REVIEW ARTICLE

Myths and facts in the use of anti-inflammatory drugs

RICHARD H. HUNT1, ANGEL LANAS2, DIRK O. STICHTENOTH3 &

CARMELO SCARPIGNATO4

1McMaster University Medical Centre, Hamilton, ON, Canada, 2University Hospital of Zaragoza, Zaragoza, Spain,3Medizinische Hochschule Hannover, Germany, and 4School of Medicine & Dentistry, University of Parma, Parma, Italy

AbstractBackground. Because of the prominence of pain-related conditions and the growing complexities of clinical management weaimed to explore and attempt to dispel the several myths that surround these serious therapeutic issues.Aims. We aimed to provide a careful analysis of the evidence and draw factually based guidance for physicians who managethe broad range of patients with pain.Methods. Current myths were identified based on the authors’ clinical, scientific, and academic experience. Each contributoraddressed specific topics and made his own selection of primary references and systematic reviews by searching inMEDLINE, EMBASE, and CINAHL databases (1990�2008) as well as in the proceedings of the major digestive andrheumatology meetings. The writing and references provided by each contributor were collectively analyzed and discussedby all authors during several meetings until the final manuscript was prepared and approved.Results. Seven major ‘historical’ myths that may perpetuate habits and beliefs in clinical practice were identified. Each ofthem was thoroughly examined and dispelled, drawing conclusions that should help guide physicians to better managepatients with pain.Conclusions. Pain relief must be considered a human right, and patients with osteoarthritis pain should be treatedappropriately with analgesic or/and anti-inflammatory drugs. The risk of gastrointestinal (GI) complications with traditionalnon-steroidal anti-inflammatory drugs (t-NSAIDs) is present from the first dose (with both short-term and long-term use),and strategies to prevent GI complications should be considered regardless of the duration of therapy. Compared with t-NSAIDs, coxib use is associated with a small but significant reduction of dyspepsia. While protecting the stomach, protonpump inhibitors do not prevent NSAID-induced intestinal damage. To this end, coxib therapy could be the preferred option,although further randomized studies are needed. A substantial number of patients who need NSAIDs are also taking low-doseaspirin for cardiovascular prophylaxis. From a GI perspective, the combination of aspirin plus a coxib provides a preferredoption compared with aspirin plus a t-NSAID, for patients at high GI risk. As the incidence of renovascular adverse effectswith t-NSAIDs and coxibs is similar, blood pressure should be monitored and managed appropriately in patients taking thesedrugs, although they should be avoided in those with severe congestive heart failure. Due to increased cardiovascular risk,which is dependent on the dose, duration of therapy, and base-line cardiovascular risk, both t-NSAIDs and coxibs should beused with caution in patients with underlying prothrombotic states and/or concomitant cardiovascular risk factors.

Key words: Anti-inflammatory therapy, arthritis, aspirin, cardiovascular system, coxibs, GI tract, kidney, myths, NSAIDs,side-effects

Introduction

There is currently no established treatment to reverse

or slow the progression of osteoarthritis (OA). Thus,

the primary goal of treatment is optimal pain control

and preservation of joint function, thereby breaking

the vicious circle of pain and loss of motion, leading

to instability, frailty, and total disability. To achieve

this goal, pharmacological, non-pharmacological,

and, if necessary, surgical treatment regimes must

form an integrated approach (1).

Pain is a common reason for patients to visit their

family physician (2,3), and the numbers seeking

treatment for pain are anticipated to rise as the

Correspondence: Carmelo Scarpignato, MD, Professor of Pharmacology & Therapeutics, Associate Professor of Gastroenterology, School of Medicine &

Dentistry, University of Parma, Parma, Italy. Fax: �1-603-843-5621. E-mail: scarpi@tin.it

(Received 18 August 2008; revised 30 January 2009; accepted 4 March 2009)

Annals of Medicine. 2009; 41: 423�437

ISSN 0785-3890 print/ISSN 1365-2060 online # 2009 Informa UK Ltd.

DOI: 10.1080/07853890902887295

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population ages and chronic conditions such as OA

increase. In the UK, annually, more than 17 million

prescriptions are written for anti-inflammatory and

analgesic drugs (4).

Paracetamol (acetaminophen) is the oral analgesic

of first choice. Although it is less effective than non-

steroidal anti-inflammatory drugs (NSAIDs), it is

safe when taken within the recommended dose range

(5). However, its hepatotoxicity must be considered,

and paracetamol hepatotoxicity far exceeds other

causes of acute liver failure in the USA (6).

Opioid analgesics show efficacy comparable with

paracetamol but are less effective than NSAIDs

alone (7). Opioids often cause adverse effects,

particularly in the elderly, including constipation,

central nervous system (CNS) reactions, increased

risk of falls, and even death (8).

