Determinants of drug costs in hopitalised patients with haemophilia: impact of recombinant activated factor VII

OBJECTIVE: To analyse the determinants of anti-haemophilic drug costs in hospitalised patients with haemophilia and to estimate the impact of recombinant activated factor VII (rFVIIa) therapy on this expenditure. PERSPECTIVE: The perspective of the study was from the viewpoint of the hospital. DESIGN AND SETTING: A prospective study was carried out. All patients with haemophilia who were hospitalised in 1999 in Bicêtre public hospital, Paris, France were included in the cohort. MAIN OUTCOME MEASURES AND RESULTS: For each of the 96 patients (154 hospital stays), we estimated the costs of anti-haemophilic drugs (coagulation concentrates) used. Costs were then stratified by different variables (severity of the disease, presence of a circulating inhibitor to coagulation factors, etc.) and a multivariate model was developed to determine the relationship between these variables and total anti-haemophilic drug costs, while controlling for potential confounders. Our study revealed: (i) the independent role of the five following variables in contributing to high anti-haemophilic drug expenditure: presence of a circulating inhibitor to coagulation factors, odds ratio (OR) = 16.9 (95% CI: 4.3-66); severity of the disease (factor VIII or factor IX < or =0.01 IU/mL), OR = 3.7 (95% CI: 1.6-8.6); length of hospital stay >4 days, OR = 8 (95% CI: 2.2-29.4); age >18 years old, OR = 6.2 (95% CI: 1.6-24.5); and surgical reasons for hospitalisation (whether surgery was haemophilia related [OR = 35.7 (95% CI: 7.3-175)] or not [OR = 5.4 (95% CI: 1.3-22.5)]); (ii) the large share that rFVIIa represented in this expenditure on medicines: rFVIIa was used in 20.1% of hospital stays and accounted for 56.2% of the total anti-haemophilic drug costs, which were estimated at 4,384,732 Euros (2000 values). CONCLUSIONS: Our data underline the heavy cost of the treatment of haemophilic patients with an inhibitor to coagulation factors. But, to the question of whether the high expenditure linked to rFVIIa utilisation will be balanced out by later benefits, it is not yet possible to reply with any certainty; further cost-benefit evaluation should be carried out.     

Therapeutic approaches for haemophilia

The life-long episodic bleeding associated with inherited deficiencies of blood coagulation Factor VIII (FVIII) or Factor IX (FIX) can be well controlled with periodic iv. injections of FVIII or FIX concentrates. Either concentrate can be isolated from large human pools (i.e., plasma-derived FVIII or FIX concentrate) or from culture supernatants of recombinant cells engineered to secrete FVIII or FIX. The validated viral inactivation strategies used by manufacturers of FVIII and FIX concentrates have essentially eliminated the transmission of hepatitis B, hepatitis C and HIV viruses. The low yields and inherent instability of FVIII (and FVIIIa in particular) and the additional costs of viral inactivation methods make the annual cost/patient for prophylaxis and treatment of haemophilia very expensive. Several strategies have been adopted and proposed to improve yields of FVIII. These include: deletion of portions of FVIII which are not associated with function; mutations to prevent inactivation of FVIII by protease degradation; and synthesis of FVIII fragments to replace portions deleted in some FVIII deficient patients. An approach to improve FIX replacement involves the production of more coagulatively active FIX mutants. Another promising approach in both FVIII and FIX replacement is gene therapy. Two major issues that will have to be critically addressed before gene therapy for haemophilia can become widespread are whether the procedures will be well-tolerated in patients with significant liver impairment (due to previous exposure to hepatitis viruses) and whether consistent long-term delivery of the transgenes can be achieved.     

Pharmacokinetics of coagulation factors: clinical relevance for patients with haemophilia.

