Characteristics and outcomes of patients treated with apremilast in the real world: results from the APPRECIATE study.

BACKGROUND: APPRECIATE is a multinational, observational, retrospective, cross-sectional study in patients treated for psoriasis with apremilast, an oral phosphodiesterase 4 inhibitor. OBJECTIVES: To describe the characteristics of patients with psoriasis treated with apremilast in the clinical setting, to evaluate real-world outcomes of psoriasis treatment with apremilast and to better understand the perspectives of patients and physicians on treatment outcomes. METHODS: In six European countries, patients with chronic plaque psoriasis treated in clinical practice who could be contacted 6 (±1) months after apremilast initiation were enrolled. Patient characteristics, Dermatology Life Quality Index (DLQI) and Psoriasis Area and Severity Index (PASI) were obtained from medical records when available. Outcomes were evaluated using patient/physician questionnaires. RESULTS: In 480 patients at treatment initiation, mean [median; 95% confidence interval (CI)] PASI and DLQI scores were 12.5 (10.7; 11.6-13.4) and 13.4 (13.0; 11.4-14.2), respectively. At 6 (±1) months, 72.3% of patients (n = 347) continued apremilast treatment [discontinuations: lack of efficacy (13.5%), safety (11.7%), other (2.5%)]. In patients continuing treatment, 48.6% achieved a ≥75% reduction in PASI score; mean (95% CI) DLQI score was 5.7 (4.5-6.9), and mean (SD) Patient Benefit Index score was 2.8 (1.2). Physicians perceived clinical improvement in 75.6% of patients. Physicians' perspective on overall success of apremilast in meeting expectations correlated with patients' perception of treatment benefit (r = 0.691). Most commonly reported adverse events (>5% of patients) were diarrhoea, nausea and headache. CONCLUSIONS: Patients in APPRECIATE reported high disease burden despite more moderate skin involvement than those who enrolled in clinical trials of apremilast. Findings from APPRECIATE demonstrate the real-world value of apremilast for psoriasis treatment, as 7 of 10 patients continued therapy and showed notable improvement in disease severity and quality of life 6 (±1) months after apremilast initiation.

Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer.

BACKGROUND: This study was designed to demonstrate that efficacy [progression-free survival (PFS)] of CAELYX [pegylated liposomal doxorubicin HCl (PLD)] is non-inferior to doxorubicin with significantly less cardiotoxicity in first-line treatment of women with metastatic breast cancer (MBC). PATIENTS AND METHODS: Women (n=509) with MBC and normal cardiac function were randomized to receive either PLD 50 mg/m2 (every 4 weeks) or doxorubicin 60 mg/m2 (every 3 weeks). Cardiac event rates were based on reductions in left ventricular ejection fraction as a function of cumulative anthracycline dose. RESULTS: PLD and doxorubicin were comparable with respect to PFS [6.9 versus 7.8 months, respectively; hazard ratio (HR)=1.00; 95% confidence interval (CI) 0.82-1.22]. Subgroup results were consistent. Overall risk of cardiotoxicity was significantly higher with doxorubicin than PLD (HR=3.16; 95%CI 1.58-6.31; P<0.001). Overall survival was similar (21 and 22 months for PLD and doxorubicin, respectively; HR=0.94; 95%CI 0.74-1.19). Alopecia (overall, 66% versus 20%; pronounced, 54% versus 7%), nausea (53% versus 37%), vomiting (31% versus 19%) and neutropenia (10% versus 4%) were more often associated with doxorubicin than PLD. Palmar-plantar erythrodysesthesia (48% versus 2%), stomatitis (22% versus 15%) and mucositis (23% versus 13%) were more often associated with PLD than doxorubicin. CONCLUSIONS: In first-line therapy for MBC, PLD provides comparable efficacy to doxorubicin, with significantly reduced cardiotoxicity, myelosuppression, vomiting and alopecia.

The plasma concentration and LDL-C relationship in patients receiving ezetimibe.

