Think before or sink after: choosing an appropriate nsaid by balancing gastrointestinal and cardiovascular risks
Think Before or Sink After: Choosing an Appropriate NSAID by Balancing Gastrointestinal and Cardiovascular Risks Jyh-Ming Liou,1,2 Ming-Shiang Wu,1* Jaw-Town Lin1,3
Nonsteroidal anti-inflammatory drugs (NSAIDs)
are introduced to the market with popularity be-
have become one of the most important drugs
cause they are associated with fewer gastrointesti-
for relieving pain and reducing inflammation. nal (GI) complications than non-selective NSAIDs.
It was reported that more than 111,000,000 pre-
Unfortunately, rofecoxib and valdecoxib were
scriptions for NSAIDs were prescribed in the
withdrawn from the market because of their seri-
United States at a cost of $5 billion each year.1
ous cardiovascular risks. Emerging data suggest
Most NSAIDs derive their antipyretic, analgesic,
that nonselective NSAIDs, except for naproxen,
and anti-inflammatory effects through inhibi-
are also associated with increased risks for cardio-
tion of cyclooxygenase (COX), including COX-1
vascular events.8 Thus, the choice of appropriate
and COX-2, and hence the synthesis of prosta-
glandins. NSAIDs and other analgesic/antipyretic
drugs such as acetaminophen might also act
through inhibition of a newly discovered cyclooxy-
genase isoenzyme, COX-3, to reduce pain and pos-
sibly fever.2 In recent decades, aspirin has also
been widely used for the prevention of cardiovas-
cular disease. In addition, COX-2 inhibitors have
GI intolerance is the most common adverse ef-
the potential for chemoprevention of gastric and
fect of NSAIDs, and a meta-analysis has revealed
that NSAIDs increased the risk of dyspepsia by
However, the anti-inflammatory and analgesic
36%.9 In the United States, NSAID-associated
effects of NSAIDs are not obtained without cost.
upper GI adverse events are estimated to result in
NSAIDs are an important cause of bleeding pep-
103,000 hospitalizations and 16,500 deaths per
tic ulcers in countries where the prevalence of
year.10 NSAID users had a 12.5 per 1000 person-
Helicobacter pylori infection is decreasing. A recent
years excess rate of ulcer-related hospitalization
study from Taiwan revealed that about 57.2% of
compared to non-NSAID users.11 A nationwide
patients with bleeding peptic ulcer reported re-
study of mortality associated with hospital admis-
cent use of NSAIDs or antiplatelet agents.7 NSAIDs
sion due to severe GI events in Spain revealed that
that are selective for COX-2 inhibition (coxibs)
the death rate attributed to NSAID/aspirin use was
1Department of Internal Medicine, College of Medicine, and 2Graduate Institute of Epidemiology, College of PublicHealth, National Taiwan University, Taipei, and 3Department of Internal Medicine, E-Da Hospital/I-Shou University,Kaohsiung, Taiwan. *Correspondence to: Professor Ming-Shiang Wu, Departments of Internal Medicine and Primary Care Medicine, National Taiwan University, 7 Chung-Shan South Road, Taipei 100, Taiwan. E-mail: mingshiang@ntu.edu.tw
15.3 deaths/100,000 NSAID/aspirin users, and
hypothesis that anti-inflammatory effects are usu-
that up to one third of all NSAID/aspirin deaths
ally due to COX-2 inhibition and that adverse
can be attributed to low-dose aspirin use.12 In an
effects usually occur because of COX-1 inhibi-
endoscopic evaluation of patients who had contin-
tion, selective COX-2 inhibitors (celecoxib, rofe-
uously used NSAIDs over the previous 6 months,
coxib, valdecoxib, etc.) were developed to reduce
gastroduodenal ulcers were detected in 24% of
NSAID-associated GI toxicities.19 Several clinical
patients, and approximately 1–2% of NSAID users
trials showed a 41–57% reduction in the rate of
developed ulcer-related complications (bleeding,
GI toxicities with the use of selective COX-2 in-
perforation, obstruction) annually.13,14 Notably,
hibitors.20 However, the VIGOR trial raised the
the majority of patients with NSAID-related GI
issue of the cardiovascular safety of the coxibs
complications did not have preceding abdomi-