Haemophilia is a recessively inherited coagulation disorder, in which an X-chromosome mutation causes a deficiency of either coagulation factor VIII (FVIII) in haemophilia A, or factor IX (FIX) in haemophilia B. Intravenous administration of FVIII or FIX can be used to control a bleeding episode, to provide haemostasis during surgery or for long term prophylaxis of bleeding. In special cases, activated factor VII (FVIIa) may be used instead of FVIII or FIX. The aim of this work is to review the pharmacokinetics of FVIII, FIX and FVIIa and to give an outline of the use of pharmacokinetics to optimise the treatment of patients with haemophilia. The pharmacokinetics of FVIII are well characterised. The systemic clearance (CL) of FVIII is largely determined by the plasma level of von Willebrand factor (vWF), which protects FVIII from degradation. Typical average CL in patients with normal vWF levels is 3 ml/h/kg, with an apparent volume of distribution at steady state (Vss) that slightly exceeds the plasma volume of the patient, and the average elimination half-life (t1/2) is around 14 hours. There are still some discrepancies in the literature on the pharmacokinetics of FIX. The average CL of plasma-derived FIX seems to be 4 ml/h/kg, the Vss is 3 to 4 times the plasma volume and the elimination t1/2 often exceeds 30 hours. FVIIa has a much higher CL (average of 33 ml/h/kg), and a short terminal t1/2 (at 2 to 3 hours). The Vss is 2 to 3 times the plasma volume. Since the therapeutic levels of coagulation factors are well defined in most clinical situations, applied pharmacokinetics is an excellent tool to optimise therapy. Individual tailoring of administration in prophylaxis has been shown to considerably increase the cost effectiveness of the treatment. Dosage regimens for the treatment of bleeding episodes or for haemostasis during surgery are also designed using pharmacokinetic data, and the advantages of using a constant infusion instead of repeated bolus doses have been explored. The influence of antibodies (inhibitors) on the pharmacokinetics of FVIII and FIX is in part understood, and the doses of coagulation factor needed to treat a patient can tentatively be calculated from the antibody titre. In conclusion, therapeutic monitoring of coagulation factor levels and the use of clinical pharmacokinetics to aid therapy are well established in the treatment of patients with haemophilia.     

Population pharmacokinetics of plasma-derived factor IX in adult patients with haemophilia B: implications for dosing in prophylaxis

Purpose

Knowledge of the pharmacokinetics (PK) of plasma-derived factor IX (FIX) is still inadequate, with conflicting findings on its elimination half-life and as yet no analysis of the variance in PK between and within individuals. The aim of the study was thus to characterize the PK of plasma-derived FIX, including estimates of variance between and within patients, in adult patients and to predict the variation between individuals in dose requirement to produce a target trough level during regular prophylaxis.

Methods

Plasma FIX versus time data were compiled from four published and one unpublished PK study involving a total of 26 adult patients with severe haemophilia B. The number of PK assessments per patient varied between one and eight, yielding in total 893 measured FIX levels from 80 study occasions. A population PK model was developed to describe the whole dataset. Parameter values from the model were used to calculate the dose requirement to maintain a trough level of 1% of normal FIX activity in each patient.

Results

The disposition of FIX was well described by a three-compartment PK model. The median elimination half-life was 31 h, and the variation between individuals was modest both in PK and in dose requirement during twice-weekly prophylaxis.

Conclusion

With twice weekly dosing, the need for PK-based dose tailoring of FIX in adult patients appears to be limited. However, monitoring FIX levels should be considered in children, in patients who do not respond satisfactorily to standard dosing, and if treatment is switched from plasma-derived to recombinant FIX.     

Pharmacokinetics of factor IX in patients with haemophilia B

The aims of this study were to investigate the influence of total blood sampling time on the estimated pharmacokinetic parameters of Factor IX procoagulant activity (FIX:C) and to relate the pharmacokinetics of FIX:C to the putative physiological disposition of Factor IX (FIX). Six patients with severe haemophilia B each received 2 infusions of FIX and on both occasions blood samples were collected for 104 h. Each FIX:C decay curve was processed with successive deletion of the last (remaining) datapoint. The fitted terminal half-life (t_1/2) and the calculated model-independent mean residence time (MRT_MI), elimination clearance (CL_MI) and volume of distribution at steady state (V_ss) stabilised close to their final values when FIX:C data corresponding to at least 56 h of sampling were used.The final mean values were t_1/2=34 h, MRT_MI=37 h, CL_MI=4.0 ml · h^-1 · kg^-1 and V_ss=0.15 l · kg^-1. The disposition of FIX could be characterised by a two-compartment pharmacokinetic model. On average, FIX molecules spent 44% of their total MRT in the second (or extravascular) compartment. The distribution clearance was comparable to estimated total lymph flow. The volume of the central compartment was twice the estimated plasma volume, which may reflect the rapid and reversible binding of FIX to vascular endothelium. This explains the common clinical finding that the peak activity of FIX:C is less than the injected dose divided by the estimated plasma volume of the patient.     

