American Journal of Medicine 1998 (Jul 27); 105 (1B): 31S–38S ~ FULL TEXT
Gurkirpal Singh, MD
Department of Medicine, ARAMIS Postmarketing Surveillance Program,
Stanford University of Medicine, Palo Alto, California 94303, USA
Conservative calculations estimate that approximately 107,000 patients are hospitalized annually for nonsteroidal anti-inflammatory drug (NSAID)-related gastrointestinal (GI) complications (internal bleeding) and at least 16,500 NSAID-related deaths occur each year among arthritis patients alone.
The figures for all NSAID users would be overwhelming, yet the scope of this problem is generally under-appreciated.
In the following year (June 1999) the prestigious New England Journal of Medicine published a similar statement:
“It has been estimated conservatively that 16,500 NSAID-related deaths occur among patients with rheumatoid arthritis or osteoarthritis every year in the United States. This figure is similar to the number of deaths from the acquired immunodeficiency syndrome and is considerably greater than the number of deaths from multiple myeloma, asthma, cervical cancer, or Hodgkin’s disease.
If deaths from gastrointestinal toxic effects from NSAIDs were tabulated separately in the National Vital Statistics reports, these effects would constitute the 15th most common cause of death in the United States. Yet these toxic effects remain mainly a “silent epidemic,” with many physicians and most patients unaware of the magnitude of the problem.
Furthermore these mortality statistics do not include deaths ascribed to the use of over-the-counter NSAIDS.”
Another statement that just happened to catch my eye:
On the basis of these conservative figures and ARAMIS data, the annual number of hospitalizations in the United States for serious gastrointestinal complications is estimated to be at least 103,000. At an estimated cost of $15,000 to $20,000 per hospitalization, the annual direct costs of such complications exceed $2 billion. 
Thanks to the American Nutrition Association
for access to this picture!
The Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) Post-Marketing Surveillance Program (PMS) has prospectively followed patient status and outcomes, drug side effects, and the economic impact of illness for >11,000 arthritis patients at 8 participating institutions in the United States and Canada.
Analysis of these data indicates that:
osteoarthritis (OA) and rheumatoid arthritis (RA) patients are 2.5—5.5 times more likely than the general population to be hospitalized for NSAID-related GI events;
the absolute risk for serious NSAID-related GI toxicity remains constant and the cumulative risk increases over time;
there are no reliable warning signals- >80% of patients with serious GI complications had no prior GI symptoms;
independent risk factors for serious GI events were age, prednisone use, NSAID dose, disability level, and previous NSAID-induced GI symptoms; and
antacids and H2 antagonists do not prevent NSAID-induced gastric ulcers, and high-risk NSAID users who take gastro-protective drugs are
more likely to have serious GI complications than patients not taking such medications
The author concludes:
Currently, limiting NSAID use is the only way to decrease the risk of NSAID-related GI events.
No one has yet calculated the total cost for hospitalizing the 107,000 patients, or the pain and suffering experienced by the families of those 16,500 individuals who die, simply for using NSAIDs for pain relief.
Research has clearly demonstrated that Omege-3 Fatty acids provides the same level of pain relief as NSAIDs, and investigators have reported that rheumatoid arthritis patients, consuming omega-3 dietary supplements, were able to either lower or discontinue their background doses of nonsteroidal antiinflammatory drugs.
Considering that patients with arthritis are one of the leading group-users of NSAIDs, perhaps it's time for medical guidelines to recommend Omega-3 fatty acids FIRST for pain relief, before resorting to the more dangerous NSAIDs.
