4. Discussion
We developed a clinical risk
prediction score to predict the possibility of serious GI complications
in elderly patients receiving NSAIDs using geriatric population data
from South Korea. By demonstrating the good performance of the
prediction model through external validation, we confirmed that it is
not limited to patients with arthritis and can be applied to the general
elderly population that uses NSAIDs. Because the factors contributing to
the risk of GI bleeding are different in the elderly and young
populations using NSAIDs, risk prediction models specific to the elderly
population should be considered. To the best of our knowledge, this is
the first study to predict GI complications associated with NSAID use in
the elderly population.
In our study, high-dose NSAID use was the greatest risk factor for
serious GI complications as well as a history of complicated GI ulcers.
The history of complicated GI ulcers is, as already known, a potent risk
factor for NSAID-induced ulcers and a critical criterion in GI ulcer
prevention algorithms [17] [18].
We found that NSAID use in excess
of the daily recommended dose (e.g., ibuprofen 1200 mg, naproxen 500 mg,
celecoxib 400 mg) or multiple NSAID use was a risk factor similar to a
history of complicated GI ulcers in the elderly population. Multiple
NSAIDs may be prescribed simultaneously, which may result in patients
taking high-dose NSAIDs. Multiple prescribers may prescribe different
NSAIDs. Patients may use multiple pharmacies or pharmacists may not
detect multiple NSAID prescriptions. Therefore, a systematic medication
management system for the elderly is required.
Our study identified new risk
factors not included in the current guidelines [19]: male sex, very
old age, and concomitant use of SSRI. Previous risk prediction studies
[1] [6] for upper GI bleeding related to NSAID use have reported
risk factors similar to those identified in our study, although their
study populations were not specific to the elderly. In one study, age,
male sex, anemia, aspirin, and anticoagulants were identified as
predictors, while GI history and co-treatment with corticosteroids and
SSRIs were not [6]. In another study, age; history of GI bleeding or
perforation; concomitant use of corticosteroids, SSRIs, and
antithrombotic agents; and male sex were identified [1]. Although
these factors were included in our analysis, they were not identified as
predictors. In our study, concomitant PPI or H2RA treatment with NSAID
reduced the risk of serious GI complications, whereas the use of
rebamipide or Artemisia herb soft extract did not. According to
the guidelines, PPIs are recommended to prevent NSAID-related GI damage
[17], but in practice, alternative GPAs are sometimes prescribed
because of concerns about the long-term safety of PPI [12].
According to our previous study that reported the pattern of GPA
prescription in the elderly (≥ 65 years) using NSAIDs, PPI, H2RA,
rebamipide, and Artemisia herb soft extract accounted for 11.4%,
24.8%, 8.0%, and 6.8% of the total GPA prescriptions in Korea,
respectively [20]. In a previous study investigating whether GPAs
effectively prevent NSAID-related GI injury in patients with arthritis,
mucoprotective agents such as rebamipide and misoprostol were effective
in reducing the risk of GI bleeding in NSAID users as acid suppressants
(PPI or H2RA) [12]. However, the population in this study who used
NSAIDs were over 20 years of age, a population with a relatively low GI
risk compared to the population in our study.
In our evaluation of GPAs, only
PPI and H2RA, which acted as offset factors that reduced the risk of
serious GI complications, were included in the prediction model.
We developed a risk model for
capturing expanded cases compared
to the risk classification system of the current guidelines, which
counts the number of risk factors [19]. All of the ten cases with
high frequency predicted as high-risk patients had the following
factors: age ≥75 years, male sex, concurrent use of antithrombotic
agents, and concurrent use of corticosteroids. If avoidable factors,
such as high-dose NSAIDs, concomitant glucocorticoids, and
antiplatelets, were eliminated, all ten high-risk cases were no longer
high-risk.
Our study evaluated the use of
GPAs as risk prediction factors for NSAID users. PPI or H2RA use was not
sufficient to offset serious GI complications in all cases. According to
our prediction model, men over 75 years of age using nsNSAIDs with
concomitant single antiplatelet and glucocorticoid therapy were still at
high risk even though they had used PPIs. Therefore, it is important to
closely monitor and eliminate avoidable risk factors, if possible, when
a patient is predicted to be at high risk, even when using a PPI.
The development of a convenient risk prediction score for the safe use
of commonly used medications such as NSAIDs could benefit public health.
The risk prediction calculator for serious GI complications developed in
our study demonstrated acceptable performance and discrimination in the
external validation, even without individual laboratory tests or
specific information known only to experts. It is beneficial to quickly
calculate the risk scores using only the patient’s prescription and
severe comorbidities known to themselves. By deriving cutoff values,
high-risk patients can be easily identified.
Our study had several limitations that should be considered. First, as
our assessment of predictors of GI complications depends on the factors
available in the claims database, there might have been unmeasured risk
factors. We could not include Helicobacter pylori infection, genetic
susceptibility, or social factors such as smoking and alcohol
consumption. However, smoking is not a significant risk factor for GI
ulcers [1], and NSAID-induced GI complications are unrelated to H.
pylori infection [2]. Second, the identification of serious GI
complications and risk factors from claims data might be inaccurate, as
it was based on the ICD-10 diagnostic codes [21]. Third, since age
information over 80 years was not provided in the external validation
data, we were unable to evaluate how well our model discriminated this
age group with high confidence. Fourth, our model may not be
generalizable to populations other than those used to derive and
validate the model [21]. Additional external validation should be
conducted to generalize the results to other populations (e.g., Western
countries). Fifth, some of the medications sold over the counter,
including NSAIDs and H2RA, could not be identified in the claims data.