Erythropoiesis-stimulating agents in anaemia due to chronic kidney disease: a cost-minimization analysis

Background Some publications have shown that equivalent doses of erythropoiesis-stimulating agents (ESA) defined on label differ from those effective in clinical practice. Therefore, real costs could vary from theoretical costs in the treatment of anaemia in chronic kidney disease (CKD). Objectives To perform a cost-minimization analysis to establish the economic impact of the principal ESAs used in treating anaemia secondary to CKD in daily practice. Secondary objectives: to determine patient-month cost based on the erythropoietin resistance index (ERI); to analyze the difference in cost between pre-dialysis and peritoneal dialysis (PD) patients; and to analyze the association between iron deposits and ESA cost. Setting This study was carried out at 2 tertiary hospitals in Spain. Method A multicentre cost-minimization analysis was performed in adult outpatients treated with ESAs for anaemia due to CKD. Main outcome measure The primary outcome was the patient-month cost for each ESA. Results 409 patients were included. Median patient-month cost was: epoetin (103.2 [63.7, 187.8] euros), darbepoetin α (134.4 [67.2, 216.0] euros) and CERA (147.5 [98.3, 196.7] euros). Median patient-month cost according to ERI was: epoetin (1.60 [0.90, 2.60] euros/kg), darbepoetin α (2.01 [0.95, 3.48] euros/kg) and CERA (1.87 [1.33, 3.00] euros/kg). Median patient-month cost in pre-dialysis was 126.0 (73.7, 201.6) euros and in PD 153.0 (100.2, 275.4) euros. Median patient-month cost for patients with TSI < 20 % was 147.5 (98.3, 224.9) euros compared to 100.9 (67.2, 196.7) euros which was the cost for patients with IST ≥ 20 %. The median patient-month cost for patients with ferritin < 100 mcg/l was 134.4 (85.0, 201.6) euros compared to 100.8 (68.8, 196.7) euros, which was the cost for patients with ferritin ≥ 100 mcg/l (p = 0.242). Conclusion Doses of CERA used in clinical practice are lower than those recommended on label, which directly influences cost and treatment efficiency. Cost stratification based on iron deposits has shown that patients with low TSI or ferritin require higher doses and consequently an associated higher cost. Thus, to guarantee adequate iron levels is essential in the rational use of ESAs.     

Clinical features and natural history of hepatocellular adenomas: the impact of obesity

Aliment Pharmacol Ther 2011; 34: 664–674

Summary

Background Hepatocellular adenoma is a benign tumour associated with bleeding and malignant transformation. Obesity has been linked to hepatic tumourigenesis. Aim To evaluate the presentation of hepatocellular adenoma in obesity, and the impact of obesity on the clinical course. Methods Records of 60 consecutive patients (between 2005 and 2010) with a diagnosis of hepatocellular adenoma from a single tertiary centre were analysed. Results Fifty six of 60 patients were women, median age was 36 years, 75% had history of contraceptive use, 18% were overweight and 55% were obese (BMI ≥30 kg/m²). Majority (63%) were asymptomatic; seven patients presented with bleeding. Single (28%) and multiple adenomas (72%) were encountered; size ranged from 1 to 19.7 cm. Obesity was more often associated with multiple adenomas (85% vs. 48%, P = 0.005), bilobar distribution (67% vs. 33%, P = 0.01), lower serum albumin (P = 0.007) and co‐morbidities of fatty liver (P = 0.006), diabetes (P = 0.003), hypertension (P = 0.006) and dyslipidemia (P = 0.03). During median follow‐up of 2.6 years, there were no instances of bleeding, malignant transformation or death. Thirty four patients underwent therapeutic intervention (17 surgical resection, nine transarterial embolization and eight both interventions sequentially). The rate of complete resection of adenoma(s) was significantly lower in obese patients (8% vs. 69%, P = 0.004). In the 26 patients without intervention, tumour size progression was more frequently observed in obese patients (33% vs. 0%, P = 0.05). Three of 15 obese patients (20%) lost ≥5% body weight and there was no progression in the liver lesions. Conclusions  Obesity and features of metabolic syndrome were frequently observed in hepatocellular adenoma. Multiple and bilobar adenomas were more frequent in obese patients. Among patients who were conservatively managed, tumour progression was more often associated with obesity.     