From the FULL TEXT Article:
American Journal of Medicine 1998 (Jul 27); 105 (1B): 31S–38S ~ FULL TEXT
Gurkirpal Singh, MD
Department of Medicine, ARAMIS Postmarketing Surveillance Program,
Stanford University of Medicine, Palo Alto, California 94303, USA
Conservative calculations estimate that approximately 107,000 patients are hospitalized annually for nonsteroidal anti-inflammatory drug (NSAID)-related gastrointestinal (GI) complications and at least 16,500 NSAID-related deaths occur each year among arthritis patients alone. The figures for all NSAID users would be overwhelming, yet the scope of this problem is generally under-appreciated. The Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) Post-Marketing Surveillance Program (PMS) has prospectively followed patient status and outcomes, drug side effects, and the economic impact of illness for >11,000 arthritis patients at 8 participating institutions in the United States and Canada. Analysis of these data indicates that: (1) osteoarthritis (OA) and rheumatoid arthritis (RA) patients are 2.5-5.5 times more likely than the general population to be hospitalized for NSAID-related GI events; (2) the absolute risk for serious NSAID-related GI toxicity remains constant and the cumulative risk increases over time; (3) there are no reliable warning signals- >80% of patients with serious GI complications had no prior GI symptoms; (4) independent risk factors for serious GI events were age, prednisone use, NSAID dose, disability level, and previous NSAID-induced GI symptoms; and (5) antacids and H2 antagonists do not prevent NSAID-induced gastric ulcers, and high-risk NSAID users who take gastro-protective drugs are more likely to have serious GI complications than patients not taking such medications. Currently, limiting NSAID use is the only way to decrease the risk of NSAID-related GI events. Ongoing ARAMIS research is aimed at developing a simple point-score system for estimating individual risks of developing serious NSAID-related GI complications.
Gastrointestinal (GI) symptoms are the most common
adverse events associated with nonsteroidal
anti-inflammatory drug (NSAID) therapy. Because
patients with arthritis are frequent users of NSAIDs
and often have other risk factors, this patient population
is particularly at risk for serious GI complications. To
better characterize NSAID-related GI complications in
patients with rheumatic disease and to determine methods
for reducing their frequency, a series of studies was
begun several years ago by the Arthritis, Rheumatism,
and Aging Medical Information System (ARAMIS).
ARAMIS, which has been funded by the National Institutes
of Health for the past 25 years, is a prospective
observational data bank system that systematically collects
data on individuals with chronic rheumatic disease. 
Data are reported by both physicians and patients; the
database currently contains information on >36,000
rheumatic disease patients with >300,000 patient-years
of follow-up from 17 centers in the United States and
Canada.  Within this larger population are >11,000 arthritis
patients that comprise the patient population of
the ARAMIS Post-Marketing Surveillance Program
(PMS; Table 1). This program prospectively follows patient
status and outcomes, drug side effects, and the economic
impact of illness for consecutively diagnosed patients
at each participating institution.
Patient characteristics and study design have been described
in detail elsewhere. [3-5] Patients in the ARAMISPMS
program come from a wide variety of sources, including
academic institutions and urban and community
populations, and are generally representative of rheumatology
patients in North America. 
Diagnosis of rheumatoid arthritis (RA) and osteoarthritis
(OA) is made and documented according to
American College of Rheumatology (ACR) criteria. Additionally,
a random 10% subgroup of the Santa Clara
County community sample was examined to confirm the
Enrolled patients complete the Stanford Health Assessment
Questionnaire (HAQ) every 6 months. The Stanford
HAQ is a validated instrument that evaluates the
patient’s functional ability and quality of life, use of
healthcare resources and medication, costs of care, and
side effects. [6, 7] The study protocol includes following-up
with nonresponders, contacting patients to fill in missing
information, and the quality control of questionnaire
coding and data entry to ensure accuracy. Follow-up data
are available for 95.4% of patients.
The extensive data available in ARAMIS has provided
an unparalleled opportunity to consider some of the outstanding
issues relating to NSAID-induced adverse
(1) what are the GI side effects of NSAID use;
(2) what is the extent of the problem;
(3) are there warning signs for serious GI complications;
(4) who is at greatest risk of serious GI complications;
(5) do some NSAIDs cause more GI toxicity than others; and
(6) do H2 antagonists and antacids help prevent serious GI complications?
This article will discuss some of those issues using results
from the literature and updated findings from the
ARAMIS studies and will outline some areas of current
and potential future research.
What Are The GI Side Effects Of NSAID Use?
