Non-steroidal anti-inflammatory drugs (NSAIDs) frequently cause gastropathy, symptomatic gastrointestinal (GI) ulcers and complications of ulcers (perforations and bleeds).1^–3 In 1997 rheumatologists in Amsterdam, The Netherlands, decided to use a prophylactic strategy for patients with high risk of NSAID gastropathy, defined as age ⩾60 years and/or previous GI ulcer. The choice of the prophylactic agent was open, but consisted only of acid-suppressive drugs (proton pump inhibitors (PPIs), prostaglandin analogues (PAs) or high doses of H2 antagonist (H2A), because selective cyclo-oxygenase-2 inhibitors (COXIBs) were at that time not available.

The results of this policy were evaluated by an observational study on the incidence of GI events.4 In 1997, the incidence of symptomatic GI events in patients with rheumatoid arthritis (RA) at high risk on NSAID gastropathy was found to be 2.1% (95% CI 1.0–3.1). Recently, a decline (from 1.5% to 0.5%; p<0.001) in serious GI events from 1993 to 2000 was shown for RA patients in the US.5

We conducted a new, prospective, observational study in the same area as our previous work with RA patients in The Netherlands. The purpose of this study was to compare the incidence of GI events with our previous study, to estimate dyspepsia in NSAID and COXIB users, and to evaluate the adherence to the guidelines for preventive strategies of NSAID gastropathy in high-risk patients now compared to 7 years ago.

PATIENTS AND METHODS

Between September 2003 and August 2004, three questionnaires (the same questionnaires as used in our previous study) were sent to all our RA patients at 4-month intervals. The patients were selected from our database registry, with the diagnosis of rheumatoid arthritis according to American College of Rheumatology (ACR) 1987 criteria. The RA survey consisted of outpatients of the Department of Rheumatology of the Jan van Breemen Institute, Slotervaart Hospital and VU University Medical Centre, both in Amsterdam, The Netherlands.

In the questionnaires patients were asked about medication, previous GI ulcers, GI complaints, and whether they had had a gastroscopy and a symptomatic GI ulcer or complication of a GI ulcer in the previous months.

The patients with a possible GI event were checked by chart review and, if necessary, the patient or family doctor were contacted to complete the questionnaire. Deaths and their causes were also verified.

Symptomatic GI events were defined as: (1) clinical manifest GI ulcer diagnosed by endoscopy, (2) GI bleeding with GI ulcer, haematoemesis or melaena, and (3) GI perforation.

Dyspepsia was divided into epigastric pain, heartburn, acid regurgitation, hunger pains, nausea, bloating and belching on a five-point scale ranging between absent, mild, moderate, severe and very severe.

In 1997, preventive strategies in high-risk patients for NSAID gastropathy consisted of only the prescription of acid-suppressive drugs (PPI, PA and H2A). With the introduction of the safer gastrointestinal NSAIDs, the COXIBs, these drugs were also indicated as a preventive strategy for NSAID gastropathy. Therefore in our new study, COXIBs were included in the guidelines for gastroprotection in patients at risk for NSAID gastropathy.

STATISTICAL ANALYSIS

SPSS version 14.0 for Windows (SPSS Inc., Chicago, Illinois) was used for data collection and statistical procedures. The percentage of GI events (with 95% CIs) was calculated as the total of GI events per patient years in the total RA group and in the NSAID users group. In addition, the percentage of GI events in RA patients with high risk on NSAID gastropathy was compared to our previous study.

In a smaller case-control study, we compared patients with and without GI events (matched for age and sex), with the χ² test. The χ² test was also used to compare GI complaints in NSAID and COXIB users.

RESULTS

We sent a total of 12 532 questionnaires to 4125 RA patients. In all, 2099 (51%) RA patients returned at least one questionnaire, encompassing 1557 patient years of exposure. There were no differences between the baseline characteristics of the patients with a returned questionnaire and of patients without a returned questionnaire.

The baseline characteristics of the RA survey are shown in table 1. Compared to 1997, the use of classical NSAIDs decreased from 67% to 51% in 2003. In the present study COXIBs were prescribed for 14% of the RA patients. In 2003, the use of NSAIDs and COXIBs together was 65%, almost the same as in 1997.

Other differences in comparison to 1997 were the use of biologicals: 0% in 1997 and 16% in 2003, and the use of DMARDs (including methotrexate): 76% in 1997 and 70% in 2003. Altogether more “aggressive” therapy, defined as the use of DMARDs and biologicals, was 86% in 2003 and 76% in 1997.

The annual incidence of symptomatic GI events in the total RA group was 0.8% (0.3–1.2), including three GI ulcers and nine complications of ulcers (eight bleeds and one perforation). Table 2 shows the demographic and disease characteristics of the 12 RA patients with GI events (cases) vs 36 matched controls. Patients with GI event had more previous GI events and used more anticoagulants than patients without GI events.