High-dose ursodeoxycholic acid increases risk of adverse outcomes in patients with early stage primary sclerosing cholangitis

Aliment Pharmacol Ther 2011; 34: 1185–1192

Summary

Background Ursodeoxycholic acid (UDCA) in a dose of 28–30 mg/kg/day increases the likelihood of clinical deterioration of primary sclerosing cholangitis (PSC) patients. Aim To compare the risk of adverse clinical endpoints in patients with varying disease status. Methods We reviewed records from patients previously enrolled in a study evaluating the effects of high dose (28–30 mg/kg/day) UDCA in PSC. Patients were grouped according to treatment (UDCA vs. placebo) and baseline disease status (histological stage of PSC, total serum bilirubin). Development of clinical endpoints including death, liver transplantation, cirrhosis, oesophageal varices and cholangiocarcinoma was sought. Results A total of 150 patients were included of whom 49 patients developed endpoints. There was an increased development of endpoints among patients using UDCA vs. placebo (14 vs. 4, P = 0.0151) with early histological disease (stage 1–2, n = 88) but not with late stage (stage 3–4, n = 62) disease (17 vs. 14, P = 0.2031). Occurrence of clinical endpoints was also higher in patients receiving UDCA vs. placebo (16 vs. 2, P = 0.0008) with normal bilirubin levels (total bilirubin ≤1.0 mg/dL) but not in patients with elevated bilirubin levels (15 vs. 16, P = 0.6018). Among patients not reaching endpoints 31.7% had normalisation of their alkaline phosphatase levels when compared to 14.3% in patients who reached endpoints (P = 0.073). Conclusion The increased risk of adverse events with UDCA treatment when compared with placebo is only apparent in patients with early histological stage disease or normal total bilirubin.     

Hospital pharmacists'' reinforcement of guidelines for switching from parenteral to oral antibiotics: a pilot study

Objective: The cost of antibiotics in hospitals may be reduced by streamlining, and, particularly, by early switching from the intravenous (i.v.) to the oral route of administration. The aim of the study was to evaluate the feasibility and impact of guidelines for switching, reinforced by pharmacists. Method: Patients admitted to internal medicine wards and treated with i.v. antibiotics for various infections were included for six weeks before (group A) and six weeks after (group B) the intervention. Differences in patient characteristics and their outcomes were sought between the two groups.Results: The 26 patients in group B stayed longer in hospital than the 29 in group A (13.3 vs. 9.7 days; P = 0.05). They also tended to need more time to reach the predefined criteria for switching (3.6 vs. 2.4 days; P = 0.09). From that point on, they were switched more rapidly to oral antibiotics (1.5 vs. 3.2 days; P = 0.02), which resulted in a trend toward a lower treatment cost until their discharge (44 vs. 92 euros; P = 0.08). No difference was found between the 2 groups for the duration of the i.v. therapy, or the total inhospital cost of antibiotics. Conclusion: Pharmacists may help implement and reinforce guidelines for switching to oral antibiotics. The evaluation of such interventions implies the choice of appropriate outcomes and the awareness of confounding factors.     

Differences in phenotype and disease course in adult and paediatric inflammatory bowel disease--a population-based study