NSAID-related GI side effects result from inhibition of
prostaglandins, which play a key role in maintaining the
integrity of the gastric mucosa. Although NSAID use is
associated primarily with upper GI events and gastric ulcers,
lower GI problems can also occur, including:
(1) inflammation and permeability changes of the intestine and lower bowel;
(2) hemorrhage of the ileum, duodenum, and colon;
(3) perforation; and
(4) stricture formation. [8-11]
The adverse GI events associated with NSAID use can be broadly categorized into 3 groups:
(1) “nuisance symptoms” (heartburn, nausea, dyspepsia, vomiting, abdominal pain);
(2) mucosal lesions as seen on endoscopy or x-rays; and
(3) serious GI complications (perforated ulcers, catastrophic bleeding that requires hospitalization).
In any study of NSAID-induced GI complications, it is
important to distinguish between the nuisance symptoms
or endoscopic lesions and the serious GI complications.
For this reason, endpoints for all ARAMIS studies
have been defined as clinically significant events or lesions
serious enough to result in a hospital stay of at least
24 hours. They include GI bleeding, clinically symptomatic
gastritis, ulcers, or gastric outlet obstructions.  A definite
diagnosis was not always possible despite severe GI
symptoms requiring hospitalization. Gastrointestinal
events were determined from the self-administered HAQ
and confirmed by review of hospital records.
What Is The Magnitude Of The Problem?
Endoscopic lesions are common and may occur in up to
80% of NSAID users.  Approximately 15% of patients
will have the nuisance symptoms. Using a liberal definition
of an ulcer as a break of ≥3 mm in the gastric mucosa,
about 25% of patients will have a gastric ulcer, and
40–50% will have either a gastric or duodenal ulcer.
However, only 1–4% of patients will have clinically important
GI complications each year. [10, 13, 14–17] Furthermore,
reducing the incidence of endoscopic ulcers (e.g.,
with misoprostol) does not result in a comparable reduction
in clinically significant GI complications.  Thus,
there is little correlation between the occurrence of endoscopic
ulcers and clinically significant events. For this reason,
the ARAMIS studies reported here have limited the
definition of GI adverse events to those requiring hospitalization.
Numerous studies have attempted to correlate NSAID
use with serious GI complications by determining the
ratio of NSAID-related events to non–NSAID-related
events. Langman et al (1994)  found an odds ratio of 4.5
for NSAID-related peptic ulcer bleeding; Garcia-Rodriguez
and Jick (1994)  reported a risk ratio of 3.9 for
hospitalizations; and a meta-analysis of 40 studies published
over 25 years found an overall odds ratio of 2.74 for
serious GI complications and 7.75 for GI surgery.  The
goal of current ARAMIS research is to better correlate GI
events with NSAID use by determining adjusted odds ratios
for specific causes of GI adverse events in patients
taking NSAIDs versus control patients not taking
Incidence of GI Complications: ARAMIS Epidemiologic Study
In this study, GI complications were defined as hospitalizations
and deaths due to GI events. Complications were
considered to be NSAID-related if the HAQ indicated
NSAID use immediately before the event or if NSAIDs
were noted on the hospital discharge summary. The patient
population consisted of >4,000 arthritis patients
with about 15,500 patient-years of observation (Table 2).
Hospitalizations. Of the hospitalizations for GI events
in the RA patient group, 92.5% (124/134) were related to
NSAID use, with an annual rate of 1.46% versus 0.27%
for patients not taking NSAIDs. The relative risk of hospitalization
for GI events for NSAID users was 5.49, only
slightly less than the relative risk of lung cancer for smokers
(7– 8). The annual hospitalization rate for NSAIDrelated
complications was significantly lower for OA patients than for RA patients and the relative risk about half
that of RA patients. A likely explanation for the lower risk
is that OA is a milder disease for which NSAID doses are
generally lower, OA patients have fewer comorbid conditions,
and prednisone (known to double the risk for
NSAID-related GI events) is rarely used.
