Liver function abnormalities, clinical profile, and outcome in acute decompensated heart failure.

AIMS: The aim of this study was to assess the prevalence of abnormal liver function tests (LFTs) and the associated clinical profile and outcome(s) in acute decompensated heart failure (ADHF) patients. Alteration in LFTs is a recognized feature of ADHF, but prevalence and outcomes data from a broad contemporary cohort of ADHF are scarce and the mechanism(s) of ADHF-induced cholestasis is unknown. METHODS AND RESULTS: We conducted a post hoc analysis of SURVIVE, a large clinical trial including ADHF patients treated with levosimendan or dobutamine. All LFTs were available in 1134 patients at baseline. Abnormal LFTs were seen in 46% of ADHF patients: isolated abnormal alkaline phosphatase (AP) was noted in 11%, isolated abnormal transaminases in 26%, and a combination of abnormal AP and transaminases in 9%. Abnormal AP was associated with marked signs of systemic congestion and elevated right-sided filling pressure. Abnormal AP had no relationship with 31-day mortality but was associated with worse 180-day mortality (23.5 vs. 34.9%, P = 0.001 vs. patients with normal AP). Abnormal transaminases were associated with clinical signs of hypoperfusion and with greater 31-day and 180-day mortality compared with normal transaminase profiles (17.6 vs. 8.4% and 31.6 vs. 22.4%, respectively; both P < 0.001). There was no additive value of abnormal AP plus abnormal transaminase on a long-term outcome. CONCLUSION: Abnormal LFTs were present in about a half of patients presenting with ADHF treated with inotropes. Abnormal AP and abnormal transaminases were associated with specific clinical, biological, and prognostic features, including a short-term overmortality with increased transaminases but not with biological signs of cholestasis, in ADHF patients.

Effect of Multiple Doses of Sparsentan on the Single-Dose Pharmacokinetics of Dapagliflozin: An Open-Label Drug-Drug Interaction Study in Healthy Adults.

Sparsentan is a single-molecule dual antagonist of the endothelin type A receptor and angiotensin II type 1 receptor under investigation for the treatment of focal segmental glomerulosclerosis and immunoglobulin A nephropathy. Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, has recently been indicated in chronic kidney disease. Sparsentan may be considered for concomitant use with dapagliflozin. The purpose of this open-label, 1-sequence crossover study was to determine whether drug-drug interactions between sparsentan and dapagliflozin affect dapagliflozin pharmacokinetics (PK). In addition, exposure to the inactive metabolite of dapagliflozin, dapagliflozin-3-O-glucuronide, was used to evaluate the effect of sparsentan on the primary metabolizing enzyme of dapagliflozin, uridine 5'-diphospho-glucuronosyltransferase 1A9. The study included 22 healthy adults treated with 10 mg of dapagliflozin on day 1, and 800 mg/day of sparsentan on days 5-14, with a 10-mg dose of dapagliflozin coadministered on day 11. PK samples were taken for dapagliflozin, dapagliflozin-3-O-glucuronide, and sparsentan before and after treatment throughout the study. Steady-state concentrations of sparsentan following daily dosing did not affect the PK of single-dose dapagliflozin in healthy adults. Dapagliflozin-3-O-glucuronide PK suggests a minimal effect of sparsentan on metabolism of dapagliflozin by uridine 5'-diphospho-glucuronosyltransferase 1A9. No deaths, serious adverse events, or unusual safety signals occurred. Results suggest dapagliflozin PK is not affected by sparsentan daily dosing.

Beneficial association of ß-blocker therapy on recovery from severe acute heart failure treatment: data from the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support trial.

OBJECTIVES: Beta-blocker therapy is recommended for most patients with chronic heart failure, although such therapy may be discontinued or reduced during hospitalizations. The aim is to determine whether ß-blocker use at study entry and/or at discharge has an impact on 31- and 180-day survival. DESIGN: Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support study was designed as a randomized, double-blind, active-controlled, multi-center study. SETTING: Multinational. PATIENTS: A total of 1,327 critically ill patients hospitalized with low-output heart failure in need of inotropic therapy. INTERVENTION: Levosimendan versus dobutamine. MEASUREMENTS: All-cause mortality at 31 and 180 days in patients who survived initial hospitalization with/without ß-blocker use at entry and/or at discharge. RESULTS: Patients on ß-blockers at entry and at discharge had significantly lower 31-day (p < .0001) and 180-day (p < .0001) mortality compared to patients without ß-blockers use at both time points. The association was robust when adjusted for age and co-morbidities (p = .006 at 31 days; p = .003 at 180 days). CONCLUSIONS: Those results strongly suggest, in severe acutely decompensated heart failure patients, admitted on ß-blockers, to continue on them at discharge.

