATED MACULAR DEGENERATION TREATED WITH INTRAVITREAL RANIBIZUMAB IN DAILY CLINICAL PRACTICE: The TWIN Study.

PURPOSE: The real-life LUMIERE study on patients with wet age-related macular degeneration treated with intravitreal ranibizumab in 2006 to 2009 showed that failure to follow recommendations was associated with lower efficacy than had been observed in the development phase. The TWIN Study reviewed the situation in 2010 to 2011. METHODS: Retrospective, descriptive purely observational study of data acquired after 12 months of treatment with intravitreal ranibizumab. RESULTS: In 881 patients (68% women, mean age, 79 years) treated by 21 ophthalmologists, the mean gain in visual acuity was +4.3 ± 15.4 letters (up from 3.2 ± 14.8 in 2006-2009; NS). Significant improvements were documented in the mean interval between diagnosis and treatment initiation (down from 12.6 ± 26.4-7.7 ± 10.9 days; P < 0.001), and in the percentage of patients who received a full course of induction treatment (56.6 vs. 39.6%; P < 0.001). After induction, hardly any patients were monitored every month as recommended, although retreatment was more assiduous (5.6 ± 2.3 vs. 5.1 ± 2.1 injections; P < 0.001). CONCLUSION: Despite improvements in key parameters, the effectiveness of intravitreal ranibizumab is still compromised by poor compliance with the guidelines, especially the frequency of postinduction monitoring that is now the most important determinant of successful treatment.

Glycemic control according to glomerular filtration rate in patients with type 2 diabetes and overt nephropathy: a prospective observational study.

BACKGROUND AND OBJECTIVE: Type 2 diabetes (T2D) and chronic kidney disease (CKD) are closely linked. This study aimed to describe and analyze the relations between renal function and glycemic control in T2D patients with overt nephropathy. PATIENTS AND METHODS: Data were collected from a French observational prospective multicenter study. Patients included were adults with T2D, clinical proteinuria and an estimated glomerular filtration rate (eGFR) over 15 mL/min/1.73 m(2). Baseline data and glycemic control after a one-year follow-up are presented here. RESULTS: Data from 986 adult patients were analyzed. Mean age was 70 years. Mean eGFR was 42 mL/min/1.73 m(2), 66% of patients had proteinuria above 1g/day. HbA1c was higher in patients with lower eGFR in a model adjusted to age, gender, body mass index, hemoglobin level and erythropoietin use. Statistical significance was lost when stepwise multivariate analysis took into account the type of pharmacological treatment used to treat hyperglycemia.The type of antidiabetic agents differed across eGFR strata. Below 60 mL/min/1.73 m(2), the use of metformin declined while the use of insulin increased.After one year of follow up, 35% of patients had persistently poor or worsened glycemic control (HbA1c>8%). The only covariate independently associated with this characteristic was the duration of insulin therapy. CONCLUSION: In patients with T2D and overt nephropathy, the observed correlation of low eGFR with high HbA1c was not predicted by eGFR. Our data rather underscore a different use of antidiabetic treatments in patients with advanced renal dysfunction, and the difficulty to improve glycemic control in patients with long standing insulin therapy.

How are patients with type 2 diabetes and renal disease monitored and managed? Insights from the observational OREDIA study.

