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The goal of long-term prophylactic treatment of hereditary angioedema (HAE) is to normalize patients’ lives by reducing the frequency and severity of attacks.1,2Berotralstat is a once-daily (QD) oral prophylactic indicated for the treatment of HAE in patients ≥12 years. Here, we present the safety and effectiveness of berotralstat 150mg QD in patients enrolled in the APeX-S trial with self-reported baseline attack rates.

Goals Currently, there is some debate concerning the haemoglobin level at which treatment of anaemia with erythropoiesis-stimulating agents should be initiated in cancer patients on chemotherapy. We report several analyses of data from a phase III trial of darbepoetin alfa versus placebo, comparing outcomes for patients with mild and moderate-to-severe anaemia. Patients and methods Data were obtained from a phase III trial of darbepoetin alfa versus placebo in anaemic patients with lung cancer receiving chemotherapy ( n=314). Outcomes were compared for patients with baseline haemoglobin =10–11 g/dl and <10 g/dl. Results Darbepoetin alfa significantly reduced transfusions compared with placebo, irrespective of haemoglobin level at treatment initiation. For patients with baseline haemoglobin <10 g/dl, 31% and 59% of those receiving darbepoetin alfa and placebo, respectively, required a transfusion from week 5 to the end of the treatment phase ( P<0.038). For patients with baseline haemoglobin =10 g/dl, the proportions were 15% and 41%, respectively ( P<0.001). Darbepoetin alfa also improved fatigue compared with placebo in both haemoglobin categories. Conclusions These findings show that initiating treatment at haemoglobin levels both <10 g/dl and =10–11 g/dl results in substantial clinical benefits, supporting the use of erythropoietic therapy also in patients with mild anaemia.

Despite the well-recognized association between oral contraceptives and deep venous thromboembolism, little is known about the risks associated with currently marketed formulations containing less than 50 micrograms of estrogen. To assess the venous thrombogenicity of low-estrogen oral contraceptives (those containing less than 50 micrograms of estrogen) relative to intermediate-dose (50 micrograms of estrogen) and high-dose (greater than 50 micrograms of estrogen) formulations, we conducted a cohort study of oral contraceptive users between the ages of 15 and 44 years in the Michigan Medicaid population. The period of the study was from 1980 through the third quarter of 1986. A total of 2,739,400 oral contraceptive prescriptions received by 234,218 women were analyzed. Using the low-estrogen cohort as the referent group, the age and calendar period adjusted relative risk of venous thromboembolism in users of intermediate-dose formulations was 1.5 (95% confidence interval (CI) 1.0-2.1, p = 0.04), and the relative risk in users of high-dose formulations was 1.7 (95% CI 0.9-3.0, p = 0.06). These data provide evidence that the dose-response relation between oral contraceptive estrogen and venous thromboembolism extends from 50 to 30 micrograms of estrogen, the dose range of currently marketed formulations.

Background: Recent clinical trial data have generated safety concerns regarding ESA use, particularly as to whether the results observed in certain patients with breast cancer, lung cancer, and hematologic malignancies are generalizable to all patients with those tumor types. It is critical that the results of these studies are appropriately integrated into the total body of evidence in order to enable balanced conclusions to be drawn. We conducted a systematic literature review to assess the safety and efficacy of ESA therapy in patients with breast cancer, lung cancer, and hematologic malignancies. Methods: The search was aligned with that conducted by the Cochrane Collaborative group (Bohlius 2006) and was therefore limited to randomized, controlled clinical trials in cancer patients that compared the use of ESAs with either observation (RBC transfusion as required) or placebo and that collected survival data (either long-term or during the study period). Results from trials were meta-analyzed using Comprehensive Meta-Analysis v 2.2 software. Heterogeneity between studies was evaluated using a chi-square test (Q). Random and fixed-effects models were used to estimate an overall odds ratio and 95% confidence interval; the inconsistency statistic, I2, is also provided. Results: For breast cancer, seven studies were identified. Meta-analysis of data from these studies indicated an overall neutral risk of death for patients receiving ESAs, despite the large contribution (weighted at about 40% of the overall result) of the BEST study results (Leyland-Jones, 2005) (Table). Five ESA-controlled lung cancer studies were identified in CIA, one in radiotherapy, and one in anemia of cancer (AOC). In each of the studies in CIA, the ESA groups had neutral survival risks relative to the control group. Meta-analysis of the CIA, radiotherapy, and AOC lung cancer data combined indicated an overall neutral risk of death for patients receiving ESAs (Table). For hematologic malignancies, eight studies were identified (one of which had no deaths). Meta-analysis indicated an overall neutral risk of death for patients receiving ESAs (Table). Conclusions: The results of some studies have suggested a detrimental effect on survival associated with ESA use in certain patients with breast, lung, and hematological malignancies. However, results do not appear to be generalizable to similarly designed, randomized controlled trials conducted in the same tumor types. Additionally, when these studies are integrated into the total body of evidence, ESAs have a neutral effect on survival in these patients.