Aliment Pharmacol Ther 2011; 34: 1217–1224

Summary

Background Few studies have compared phenotype and disease course in children and adults with inflammatory bowel disease (IBD). Aim To compare phenotype, treatment and disease course in children (<15 years) and adults (≥18 years) with IBD. Methods Two population‐based cohorts comprising paediatric (2001–2006) and adult (2003–2004) patients from Copenhagen County and City were studied. Results Twenty children and 106 adults with ulcerative colitis (UC), and 29 children and 67 adults with Crohn′s disease (CD) were included. Median follow‐up time was 4.8 years (children) and 5.2 years (adults). Children with UC had more extensive disease compared to adult patients [14 (70%) vs. 20 (19%), P < 0.001]. The risks of starting systemic steroid treatment and AZA/MP were higher for paediatric UC patients compared to adult UC patients; hazard ratio (HR): 3.1 (95% CI: 1.8–5.3) and HR: 2.5 (1.3‐5‐9), respectively. Steroid dependency was more frequent in paediatric than in adult UC patients [9 (45%) vs. 9 (8%), P < 0.001]. Mild disease course was less frequent in children with UC compared to adult patients [7 (35%) vs. 76 (72%), P = 0.002]. Paediatric and adult CD patients did not differ regarding treatment or disease course. Cumulative 5‐year surgery rates for paediatric and adult patients were 5% and 9% for UC (N.S.) and 18% and 21% for CD (N.S.), respectively. Conclusions Paediatric UC patients had more extensive disease, were more often treated with systemic steroids and AZA, had a higher frequency of steroid dependency and a more severe disease course compared to adult UC patients. No differences were found when comparing paediatric and adult CD patients.     

Use of the AST to platelet ratio index in HCV/HIV co-infected patients

Aliment Pharmacol Ther 2011; 33: 566–577

Summary

Background The AST to platelet ratio index (APRI), a non‐invasive marker of liver fibrosis, has not been well studied in HCV/HIV (hepatitis C virus/human immunodeficiency virus) co‐infected patients with advanced HIV. Aim To compare the accuracy of APRI in HCV/HIV co‐infected patients to that in HCV mono‐infected patients and to determine the impact of CD4+ T‐cell counts on its performance. Methods We identified 106 consecutive HCV/HIV co‐infected patients and 105 matched HCV mono‐infected patients who underwent liver biopsy at Harborview Medical Center over a 5‐year period. Performance characteristics were calculated and receiver operating characteristic (ROC) analysis conducted. Results The area under the ROC curve (AUROC) of APRI for predicting significant fibrosis was similar when comparing those with and without HIV co‐infection (0.77 vs. 0.86, P = 0.18), but was lower in HIV co‐infected patients with CD4 counts <250 cells/mm³ (0.64 vs. 0.86, P = 0.05). In HIV co‐infected patients with CD4 counts ≥250, APRI had higher negative predictive value (93% vs. 88%, P = 0.57), positive predictive value (63% vs. 40%, P = 0.43) and specificity (95% vs. 88%, P = 0.05) than in those with lower CD4 counts. Conclusions The AST to platelet ratio index (APRI) performance characteristics appear to be suboptimal in HCV/HIV co‐infected patients with CD4 counts <250 and they require further study in this population at increased risk for advanced liver disease.     

Management and costs of treating lung cancer patients in a university hospital

BACKGROUND: New diagnostic tools and emerging medications have significantly changed the existing medical treatment options for lung cancer over the last 5 years. However, the increase in healthcare costs in all developed societies has put the more economical treatments on centre stage. OBJECTIVE: To examine the patterns and costs of lung cancer management at a Swiss University hospital at which there is a focus on interdisciplinary treatment. PATIENTS AND METHODS: All patients encountered during 1998 at the University Hospital of Zurich (USZ) with any diagnosis of lung cancer were selected for this retrospective study. Medical and sociodemographic data were collected by medical chart review for a period beginning with the first contact and ending with the last follow-up examination up to 30 months afterwards. Costs were calculated by assessing all resources used by each patient, multiplied by a uniform average cost factor. Results are in euros at 1999 prices. RESULTS: The sample included 118 patients (72% male) with a mean age of 64.2 years (SD 9.8, range 34-85 years) and a mean smoking history of 45 pack-years (SD 31.8, range 0-13 pack-years). Eighty-nine percent of all patients showed histology of non-small cell lung cancer (NSCLC), whereas 11% showed small cell lung cancer (SCLC). Of the NSCLC patients, 27% were classified as stage I, 14% as stage II, 19% as stage IIIA, 11% as stage IIIB and 26% as stage IV disease. The overall survival rate after 1 year was 55% and after 2 years was 29%. Gender and health insurance status were not associated with overall survival. The median length of hospitalisation during the first year of treatment was 14 days (range 0-112 days). For the entire patient sample, the mean cost per patient was 19,408 euros (median 14,691 euros, range 1821-80,020 euros), 71% of which was due to the hospitalisation costs. The mean cost per NSCLC patient was 19,212 euros (median 14,511 euros, range 1821-80,020 euros) and for SCLC patients it was 20,992 euros (median 15,367 euros, range 5282-51,840 euros). CONCLUSION: This is the first study attempting to estimate the hospital cost of treatment for lung cancer patients in Switzerland and central Europe. The major part of the total cost was due to hospitalisation costs. Patients with advanced stages of lung cancer show the highest cost, mainly due to the costs of chemotherapy. We found that the distribution of total cost is asymmetric: a small number of patients with an excessively long hospital stay cause very high costs.     

