A Cost-Effectiveness Analysis of Nintedanib in Idiopathic Pulmonary Fibrosis in the UK.

BACKGROUND: International guidelines recommend nintedanib (OFEV®) as an option for the treatment of idiopathic pulmonary fibrosis (IPF). OBJECTIVE: The objective of this study was to assess the cost effectiveness of nintedanib versus pirfenidone, N-acetylcysteine and best supportive care (BSC) for the treatment of IPF from a UK payer's perspective. METHODS: A Markov model was designed to capture the changes in the condition of adults with IPF. Efficacy outcomes included mortality, lung function decline and acute exacerbations. Treatment safety (serious adverse events) and tolerability (overall discontinuation) were also considered. The baseline risk of these events was derived from patient-level data from the placebo arms of nintedanib clinical trials (TOMORROW, INPULSIS-1, INPULSIS-2). A network meta-analysis (NMA) was conducted to estimate the relative effectiveness of the comparator treatments. Quality of life and healthcare resource use data from the clinical trials were also incorporated in the economic model. RESULTS: Nintedanib showed statistically significant differences against placebo on acute exacerbation events avoided and lung function decline. In the cost-effectiveness analysis, the results were split between two treatments with relative low costs and modest effectiveness (BSC and N-acetylcysteine) and two that showed improved effectiveness (lung function) and higher costs (nintedanib and pirfenidone). All comparators were assumed to have similar projected survival and the difference in quality-adjusted life-years (QALYs) was driven by the acute exacerbations and lung function estimates. In the base-case deterministic pairwise comparison with pirfenidone, nintedanib was found to have fewer acute exacerbations and resulted in less costs and more QALYs gained. CONCLUSIONS: Compared with BSC (placebo), nintedanib and pirfenidone were the only treatments to show statistical significance in the efficacy parameters. We found substantial uncertainty in the overall cost-effectiveness results between nintedanib and pirfenidone. N-Acetylcysteine was largely similar to BSC but with a worse survival profile. INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.

Preventive nebulization of mucolytic agents and bronchodilating drugs in invasively ventilated intensive care unit patients (NEBULAE): study protocol for a randomized controlled trial.

BACKGROUND: Preventive nebulization of mucolytic agents and bronchodilating drugs is a strategy aimed at the prevention of sputum plugging, and therefore atelectasis and pneumonia, in intubated and ventilated intensive care unit (ICU) patients. The present trial aims to compare a strategy using the preventive nebulization of acetylcysteine and salbutamol with nebulization on indication in intubated and ventilated ICU patients. METHODS/DESIGN: The preventive nebulization of mucolytic agents and bronchodilating drugs in invasively ventilated intensive care unit patients (NEBULAE) trial is a national multicenter open-label, two-armed, randomized controlled non-inferiority trial in the Netherlands. Nine hundred and fifty intubated and ventilated ICU patients with an anticipated duration of invasive ventilation of more than 24 hours will be randomly assigned to receive either a strategy consisting of preventive nebulization of acetylcysteine and salbutamol or a strategy consisting of nebulization of acetylcysteine and/or salbutamol on indication. The primary endpoint is the number of ventilator-free days and surviving on day 28. Secondary endpoints include ICU and hospital length of stay, ICU and hospital mortality, the occurrence of predefined pulmonary complications (acute respiratory distress syndrome, pneumonia, large atelectasis and pneumothorax), and the occurrence of predefined side effects of the intervention. Related healthcare costs will be estimated in a cost-benefit and budget-impact analysis. DISCUSSION: The NEBULAE trial is the first randomized controlled trial powered to investigate whether preventive nebulization of acetylcysteine and salbutamol shortens the duration of ventilation in critically ill patients. TRIAL REGISTRATION: NCT02159196, registered on 6 June 2014.

Paracetamol toxicity: what would be the implications of a change in Australian treatment guidelines?