The annual incidence of symptomatic GI events in the RA patients with NSAIDs and COXIBs was 0.8% (0.2–1.5), this figure is the same in the total RA group (as mentioned above).

Of the NSAID and COXIB users, 706 (53%) patients were classified as high risk, defined as 60 years or older and/or previous ulcer. The incidence of GI events in high-risk patients (on NSAIDs or COXIBs) was 1.2% (0.2–2.3), which appears to be substantially lower than the 2.1% (1.0–3.1) found in 1997, although this difference did not reach statistical significance (p = 0.3).

In this study 64% (95% CI 61–68) of the high-risk patients used acid-suppressive drugs (PPI, PA and high dose H2A). In 1997 this percentage was significantly lower, at 49% (45–52; p<0.001).

The adherence to the preventive strategy for NSAID gastropathy in our previous study in 1997 incorporated only the use of acid-suppressive drugs and was 49%. In 2003 this percentage was 73% (p<0.001), now also including COXIBs in addition to the use of acid-suppressive drugs in high-risk NSAID users.

The moderate, severe or very severe vs absent or mild GI complaints in RA patients with and without NSAIDs and COXIBs are depicted in table 3. There was more dyspepsia in patients with COXIBs than in patients with NSAIDs or without NSAIDs or COXIBs (p<0.005; five of seven GI complaints). GI events can occur without dyspepsia, as mentioned in our study, because seven GI events occurred with NSAIDs and zero with COXIBs.

DISCUSSION

In this large observational study performed in 2003 on Dutch RA patients, we found a lower incidence of symptomatic GI ulcers and associated complications than in 1997, which is in line with the decline of serious GI events in the US.

This remarkable decline of NSAID gastropathy in RA in the US can be attributed to the use of lower doses of NSAIDs, decreased use of “more toxic” NSAIDs, increased use of “safer” NSAIDs and increasing use of proton pump inhibitors.5

In our present study RA patients used less non-selective NSAIDs and more COXIBs as compared to our previous study, although the total number of COXIB and NSAID users was nearly the same. In addition, through the years patients at risk for NSAID gastropathy used more acid-suppressive agents. These reasons for the decline of GI events in our study resemble the US data, despite socioeconomic, ethnic and RA treatment regime differences.

A limitation of our study is that we were not informed about the dosage of NSAID use, consequently we could not confirm the use of lower doses of NSAIDS. With the more aggressive treatment of RA with the biologicals, high dosage or combination of disease-modifying antirheumatic drugs (DMARDs) it is conceivable that the dosages of NSAIDs decline, and patient use of NSAIDs becomes more on-demand. In addition, more “aggressive” treatment of RA will also lead to less inflammation and could be a possible explanation of decreasing GI events. In an earlier study from Amsterdam,6 it was shown that the rate of ulcer complications was particularly related to vasculitis. Nowadays, clinically manifest vasculitis is very scarce in RA, illustrating that modern RA treatment is more effective.

As the number of GI events was low, we were very cautious with drawing conclusions, ie, with regard to identifying risk factors for NSAID gastropathy in the case control study. Some variables seem to be predictive, but are probably related to other prognostic variables. When we have more cases we will perform a multiple regression analysis. In the present case control study, further conclusions could not be made.

Because of the huge impact of NSAID gastropathy, interventions for preventive strategies on NSAID gastropathy are described in different guidelines.7 8 Preventive strategies in high-risk NSAID users are the prescription of acid-suppressive drugs, the use of COXIBs and eradication of Helicobacter pylori (H pylori). Although not explored in this study, NSAID gastropathy is associated with H pylori infection. However, the mechanism behind this association remains controversial; there is enough evidence that eradication of H pylori before the use of NSAIDs is meaningful, but not in chronic NSAID users.9^–11

Presently, NSAID- and COXIB-associated dyspepsia are still common and can influence quality of life. In the present study there was more dyspepsia with COXIBs than with NSAIDs or without NSAIDs or COXIBs. This might be due to confounding by indication, as doctors will be more likely to prescribe COXIBs to patients with pre-existing GI complaints. However, it is important to realise that in general the presence of dyspepsia is not a predictor of GI events because most GI events occur without previous complaints, as in our study seven GI events occurred with NSAIDs and none with COXIBs.

In summary, the present study reveals a decline of NSAID-induced gastrointestinal ulcers and complications of ulcers, which confirms the US findings. Most likely this is due to a more strict adherence to guidelines for prevention of NSAID gastropathy, ie a more frequent use of acid-suppressive drugs and COXIBs. Other contributing factors could be a better treatment of RA and eradication of H pylori.