Clinical trial: short‐term effects of combination of satavaptan,a selective vasopressin V2 receptor antagonist,and diuretics on ascites in patients with cirrhosis without hyponatraemia – a randomized,double‐blind,placebo‐controlled study

Aliment Pharmacol Ther 31 , 834–845

Summary

Background There is little information on the effects of vaptans in patients with cirrhosis. Aim To investigate the short‐term effects of satavaptan, a selective vasopressin V₂ receptor antagonist on ascites in cirrhosis without hyponatraemia. Methods A total of 148 patients with cirrhosis, ascites and serum sodium >130 mmol/L were included in a multicentre, double‐blind, randomized, controlled study of 14 days comparing three fixed doses of satavaptan (5 mg, 12.5 mg or 25 mg once daily) vs. placebo. Average MELD scores were: 13.4, 12.3, 13.8 and 13.1 respectively. All patients received spironolactone 100 mg/day plus furosemide 20–25 mg/day. Results Satavaptan treatment was associated with a decrease in ascites (mean change in body weight was ?0.36 kg (±3.03) for placebo vs. ?2.46 kg (±3.11), ?2.08 kg (±4.17) and ?2.28 kg (±3.24) for the 5 mg, 12.5 mg and 25 mg doses respectively; P = 0.036, P = 0.041 and P = 0.036 for satavaptan 5, 12.5 and 25 mg/day vs. placebo respectively). Thirst and slight increases in serum sodium were more common in patients treated with satavaptan compared with placebo, while other adverse events were similar. Conclusions The administration satavaptan for a 14‐day period is associated with reduction in ascites in patients with moderately severe cirrhosis without hyponatraemia under diuretic treatment.

     

Comparison of treatment patterns,resource utilization,and cost of care in patients with metastatic pancreatic cancer treated with first-line nab-paclitaxel plus gemcitabine or FOLFIRINOX

Background: We compared real-world treatment patterns, resource utilization, and cost of care for patients with metastatic pancreatic cancer treated with first-line nab-paclitaxel + gemcitabine or FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin).

Methods: This was a retrospective study of inpatient and hospital-based outpatient data in the United States. Primary endpoints included median time to treatment discontinuation (TTD) and total cost of care per patient per month. Secondary endpoints included supportive care costs and hospitalization rate and length.

Results: Overall, 345 patients were included (nab-paclitaxel + gemcitabine, n = 182; FOLFIRINOX, n = 163). Median TTD was significantly longer with nab-paclitaxel + gemcitabine vs FOLFIRINOX (4.3 vs 2.8 months; P = .0009). Mean acquisition cost was higher with nab-paclitaxel + gemcitabine ($10,643 vs $6549; P = .0043), but mean total cost of care was lower ($16,628 vs $19,936; P = .1740). Supportive care cost was significantly lower with nab-paclitaxel + gemcitabine ($1995 vs $6456; P < .0001). Hospitalization rate and length were both significantly lower with nab-paclitaxel + gemcitabine.

Conclusions: Despite higher acquisition costs with nab-paclitaxel + gemcitabine, FOLFIRINOX-treated patients had higher total costs driven by supportive care. Toxicity-related costs and drug acquisition costs should be considered when evaluating total cost of care.     