after a statistically insignificant increase in the
nal symptoms. The first sign of an ulcer was a life-
incidence of myocardial infarctions in patients
threatening complication in 58.2% of patients
on rofecoxib was found.20 The first well-known
cardiovascular toxicities of coxibs arose from che-
Nonselective NSAIDs increase the risk of GI
moprevention trials for colorectal polyps, when
bleeding not only in the upper GI tract but also
large doses and longer durations of treatment
in the lower GI tract. Wilcox and Clark reported
were needed. In the APPROVe trial, a significantly
that the odds ratio (OR) for NSAID-associated
increased risk (relative risk, 1.97) of cardiovascu-
upper and lower GI bleeding were 3.2 and 2.6,
lar events as compared to placebo was shown.21
respectively.17 NSAID-related GI toxicities are re-
The results led to the withdrawal of rofecoxib in
lated to direct irritation of GI mucosa and re-
2004. A meta-analysis including 17 case-controlled
duction of protective prostaglandins through the
studies and six cohort studies revealed a dose-
inhibition of COX-1. The risk of peptic ulcer
related cardiovascular risk for rofecoxib.8 The
varies according to duration of therapy, dosage
ORs for the cardiovascular risks of rofecoxib
of drugs, and type of NSAID.10–18 Weil et al re-
were 1.33 and 2.19 for dosages of ≤ 25 mg/day
ported that the OR for duodenal ulcer bleeding
and > 25 mg/day, respectively.8 Celecoxib at the
also increased with dosage of aspirin and other
usual doses was not associated with an elevated
NSAIDs.18 Longer duration of therapy was also
risk of vascular occlusion, with a relative risk of
associated with increased risk of GI toxicity.
1.06 (95% confidence interval [CI], 0.91–1.23).8
Indomethacin, ketoprofen and piroxicam appear
This meta-analysis also raised serious questions
to be associated with the highest prevalence of
about the increased cardiovascular risks of di-
GI toxicity, whereas ibuprofen and diclofenac
clofenac, with a relative risk of 1.40 (95% CI,
1.16–1.70). Naproxen was not associated with
an increased risk of cardiovascular events, with a
relative risk of 0.97 (95% CI, 0.87–1.07).8 Taken
together, the cardiovascular toxicities seem to
vary depending on type, dosage and duration
of NSAID treatment. Intriguingly, geographic or
The discovery of COX-2 provided the basis for
ethnic differences may also play a role. A recent
the development of selective COX-2 inhibitors.
population-based analysis in Taiwanese adults
COX-1 is a constitutively expressed enzyme which
with long-term (≥ 180 days) use of NSAIDs re-
mediates the synthesis of thromboxane A2 in
ported that no significant differences in the risk
platelets and the production of protective pros-
of treatment-related cardiovascular events were
taglandin of the gastric endothelium. COX-2 cat-
observed between groups treated with nonselec-
alyzes prostaglandin synthesis in the inflammatory
tive NSAIDS (etodolac, nabumetone, ibuprofen,
cells and leads to inflammation. Based on the
taking various NSAIDs showed that serious upper
GI complications were reduced by 40% among
patients who received misoprostol compared to
Owing to the potential serious GI complications
those who received placebo (OR, 0.6; 95% CI,
associated with nonselective NSAIDs, several
0.364–0.982).25 However, misoprostol was poorly
strategies have been used to decrease the risks,
tolerated because of diarrhea and related prob-
including: (1) use of selective COX-2 inhibitors;
lems.25 H2-blockers have also been used to pre-
(2) eradication of H. pylori infection; and (3) co-
vent NSAID-related ulcers. However, a randomized
prescription of gastroprotective agents. Selective
controlled trial revealed that omeprazole healed
COX-2 inhibitors are indeed effective for reduc-
and prevented ulcers more effectively than did
ing GI adverse events, but their cardiovascular
toxicities might restrict their utilization, espe-
cially when large-dose and long-term use are Which strategy would be better in the required. The other two strategies deserve further prevention of GI toxicity?