The Arthritis Foundation conservatively estimates that
at least 13 million individuals in the United States with
OA or RA regularly take NSAIDs (Table 3). Applying the
ARAMIS data to these figures, the number of potential
hospitalizations for serious GI complications is about
107,000 per year. These data correspond well to the figures
obtained from the Tennessee Medicaid database. 
At a conservative estimated cost of $10,000–$15,000 per
hospitalization, the total annual cost exceeds $1 billion —
a huge drain on national medical resources.
Overall, approximately 10% of hospitalizations
for upper GI bleeding result in death, and 80% of all ulcer-
related deaths occurred in patients using an anti-inflammatory
agent.  In the ARAMIS study, 26 deaths (all
in RA patients) resulted from GI complications observed
in the 12,224 patient-years of exposure to NSAIDs. Of
these, 19 could be definitely attributed to NSAID use, for
a raw annual GI death rate of 0.22% and a relative risk of
4.21. Although an incidence of 0.22% per year may sound
trivial, over the 20–30 years that chronic arthritis patients
may take NSAIDs, the incremental risk per patient and
the total number of deaths add up very quickly.
Conservative calculations based on ARAMIS data estimate
that the annual number of NSAID-related deaths
(16,500) among patients with definite or probable RA or
OA is comparable to the number of deaths from other
common causes (Table 3; Figure 1).  NSAIDs cause
more than one third as many deaths as human immunodeficiency
virus (HIV) infection and almost as many
deaths as asthma, cervical cancer, and malignant melanoma
combined. If the estimates were to include all patients
who take NSAIDs, the numbers would be overwhelming,
yet the scope of this problem is generally
Are There Warning Signs For Serious GI Complications?
Dyspepsia is a common side effect of NSAID use, but is
poorly correlated with endoscopic lesions or GI bleeding. [9, 10, 25] Of patients who develop ulcers or life-threatening
GI complications, 50–60% will have had no previous
warning signs or symptoms. [10, 23, 26, 27]
ARAMIS conducted a cohort study1 involving 1,921
patients on NSAIDs during their first 2.5 years of observation.
Documented events included GI hospitalizations,
upper GI endoscopies, NSAID-induced GI side effects
not serious enough to warrant hospitalization (nausea,
vomiting, upper or lower abdominal pain, heartburn, diarrhea,
or blood in stools), and use of GI medications (H2
antagonists, sucralfate, or antacids). Patients who took
misoprostol were excluded from analysis for 2 reasons:
(1) the patient numbers were too small to allow independent analysis; and
(2) the mechanism of action differs from that of the other GI medications.
During the 2.5-year observation period, the overall incidence of NSAIDrelated
GI side effects was 15%, with a 2.2% incidence of
serious GI complications requiring hospitalization. Patients
who did have GI symptoms were slightly more
likely to have a serious GI complication than those who
had no warning symptoms (2.7% vs 2.0%), but the converse
was not true: a staggering 81% (34/42) of patients
who had serious GI complications had no prior GI symptoms.
Who Is At Risk For Serious GI Complications?
Since GI side effects are not a reliable warning sign, it is
important to define risk factors for serious GI complications
and to find ways to reduce that risk. A number of
studies have addressed this issue with fairly consistent
results, identifying as risk factors
advanced age, [16, 22, 28–30]
higher NSAID dosages, [18, 19, 22, 31]
shorter duration of therapy, [16, 18, 19]
a history of GI problems, [18, 20, 31]
concomitant corticosteroid [20, 32, 33]
anticoagulant use. [20, 34]
Most of these studies performed only univariate analyses.
ARAMIS evaluated risk factors for 114 RA patients
who had GI events versus 1,921 RA patients who did not
have GI events. Univariate analysis identified 11 variables
associated with hospitalization or death at the predictive
visit (before the event): age; disease duration; disability
index (0–3); NSAID dose (% of maximum); number of
categories of nonrheumatic drugs taken (0–8); NSAID
GI side effects (ever); use of prednisone, antacids, or GI
protective drugs; and comorbid conditions (ever).
