Patients and methods

The study was carried out in Denmark, Finland, Norway, and Sweden and, according to the protocol, comprised a five year follow up period. Patient recruitment started in February 1991 and follow up ended in April 1999.

Eligible for inclusion into the clinical study were patients with chronic reflux symptoms and oesophagitis (of at least grade II according to the Savary-Miller classification) verified at endoscopy performed prior to inclusion.13 ,14 These patients were initially given either 20 or 40 mg of omeprazole daily for up to four months to control symptoms and to heal oesophagitis. Successfully treated patients were then randomised to either maintenance treatment with omeprazole, using the same dose as needed to heal oesophagitis (20 or 40 mg once daily) or to open ARS. Patients randomised to surgery could be given omeprazole until the time of operation which should, according to the protocol, have been performed within three months of randomisation (actual median interval was 71 days). Details of surgery have been reported previously.13

Patients whose oesophagitis did not heal or who had incomplete symptom control at the preoperative endoscopy (n=34) were treated surgically and followed according to the protocol, but otherwise these patients did not participate in the health economic analysis. This means that the economic analysis, as well as the clinical study itself, was set up to compare continuous medical treatment with surgery in patients initially treated successfully with omeprazole.

The protocol stated that each patient should have a hospital based follow up visit every six months for scoring of symptoms and registration of eventual adverse events. After three and nine months of therapy, a similar assessment was done by telephone.

Endoscopic examinations of the oesophagus, stomach, and duodenum were performed within nine days prior to inclusion to verify that oesophagitis was healed. Endoscopic examinations were thereafter performed at the 12, 36, and 60 month visits or at the time of an eventual relapse of symptoms.

In patients allocated to omeprazole, a dose adjustment was allowed in case of symptom and/or oesophagitis relapse. Of the 155 patients allocated to omeprazole, 139 had 20 mg and 16 patients 40 mg daily. Only a minority of patients had the dose subsequently adjusted due to symptom relapse.15 ,16 Only one patient took the maximally allowed dose of 60 mg daily. Patients not responding to higher daily doses of omeprazole (⩾60 mg) were offered surgical treatment. Likewise, patients who relapsed after surgery could, according to the protocol, either have a reoperation or be prescribed omeprazole whereupon the respective costs of these remedial therapies were recorded.

Results

Initially 155 patients were randomised to ARS but nine refused surgery, one was excluded due to a subsequently diagnosed bronchial carcinoma, and one patient was found to lack verified oesophagitis at the preinclusion endoscopy. A total of 155 patients were randomised to long term medical treatment but one patient who never took any study medication was excluded from the analysis. During the five years, 22 patients were withdrawn from the surgical treatment group and 21 from the medical treatment group. The average time in the study for these patients was 864 days. Reasons for withdrawal are given in table 2. Patients in the two arms were well matched with regard to baseline characteristics (table 2).

At baseline, 99 patients in the surgical arm and 103 randomised to omeprazole completed the health economic questionnaire. The number of patients who completed the questionnaire at the subsequent visits varied between 60 and 86 among the operated patients and between 72 and 93 among those treated with omeprazole.

The clinical results are presented elsewhere,16 ,17 but the main result was that analysis of time to treatment failure revealed a significant difference in favour of surgery (p<0.001). However, when dose adjustment of omeprazole was allowed to control symptoms, no significant difference was found between the two arms (p=0.088). The two treatments were also found to result in maintained normalisation of quality of life.

Resource consumption in non-monetary terms during years 1–5 is presented in table 3. Seven patients in the medical arm had an antireflux operation during the first year, six patients in year 2, and three in year 4. The mean postoperative hospital stay after ARS was 7.2 days.

The total number of endoscopies was similar in the two treatment groups: 442 in the omeprazole group and 424 in the operated patients. When protocol driven endoscopies were excluded, the respective numbers were reduced to 52 and 69. Thus the number of endoscopies per patient during the five years was 0.34 in the medical arm and 0.44 in the surgical arm.