BACKGROUND AND AIM: Chronic kidney disease (CKD) is frequent in type 2 diabetes mellitus (T2DM), and therapeutic management of diabetes is more challenging in patients with renal impairment (RI). The place of metformin is of particular interest since most scientific societies now recommend using half the dosage in moderate RI and abstaining from use in severe RI, while the classic contraindication with RI has not been removed from the label. This study aimed to assess the therapeutic management, in particular the use of metformin, of T2DM patients with CKD in real life. METHODS: This was a French cross-sectional observational study: 3,704 patients with T2DM diagnosed for over 1 year and pharmacologically treated were recruited in two cohorts (two-thirds were considered to have renal disease [CKD patients] and one-third were not [non-CKD patients]) by 968 physicians (81% general practitioners) in 2012. RESULTS: CKD versus non-CKD patients were significantly older with longer diabetes history, more diabetic complications, and less strict glycemic control (mean glycated hemoglobin [HbA(1c)] 7.5% versus 7.1%; 25% of CKD patients had HbA1c ≥8% versus 15% of non-CKD patients). Fifteen percent of CKD patients had severe RI, and 66% moderate RI. Therapeutic management of T2DM was clearly distinct in CKD, with less use of metformin (62% versus 86%) but at similar mean daily doses (~2 g/d). Of patients with severe RI, 33% were still treated with metformin, at similar doses. For other oral anti-diabetics, a distinct pattern of use was seen across renal function (RF): use of sulfonylureas (32%, 31%, and 20% in normal RF, moderate RI, and severe RI, respectively) and DPP4-i (dipeptidyl peptidase-4 inhibitors) (41%, 36%, and 25%, respectively) decreased with RF, while that of glinides increased (8%, 14%, and 18%, respectively). CKD patients were more frequently treated with insulin (40% versus 16% of non-CKD patients), and use of insulin increased with deterioration of RF (19%, 39%, and 61% of patients with normal RF, moderate RI, and severe RI, respectively). Treatment was modified at the end of the study-visit in 34% of CKD patients, primarily to stop or reduce metformin. However, metformin was stopped in only 40% of the severe RI patients. CONCLUSION: Despite a fairly good detection of CKD in patients with T2DM, RI was insufficiently taken into account for adjusting anti-diabetic treatment.

How are physicians prescribing the direct renin inhibitor aliskiren in the management of essential hypertension? A French observational study.

OBJECTIVES: The aim of this French observational study was to evaluate how the direct renin inhibitor aliskiren is being prescribed to treat hypertension by primary care providers (PCPs) and office-based cardiologists. METHODS: Each participating physician included the first three consecutive hypertensive patients who had been prescribed aliskiren at least 4 weeks beforehand and noted whether aliskiren was prescribed: alone or as part of a combination; as first-line therapy, to replace another drug or as an add-on therapy. RESULTS: Five thousand, four hundred and eleven patients were analyzed [mean age, 63; 58% men; 24% diabetic; mean blood pressure (BP) 148/85 mmHg]. A total of 23.6% of patients had a controlled BP. Aliskiren was prescribed alone in 49.4% patients and as part of a combination in 50.6% (bitherapy 28.3%, tritherapy 14.7%, and quadri+therapy 7.6%), at the higher recommended dosage (300 mg daily) to two-thirds of cases. Aliskiren replaced another drug in 71.9% [mainly an angiotensin receptor blocker (ARB) or an angiotensin-converting enzyme inhibitor (ACEi)] and was added to an existing regimen in 22.5%. For bitherapy, aliskiren was combined with a diuretic (D; 39%) or a calcium channel blocker (CCB; 32%). For tritherapy, it was prescribed with CCB and D in 28% and ß-blocker and D in 26%. In 8.9% of patients, aliskiren was prescribed with an ACEi or an ARB. CONCLUSION: French physicians are generally following the current prescribing recommendations for aliskiren, but the place of this new class of antihypertensive in the management of essential hypertension will become clearer with longer experience, especially concerning effective doses and combinations.

Experience with Vildagliptin in Type 2 Diabetic Patients Fasting During Ramadan in France: Insights from the VERDI Study.

AIM: To assess in real life the rate of hypoglycemia during Ramadan in patients with type 2 diabetes (T2DM) in France, according to their ongoing dual therapy of metformin-vildagliptin or metformin-sulfonylurea/glinide (IS). METHODS: Prospective, non-interventional study with 2 visits (within 8 weeks before and 6 weeks after the end of Ramadan 2012). Study diaries were not used to collect events or record values of glucose monitoring. One hundred and ninety-eight patients on stable oral dual therapy for ≥2 months and with glycosylated hemoglobin (HbA1c) ≤8.0% were recruited by 62 centers: 83 in the IS cohort and 115 in the vildagliptin cohort. RESULTS: Approximately 90% of patients were from Maghreb. The two cohorts were well balanced: 60% men, mean age 59 years, BMI 28 kg/m(2), metformin dose ~2,000 mg/day, and HbA1c 7.2%. Distinct therapeutic management was planned in view of Ramadan with drug-adaptation intended in 61.4% of IS and 18.3% of vildagliptin patients. Hypoglycemia was reported in 37% of IS and 34% of vildagliptin patients; episodes declared as confirmed in 30.8% and 23.5%, respectively, and episodes documented as adverse event (AE) in 17.9% (22 episodes) and 7.5% (13 episodes), respectively (P = 0.025). Severe episodes were reported in 3.9% of IS and 1.7% of vildagliptin patients. 10.4% of IS and 2.6% of vildagliptin patients reported severe episodes and/or unscheduled medical visits due to hypoglycemia (P = 0.029). Glycemic control remained stable in both cohorts. Compliance with fasting was high, as well as adherence to drug with ≥5 missed-dose for 15.4% of IS and 8.5% of vildagliptin patients. CONCLUSION: Although the overall frequency of malaise suggestive of hypoglycemia was high, which would be expected with prolonged fasting in a well-controlled T2DM population during hot summer days, the incidence of more severe and better-documented episodes (AE, severe event, event leading to unscheduled medical visit) were much lower, with consistently less events with vildagliptin therapy.

Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the LUMIERE study.

PURPOSE: To survey compliance with recommended intravitreal ranibizumab treatment protocols in daily clinical practice in France, with reference to outcomes. METHODS: A retrospective, descriptive, observational study in patients with subfoveal wet age-related macular degeneration treated with ranibizumab. All historical data for the study period, including demographic, treatment, and disease details and visual acuity measurements (baseline, Month 3, and Month 12), were recorded retrospectively at least 12 months after the beginning of treatment. RESULTS: In 551 patients followed by 16 ophthalmologists, 12 months of intravitreal ranibizumab treatment induced a mean visual acuity gain of 3.2 ± 14.8 Early Treatment Diabetic Retinopathy Study-equivalent letters. Fewer than 40% of patients received the recommended treatment of initial 3 monthly injections. More than 50% had to wait >8 days between diagnosis and treatment. At Month 3, visual acuity gain was greater in patients who had received recommended induction and in whom treatment was initiated quickly. At Month 12, the induction-related effect had largely disappeared but the time-to-treatment effect persisted. Patients had an average of 5.1 injections (2.6 during induction period). No patients were monitored monthly as stipulated in the guidelines. CONCLUSION: Although poor compliance with recommendations has been reflected in mediocre outcomes, there is evidence that practice is improving.

Gender-related differences in the management of hypertension by cardiologists: the PARITE study.

BACKGROUND: Several studies have shown gender differences in the management of cardiovascular risk factors and diseases. Whether the management of hypertension by cardiologists in France differs according to patient gender has not been fully investigated. AIMS: The main objective of this cross-sectional, multicentre study was to examine the management according to gender of hypertensive patients by office-based cardiologists in France. METHODS: Cardiologists were asked to include consecutively two men and two women attending a routine consultation for essential hypertension. Therapeutic management was evaluated by comparing cardiovascular investigations in the preceding 6 months and hypertension control according to gender and the patients' global cardiovascular risk. RESULTS: Overall, data from 3440 adult patients (53% men) referred to 654 cardiologists were analysed. Hypertension was uncontrolled in 76% of both men and women and 69% were at high global cardiovascular risk (75% of men, 62% of women; P<0.001). Significantly fewer cardiovascular investigations had been performed in the preceding 6 months in women (22.6% vs 44.2% in men; P<0.001). The treatment regimen was changed by the cardiologist in approximately 50% of patients regardless of gender or global cardiovascular risk. CONCLUSIONS: The PARITE study shows that in French office-based cardiology practice, the antihypertensive regimen is adjusted as often in female as in male patients. However, the results suggest that there is room for improvement in the investigation of cardiovascular disease in women. Healthcare providers could be encouraged to implement established guidelines on the prevention of cardiovascular disease in women.

Steroid avoidance with early intensified dosing of enteric-coated mycophenolate sodium: a randomized multicentre trial in kidney transplant recipients.

