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Cost-effectiveness analysis of the terlipressin-glycerin trinitrate combination in the pre-hospital management of acute gastro-intestinal haemorrhage in cirrhotic patients |
Combier E, Levacher S, Letoumelin P, Joseph A, Pourriat J L, de Pouvourville G |
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Record Status This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn. Health technology A terlipressin (triglycyl-lysine vasopressin, TER) and glycerin trinitrate (GTN) combination, administered before endoscopy, was used for the early treatment of upper gastrointestinal haemorrhages due to rupture of oesophageal varices (ROV), in cirrhotic patients suffering from portal hypertension. TER was administered through intravenous injections at home, then associated with GTN via the application of a patch (10 mg GTN over 24 hours). This was followed by the endoscopic diagnosis of ROV and admission to the intensive care unit (ICU). Intravenous administration of TER comprised 1 mg for patients under 50 kg, 1.5 mg for patients weighing 50 to 70 kg, 2 mg for patients over 70 kg; repeated at the 4th and 8th hour.
Economic study type Cost-effectiveness analysis.
Study population The study population comprised cirrhotic patients suffering from portal hypertension, who were eligible for the early treatment of upper gastrointestinal haemorrhages due to ROV.
Setting The setting was a hospital. The economic study was carried out at the Hopital Jean Verdier, Bondy, Assistance Publique-Hopitaux de Paris, France.
Dates to which data relate The effectiveness and resource use data were gathered from October 1990 to June 1993. The price year was 1997.
Source of effectiveness data The effectiveness evidence was derived from a single study.
Link between effectiveness and cost data The costing was undertaken prospectively on the same patient sample as that used in the effectiveness analysis.
Study sample Power calculations were not performed to determine the sample size. The sample consisted of 76 patients presenting at the institution (ICU and emergency services) during the study period, some of whom had more than one episode of bleeding. Overall, 83 cases were included in the study. Of these, 40 patients were administered TER-GTN and 43 patients were administered placebo.
Study design The study was a double-blind, placebo-controlled, clinical trial, carried out in a single centre. The methods of randomisation and blinding were not reported. The patients were followed until day 42 after the haemorrhage episode due to ROV.
Analysis of effectiveness It was not reported whether the effectiveness analysis was conducted on an intention to treat basis or on treatment completers only. However, it appears that all the patients participating in the study have been accounted for in the analysis. The primary health outcomes assessed were:
the death rates at day 42;
the length of stay in the ICU and gastroenterology departments;
the use of blood products, such as blood units, albumine, and fresh frozen plasma;
additional examinations, such as blood plus urinary laboratory tests, complete blood count plus platelets, haemostasia check-up, hepatic check-up, blood gas, and lung X-ray;
haemostatic procedures, such as endoscopy plus sclerosis, blackmore tamponade, and transjugular intrahepatic porto-systemic shunt; and
complications, such as hepatic encephalopathy, delirium tremens, kidney insufficiency, cardio-respiratory failure, infection, and other intensive care conditions.
Statistical analyses showed that the groups were similar in terms of both their demographics (gender and age) and clinical characteristics. The clinical characteristics included weight, blood-pressure, haematocrit, haemoglobin and prothrombin levels, endoscopic scleroses, and severity of liver disease (Child-Pugh classification).
Effectiveness results The mortality rates at day 42 were 46.5% in the placebo group and 27.5% in the TER-GTN group.
The reduction in mortality related to the use of TER-GTN was estimated to be 19% (90% confidence interval: 2 - 36), that is 8 deaths (range: 1 - 15) were avoided for a group of 40 patients.
The overall mean length of stay was 17.9 (standard deviation, SD 11.4) days in the TER-GTN group and 12.8 (SD 8.8) days in the placebo group, (p=0.0239).
The length of stay in the ICU was 7.1 (SD 6.3) days in the TER-GTN group and 5.7 (SD 5.3) days in the placebo group, (p=0.2987). The length of stay in the gastroenterology department was 10.8 (SD 10) days in the TER-GTN group and 7.1 (SD 6.7) days in the placebo group, (p=0.0481).
In terms of the average use of blood products, there were:
36 blood units (90%) consumed in the TER-GTN group, compared with 42 (97.7%) in the placebo group, (p=0.191);
8 albumin units (20%) used in the TER-GTN group, compared with 7 (16.3%) in the placebo group, (p=0.999), and
11 fresh frozen plasma units (27.5%) in the TER-GTN group, compared with 14 (32.6%) in the placebo group, (p=0.999).
In terms of the average numbers of additional examinations performed, there were:
7.60 (SD 5.6) blood plus urinary laboratory tests in the TER-GTN group and 5.56 (SD 5.2) in the placebo group, (p=0.040);
11.56 (SD 8.5) complete blood counts with platelets in the TER-GTN group and 8.86 (SD 5.6) in the placebo group, (p=0.130);
8.13 (SD 5.8) haemostasia check-ups in the TER-GTN group and 5.95 (SD 3.9) in the placebo group, (p=0.080);
4.30 (SD 3) hepatic check-ups in the TER-GTN group and 3.26 (SD 2.9) in the placebo group, (p=0.030);
4.85 (SD 9) blood gas tests in the TER-GTN group and 2.28 (SD 3) in the placebo group, (p=0.060); and
4.62 (SD 4.8) lung X-rays in the TER-GTN group and 3.60 (SD 3.7) in the placebo group, (p=0.051).
The haemostatic procedures and complications were generally not statistically different between the groups. The exception was cardio-respiratory failure, which was more frequent in the placebo group (23.3%) than in the TER-GTN group (7.5%), (p=0.048).