Background: Recent clinical trial data have generated safety concerns regarding ESA use, particularly as to whether the results observed in certain patients with breast cancer, lung cancer, and hematologic malignancies are generalizable to all patients with those tumor types. It is critical that the results of these studies are appropriately integrated into the total body of evidence in order to enable balanced conclusions to be drawn. We conducted a systematic literature review to assess the safety and efficacy of ESA therapy in patients with breast cancer, lung cancer, and hematologic malignancies.

Background: We recently reported final results of a randomized, open-label, multicenter study assessing the efficacy of DA (Aranesp®) 300 mcg Q3W (Rearden et al, ASCO 2004). In this study of 201 pts, pts with grade 1 anemia were treated early with DA (n=102; early group) compared with pts treated late after developing grade 2/3 anemia (ie, hemoglobin [Hb] < 10 g/dL; n=99; observation/late intervention group [obs]). When pts were untreated in the obs group, Hb declined. DA treatment maintained Hb within the NCCN Hb target range for pts in the early group and increased Hb once administered in the obs group. The objective of this analysis was to explore the impact of declining Hb levels on pt-reported outcomes using the FACT-Fatigue (FACT-F) subscale. Methods: Pts with baseline (BL) Hb ≥10.5 and ≤12 g/dL were randomized 1:1 to either the early or obs group for up to 22 weeks. To analyze pt-reported fatigue, the FACT-F subscale was administered Q3W and at the end of treatment. The FACT-F analysis set included pts who were randomized, received study drug, and had a BL and at least 1 post-BL FACT-F score. Analyses of changes in FACT-F scores during treatment from BL were conducted; missing values were not imputed. Results: In 201 randomized and treated pts, mean BL (SD) Hb was similar for each group, 11.1 (0.7) g/dL for the early and 11.2 (0.6) g/dL for the obs groups. In the early group, mean Hb increased to near 12 g/dL in approximately 7 weeks, and due to dose-withholding rules, remained near 12 g/dL for the remainder of the study. In the obs group, Hb declined to < 10 g/dL in 65% of pts. The FACT-F analysis set included 94 pts in the early group and 86 in the obs group. Mean (SD) FACT-F scores at BL were 31.6 (11.7) for the early group and 27.7 (12.8) for the obs group. With categories of Hb change at the end of treatment, a significant trend towards greater improvements in fatigue with increasing Hb levels was observed in both groups (table). In pts in whom Hb was stabilized or improved, no decrease in fatigue scores was noted. However, when Hb declined (Hb change < 0 g/dL), a statistically significant and clinically meaningful (>3 point change in FACT-F score) increase in fatigue was observed (negative change in FACT-F score). Consistent with previous studies, pts with Hb change > 2 g/dL had clinically and statistically significant improvements in fatigue. Conclusion: In the absence of treatment, most mildly anemic cancer pts receiving ctx are at risk of developing grade 2/3 anemia within approximately 7 weeks. This decline in Hb is associated with a statistically significant and clinically meaningful increase in pt-reported fatigue. Our results indicate that DA 300 mcg Q3W may effectively ameliorate the impact of ctx on Hb levels and consequently prevent a decline in fatigue. Further, Q3W DA may provide benefits associated with less-frequent dosing. Mean (95%CL) Change in FACT-F Scores At End of Treatment By Change in Hb Category Early Obs N=94 N=86 Categories of Hb Change < 0 g/dL −6.2 (−12.9, 0.6) −2.8 (−7.2, 1.5) n=23 n=38 >0 to 2 g/dL 0.9 (−2.2, 4.0) 1.7 (−3.9, 7.3) n=52 n=32 > 2 g/dL 8.3 (3.3, 13.2) 6.4 (0.3, 12.5) n=19 n=16 P -value (Jonckheere-Terpstra Trend Test) 0.0003 0.049

Background: We recently reported final results of a randomized, open-label, multicenter study assessing the efficacy of DA (Aranesp®) 300 mcg Q3W (Rearden et al, ASCO 2004). In this study of 201 pts, pts with grade 1 anemia were treated early with DA (n=102; early group) compared with pts treated late after developing grade 2/3 anemia (ie, hemoglobin [Hb] < 10 g/dL; n=99; observation/late intervention group [obs]). When pts were untreated in the obs group, Hb declined. DA treatment maintained Hb within the NCCN Hb target range for pts in the early group and increased Hb once administered in the obs group. The objective of this analysis was to explore the impact of declining Hb levels on pt-reported outcomes using the FACT-Fatigue (FACT-F) subscale.