BACKGROUND: Short-term intensified dosing using enteric-coated mycophenolate sodium (EC-MPS) reduces rejection after kidney transplantation without compromising safety and may facilitate steroid avoidance. METHODS: In a 6-month, multicentre open-label trial, 222 de novo kidney transplant recipients at low-immunological risk were randomized to steroid avoidance or maintenance steroids with interleukin (IL)-2 receptor antibody (IL-2RA) induction, EC-MPS (2160 mg/day to Week 6, 1440 mg/day thereafter) and cyclosporine. RESULTS: The primary end point; treatment failure at Month 6 [biopsy-proven acute rejection (BPAR), graft loss, death or loss to follow-up], occurred in 17.9% (20/112) of steroid-avoidance patients and 14.5% (16/110) of controls (difference 3.4%, 95% confidence interval -6.3 to 13.1, P = 0.47 for superiority testing). BPAR occurred in 11.6 and 7.3% of patients in the steroid-avoidance and control arms, respectively (P = 0.27). Creatinine clearance was similar at Month 6 (steroid-avoidance 56 ± 18 mL/min/1.73 m(2), controls 60 ± 22 mL/min/1.73 m(2), P = 0.34). Cytomegalovirus infection, as reported by investigators, occurred in 12.5% of steroid-avoidance patients and 22.7% of controls (P = 0.045). CONCLUSIONS: A regimen of early intensified EC-MPS dosing with calcineurin inhibitor and IL-2RA induction permits oral steroid avoidance in adult kidney transplant patients at low-immunological risk without compromising efficacy at 6 months' follow-up.

Conversion from everolimus with low-exposure cyclosporine to everolimus with mycophenolate sodium maintenance therapy in kidney transplant recipients: a randomized, open-label multicenter study.

BACKGROUND: Data in kidney transplant recipients regarding elimination of calcineurin inhibitor (CNI) therapy from a de novo regimen based on low CNI exposure and an mTOR inhibitor are sparse, and restricted to CNI elimination within the first six months post-transplant. MATERIAL/METHODS: In a 12-month, randomized, multicenter, open-label study, kidney transplant patients who had received everolimus, low-exposure cyclosporine and corticosteroids from transplantation to month 12 (with proteinuria <1 g/24 h at month 12) were randomized to convert from cyclosporine to mycophenolate sodium 720 mg/day with increased everolimus exposure (6-10 ng/mL [CNI-free group], n=15) or continue unchanged (everolimus 3-8 ng/mL [CNI group], n=15). RESULTS: Median (range) baseline mGFR was 54 (21-87) mL/min and 37 (range 18-69) mL/min (p=0.053) in the CNI-free and CNI groups, respectively, compared to 56 (18-126) mL/min and 32 (12-63) mL/min at month 12 (p=0.007). The between-group difference in change in mGFR from baseline to month 12 post-conversion (the primary endpoint) was -14.4 mL/min (95% CI -29.3 to 0.6 mL/min, p=0.059 [least squares mean]). Changes in serum creatinine and estimated GFR to month 12 were significantly in favor of CNI-free patients. One CNI patient experienced biopsy-proven acute rejection. Study drug was discontinued due to adverse events in one CNI-free patient (7%) and three CNI-treated patients (20.0%). CONCLUSIONS: Elimination of CNI from a de novo regimen of everolimus with low-exposure CNI at one year post-transplant maintained efficacy and led to a non-significant but clinically relevant improvement in renal function, although patients numbers were low (n=30). Findings from this small study require confirmation in a larger controlled trial.

A multicenter, randomized trial of increased mycophenolic acid dose using enteric-coated mycophenolate sodium with reduced tacrolimus exposure in maintenance kidney transplant recipients.