Comparative effectiveness of azathioprine in Crohn's disease and ulcerative colitis: prospective, long-term, follow-up study of 394 patients

Background The long‐term efficiacy for thiopurinic drugs in Crohn’s disease (CD), and particularly in ulcerative colitis (UC), has been insufficiently studied. Aim To evaluate prospectively and compare the long‐term effectiveness of azathioprine (AZA) in CD and UC. Methods Three hundred and ninety‐four AZA treated patients were included consecutively included. Truelove‐modified index and CDAI were used to assess effectiveness. Hospitalizations and surgical procedures were recorded. Results Two hundred and thirty‐eight patients with CD and 156 with UC received AZA for a median of 38 months. Effectiveness: Partial response/remission was achieved in 34%/49% of CD patients and in 47%/42% of UC (nonstatistically significant differences). Steroid treatment: Prior to AZA, 49% of CD patients were receiving steroids, whereas only 8% needed steroids after therapy (P < 0.001). Corresponding figures in UC patients were 39% vs. 9% (P < 0.001). Hospitalizations: Prior to AZA, the rate of hospitalizations in CD was 0.190 per‐patient‐year, while after treatment, it decreased to 0.099 (P < 0.001). Corresponding hospitalization rates in UC were 0.108 vs. 0.038 (P < 0.001). Surgery: The rate of surgery in CD prior/after AZA was 0.038/0.011 per‐patient‐year (P < 0.001). The number of surgical interventions in UC prior/after AZA treatment was 26/0 (the rate per‐patient‐year was 0.018/0) (P < 0.001). Conclusions Our results confirm the effectiveness of AZA in inflammatory bowel disease, not only in the short term but also in the long term, resulting in a steroid sparing effect and in both a reduction in the number of hospitalizations and surgical procedures. AZA is similarly effective for both CD and UC patients.     

Direct costs of warfarin treatment among patients with atrial fibrillation in a Finnish health care setting

ABSTRACT

Objective: The main objective was to estimate the mean direct costs of warfarin treatment for atrial fibrillation (AF) patients. Secondly, the costs of initiating warfarin treatment during a 60-day period and the impact of International Normalized Ratio (INR) and co-morbidities on costs were estimated.

Design and data: The study was performed as a retrospective cohort study over a 12‐month period in a Finnish communal health care setting. All AF patients aged 65 years or older (n = 250) with warfarin treatment were identified from the database of the health service district of an urban area. Patient specific information related to co-morbidities, INR-control, complications and health care resource use were collected. Cost information was obtained from the Finnish national health care unit cost list.

Methods: The effect of treatment balance and other background variables on treatment costs were evaluated using ordinary least squares regression (OLS), log-transformed OLS and generalized linear model (GLM). The mean costs were calculated on the basis of the different models and bias corrected and accelerated (BCa) bootstrap confidence intervals (CIs) were calculated for the mean costs.

Results: The best fitting cost model was log-transformed OLS. The costs of warfarin treatment on the basis of the log-transformed model were 589.82 euros (BCa 95% CI: 586.68–591.99) per patient compared to 616.00 euros (BCa 95% CI: 579.98–652.96) obtained with the OLS-model. For the treatment initiation period, the mean costs were 263 euros (BCa 95% CI: 218.90–314.71). Depending on the way that INR-control was defined, the mean costs were 95.27 euros or 166.92 euros higher for patients who were not in the defined INR-balance.

Conclusions: The INR-control has a significant impact on the warfarin treatment costs. The choice of model influences the estimated mean costs. In addition, different models identify statistically significant effects between different background variables and costs.     

Prescribing patterns and healthcare costs of gout

Objective/methods: The Longitudinal Health Insurance Database (LHID) 2010 was used to identify gout cases and their number of gout flares.

Results: Out of 21,376 gout patients, a total of 3561 (16.7%) had frequent gout flares (≥3 gout flares/year). Average all-cause healthcare utilization (35.9 visits vs. 30.7 visits; p?<?.001) and gout-related utilization (22.7 visits vs. 15.6 visits; p?<?.001) were higher in frequent gout flare patients than in those with infrequent gout flares. The median gout-related cost (USD $369 vs. $285; p?<?.001), but not all-cause costs (p?=?.25), were higher in frequent gout flare patients compared to the infrequent group. Over 55.8% of the flares were treated with colchicine?+?NSAIDs.

Conclusions: In conclusion, patients with frequent gout flares had higher healthcare utilization and gout-related healthcare costs. Colchicine?+?NSAIDs are commonly used therapy for gout flare.     