In very high risk patients (e.g. previous ulcer
bleeding induced by nonselective NSAIDs), the
Eradication of H. pylori
most effective prevention strategy would be com-
In a meta-analysis of 25 observational studies
bination therapy. Chan et al found that celecoxib
(8843 patients), Huang et al found that H. pylori
plus esomeprazole was better than celecoxib alone
infection and NSAIDs increase the risk of peptic
for the prevention of recurrent ulcer bleeding and
ulcers independently and have synergistic ef-
could reduce the recurrent bleeding rate to 0%.27
fects.23 Compared with H. pylori-negative indi-
A recent population-based, matched case-control
viduals not taking NSAIDs, the ORs of ulcer were
analysis consisting of 1382 NSAID/COX-2 users
18.1 for H. pylori-positive non-NSAID users, 19.4
with upper GI complications and 33,957 controls
for H. pylori-negative NSAID users, and 61.1 for
compared the effects of different strategies. The
H. pylori-positive NSAID users.23 Another meta-
results demonstrated that all of the commonly ac-
analysis by Vergara and colleagues found that the
cepted gastroprotective strategies (PPI, COX-2 in-
incidence of peptic ulcer in the overall popula-
hibitors, low-dose/high-dose misoprostol), either
tion receiving NSAIDs was reduced after H. pylori
alone or in combination, can reduce the risk of
eradication (7.4%), as compared to the control
upper GI complications in NSAID users.28 This
group (13.3%).24 Sub-analyses further showed a
study also confirmed that the combination of
significant reduction in the risk of ulcer for non-
COX-2 inhibitors with PPIs offers the greatest risk
NSAID users (OR, 0.26) but not for NSAID users
reduction. However, it was shown that celecoxib
may be superior to the combination of nonselec-
tive NSAIDs with a PPI. In contrast to this study,
Co-prescription of gastroprotective agents
Chan et al found that celecoxib was as effective as
The commonly used gastroprotective agents in-
diclofenac plus omeprazole in patients with a re-
clude misoprostol, H2-blocker, and proton pump
cent history of ulcer bleeding.29 The probability
inhibitors (PPI). Prophylactic use of antacids will
of recurrent bleeding was 4.9% in the celecoxib
not only not reduce the risk of GI toxicities, but
group and 6.4% in the diclofenac plus omepra-
may even mask the symptoms of subsequent se-
zole group during the 6-month period.29 Another
rious GI complications such as bleeding.16 Miso-
important question is: would clopidogrel be bet-
prostol is a synthetic prostaglandin E1 analog used
ter than PPI plus low-dose aspirin in preventing
in the prevention of NSAID-induced peptic ulcers.
recurrent bleeding? Chan et al reported that the
A double-blind randomized controlled trial in
cumulative incidence of recurrent bleeding was
8843 patients with rheumatoid arthritis who were
8.6% in the group treated with clopidogrel and
0.7% in the group treated with aspirin plus es-
duration of NSAID use, when in the first few
omeprazole during the 12-month period; they
months of NSAID use, concomitant use of anti-
concluded that the latter strategy is better.30
coagulants and corticosteroids, and other debili-
Next, is co-prescription of PPI or H. pylori
tating diseases.10–18 Cardiovascular risk may be
eradication more effective in the prevention of
assessed by the Framingham risk-score calculator,
recurrent upper GI bleeding? Chan et al found
which estimates a patient’s 10-year risk of devel-
that for H. pylori-infected low-dose aspirin users,
oping myocardial infarction and coronary death.
eradication therapy is equivalent to co-prescription
The patient’s age, sex, smoking status, total and
of PPI in the prevention of recurrent upper GI
high-density lipoprotein cholesterol levels, sys-
bleeding.31 However, for other NSAID users who
tolic blood pressure, and whether or not the
were H. pylori-infected, co-prescription of PPI is
patient is on antihypertensive treatment are
more effective than eradication therapy in the pre-
vention of recurrent bleeding.31 A meta-analysis
The general principles are that COX-2 in-
including two randomized controlled trials also
hibitor is preferred for patients with high GI risk,
revealed that co-prescription of PPI might be more
whereas naproxen is preferred for patients with
effective (0%) than H. pylori eradication (2.6%)
high cardiovascular risk. Gastroprotective agents
in the prevention of recurrent ulcer bleeding.24
are recommended for patients receiving naproxen
However, whether co-prescription of PPI plus or with high GI risk. The recommended strate-
H. pylori eradication would be better than co-
gies according to cardiovascular and GI risks are
prescription of PPI alone in the primary prophy-
shown in the Table.1,32 For patients with low car-
laxis of ulcer bleeding remains unknown.
diovascular risk, the choices of NSAIDs and gas-
troprotective agents can be managed according
Strategies for choosing appropriate NSAID
to their GI risk. Patients with low GI risk (without
according to cardiovascular and GI risks
GI risk factors as described above) can be treated
It is recommended that a patient’s cardiovascular
with nonselective NSAIDs alone. For patients with
and GI risks be evaluated before the prescription
medium GI risk, either COX-2 inhibitor alone or
of NSAIDs.1,32 Risk factors for the development
nonselective NSAID plus a PPI or misoprostol is
of serious NSAID-related GI events include old
appropriate. For patients with high GI risk, COX-2
age (> 60–65 years), history of peptic ulcer dis-
inhibitor plus a PPI or misoprostol is recom-
ease, H. pylori infection, higher dose or longer
mended. Among patients with high cardiovascular
Table. Recommendations on the use of NSAIDs according to CV and GI risks1,32 NSAIDs = nonsteroidal anti-inflammatory drugs; CV = cardiovascular; GI = gastrointestinal; COX-2 = cyclooxygenase-2.