Mycophenolic acid (MPA) dose is frequently reduced in tacrolimus-treated kidney transplant patients, but alternatively the recommended MPA dose can be maintained with reduced tacrolimus exposure. In a 6-month, multicenter, randomized, openlabel study, maintenance kidney transplant patients receiving MPA (mycophenolate mofetil 1g/d or enteric-coated mycophenolate sodium (EC-MPS) 720 mg/d) and tacrolimus were randomized to convert to EC-MPS 1,440 mg/d with reduced tacrolimus (n = 46), or receive EC-MPS 720 mg/d with unchanged tacrolimus (n = 48). Mean estimated GFR (eGFR, aMDRD) at Month 6 was 49.1 ± 11.1 and 44.7 ± 11.5 ml/min/1.73 m2 in the EC-MPS 1,440 mg and 720 mg groups, respectively (p = 0.07). The primary endpoint, change in eGFR from Day 0 to Month 6, was 2.48 ± 0.95 ml/min/1.73 m2 with EC-MPS 1,440 mg and -0.48 ± 0.93 ml/min/1.73 m2 with EC-MPS 720 mg (difference 2.96 ml/min/1.73 m2; 95% CI 0.32 - 5.60; p = 0.028). There were no deaths, graft losses or acute rejections. Adverse events were more frequent with EC-MPS 1,440 mg than 720 mg (66.7% vs. 44.7%, p = 0.034). Adverse events with suspected relation to EC-MPS occurred in 26.7% and 21.3% of patients, respectively (p = 0.59). Conversion of kidney transplant patients to increased MPA dosing using EC-MPS 1,440 mg/d, with reduced tacrolimus exposure, appears an effective immunosuppression strategy and may improve renal function. Adverse events overall, but not those with a suspected relation to EC-MPS, were higher with ECMPS 1,440 mg/d.

Efficacy of morning and evening dosing of amlodipine/valsartan combination in hypertensive patients uncontrolled by 5 mg of amlodipine.

OBJECTIVES: This study compared the effects of morning and evening dosing of amlodipine/valsartan combination on 24-h blood pressure (BP) in patients uncontrolled by amlodipine (5 mg). METHODS: This was a multicenter study that used a prospective, randomized, open-label, blinded endpoint design. Patients with essential hypertension, who's ambulatory BP was uncontrolled after 4 weeks on amlodipine (5 mg) were randomized to receive amlodipine/valsartan (5/160 mg) for 8 weeks in the morning or evening (n=231, 232, respectively), with optional uptitration up to 10/160 mg after 4 weeks if the office BP was uncontrolled. A 30-h ambulatory BP measurement was taken at randomization and at the end of the study. RESULTS: Morning and evening dosing with amlodipine/valsartan had equivalent effects on systolic BP (mean 24 h, daytime, night-time, and 24-30 h) and diastolic BP (mean 24 h, daytime, night-time, and 24-30 h). There was a small difference in the night-time diastolic BP (-4.92 vs.-6.20 mmHg; P=0.02) and a slight but nonsignificant trend for higher BP reduction during daytime for morning intake and during night-time for evening intake. BP control rates based on 24-h ambulatory BP measurement values (<120/80 mmHg) were similar between morning and evening dosing (47 vs. 45%). CONCLUSION: These results indicate that, in patients with BP uncontrolled by amlodipine (5 mg), morning and evening treatment with amlodipine/valsartan combination have similar effects on circadian BP, especially when 24-h mean values are considered.

Efficacy and safety of de novo or early everolimus with low cyclosporine in deceased-donor kidney transplant recipients at specified risk of delayed graft function: 12-month results of a randomized, multicenter trial.

Immediate or early use of proliferation signal inhibitor (PSI)/mammalian target of rapamycin (mTOR) inhibitor therapy can avoid high exposure to calcineurin inhibitors but concerns exist relating to the risk of delayed graft function (DGF) and impaired wound healing with the mTOR sirolimus. CALLISTO was a 12-month, prospective, multicenter, open-label study. Deceased-donor kidney transplant patients at protocol-specified risk of DGF were randomized to start everolimus on day 1 (immediate everolimus, IE; n = 65) or week 5 (delayed everolimus, DE; n = 74). Incidence of the primary endpoint (biopsy-proven acute rejection, BPAR; graft loss, death, DGF, wound healing complications related to transplant surgery or loss to follow-up) was 64.6% and 66.2% in the IE and DE groups, respectively, at month 12 (P = 0.860). The overall incidence of BPAR was 20.1%. Median estimated glomerular filtration rate was 48 ml/min/1.73 m(2) and 49 ml/min/1.73 m(2) in the IE and DE groups, respectively, at month 12. DGF and wound healing complications were similar between groups. Adverse events led to study drug discontinuation in 17 IE patients (26.2%) and 28 DE patients (37.8%) (NS). In conclusion, introduction of everolimus immediately or early posttransplant in DGF-risk patients is associated with good efficacy, renal function and safety profile. There seems no benefit in delaying initiation of everolimus.