OBJECTIVES: The present study aims to study the implications for resource utilisation if Australia adopted recent revised UK treatment guidelines for paracetamol poisoning. METHODS: Retrospective database review of paracetamol toxicity presentations and calls from the Victorian Poisons Information Centre (VPIC) and Austin Hospital, Victoria, Australia, from 1 January 2010 to 31 December 2011. There were 200 presentations at the Austin Hospital, and the VPIC received 4272 calls regarding paracetamol toxicity. An analytical model was designed to estimate the cost of this additional treatment and referral to hospital. The main outcome measures were the potential increase in number of admissions requiring treatment with N-acetylcysteine (NAC), costs involved and increased number of referrals to hospitals by the VPIC. RESULTS: Twenty-five (12.5%, 95% confidence interval 8.4-17.6%, P < 0.01) patients in our study who did not qualify for NAC therapy based upon the current Australasian paracetamol treatment guideline would have received it if the revised UK guideline was followed. Eighteen (72%) of these presented with acute single ingestions of paracetamol. No patients re-presented to our hospital with acute liver injury or required admission to the liver transplant unit. CONCLUSIONS: Alignment of current Australian paracetamol treatment guidelines with those in the UK would result in an increase in ED attendances as directed by Poisons Information Centres and hospital admissions for antidotal treatment. This would be associated with increased health expenditure and inpatient bed utilisation. The present study does not support the clinical need for adoption of UK paracetamol treatment guidelines in Australia.

Paracetamol toxicity: What would be the implications of a change in UK treatment guidelines?

BACKGROUND: Treatment of single-time-point ingestion acute paracetamol (acetaminophen) poisoning with N-acetylcysteine (NAC) is guided by plotting a timed plasma paracetamol concentration on established nomograms. Guidelines in the UK differ from those in the U.S. and Australasia by having two treatment lines on the nomogram. Patients deemed to be at 'normal' risk of hepatotoxicity are treated using the treatment line starting at 200 mg/L at 4 h post-ingestion; those at higher risk are treated using the 'high risk' treatment line starting at 100 mg/L at 4 h post-ingestion. AIM: To examine the effect on treatment numbers if UK guidelines were to adopt a single treatment line nomogram or lower, risk-stratified treatment lines. METHODS: We undertook a retrospective analysis of a series of acute single-time-point paracetamol poisonings presenting to our inner city emergency department. Treatment numbers and effect on treatment costs were modelled for three alternative scenarios: a 150 line-a combined single treatment line starting at a 4 h concentration of 150 mg/L, a 100 line-a combined single treatment line starting at a 4 h concentration of 100 mg/L, and a 150/75 line-a double treatment line at the lower concentrations of 150 mg/L for normal risk and 75 mg/L for high risk patients. RESULTS: A total of 1,214 cases were identified. Under current UK guidance, 133 (11.0%) high risk cases and 98 (8.1%) normal risk cases needed treatment (total 231, 19.0%). A 150 line would result in 87 (7.2%) high risk cases and 155 (12.8%) normal risk cases needing treatment (total 242, 19.9%). A 100 line would result in 133 (11.0%) high risk and 251 (20.7%) normal risk cases needing treatment (total 384, 31.6%). A 150/75 line would result in 153 (12.6%) high risk and 155 (12.8%) normal risk cases needing treatment (total 308, 25.4%). CONCLUSIONS: Both a 100 line and a 150/75 line would result in a large increase in the number of patients being treated and an associated increase in the costs of treatment. A single 150 mg/L treatment line would simplify treatment algorithms and lead to a similar number of patients being treated with NAC overall. A potential concern however is whether any of the high risk cases that would no longer be treated might develop significant hepatotoxicity. After consideration of the evidence for dual treatment lines, we feel that these risks are small and that it is worth reconsidering a change of treatment recommendations to a single 150 line.

A cost effectiveness analysis of the preferred antidotes for acute paracetamol poisoning patients in Sri Lanka.