Ezetimibe is a novel selective inhibitor of intestinal cholesterol absorption, which has been shown to significantly decrease low-density lipoprotein cholesterol (LDL-C). In this article, the relationship between plasma ezetimibe concentrations and lowering of LDL-C is determined using Emax and regression models. Data from two phase II double-blind placebo-controlled studies (n = 232 and 177) were used in which daily doses of ezetimibe ranging from 0.25 to 10 mg were administered for 12 weeks. Ezetimibe concentrations correlated significantly with percentage change in LDL-C from baseline (%LDL-C). Reductions in %LDL-C of 10%, 15%, and 20% were achieved with concentrations in the ranges 0 to 2, 2 to 15, and > 15 ng/ml, respectively, as compared with placebo. To achieve > 15% reduction in LDL-C, patients need to maintain trough concentrations > 15 ng/ml, taking plasma concentrations as a surrogate for concentrations at the enterocyte. Based on the doses administered, the 10 mg dose had the highest likelihood of sustaining such concentrations, confirming that a daily 10 mg dose of ezetimibe is an optimal therapeutic dose in the treatment of hypercholesterolemia.

Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies.

BACKGROUND: Ezetimibe (SCH 58235) is a novel cholesterol absorption inhibitor that selectively and potently blocks intestinal absorption of dietary and biliary cholesterol. OBJECTIVE: Data from 2 multicenter, placebo-controlled, double-blind, randomized, parallel-group, 12-week studies of ezetimibe were pooled to evaluate the drug's effect on lipid parameters in patients with primary hypercholesterolemia. METHODS: After dietary stabilization (National Cholesterol Education Program Step I diet or a stricter diet), washout of lipid-altering drugs, and a 6-week placebo lead-in period, patients with baseline plasma low-density lipoprotein cholesterol (LDL-C) levels > or = 130 and < or = 250 mg/dL and plasma triglyceride (TG) levels < or = 300 mg/dL were randomized to receive either ezetimibe 0.25, 1, 5, or 10 mg, or placebo administered once daily before the morning meal in study A (dose-response study) or ezetimibe 5 or 10 mg or placebo administered once daily before the morning meal or at bedtime in study B (dose-regimen study). RESULTS: A total of 432 patients were included in this pooled analysis, 243 in study A and 189 in study B. The 5- and 10-mg doses of ezetimibe significantly reduced LDL-C levels by 15.7% and 18.5%, respectively (P < 0.01 vs placebo) and significantly increased high-density lipoprotein cholesterol (hDL-C) levels by 2.9% and 3.5%, respectively (P < 0.05 vs placebo). A reduction in plasma TG levels was observed (P = NS). With the 10-mg dose of ezetimibe, 67.8% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 22.0% achieved > or = 25% reduction. With the 5-mg dose, 54.0% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 15.3% achieved > or = 25% reduction. The decrease in plasma LDL-C levels was significantly greater with ezetimibe 10 mg compared with ezetimibe 5 mg (P < 0.05). Ezetimibe was well tolerated, with an adverse event profile similar to that of placebo. CONCLUSIONS: In these two 12-week studies, ezetimibe significantly decreased plasma LDL-C levels and increased plasma HDL-C levels, with a tolerability profile similar to that of placebo.

Analysis of 24-hour blood pressure data.

Blood pressure is not constant over the course of a 24-h period, but exhibits a predictable and characteristic rise and decline during the day. Although the general shape of this pattern is similar from patient to patient, the knowledge of an individual's blood pressure at one or two points on this curve is of no predictive value in estimating the remainder of the curve. Since critical events are associated with both the maximum and minimum blood pressures that an individual experiences, a characterization of this curve can be very important. The development of antihypertensive agents historically presumed that the reduction in blood pressure associated with therapy would be, if not constant, at least adequate throughout the entire period. However, with the advent of less frequent dosing, the importance of assuring that blood pressure was adequately controlled over the 24-h period became important. This created interest in two basic types of comparisons. One is the comparison of dosing regimens, e.g., comparing a once-a-day regimen with a twice-a-day regimen. The second is a comparison of two therapies with the same regimen; for example, two doses designed to be administered twice a day. The shape of the curves in the first case is inherently different, whereas they have a similar configuration in the second. Many techniques have been attempted, but few recommended for these types of comparisons. Examples include time series, the use of composite indices, univariate statistical procedures, multivariate procedures, and mathematical characterization of the curves with subsequent comparison of model parameters. This presentation will provide a background and overview of several of these methodologies and their relative utility.