Optimising immune tolerance induction strategies in the management of haemophilia patients with inhibitors: a cost-minimisation analysis

ABSTRACT

Background: The objective of this study was to model the economic impact of optimal dosing of immune tolerance induction (ITI) in haemophilia patients with inhibitors. Evidence based research suggests that, in the right patient population characterised by ITI risk status, the use of high-dose ITI regimen in ‘poor risk’ patients, and the low-dose regimen in ‘good risk’ patients, would be the cost effective strategy. The model also explored the impact of anamnestic response (AR), a phenomenon which worsens patients’ ITI risks.

Method: A cost-minimisation technique was used to compare the cost of managing inhibitor patients whose bleeds were managed pre-ITI with an immunogenic bypassing agent, activated prothrombin complex concentrate (APCC), with patients previously on a non-immunogenic product, recombinant activated factor VII (rFVIIa). Patients were subsequently offered a low-dose or high-dose ITI regime depending on their ITI risk status. The study perspective was that of the United Kingdom NHS, hence, all resources used were based on UK costs.

Results: The model estimated the mean cost of managing inhibitor patients from detection of titres through ITI to be £959?250.39 and £770?834.17 in the APCC and rFVIIa treatment options, respectively. Meanwhile, the costs per effectively tolerised patients were £1?505?279 and £1?196?706 for APCC and rFVIIa treated patients, respectively. Of the incremental cost in the APCC-treated patients in the model, £129?367 (68%) represents additional ITI cost attributable to anamnestic response to earlier treatment with an immunogenic bypassing agent (APCC).

Conclusion: The study concludes that decreasing factor VIII usage during ITI, through the identification and management of ‘good risk’ ITI patients with low-dose protocol, while managing ‘poor risk’ patients with high-dose regimen, will significantly lower the cost of ITI. Furthermore, avoiding AR prior to ITI by using non-immunogenic bypassing agents to manage spontaneous bleeds also has the potential for significant cost savings.     

Maintenance plus reliever budesonide/formoterol compared with a higher maintenance dose of budesonide/formoterol plus formoterol as reliever in asthma:an efficacy and cost-effectiveness study

ABSTRACT

Objective: To evaluate efficacy and costeffectiveness of budesonide/formoterol (Symbicort) maintenance (one dose once or twice daily) plus additional doses as needed (Symbicort Maintenance And Reliever Therapy, SMART) compared with a higher fixed dose of budesonide/ formoterol with formoterol as needed in patients with persistent asthma.

Study design and methods: 6‐month, open, randomised study of 465 patients either not well controlled on an inhaled corticosteroid (ICS), or well controlled on a combination of ICS and a long-acting β₂‐agonist (LABA). Treatments: budesonide/formoterol 160/4.5?µg, one inhalation, once or twice daily maintenance plus additional doses as-needed (1 × SMART or 2 × SMART), or budesonide/formoterol 160/4.5?µg two inhalations twice daily plus formoterol 4.5?µg as needed (2 × 2 FIX + F). Children 6–11 years old used an 80/4.5?µg dose strength. Primary variables of efficacy were the changes in the Asthma Control Questionnaire (ACQ₅) and morning peak expiratory flow (PEF).

Results: Mean age of patients 40 years (range 6–82 years); 53% female. No differences between the groups were found in ACQ₅ scores or asthma exacerbation rates. Morning PEF was higher in the 2 × 2 FIX + F group vs. the 1 × SMART and 2 × SMART groups (differences 13?L/min and 9?L/min, respectively; p < 0.002). The 1 × SMART group showed a significant decrease in asthma controlled days compared with the two other groups. No difference was seen between the 2 × SMART group and the 2 × 2 FIX + F group. Treatment costs were significantly lower in the SMART groups compared with the 2 × 2 FIX + F group.

Conclusion: Compared with the 2 × 2 FIX + F treatment the use of budesonide/formoterol was 30–40% lower in the SMART groups while maintaining equal ACQ₅ scores. Daily asthma control improved equally with 2 × SMART compared to 2 × 2 FIX + F with a reduction in asthma medication cost. The one dose once daily maintenance treatment (1 × SMART) resulted in a low level of treatment failure (exacerbations) but led to more days with symptoms. Therefore, a daily dose of two inhalations seems to be the lowest appropriate dose in patients with moderate persistent asthma.