BACKGROUND: Acute paracetamol poisoning is a rapidly increasing problem in Sri Lanka. The antidotes are expensive and yet no health economic evaluation has been done on the therapy for acute paracetamol poisoning in the developing world. The aim of this study is to determine the cost effectiveness of using N-acetylcysteine over methionine in the management of acute paracetamol poisoning in Sri Lanka. METHODS: Economic analysis was applied using public healthcare system payer perspective. Costs were obtained from a series of patients admitted to the National Hospital of Sri Lanka with a history of acute paracetamol overdose. Evidence on effectiveness was obtained from a systematic review of the literature. Death due to hepatotoxicity was used as the primary outcome of interest. Analysis and development of decision tree models was done using Tree Age Pro 2008. RESULTS: An affordable treatment threshold of Sri Lankan rupees 1,537,120/death prevented was set from the expected years of productive life gained and the average contribution to GDP. A cost-minimisation analysis was appropriate for patients presenting within 10 hours and methionine was the least costly antidote. For patients presenting 10-24 hours after poisoning, n-acetylcysteine was more effective and the incremental cost effectiveness ratio of Sri Lankan rupees 316,182/life saved was well under the threshold. One-way and multi-way sensitivity analysis also supported methionine for patients treated within 10 hours and n-acetylcysteine for patients treated within 10-24 hours as preferred antidotes. CONCLUSIONS: Post ingestion time is an important determinant of preferred antidotal therapy for acute paracetamol poisoning patients in Sri Lanka. Using n-acetylcysteine in all patients is not cost effective. On economic grounds, methionine should become the preferred antidote for Sri Lankan patients treated within 10 hours of the acute ingestion and n-acetylcysteine should continue to be given to patients treated within 10-24 hours.

Assessment of the clinical use of intravenous and oral N-acetylcysteine in the treatment of acute acetaminophen poisoning in children: a retrospective review.

BACKGROUND: N-acetylcysteine (NAC) is the most effective therapy for acetaminophen (APAP) toxicity and is currently available for oral and intravenous (IV) administration. Although both routes are effective, use of the IV formulation has been increasing since becoming available in the United States in 2004, raising questions about cost/benefit comparisons between the 2 formulations. Decreased length of treatment and hospital stay have been used to justify the use of IV NAC; however, some patients may receive extended therapy of either NAC regimen. OBJECTIVE: This retrospective review assessed the clinical use of oral and IV NAC in pediatric patients with APAP intoxication from June 1, 2004 through May 31, 2008. METHODS: Electronic medical charts for patients aged ≤21 years were identified with International Classification of Diseases, Ninth Revision (ICD-9) codes for APAP overdose. Descriptive statistics were used to describe the overall patient population and route of NAC administration. The primary outcome variable was the length of treatment with IV and oral NAC therapy. RESULTS: A total of 62 charts for patients with APAP toxicity were reviewed; 37 patients (60%) received IV NAC and 25 patients (40%) received oral NAC. The average lengths of treatment and stay for IV dosing were 23.5 hours (range, 17.6-54.9 hours) and 1.6 days (range, 1-3 days), respectively; those for oral dosing were 69.5 hours (range, 33-133 hours) and 1.95 days (range, 1-5 days), respectively. Of 16 patients who received oral NAC and were admitted for <3 days, 14 were transferred to an inpatient psychiatric unit and completed the 72-hour therapy. A total of 3 patients received extended NAC dosing-2 with IV dosing and 1 with oral dosing. CONCLUSIONS: Based on our review, the majority of patients received recommended dosing of NAC therapy; however, 3 patients received extended NAC therapy. Patient-specific factors should be considered when assessing whether NAC therapy should be extended and if one route of administration may be preferred. ClinicalTrials.gov identifier: NCT00725179.

Cost minimization analysis comparing enteral N-acetylcysteine to intravenous acetylcysteine in the management of acute acetaminophen toxicity.