risk, naproxen plus a PPI or misoprostol are pre-
ferred if they have low/medium GI risk. Low-
dose COX-2 inhibitor alone is also acceptable 1. Graham DY, Chan FK. NSAIDs, risks, and gastroprotective
for patients with low GI risk. For patients with
strategies: current status and future. Gastroenterology 2008;
high cardiovascular risk and high GI risk, it is rec-
2. Chandrasekharan NV, Dai H, Roos KL, et al. COX-3, a
ommended that NSAIDs and COX-2 inhibitors
cyclooxygenase-1 variant inhibited by acetaminophen and
be avoided if possible. If anti-inflammatory ther-
other analgesic/antipyretic drugs: cloning, structure, and
apy is necessary, the choice of NSAID should be
expression. Proc Natl Acad Sci USA 2002;99:13926–31.
based on the relative importance of the GI and
3. Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the pre-
cardiovascular risks of an individual patient. There
vention of colorectal adenomatous polyps. N Engl J Med
is currently no evidence to recommend which
4. Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for
combination would be better for this group of
the prevention of sporadic colorectal adenomas. N Engl J
patients, but co-prescription of a PPI or miso-
prostol is suggested. If the cardiovascular risk
5. Chang YJ, Wu MS, Lin JT, et al. Induction of cyclooxygenase-2
outweighs the GI risk, then naproxen is preferred
overexpression in human gastric epithelial cells by Heli-cobacter pylori involves TLR2/TLR9 and c-Src-dependent
over low-dose COX-2 inhibitor and vice versa.
nuclear factor-kappaB activation. Mol Pharmacol 2004;
Randomized controlled trials are warranted to test
the safety and efficacy of these recommendations
6. Chang YJ, Wu MS, Lin JT, et al. Helicobacter pylori-induced
for patients with high cardiovascular and high
invasion and angiogenesis of gastric cancer is mediated
by COX-2 induction through TLR2/TLR9 and promoter
regulation. J Immunol 2005;175:8242–52.
Liu NJ, Lee CS, Tang JH, et al. Outcomes of bleeding pep-
Perspectives
tic ulcers: a prospective study. J Gastroenterol Hepatol
There remain some unresolved questions regard-
ing the prevention of NSAID-related GI toxici-
8. McGettigan P, Henry D. Cardiovascular risk and inhibition
ties. First, whether or not routine screening for
of cyclooxygenase: a systematic review of the observational
and treatment of H. pylori infection before the
studies of selective and nonselective inhibitors of cyclooxy-
genase 2. JAMA 2006;296:1633–44.
use of NSAID is effective in the primary prophy-
9. Straus WL, Ofman JJ, MacLean C, et al. Do NSAIDs cause
laxis of upper GI bleeding remains unknown
dyspepsia? A meta-analysis evaluating alternative dyspep-
because most of the previous studies used reduc-
sia definitions. Am J Gastroenterol 2002;97:1951–8.
tion in recurrent bleeding (secondary prophy-
10. Singh G, Triadafilopoulos G. Epidemiology of NSAID in-
laxis) as the end point. Second, whether or not
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the application of the recommended strategies as
11. Smalley WE, Ray WA, Daugherty JR, et al. Nonsteroidal
shown in the Table will reduce the occurrence
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(primary prophylaxis) of NSAID-related compli-
tions for peptic ulcer disease in elderly persons. Am J
cations is also not known. Third, some host
genetic factors (such as variant CYP2C9*3 allele)
12. Lanas A, Perez-Aisa MA, Feu F, et al. A nationwide study
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lele is very rare in Chinese populations.35 Further
13. Geis GS, Stead H, Wallemark CB, et al. Prevalence of mu-
studies are warranted to identify the susceptible
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reduces serious gastrointestinal complications in patients
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A good reputation, goes the adage, is hard to acquire but easy to lose. It is indispensable to both individuals and companies, and devices such as name changes and PR are often employed in attempts to acquire one. But, at bottom, says Morgen Witzel , the only convincing way to win and keep a good reputation is to demonstrate that it is merited The reputation of the House of they are not, then a