Over the 26-month prospective observational period the cohort of NSAID users contained 51,903 NSAID users with 10,402 patient years of NSAID exposure. From this cohort, 104 cases were hospitalised with serious NSAID ulcer complications. Because of the geographically isolated position, referral to other hospitals, especially for acute gastrointestinal events, is extremely rare. Therefore, in this population the incidence of hospitalisation due to serious NSAID ulcer complications can be reliably calculated at 1% per year of NSAID use.
Table shows demographic characteristics and co-morbidities. The typical case is an elderly patient, age at diagnosis 70.4 ± 16.7 years (mean ± SD; range 22 to 98 years), 55.8% were female. Many patients reported concurrent disease or previous medical events suggesting serious, especially cardiovascular, co-morbidity. This self-reported co-morbidity was supported by the concomitant medication used (Table ). The 104 cases together used 12 different NSAIDs (Table ). The duration of NSAID use before the gastrointestinal event varied; the median was 1.13 months (interquartile range 10 days to 12 months). Most patients did not exceed their prescribed maximum daily dose. However, occasional use of more than one NSAID simultaneously was reported by 12 patients (11.5%).
Sociodemographic characteristics and co-morbidities for cases and controls
NSAIDs and concurrent medication in use at the time of the gastrointestinal event
In most cases (80 patients, 76.9%), serious NSAID ulcer complication was the reason for presentation and hospitalisation. In the remainder a serious NSAID ulcer complication took place during hospitalisation for another reason. Characteristics of the gastrointestinal events are presented in Table . No diagnostic procedure was performed in only six (5.8%) patients, because of co-morbidity or advanced age. The mean haemoglobin level at presentation was 6.1 ± 1.9 mmol/l (mean ± SD; range 1.8 to 9.8). In those using coumarin, the international normalized ratio (INR) at presentation was 4.87 ± 1.41 (mean ± SD) but the mean haemoglobin level at presentation did not differ from that in patients not taking coumarin, and neither did the number of units of blood administered during hospitalisation.
Characteristics of the gastrointestinal event attributable to use of non-steroidal anti-inflammatory drugs
Mortality due to serious NSAID ulcer complications was high: 11 patients (10.6%) died in hospital, and another 4 (3.8%) died within 3 months of the diagnosis. The incidence of in-hospital mortality due to serious NSAID ulcer complications can be calculated at 21.2 per 100,000 NSAID users.
For 104 cases, 757 controls were selected from the remaining cohort of NSAID users. On receiving the first questionnaire 225 controls responded, of whom 203 were included. On receiving a second questionnaire, a further 123 responded, of whom 81 were included. From the 64 excluded responders, 18 questionnaires were returned by someone other than the selected control, 15 denied taking NSAIDs, 17 refused, 1 had been hospitalised in a psychiatric hospital, 1 was a case who had already been included as such, and for 12 controls relatives informed us that the selected person had died. In the group of 20 randomly selected non-responders who were telephoned, no bias for non-responding was found.
In total 284 controls, frequency matched for age and sex, with NSAID use on the index date were included. Demographic characteristics, co-morbidities and current medication use are summarised in Tables and . The mean age was slightly lower for the controls than for the cases because insufficient numbers of controls could be found for some of the extremely elderly cases.
In univariate analysis, cases and controls differ significantly with regard to body mass index, smoking habits, marital status, medical history of heart failure, myocardial infarction, stroke and renal insufficiency (Table ). Significant differences in medication use were found for PPIs, coumarin, low-molecular-mass heparin, analgesics, diuretics, angiotensin-converting-enzyme inhibitors, oral glucose-lowering drugs, benzodiazepines and disease-modifying anti-rheumatic drugs (Table ).
Concomitant use of PPIs was significantly higher in the controls than in the cases (cases 13.5%; controls 27.1%; p = 0.005). Use of selective COX-2 inhibitors was comparable (cases 16.4%; controls 17.6%; p = 0.77). Use of the preferential COX-2 inhibitor meloxicam differed, but not significantly, and numbers were small (cases 1%; controls 4.2%; p = 0.20).
A full logistic regression model of all significant and other likely causational variables was reduced stepwise to a parsimonious model, finally containing concomitant use of PPIs, low-molecular-mass heparin, acetaminophen, coumarin, and history of heart failure (Table ). Use of selective COX-2 inhibitors was not associated with a significantly reduced risk for serious NSAID ulcer complications (p = 0.74); neither was the use of preferential COX-2 inhibitors (p = 0.22). Concomitant use of PPIs was associated with a significantly reduced risk for serious NSAID ulcer complications (adjusted odds ratio 0.33; 95% confidence interval 0.17 to 0.67; p = 0.002).
Multivariate analysis of significant variables and other likely causational variables for serious NSAID ulcer complications
In a post hoc subgroup analysis of selective COX-2 inhibitor users, there were no significant differences in concomitant use of low-dose aspirin (8 cases (47%); 19 controls (38%); p = 0.51), non-selective NSAIDs (3 cases (18%); 10 controls (20%); p = 0.83) or PPIs (3 cases (18%); 17 controls (34%); p = 0.20); neither were there significant differences in concomitant use of coumarin, heparin, steroids or high-dose H2RAs or in ulcer history.
Furthermore, among those taking selective COX-2 inhibitors, cases and controls did not differ significantly with regard to the number of risk factors for NSAID-associated gastropathy, suggesting comparable risk profiles. Similarly, in a post hoc subgroup analysis for those taking either proton-pump inhibitors or high-dose H2RAs, cases and controls again did not differ significantly with regard to the number of risk factors for NSAID-associated gastropathy.
In six patients no diagnostic procedure was performed because of co-morbidity or advanced age. In a post hoc analysis these patients with probable NSAID ulcers were compared with the 98 patients with definite NSAID ulcers. Significant differences between patients with probable or definite NSAID ulcers were age (mean 87.3 and 69.4 years, respectively; p = 0.01), medical history of diabetes mellitus, chronic obstructive pulmonary disease and in-hospital mortality (66.7% and 7.1%, respectively; p = 0.001). Excluding these patients with probable NSAID ulcers from the cases did not significantly change the results of the univariate or multivariate analyses.
In 24 patients, serious NSAID ulcer complications occurred in hospital. These patients were compared with the 80 patients who presented with NSAID ulcer complications. Significant differences between in-hospital or presenting patients were sex (37.5% and 61.3% female, respectively; p = 0.04), ulcer history (29.2% and 11.3%, respectively; p = 0.03), medical history of a malignancy, diabetes mellitus, use of oral glucose-lowering drugs and use of low-molecular-mass heparin (45.5% and 3.8%, respectively; p < 0.001). Exclusion of these in-hospital patients from the cases resulted in a significant change in the univariate analyses for use of oral glucose-lowering drugs (cases 6.3%; controls 5.3%; p = 0.74) and for use of low molecular mass heparin (cases 3.8%; controls 0.7%; p = 0.04). The results of the multivariate analysis also changed (Table ).
Multivariate analysis after exclusion of patients with in-hospital NSAID ulcer complications