CONTEXT: Acetaminophen poisoning is one of the most common exposures and causes of poisoning-related fatalities as reported to U.S. poison information centers. Acetylcysteine is indicated for the antidotal treatment of acetaminophen poisoning to prevent or minimize acetaminophen-related hepatotoxicity. Available as either an enteral or intravenous (IV) formulation, both forms of acetylcysteine have been proven to be efficacious. Because of the differences in the acquisition costs and the length of treatment, it is unclear which treatment route is the most cost-effective. OBJECTIVE: The purpose of this study was to compare the total hospitalization charges associated with patients who received either enteral or IV acetylcysteine therapy. MATERIALS AND METHODS: A retrospective, IRB-approved cohort study of patients treated with either enteral or IV acetylcysteine at a university-related hospital for the treatment of acute acetaminophen overdose was conducted. Patients included were over 18 years of age, admitted during the 5-year periods of 1996-2000 (enteral) and 2004-2008 (IV), had an ICD-9 discharge diagnosis for acetaminophen overdose, had no transplant history, and were admitted within 24 h of the overdose. The primary endpoint was the total cost associated with the hospital stay. The Consumer Price Index (CPI) inflation calculator from the U.S. Bureau of Labor Statistics was used to adjust all monetary values to 2008 dollars. RESULTS: Of a total of 1,647 patients, 261 met the inclusion criteria with 70 patients being treated with enteral acetylcysteine and 191 patients treated with IV acetylcysteine. The associated cost was greater in the enteral group than in the IV group ($18,287.63 vs. $7,607.82; p < 0.001). The average length of stay was longer in the enteral group compared to the IV group (7 days vs. 4 days; p < 0.001). CONCLUSIONS: Patients who were treated with IV acetylcysteine had a decreased length of stay and cost of hospitalization compared with those patients who were treated with enteral acetylcysteine.

Thiopurine S- methyltransferase [corrected] testing in idiopathic pulmonary fibrosis: a pharmacogenetic cost-effectiveness analysis.

Azathioprine in combination with N-acetylcysteine (NAC) and steroids is a standard therapy for idiopathic pulmonary fibrosis (IPF). Its use, however, is limited by its side effects, principally leukopenia. A genotypic assay, thiopurine S-methyltransferase (TPMT), has been developed that can potentially identify those at risk for developing leukopenia with azathioprine, and thereby limit its toxicity. In those with abnormal TPMT activity, azathioprine can be started at lower dose or an alternate regimen selected. Determine the cost-effectiveness of a treatment strategy using TPMT testing before initiation of azathioprine, NAC, and steroids in IPF by performing a computer-based simulation. We developed a decision analytic model comparing three strategies: azathioprine, NAC and steroids with and without prior TPMT testing, and conservative therapy, consisting of only supportive measures. Prevalence of abnormal TPMT alleles and complication rates of therapy were taken from the literature. We assumed a 12.5% incidence of abnormal TPMT alleles, 4% overall incidence of leukopenia while taking azathioprine, and that azathioprine, NAC, and steroids in combination reduced IPF disease progression by 14% during 12 months. TPMT testing before azathioprine, NAC, and steroids was the most effective and most costly strategy. The marginal cost-effectiveness of the TPMT testing strategy was $49,156 per quality adjusted life year (QALY) gained versus conservative treatment. Compared with azathioprine, NAC and steroids without prior testing, the TPMT testing strategy cost only $29,662 per QALY gained. In sensitivity analyses, when the prevalence of abnormal TPMT alleles was higher than our base case, TPMT was "cost-effective." At prevalence rates lower than our base case, it was not. TPMT testing before initiating therapy with azathioprine, NAC, and steroids is a cost-effective treatment strategy for IPF.

Managing acute acetaminophen poisoning with oral versus intravenous N-acetylcysteine: a provider-perspective cost analysis.

