- Email: [email protected]
Acetazolamide to Increase Natriuresis in Congestive Heart Failure at High Risk for Diuretic Resistance
The 23rd Annual Scientific Meeting HFSA selective, receptor-mediated delivery to hepatocytes, the principal source of systemically circulating TTR. This delivery approach has yielded a 20 to 30-fold increase in potency and improved the safety and tolerability profiles of ASOs in human clinical trials. In preclinical studies, AKCEA-TTR-LRx produced significant dose-dependent reductions of TTR messenger RNA and protein levels, with a marked increase in potency compared to inotersen. AKCEA-TTR-LRx is currently in early phase development for the treatment of both hereditary and wild-type ATTR. Hypothesis: Based on prior clinical experience with ligand-conjugated ASOs and supporting preclinical results, AKCEA-TTR-LRx is expected to have an increased potency and improved tolerability and safety profile compared to inotersen. Methods: A phase 1/2 study was designed to evaluate AKCEA-TTR-LRx in healthy volunteers and patients with transthyretin-mediated amyloidosis (NCT03728634). In phase 1, eligible subjects were assigned to one of two multiple-dose cohorts (45 and 90 mg, n=12 per cohort) and randomized 10:2 (active:placebo) to receive 4, once monthly, SC doses of study drug. A higher, single-dose cohort of healthy volunteers was also evaluated. Results: This study is ongoing. Assessment of the safety, tolerability, pharmacokinetics and pharmacodynamics of AKCEA-TTR-LRx in the phase 1 healthy volunteer cohorts will be presented. Conclusions: These phase 1 results will guide selection of the dose and treatment schedule for near-term studies to be initiated in patients with ATTR, including phase 3 studies.
214 Acetazolamide to Increase Natriuresis in Congestive Heart Failure at High Risk for Diuretic Resistance Frederik H. Verbrugge1, Pieter Martens1, Koen Ameloot1, Veerle Haemels2, Joris Penders1, Matthias Dupont1, W.H. Wilson Tang3, Walter Droogne2, Wilfried Mullens1; 1Ziekenhuis Oost-Limburg, Genk, Belgium; 2UZ Leuven, Leuven, Belgium; 3 Cleveland Clinic, Cleveland, OH Introduction: Signs and symptoms of congestion are the predominant reason for hospital admission with acute heart failure (AHF). Diuretics are mainstay treatment, but their optimal type and dose regimen remains unclear. Hypothesis: Acetazolamide in addition to loop diuretics increases natriuresis without further neurohumoral activation, potentially improving decongestion and outcomes in AHF. Methods: This prospective, 2-center study included 34 AHF patients on loop diuretics with volume overload. All patients had a serum sodium concentration <135 mmol/L and/or
S81
serum urea/creatinine ratio >50 and/or admission serum creatinine increased with >0.3 mg/dL compared to baseline. Patients were randomized towards acetazolamide 500 mg OD plus bumetanide 1-2 mg BID versus high-dose loop diuretics (bumetanide BID with bolus dose equal to oral maintenance dose). The primary end-point was natriuresis after 24h. Results: Natriuresis after 24h was similar in the combinational treatment versus loop-diuretic only arm (264§126 versus 234§133 mmol, respectively; P-value=0.515). Loop diuretic efficiency, defined as natriuresis corrected for loop diuretic dose, was higher in the group receiving acetazolamide (84§ 46 versus 52§42 mmol/mg bumetanide, respectively; P-value=0.048; Figure). More patients in the combinational treatment arm had an increase in serum creatinine levels >0.3 mg/dL (P-value=0.046). NT-proBNP reduction and peak neurohumoral activation within 72h were comparable among treatment arms. Median time to all-cause mortality or heart failure readmission was 273 versus 803 days in the group receiving high-dose loop diuretic monotherapy versus acetazolamide with low-dose loop diuretics, which favoured the latter group but was not statistically significant (P-value=0.098). Conclusion: Addition of acetazolamide increases the natriuretic response to loop diuretics with similar neurohumoral responses compared to an increase in loop diuretic dose in AHF at high risk for diuretic resistance. ClinicalTrials.gov identifier: NCT01973335.
214 Acetazolamide to Increase Natriuresis in Congestive Heart Failure at High Risk for Diuretic Resistance Frederik H. Verbrugge1, Pieter Martens1, Koen Ameloot1, Veerle Haemels2, Joris Penders1, Matthias Dupont1, W.H. Wilson Tang3, Walter Droogne2, Wilfried Mullens1; 1Ziekenhuis Oost-Limburg, Genk, Belgium; 2UZ Leuven, Leuven, Belgium; 3 Cleveland Clinic, Cleveland, OH Introduction: Signs and symptoms of congestion are the predominant reason for hospital admission with acute heart failure (AHF). Diuretics are mainstay treatment, but their optimal type and dose regimen remains unclear. Hypothesis: Acetazolamide in addition to loop diuretics increases natriuresis without further neurohumoral activation, potentially improving decongestion and outcomes in AHF. Methods: This prospective, 2-center study included 34 AHF patients on loop diuretics with volume overload. All patients had a serum sodium concentration <135 mmol/L and/or
S81
serum urea/creatinine ratio >50 and/or admission serum creatinine increased with >0.3 mg/dL compared to baseline. Patients were randomized towards acetazolamide 500 mg OD plus bumetanide 1-2 mg BID versus high-dose loop diuretics (bumetanide BID with bolus dose equal to oral maintenance dose). The primary end-point was natriuresis after 24h. Results: Natriuresis after 24h was similar in the combinational treatment versus loop-diuretic only arm (264§126 versus 234§133 mmol, respectively; P-value=0.515). Loop diuretic efficiency, defined as natriuresis corrected for loop diuretic dose, was higher in the group receiving acetazolamide (84§ 46 versus 52§42 mmol/mg bumetanide, respectively; P-value=0.048; Figure). More patients in the combinational treatment arm had an increase in serum creatinine levels >0.3 mg/dL (P-value=0.046). NT-proBNP reduction and peak neurohumoral activation within 72h were comparable among treatment arms. Median time to all-cause mortality or heart failure readmission was 273 versus 803 days in the group receiving high-dose loop diuretic monotherapy versus acetazolamide with low-dose loop diuretics, which favoured the latter group but was not statistically significant (P-value=0.098). Conclusion: Addition of acetazolamide increases the natriuretic response to loop diuretics with similar neurohumoral responses compared to an increase in loop diuretic dose in AHF at high risk for diuretic resistance. ClinicalTrials.gov identifier: NCT01973335.