Of note in this cohort study is the fact that female sex
was not associated with an increased risk, whereas in casecontrol
studies that is often the case, possibly due to the
predominance of middle-aged women who are taking
NSAIDs. Other categorical variables that univariate analysis
did not correlate with an increased risk included
white race, smoking (ever), and alcohol (ever). Continuous
variables that were not significantly associated with
an increased number of GI events included educational
level, smoking (packs/day), alcohol (drinks/day), number
of concurrent disease-modifying antirheumatic
drugs (DMARDs), and 0–6 categories of comorbid conditions
A multivariate model consisting of 5 variables — age,
prednisone use, NSAID dose (% of maximum), disability
index, and previous NSAID-induced GI side effect — was
identified by stepwise logistic regression analysis
(Table 4). The odds ratios (OR) for these variables can be
used to estimate a patient’s risk of hospitalization for the
Although “advanced age” is usually defined as ≥65
years, this is an arbitrary point. It is important to remember
that individuals do not suddenly become “at risk” at
the age of 65. Ongoing ARAMIS studies show that the risk
increases steadily by roughly 4% per year increase in age.
The question of whether the risk for NSAID-related
gastropathy is constant over time has been controversial.
One school of thought — the mucosal adaptation theory —
is that patients who are going to bleed will do so early
in therapy and will discontinue taking NSAIDs or die, so
that those who continue are “tolerant,” with a reduced
risk of serious GI complications. The US Food and Drug
Administration (FDA), in the process of deciding on revised
labeling for NSAIDs, requested an ARAMIS study
to look at this issue. The study followed approximately
1,600 new NSAID users or patients who restarted taking
NSAIDs after a washout period of at least 6 months. The
precise date and time of bleeding was obtained from hospital
discharge summaries. A Kaplan-Meier survival analysis
was performed to determine a continuous approximation
of the hazard function, and the results indicate
that throughout most of the 10-year follow-up period,
the risk of GI bleed (the hazard function) remained constant.
Patients on NSAIDs for 5 years have a 5-times
greater risk of bleeding than do patients on NSAIDs for 1
year, whereas the risk after 3 months of NSAID therapy is
approximately one-fourth the risk after 1 year. Thus,
from the data, it appears that the body does not adapt to
the insult that occurs with the use of NSAIDs.
The single most important factor that predicts GI
bleeding is the duration of NSAID therapy. This factor
was not included in the ARAMIS study because longitudinal
data (e.g., duration of NSAIDs therapy) is not handled
well by logistic regression methods. However, ongoing
ARAMIS research is developing Cox proportional
hazard models based on life-table analysis to incorporate
this risk factor. The ultimate goal of this research is to
develop point-based risk-factor algorithms — a simple
one for patients themselves and a more complex and accurate
one for physicians — to estimate individual risks
from NSAID therapy.
Are Some NSAIDs More Toxic Than Others?
All NSAIDs cause a full range of GI side effects, although
they vary in frequency and severity. [10, 13, 19, 20, 35–40] Some
of the ARAMIS studies have previously found substantial
variations in the relative overall toxicity of NSAIDs using
the Toxicity Index (TI). [41–45] A recent study utilized a
subset of the TI to evaluate GI toxicity for 6,276 courses of
12 NSAIDs during 9,860 patient-years of observation.
The GI-TI is a sum of GI symptoms per patient-year of
exposure, weighted by severity and number of hospital
days and adjusted for risk factors and other key variables
(e.g., age, sex, center, drug initiation, disease duration,
disability, educational level, duration of NSAID therapy,
concurrent medications). Gastrointestinal toxicity, expressed
as the GI-TI, varied from a low of 1 for salsalate
to almost 4 for meclofenamate (Table 5). The differences
in GI toxicity only become clinically or statistically significant
between the NSAIDs at the upper and lower end of
the range. The majority of the NSAIDs are in the middle
range from 1.68–2.0.