BACKGROUND: Acetaminophen (APAP) overdose, which can lead to hepatotoxicity, is the most commonly reported poisoning in the United States and has the highest rate of mortality, with more than 100,000 exposures and 300 deaths reported annually (1) . The treatment of choice, N-acetylcysteine (NAC), is effective in both oral (PO) and intravenous (IV) formulations. The main difference in therapies, other than administration route, is time to complete delivery--72 hours for PO NAC versus 21 hours for IV NAC, according to full prescribing information. This distinction is the primary basis for variation in management costs for hospitalized patients receiving these products. OBJECTIVES: To quantify and compare full treatment costs from the provider perspective to manage acute APAP poisoning with either PO or IV NAC in a standard treatment regimen. METHODS: A cost model was developed and populated with published data comprising probabilities of potential clinical outcomes and the costs of resources consumed during patient care. RESULTS: For patients who present <10 hours post-ingestion, the estimated total cost of care with PO NAC in the treatment regimen is $5,817 (ICU patients) or $3,850, (ward patients) compared with $3,765 and $2,768 for similar care with IV NAC. Potential cost savings equal - $2,052 (-35%) or -$1,083 (-28%), respectively, in favor of IV NAC. Similar potential savings were estimated for patients presenting 10-24 hours post-ingestion. CONCLUSION: IV NAC is the less costly therapeutic option for APAP poisonings, based on simulation modeling and retrospective data. The current economic evaluation is restricted by the absence of comparative data from head-to-head, matched-cohort studies and the limitations common to retrospective APAP toxicology datasets. Additional research could refine these results.

Stability of acetylcysteine solution repackaged in oral syringes and associated cost savings.

PURPOSE: The physical and chemical stability of repackaged acetylcysteine 600 mg/3 mL solution in oral syringes stored under refrigeration or at room temperature was studied for six months; a cost analysis was also conducted. METHODS: Acetylcysteine 20% solution for inhalation was repackaged undiluted as 600 mg/3 mL in capped oral syringes and stored either under refrigeration or at room temperature exposed to fluorescent light. Four samples for each storage condition were analyzed in duplicate on day zero, weekly for the first month, and then every two weeks during months 2-6. Physical stability was assessed, and the chemical stability of acetylcysteine was evaluated by high-performance liquid chromatography. RESULTS: Acetylcysteine solution in syringes was physically stable during the entire six-month study period. When stored at room temperature, acetylcysteine retained 99% of the original concentration at three months and 95% at six months after preparation of the syringes. Loss of acetylcysteine was <2% at six months when stored under refrigeration. Packaging acetylcysteine in batches of 100 syringes instead of preparing individual syringes reduced wastage to zero syringes, saving an estimated $247 in drug costs. The estimated pharmacy time savings was 30 hours ($702). CONCLUSION: Acetylcysteine 20% solution repackaged as 600 mg/3 mL in oral syringes is both physically and chemically stable under refrigeration or at room temperature under normal fluorescent lighting for six months. The total loss of acetylcysteine was approximately 5% at room temperature under fluorescent lighting and <2% under refrigeration. Repackaging the solution in syringes in bulk rather than in single doses demonstrated a measurable cost saving.

Prehydration alone is sufficient to prevent contrast-induced nephropathy after day-only angiography procedures--a randomised controlled trial.

BACKGROUND: Contrast agents used in angiography procedures for patients with cardiovascular disease are known to cause contrast-induced nephropathy (CIN), which may be partially due to the production of nephrotoxic oxygen-free radicals. It is uncertain whether administration of intravenous (IV) anti-oxidant, N-acetylcysteine (NAC), can prevent reduction in renal function and whether this is a cost-effective approach. METHODS: Sixty-five day-only patients with renal impairment (mean serum creatinine concentration 0.16+/-0.03 mmol/l) due to undergo coronary or peripheral angiography and/or stenting were randomly assigned to IV NAC 300 or 600 mg immediately before and after the procedure or IV fluid alone. RESULTS: Of the 60 patients with complete data, none had acute CIN (increase in serum creatinine concentration > or = 0.044 mmol/l, 48 h after administration of contrast agent). Eight patients (13%) have demonstrated an increase in their serum creatinine concentration > or = 0.044 mmol/l 30 days after administration of contrast agent: 2/19 (11%) in the control group, 2/21 (10%) in the 600 mg NAC group and 4/20 (20%) the 300 mg NAC group (p = 0.66). The mean volumes of contrast agent used and prehydration given for each of the three groups did not differ significantly (p > 0.83). There was significant improvement in creatinine clearance within each group from baseline to 30 days (p < or = 0.03), but no significant difference between the groups at 48 h and 30 days (p > or = 0.43). Considering the cost of NAC and its administration, we estimate that this would translate to a saving of dollar 26,637 per annum. CONCLUSION: For day-stay patients with mild-to-moderate chronic renal impairment undergoing angiography and/or intervention, prehydration alone is less complicated and more cost-effective than a combination of IV NAC (at doses used) and hydration.