The cumulative number of visits to a doctor (excluding endoscopy visits but incorporating follow up visits after surgery) was 1199 in the medical and 1222 in the surgical groups. When the number of visits was calculated according to the rules described in the methods section, the numbers dropped to 864 and 388, respectively. The corresponding number of visits per patient during the five years was 5.6 on omeprazole and 2.7 after ARS. The number of visits to a nurse was similar in the two treatment groups (114 v 103).

A redo-fundoplication was carried out in five patients due to GORD relapse; one patient during the first year, one during the second, two had a reoperation during the fourth, and one during the fifth year after inclusion. Twenty two additional operations (in 15 patients) were done in the surgical group; six incisional hernias were operated on during the first postoperative year, seven during the second, four during the third, three during the fourth, and two during the fifth postoperative year. In the medical arm, one incisional hernia had to be repaired during the fourth year after inclusion.

In the omeprazole treatment arm the average patient consumed 1220 capsules containing 20 mg omeprazole (total 187 884 capsules in the whole group) and 296 capsules containing 40 mg of omeprazole (total 45 534 capsules in the whole group). Each patient randomised to surgery consumed on average 144 capsules (20 mg, 20 735 in total) and 80 capsules (40 mg, 11 575 in total). Consumption of omeprazole while waiting for surgery was, as noted above, not measured.

The average transportation time to an outpatient visit or to an endoscopy was calculated to be 55 minutes, based on information from 1494 questionnaires. This time period was subdivided into transportation by private car (37 minutes), by public transportation (14 minutes), by taxi (one minute), and by other modes of transportation (three minutes). Assuming a mean travelling speed of 35, 25, and 45 km per hour for private car, bus, and taxi, this corresponded to a driving distance of 21.6 km, 5.8 km, and 0.8 km, respectively.

GORD related sick leave was calculated per patient employed at baseline. In the surgical arm, 74 of the 99 patients who answered the health economic questionnaire were employed. The corresponding value in the medical treatment group was 93 of 103. GORD related sick leave differed substantially between the two treatment arms. The average days of sick leave per employed patient amounted to 35 days in the surgical arm. This estimation was based both on information from the Swedish insurance office regarding sick leave in connection with the operation (32 days), and on data from the health economic questionnaire regarding the period six months to five years after operation. As expected, substantial sick leave was required in close association with the operation, whereas after operation it decreased considerably. GORD related sick leave in the medical treatment group was only 9.1 days per employed patient.

Companions' absence from work was almost identical in the two study arms (0.11 v 0.14 days per patient).

Discussion

The present study, comparing monetary resource consumption by medical and surgical treatment of GORD, has the obvious advantage of applying a prospective protocol setting where costs were recorded when they occurred in the management of strictly comparable groups of patients. This methodological approach increases the precision of the cost estimates relevant to the two treatment options which is particularly true when our data are compared with the findings of earlier modelling studies.

Using a Markov model to assess the cost utility of long term omeprazole treatment versus laparoscopic fundoplication, Heudebert and colleagues8 reported an analysis which applied the perspective of a third party payer within the USA. Basically, both strategies were equally effective but omeprazole was found to be less expensive within the five year time horizon. Depending on the assumptions introduced into the model, a “break even” point between the two strategies was reached after about 10 years. Other studies, applying modelling and/or retrospective methodological approaches, have favoured surgical treatment reaching a “break even” point after a shorter time period of comparison.9 ,12 Accordingly, most studies comparing the cost effectiveness of modern therapies for GORD have come to the conclusion that the surgical strategy is most cost effective in the long term perspective.