As a result of the findings discussed above, the FDA has
requested that NSAID manufacturers revise their labeling
to include the following warnings:
(1) serious GI toxicity can occur at any time, with or without warning symptoms;
(2) the absolute risk remains constant and the cumulative probability increases over time,
thus increasing the likelihood of developing a serious GI event with longterm NSAID use; and
(3) the lowest effective dose should be used for the shortest possible duration to minimize
the potential risk, and alternative therapies should be considered for high-risk patients.
Do H2 Antagonists and Antacids Help Prevent Serious GI Complications?
There are significant differences between the ulcers
caused by Heliobacter pylori and those caused by NSAID
The H. pylori ulcer is a predominantly duodenal ulcer,
associated with low pH, and generally symptomatic.
NSAID-induced ulcers, on the other hand, are primarily
gastric ulcers, associated with high pH, and usually
Acid suppression (e.g., with ranitidine) is
very effective in preventing duodenal ulcers but has little
effect on gastric ulcers (Figure 2). [12, 46, 47]
pump inhibitors reduce the incidence of duodenal but
not gastric ulcers. Despite this well-established fact, approximately 34% of the 1,921 individuals in the ARAMIS
study who took NSAIDs were taking concomitant acidreduction
therapy. Of these 657 patients, 58.3% were taking
antacids, 23.0% were taking cimetidine, 6.9% were
taking ranitidine, 2.7% were taking sucralfate, and 2.2%
were taking famotidine, while 8.5% were taking combinations
of different GI medications.  Review of the
ARAMIS database showed that 75% of GI medications
co-prescribed with NSAIDS were for prophylaxis, and
only 25% were for treatment. This is a dangerous practice,
because these medications may suppress symptoms —
potential warning signs — without reducing the
risk of serious GI complications. They may provide a false
sense of security to both physician and patient, encouraging
long-term therapy with higher NSAID doses, which
could eventually result in serious GI events.
ARAMIS cohort study  showed that, of patients who had
never had any GI side effects, those who were taking prophylactic
GI medications had about 2.5 times more hospitalizations
for NSAID-related GI complications than
patients not taking GI medications (OR 2.69; 95% CI 5
1.36 –5.31, P ,0.05; Figure 3). For patients who had previous
NSAID-related GI symptoms, the incidence of serious
complications was similar for patients taking GI
medications and patients not taking GI medications (OR
0.73; 95% CI 5 0.18 –2.96). The odds ratio was not significantly
different (OR 0.57; 95% CI 5 0.13–2.45) after
adjusting for differences in patient characteristics (i.e.,
age, sex, duration of RA, disability index, educational
level, concurrent use of prednisone).
Using different methods (a case-control study design
and a newly designed propensity score to measure the
likelihood of having a gastroprotective drug prescribed),
Avorn et al (1996)  reported similar results in a large
group of New Jersey Medicaid patients (n = 3,524 with
and 14,096 without hospitalizations). High-risk individuals
taking histamine antagonist therapy, sucralfate, or
omeprazole were about twice as likely (OR 1.7–2.1;
P <0.05 each) to have serious GI bleeding as those not
taking GI medications. The likelihood of hospitalization
in the different groups compared with low-risk patients is
shown in Figure 4 (Jerry Avorn, personal communication).
In clinical trials, the newer GI medications (e.g., misoprostol,
omeprazole) have effectively reduced serious GI
complications. Future ARAMIS studies will investigate
their ability to similarly reduce serious GI events requiring
hospitalization in clinical practice.
Currently, the accepted method for decreasing the risk
of serious NSAID-related GI toxicity is to limit NSAID
use. For OA, acetaminophen is the accepted first-line
therapy when nonpharmacologic methods are insufficient;
for RA, disease modifying antirheumatic drug
(DMARD)-based strategies should be considered. Newer
agents (e.g., tramadol and selective COX-2 inhibitors)
may also be useful additions to the physician’s armamentarium
for the treatment of chronic pain.
As patients in the ARAMIS database continue to be
evaluated, research is currently underway to develop a
simple point-score system based upon risk factors to estimate
individual risks for developing serious NSAID-related
GI complications. Once completed, this system
should help the clinician quickly determine which patients
are at risk for NSAID-associated adverse events and
allow them to take the appropriate course of action.
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