A clinical and pharmacoeconomic justification for intravenous acetylcysteine: a US perspective.

Paracetamol (acetaminophen) poisoning remains the most common exposure reported to US poison information centres and the leading cause of poisoning-related fatalities, despite the availability of an effective antidote, acetylcysteine. Oral acetylcysteine solution has been approved for the management of acetaminophen poisoning in the US for four decades. Until the recent approval of intravenous acetylcysteine in the US, it was necessary to compound the oral solution for intravenous administration. The effectiveness and tolerability of oral and intravenous acetylcysteine for the prevention of hepatotoxicity induced by paracetamol poisoning are well established in the literature. Intravenous acetylcysteine may be preferred over oral administration based on improved tolerability, ease of administration and the shortened course of therapy (20 hours intravenous vs 72 hours oral). The two intravenous acetylcysteine regimens documented in the literature, 48 hours and 20 hours, have similar efficacy when started within 8-10 hours of ingestion. Although there are no legal concerns with continuing the routine compounding of the oral solution to an intravenous product, new standards for pharmacy compounding of sterile preparations set forth by the US Pharmacopoeia highlight that the risk of compounding products for intravenous use must be assessed carefully. Changing the route of administration of a sterile oral solution to an intravenous preparation, when a commercial sterile and pyrogen-free product is available, may not be advisable. The best cost-containment strategies must be used for introduction of the more costly sterile, pyrogen-free intravenous acetylcysteine formulation by hospitals and healthcare systems. The intravenous acetylcysteine product is more cost effective when given for 20 hours than other treatment protocols based on the costs of acetylcysteine and hospitalisation. If used per protocol, the 20-hour intravenous acetylcysteine regimen may decrease hospital length of stay, thereby, offsetting the increased drug cost. Data conflict on the efficacy and administration of intravenous acetylcysteine for off-label uses, such as radiographic contrast media-induced nephropathy prevention and reperfusion in orthotopic liver transplantation. The costs for the intravenous formulation for these indications is significantly higher than use of the oral formulation for oral administration in radiographic contrast media-induced nephropathy prevention and compounded for intravenous use in orthotopic liver transplantation. The oral solution should be retained by healthcare systems for oral and inhalation applications, such as respiratory conditions, oral administration for radiographic contrast media nephropathy prevention, or the use of the 72-hour oral protocol to treat paracetamol poisoning, when the intravenous preparation cannot be used.

Cost effectiveness and cost utility of acetylcysteine versus dimethyl sulfoxide for reflex sympathetic dystrophy.

OBJECTIVE: To determine the cost effectiveness and cost utility of acetylcysteine versus dimethyl sulfoxide (DMSO) for patients with reflex sympathetic dystrophy (RSD), from a societal viewpoint. DESIGN: An economic evaluation was conducted alongside a double-dummy, double-blind, randomised, controlled trial. Patients were followed for 1 year. The primary outcome measure was the Impairment-level Sum Score (ISS). Utilities were determined by the EuroQOL instrument (EQ-5D). Both cost-effectiveness and cost-utility analyses were performed. Differences in mean direct, indirect and total costs were estimated. Corresponding 95% confidence intervals were calculated by bootstrapping techniques. RESULTS: Both groups (DMSO, n = 64; acetylcysteine, n = 67) showed relevant improvement; no differences in effects were found. Only the total direct costs were significantly lower in the DMSO group for the period of 0-52 weeks. The incremental cost-effectiveness ratios showed that, in general, DMSO generated fewer costs and more effects compared with acetylcysteine. Post-hoc subgroup analyses on cost effectiveness suggested that patients with warm RSD could be best treated with DMSO and patients with cold RSD with acetylcysteine. These results were based on small subsamples. CONCLUSION: In general, DMSO is the preferred treatment for patients with RSD.