Clinical conclusions The analysis has shown that TER-GTN was highly effective in reducing the mortality rate at day 42. However, it required more laboratory tests and longer hospital stay, (especially in gastroenterology wards, compared with placebo.
Measure of benefits used in the economic analysis The health outcome measures derived from the effectiveness analysis were not aggregated to obtain a summary benefit measure. A cost-consequences analysis was therefore conducted.
Direct costs Discounting was irrelevant due to the short time horizon of the study. The cost/resource boundary was that of the hospital. The unit costs per resource used or episode occurred, and the quantities of resources used, were reported. The health service costs were for hospital stay (housing and administration expenses), the medical treatments included in the protocol, blood products, additional examinations, complications, and specific therapies.
The cost analysis assumed that the treatment had no impact on the fixed costs, and that the excess cost was due to the costs related to the treatment. The costs and the quantities of the resources consumed were estimated using a microcosting approach, which aimed to identify all the components involved in the treatment. The costs were obtained from actual expenses borne by the hospital. The resources were estimated from the daily charts of the patients enrolled in the study. Data from the gastroenterology departments were missing for five patients (three in the placebo group and two in the treatment group), and each patient was allocated the mean cost of the group to which he or she belonged. The resource use data were gathered during the trial period (October 1990 to June 1993). The price year was 1997.
Statistical analysis of costs The Wilcoxon test was used.
Indirect Costs The indirect costs were not included.
Currency French francs (Ffr). No currency conversions were conducted.
Sensitivity analysis No sensitivity analysis was conducted.
Estimated benefits used in the economic analysis See the 'Effectiveness Results' section.
Cost results The total cost per patient was 19,323.7 Ffr in the TER-GTN group and 14,226.1 Ffr in the placebo group. The excess cost in the treatment group was 5,097.7 Ffr and the difference reached statistical significance, (p=0.0150).
The total extra cost for the 40 patients in the TER-GTN group was 203,908 Ffr.
There were two main cost drivers. First, the cost of terlipressin (1,398.8 Ffr), which accounted for 27% of the mean cost per patient. Second, the hospital stay expenses, which were 4,319.9 Ffr in the TER-GTN group and 3,105 Ffr in the placebo group, with an excess cost of 1,214.9 Ffr. This accounted for 24% of the mean cost per patient.
Assuming that eight deaths were prevented with TER-GTN, the excess cost per death prevented was 25,489 Ffr.
The costs of a hospital stay for ROV in 40 public hospitals were estimated using data from a national survey by the French Ministry of Health. The findings showed that the excess cost per patient was less than 10% of the total cost of one hospital stay.
Synthesis of costs and benefits Authors' conclusions The combination of terlipressin (TER) and glycerin trinitrate (GTN) was cost-effective in the pre-hospital treatment of upper gastrointestinal haemorrhages in cirrhotic patients, because it substantially reduced the mortality rate at day 42 at a moderate cost.
CRD COMMENTARY - Selection of comparators Placebo was chosen as the comparator because the analysis aimed to assess the active value of the drug treatment. You should evaluate whether the health technology represents a widely used intervention in your own setting.
Validity of estimate of measure of effectiveness The effectiveness analysis used results from a double-blind, randomised, clinical trial, and therefore, the internal validity of the study is likely to be high. However, although appropriate statistical analyses were conducted to limit confounding and selection bias, the authors recognised that the sample size was quite small due to the rarity of the disease. Therefore, "the absence of statistical difference between the two groups for certain complications or surgical therapeutic procedures ... can be explained by the lack of statistical power in the study". Further, the patients' characteristics at baseline were not reported.
Validity of estimate of measure of benefit No summary benefit measure was used in the economic analysis even though several health outcomes were obtained from the effectiveness analysis. It would have been useful to have observed the impact of a benefit measure based on patient health.
Validity of estimate of costs It appears that all the categories of costs relevant to the perspective adopted have been included in the study. The authors limited their analysis to direct variable costs, assuming that the fixed costs were not affected by the treatment. Although the cost estimates were quite specific to the study setting, the unit costs and quantities of the resources used were reported separately. This increased the external validity of the study.
Other issues The study confirmed the results of published analyses. The authors did not explicitly address the issue of the generalisability of the study's findings to other settings. Sensitivity analyses were not carried out.
Implications of the study The results support the cost-effectiveness of TER-GTN in the pre-hospital treatment of upper gastrointestinal haemorrhages in cirrhotic patients. However, further research should focus on the evaluation of long- and short- term survival and on the patients' quality of life.
Source of funding Funded by Laboratoire Ferring SA.
Bibliographic details Combier E, Levacher S, Letoumelin P, Joseph A, Pourriat J L, de Pouvourville G. Cost-effectiveness analysis of the terlipressin-glycerin trinitrate combination in the pre-hospital management of acute gastro-intestinal haemorrhage in cirrhotic patients. Intensive Care Medicine 1999; 25(4): 364-370 Other publications of related interest Comment: Intensive Care Medicine 1999;25:345-7.
Indexing Status Subject indexing assigned by NLM MeSH Acute Disease; Antihypertensive Agents /economics /therapeutic use; Cost-Benefit Analysis; Double-Blind Method; Drug Therapy, Combination; Emergency Treatment; Esophageal and Gastric Varices /complications; Female; France; Gastrointestinal Hemorrhage /drug therapy /etiology /mortality; Humans; Intensive Care Units; Length of Stay; Liver Cirrhosis /complications; Lypressin /analogs & Male; Nitroglycerin /economics /therapeutic use; Rupture, Spontaneous; derivatives /economics /therapeutic use AccessionNumber 21999000873 Date bibliographic record published 31/08/2002 Date abstract record published 31/08/2002 |
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