Opioid-Free Recovery from Bunionectomy with HTX-011, a Dual-Acting Local Anesthetic Combining Bupivacaine and Meloxicam, as the Foundation of Non-Opioid Multimodal Analgesia.

BACKGROUND: There is a need for postoperative pain control that minimizes or eliminates opioid use during the first 72 hours following surgery, when pain is most severe. HTX-011 is an extended-release, dual-acting local anesthetic that demonstrated superior 72-hour analgesia over standard of care bupivacaine hydrochloride (HCl) and saline placebo in a phase 3 bunionectomy study (EPOCH-1). Having shown HTX-011 monotherapy is superior to bupivacaine HCl in reducing postoperative pain intensity and opioid use, this follow-on study evaluated the safety and efficacy of HTX-011 as the foundation of a multimodal analgesia (MMA) regimen using over-the-counter medications recommended by practice guidelines for pain management. METHODS: Following regional anesthesia administered as a lidocaine block, patients underwent unilateral bunionectomy with osteotomy and internal fixation. Prior to closure, HTX-011 (up to 60 mg bupivacaine/1.8 mg meloxicam) was applied without a needle. Patients received scheduled postoperative MMA alternating ibuprofen (600 mg) and acetaminophen (1 g) every 3 hours for 72 hours. Efficacy was assessed based on pain intensity (numeric rating scale [NRS; 0-10]) and consumption of opioid rescue medication (intravenous morphine milligram equivalents [MME]). Adverse event and vital sign monitoring, plus laboratory and wound healing assessments, were used to determine safety. RESULTS: Over the 72-hour assessment period following bunionectomy, mean pain scores were mild in severity (NRS <4) and 22/31 patients (71%) experienced no severe pain (NRS ≥7) with HTX-011 as the foundation of scheduled, non-opioid MMA. Patients consumed an average of 1.61 MME total, with 24/31 (77%) requiring no opioid rescue medication (opioid-free). HTX-011 was well-tolerated and demonstrated no safety concerns with the inclusion of postoperative MMA. CONCLUSIONS: HTX-011 as the foundation of an MMA regimen including scheduled ibuprofen and acetaminophen maintained mean postoperative pain scores in the mild range and enabled opioid-free recovery for 77% of bunionectomy patients through the 28-day recovery period.

The Effects of 2'-O-Methoxyethyl Oligonucleotides on Renal Function in Humans.

Systemically administered 2'-O-methoxyethyl (2'MOE) antisense oligonucleotides (ASOs) accumulate in the kidney and metabolites are cleared in urine. The effects of eleven 2'MOE ASOs on renal function were assessed in 2,435 patients from 32 phase 2 and phase 3 trials. The principle analysis was on data from 28 randomized placebo-controlled trials. Mean levels of renal parameters remained within normal ranges over time across dose groups. Patient-level meta-analyses demonstrated a significant difference between placebo-treated and 2'MOE ASO-treated patients at doses >175 mg/week in the percentage and absolute change from baseline for serum creatinine and estimated glomerular filtration rate. However, these changes were not clinically significant or progressive. No dose-related effects were observed in the incidence of abnormal renal test results in the total population of patients, or subpopulation of diabetic patients or patients with renal dysfunction at baseline. The incidence of acute kidney injury [serum creatinine ≥0.3 mg/dL (26.5 µM) increases from baseline or ≥1.5 × baseline] in 2'MOE ASO-treated patients (2.4%) was not statistically different from placebo (1.7%, P = 0.411). In conclusion, in this database, encompassing 32 clinical trials and 11 different 2'MOE ASOs, we found no evidence of clinically significant renal dysfunction up to 52 weeks of randomized-controlled treatment.

Lowered B-type natriuretic peptide in response to levosimendan or dobutamine treatment is associated with improved survival in patients with severe acutely decompensated heart failure.

OBJECTIVES: The purpose of this analysis was to examine whether decreases in B-type natriuretic peptide (BNP) levels during the first few days of hospitalization were associated with greater survival in patients with severe acutely decompensated heart failure (ADHF). BACKGROUND: BNP level is a prognostic marker for all-cause mortality (ACM) in ADHF; whether early BNP changes can also help predict outcome in patients who need inotropes for treatment of severe ADHF is not known. METHODS: We retrospectively assessed the association between changes in BNP levels and ACM in patients from the SURVIVE (Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support) trial--a randomized, controlled trial comparing levosimendan to dobutamine treatment in patients hospitalized with ADHF. BNP levels were measured at baseline and at days 1, 3, and 5. A patient was classified as a "responder" if the follow-up BNP level was >or=30% lower than baseline BNP. The relationship between early BNP response and subsequent ACM over short- (31-day) and long-term (180-day) intervals was evaluated. RESULTS: Of 1,327 SURVIVE patients, this analysis included 1,038 who had BNP samples at both baseline and day 5. Responders at days 1, 3, and 5 had lower ACM than did nonresponders (p