Cardiac contractility modulation improves long-term survival and hospitalizations in heart failure with reduced ejection fraction.

AIMS: Cardiac contractility modulation (CCM) improves symptoms and exercise tolerance and reduces heart failure (HF) hospitalizations over 6-month follow-up in patients with New York Heart Association (NYHA) class III or IV symptoms, QRS < 130 ms and 25% ≤ left ventricular ejection fraction (LVEF) ≤ 45% (FIX-HF-5C study). The current prospective registry study (CCM-REG) aimed to assess the longer-term impact of CCM on hospitalizations and mortality in real-world experience in this same population. METHODS AND RESULTS: A total of 140 patients with 25% ≤ LVEF ≤ 45% receiving CCM therapy (CCM-REG25-45 ) for clinical indications were included. Cardiovascular and HF hospitalizations, Minnesota Living with Heart Failure Questionnaire (MLHFQ) and NYHA class were assessed over 2 years. Mortality was tracked through 3 years and compared with predictions by the Seattle Heart Failure Model (SHFM). A separate analysis was performed on patients with 35% ≤ LVEF ≤ 45% (CCM-REG35-45 ) and 25% ≤ LVEF < 35% (CCM-REG25-34 ). Hospitalizations decreased by 75% (from 1.2/patient-year the year before, to 0.35/patient-year during the 2 years following CCM, P < 0.0001) in CCM-REG25-45 and by a similar amount in CCM-REG35-45 (P < 0.0001) and CCM-REG25-34 . MLHFQ and NYHA class improved in all three cohorts, with progressive improvements over time (P < 0.002). Three-year survival in CCM-REG25-45 (82.8%) and CCM-REG24-34 (79.4%) were similar to those predicted by SHFM (76.7%, P = 0.16; 78.0%, P = 0.81, respectively) and was better than predicted in CCM-REG35-45 (88.0% vs. 74.7%, P = 0.046). CONCLUSION: In real-world experience, CCM produces results similar to those of previous studies in subjects with 25% ≤ LVEF ≤ 45% and QRS < 130 ms; cardiovascular and HF hospitalizations are reduced and MLHFQ and NYHA class are improved. Overall mortality was comparable to that predicted by the SHFM but was lower than predicted in patients with 35% ≤ LVEF ≤ 45%.

Long-term add-on therapy (compassionate use) with oral artesunate in patients with metastatic breast cancer after participating in a phase I study (ARTIC M33/2).

BACKGROUND: The antimalarial artesunate (ART), a semisynthetic derivative of artemisinin from the Chinese herb artemisia annua has remarkable anticancer properties in vitro and in vivo. Its excellent safety profile known from short-term therapy in malaria was confirmed in an open phase I trial (ARTIC M33/2) for dose-finding as add-on therapy for four weeks. PURPOSE: Patients with metastatic breast cancer, who had not experienced any clinically relevant adverse events (AE) during participation in ARTIC M33/2, were offered to continue ART as compassionate use (CU). Regular monitoring was continued in order to ensure adequate individual safety and tolerability and to collect information about long-term treatment with ART. Clinically relevant AEs or second progression of disease during ART were reasons for discontinuation of the add-on therapy. STUDY DESIGN: Compassionate use was offered open-label to participants of ARTIC M33/2. METHODS: Patients continued to take 100, 150 or 200 mg oral ART daily as add-on therapy to their guideline-based oncological therapy. Clinical and laboratory monitoring included audiological and neurological examination, ECG, NTproBNP and reticulocyte determination. Cumulative treatment days and cumulative ART doses encompass both the phase I study as well as the continued add-on treatment period (CU). RESULTS: Following the 4 ±â€¯1 weeks of the phase I trial, thirteen patients continued the add-on therapy as CU, resulting in a total of 3825 treatment days. In individual patients up to 1115 cumulative treatment days (37 months) and cumulative ART doses up to 167.3 g were reached. A total of 25 AEs grade ≥ 2 at least possibly related to ART long-term add-on therapy were documented, two, six and 17 in dose groups 100, 150 and 200 mg/d ART respectively. Six of these AEs were classified as grade 3, two in patients taking 150 and four in patients on 200 mg/d, none of them being probably or certainly related to ART. CONCLUSIONS: In thirteen patients with metastatic breast cancer up to 200 mg/d long-term oral ART (2.3-4.1 mg/kg BW/d) in up to 1115 cumulative treatment days (37 months) did not result in any major safety concerns.