Pralidoxime in Acute Organophosphorus Insecticide Poisoning-A Randomised Controlled Trial

Background: Poisoning with organophosphorus (OP) insecticides is a major global public health problem, causing an estimated 200,000 deaths each year. Although the World Health Organization recommends use of pralidoxime, this antidote's effectiveness remains unclear. We aimed to determine whether the addition of pralidoxime chloride to atropine and supportive care offers benefit. Methods and Findings: We performed a double-blind randomised placebo-controlled trial of pralidoxime chloride (2 g loading dose over 20 min, followed by a constant infusion of 0.5 g/h for up to 7 d) versus saline in patients with organophosphorus insecticide self-poisoning. Mortality was the primary outcome; secondary outcomes included intubation, duration of intubation, and time to death. We measured baseline markers of exposure and pharmacodynamic markers of response to aid interpretation of clinical outcomes. Two hundred thirty-five patients were randomised to receive pralidoxime (121) or saline placebo (114). Pralidoxime produced substantial and moderate red cell acetylcholinesterase reactivation in patients poisoned by diethyl and dimethyl compounds, respectively. Mortality was nonsignificantly higher in patients receiving pralidoxime: 30/121 (24.8%) receiving pralidoxime died, compared with 18/114 (15.8%) receiving placebo (adjusted hazard ratio HR] 1.69, 95% confidence interval CI] 0.88-3.26, p = 0.12). Incorporating the baseline amount of acetylcholinesterase already aged and plasma OP concentration into the analysis increased the HR for patients receiving pralidoxime compared to placebo, further decreasing the likelihood that pralidoxime is beneficial. The need for intubation was similar in both groups (pralidoxime 26/121 21.5%], placebo 24/114 21.1%], adjusted HR 1.27 95% CI 0.71-2.29]). To reduce confounding due to ingestion of different insecticides, we further analysed patients with confirmed chlorpyrifos or dimethoate poisoning alone, finding no evidence of benefit. Conclusions: Despite clear reactivation of red cell acetylcholinesterase in diethyl organophosphorus pesticide poisoned patients, we found no evidence that this regimen improves survival or reduces need for intubation in patients with organophosphorus insecticide poisoning. The reason for this failure to benefit patients was not apparent. Further studies of different dose regimens or different oximes are required

Corrigendum

Boyer TD, Medicis JJ, Pappas SC, Potenziano J, Jamil K. A randomized, placebo-controlled, double-blind study to confirm the reversal of hepatorenal syndrome type 1 with terlipressin: the REVERSE trial design. Open Access Journal of Clinical Trials. 2012;4:39–49.Dr Jamil’s first name was incorrectly spelt as Khuramm Jamil in the author list. The correct spelling is Khurram Jamil.Read the original articl

A randomized, placebo-controlled, double-blind study to confirm the reversal of hepatorenal syndrome type 1 with terlipressin: the REVERSE trial design

Thomas D Boyer,1 Joseph J Medicis,2 Stephen Chris Pappas,3 Jim Potenziano,2 Khuramm Jamil21Department of Medicine, University of Arizona College of Medicine, Tucson, AZ, USA; 2Research and Development, Ikaria, Hampton, NJ, USA; 3Orphan Therapeutics, Lebanon, NJ, USABackground: Hepatorenal syndrome (HRS) is a rare disorder of marked renal dysfunction in patients with cirrhosis, ascites, and portal hypertension. Type 1 HRS is a rapidly progressive acute kidney injury that develops shortly after a precipitating event, followed by a deterioration of function of other organs (eg, heart, brain, liver, adrenal glands). Presently, no approved drug therapies exist for HRS type 1 in the USA, Canada, or Australia. Given the rarity of this condition and the existing unmet medical need for treatment, the US Food and Drug Administration granted orphan drug and fast-track designations for terlipressin. The objective of the REVERSE trial was to determine the efficacy and safety of intravenous terlipressin compared with placebo in the treatment of adults with HRS type 1 who were also receiving intravenous albumin.Methods: 180 subjects with HRS type 1 were enrolled at 65 investigational sites located in the USA and ten sites in Canada. Patients were randomized in a 1:1 ratio to treatment with either intravenous terlipressin administered every 6 hours or placebo for up to 14 days. The primary efficacy measure was confirmed HRS reversal, defined as the percentage of patients with two serum creatinine values of ≤1.5 mg/dL at least 48 hours apart, on treatment, and without intervening renal replacement therapy or liver transplantation. Other efficacy measures included change in renal function as reflected in serum creatinine levels, fractional excretion of sodium, recurrence of HRS type 1, transplant-free, dialysis-free, and overall survival.Discussion: Data from this pivotal study are intended to demonstrate whether terlipressin is effective in reversing HRS type 1, while providing the level of evidence necessary to define the risk–benefit profile of terlipressin.Keywords: terlipressin, Lucassin, hepatorenal syndrome, REVERSE, renal dysfunction, critical car

The cost impact to Medicare of shifting treatment of worsening heart failure from inpatient to outpatient management settings

Kathryn Fitch,1 Jocelyn Lau,1 Tyler Engel,1 Joseph J Medicis,2 John F Mohr,2 William S Weintraub3 1Milliman Inc., New York, NY, USA; 2scPharmaceuticals Inc., Burlington, MA, USA; 3MedStar Washington Hospital Center, Washington, DC, USA Purpose: The aim of this study was to quantify the potential cost savings to Medicare of shifting the site of treatment for worsening heart failure (HF) from inpatient to outpatient (OP) settings for a subset of worsening HF episodes among the Medicare fee-for-service (FFS) population.Materials and methods: A cross-sectional analysis of a random 5% sample of 2014 FFS Medicare beneficiaries was conducted. Incidence and cost of worsening HF episodes in both inpatient and OP settings were identified. These results were used to calculate cost savings associated with shifting a proportion of worsening HF episodes from the inpatient to OP settings.Results: A total of 151,908 HF beneficiaries were identified. The estimated annual cost for the treatment of worsening HF across both inpatient and OP settings ranged from US$9.3 billion to US$17.0 billion or 2.4%–4.3% of total Medicare FFS spend. The cost saving associated with shifting worsening HF treatment from inpatient hospital setting to OP settings was US$667.5 million or 0.17$2.098 billion or 0.53% of total Medicare spend when 20% of HF admissions were targeted and 90% of targeted HF admissions were successfully shifted.Conclusion: Treatment options that can shift costly hospital admissions for worsening HF treatment to less expensive OP settings potentially lead to significant cost savings to Medicare. Pursuit of OP therapy options for treating worsening HF might be considered a viable alternative. Keywords: health care resource utilization, heart failure management, hospital admission burden, administrative claims data, cost impact analysi