It is interesting to note that the present prospective, controlled, randomised study confirmed important observations in the earlier modelling and/or retrospective studies. Firstly, when interest was focused on direct medical costs, the relative costs of the operation and medication had a paramount impact on the final outcome. Other cost items were by and large marginalised. It follows from this basic observation that the result of a comparison between the costs of medical and surgical treatment of GORD will, by necessity, vary from one country to another and probably also from one time period to another. Among the four Nordic countries participating in the study, Finland had the lowest relative cost of an operation. Consequently, the five year direct cost of surgery was significantly higher than that of omeprazole in Denmark, Norway, and Sweden whereas the opposite was found in Finland.

Secondly, the study lends support to the hypothesis that the costs of medical treatment are relatively constant over time whereas those of surgical treatment are associated with a huge initial investment followed by low annual costs, eventually resulting in surgical treatment becoming less expensive than medical treatment with time.

Inclusion of indirect costs into health economic analyses is to some extent controversial but the results from this study indicate that ignoring loss of production due to absence from work would give rise to a considerable underestimation of the cost burden for the society inflicted by, for example, surgery. Furthermore, while in this study it was not possible to assess the cost of disease related decreases in productivity while at work, there is some evidence that this cost may be substantial for GORD.18

To comprehensively interpret the present observations and calculations we have to consider the limitations of the methodology presently applied. Even though our resource data base came from a randomised clinical trial, some uncertainty in the resulting estimates of costs is inevitable. A typical problem when utilising a clinical trial for collection of resource data is the inclusion/exclusion of protocol driven costs—that is, costs that are mandated by the trial protocol but which are unlikely to occur in clinical practice. In the present study we incorporated rules to exclude protocol driven visits and endoscopies from the cost analysis. Interestingly, we found that even when including those costs, the main outcomes remained unchanged. Another comment relevant to the protocol is that it defined the lowest dose of omeprazole (20 mg) to be given as maintenance treatment. Today it is well known that some patients can be maintained on a lower dose.19

A general problem in health economic evaluations is the uncertainty inherent in cost estimates. A potential problem with this particular study is that the cost estimates may stem primarily from charges rather than estimates of the true costs. However, the sensitivity analysis revealed that even large changes in the cost estimates did not alter the sign of the differences found in direct medical costs.

There are also other methodological aspects which have to be taken into consideration. Pooling of data across countries regarding resource consumption in non-monetary terms can be questioned, especially pooling of time for travelling and number of days on sick leave. Furthermore, the patient completed the questionnaire on travelling and sick leave every six months. This rather long period may give rise to recall errors. Furthermore, the response rate decreased somewhat during the course of the study. Due to these limitations, estimates of direct medical costs were deemed to be more reliable than estimates of total costs. However, the present approach to obtain a total cost analysis is the most complete so far applied to GORD patients.

In general terms it is always questionable as to which time span should be applied to be most relevant on a strict comparison of these two treatment options. It is well known that individual decision makers sometimes take rather limited time horizons into account. From a societal point of view it may be more significant to cover a limited time period. The main reason for this is that the available health care technologies, and these associated costs, are prone to change. For instance, laparoscopic fundoplication has replaced open fundoplication in many hospitals. Laparoscopic ARS has been shown to be less costly than open surgery as the number of days in hospital and also the number of days on sick leave is reduced.20-26 In a recent Swedish prospective trial comparing the total costs of open and laparoscopic fundoplication, it was found that the total societal cost during the first postoperative year was reduced from SEK 74 608 to SEK 40 289 by applying the latter operative technique.20 On the other hand, the costs of PPIs are likely to fall substantially with the passage of time. Furthermore, extrapolation of costs and effectiveness is always inferior to prospective data collection.

In summary, this study provides useful information relevant to the long term management of patients with GORD. Direct medical costs over five years (costs of medication, surgery, visits, and examination) were found to be significantly lower for omeprazole treatment than for surgical treatment in Denmark, Norway, and Sweden. However, in Finland the direct medical cost was found to be significantly lower for ARS. Including indirect costs (loss of production due to GORD related sick leave), we found the costs of surgical treatment to increase substantially.