In patients who respond inadequately to para-

cetamol or opioids, NSAIDs or coxibs at the lowest

effective dose for the shortest duration should be

prescribed. Other pharmacological treatments in-

clude the symptomatic slow-acting drugs for OA

(SYSADOA) (e.g. glucosamine sulphate, chondroi-

tin sulphate, diacerhein), topical NSAIDs, capsaicin,

and intra-articular glucocorticoid injections (1). The

data supporting these other agents are variable, but

they may be successful in some patients. However,

most of them will require a NSAID at some time

during the clinical course of their OA. It is therefore

evident that these drugs are an essential and effective

part of disease management.

About 25% of Canadians were prescribed short-

term NSAIDs, and �4% long-term (]6 months)

(9), equating to a prevalence of �6.2 million short-

term and �1.0 million long-term NSAID users in

Canada. However, this does not include over-the-

counter (OTC) NSAID use, and a US cohort study

reported point prevalence of NSAID use as 8.7%

(10). Low-dose aspirin (ASA) is also widely used for

cardiovascular risk reduction and for chemopreven-

tion. (11)

Gastrointestinal (GI) adverse events, including

dyspepsia (12) or ulcer and ulcer complications

(13), are common in patients taking NSAIDs. One

systematic review of patients taking NSAIDs for at

least 2 months found that 1 in 5 have an endoscopic

ulcer, 1 in 70 a symptomatic ulcer, and 1 in 150 have

GI bleeding (14).

Cyclo-oxygenase 2 (COX-2)-selective inhibitors

(often referred to as coxibs (15)) were introduced as

a safer alternative to traditional NSAIDs (t-

NSAIDs) based on an improved GI safety profile

but were subsequently found to be associated with

an increase in cardiovascular (CV) adverse events

(16,17). The withdrawal of rofecoxib and valdecoxib

and the subsequent evidence that most if not all t-

NSAIDs also carry a CV risk (18) have led to

confusion, and physicians are questioning how best

to manage pain, especially in older patients at

increased GI and CV risk.

Low-dose aspirin is widely used for secondary

prevention of myocardial infarction and thrombotic

stroke (19) and is increasingly taken by people with

Key messages

. Pain relief must be considered a human

right, and patients with osteoarthritis pain

should be treated appropriately. Analgesic

or/and anti-inflammatory drugs are an

essential and effective part of the treatment

concept of this condition.

. Although non-steroidal anti-inflammatory

drugs (NSAIDs) represent a very effective

class of drugs, their use is associated with a

broad spectrum of untoward reactions in

the upper and lower gastrointestinal tract,

kidney, and cardiovascular system, some of

which are shared also by the recently

introduced cyclo-oxygenase (COX)-2-

selective agents.

. Only a rational use of these drugs, alone or

in combination with other compounds, can

assure an effective and safe analgesic and

anti-inflammatory therapy.

Abbreviations

ACE angiotensin-converting enzyme

AMI acute myocardial infarction

ASA aspirin (acetylsalicylic acid)

AT1 angiotensin type 1

BP blood pressure

CHD coronary heart disease

CHF congestive heart failure

CNS central nervous system

CV cardiovascular

COX-2 cyclo-oxygenase 2

GI gastrointestinal

OA osteoarthritis

PG prostaglandin

PPIs proton pump inhibitors

RA rheumatoid arthritis

RCTs randomized clinical trials

SSRIs selective serotonin reuptake inhibitors

t-NSAIDs traditional (non-selective) non-

steroidal anti-inflammatory drugs

UGIB upper GI bleeding

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no or only a few CV risk factors (primary preven-

tion) where the risk of a serious GI complication or

hemorrhagic stroke (20) is likely equal to or greater

than any potential benefit (21).

Prescribing appropriate analgesics is further

complicated by the need for careful assessment of

concomitant medications and any underlying med-

ical conditions. Clopidogrel is also used commonly

in association with ASA in patients at high CV risk,

and such combination therapy increases the risk of

GI bleeding (19). Selective serotonin reuptake

inhibitors (SSRIs) may also cause GI bleeding, and

this risk increases with concomitant ASA or NSAID

use (22). Common co-morbidities such as cardio-

vascular disease, diabetes, metabolic syndrome, and

GI problems further confound appropriate manage-

ment.

Because of the prominence of pain-related con-

ditions and the growing complexities of clinical

management we aimed to explore and attempt to

dispel the several myths that surround these serious

therapeutic issues. We aimed to provide a careful

analysis of the evidence and draw factually based

guidance for physicians who manage the broad range

of patients with pain.

Methods

Current myths were identified based on the authors’

clinical, scientific, and academic experience. Each

contributor addressed specific topics and made their

own selection of primary references and systematic

reviews by searching in MEDLINE, EMBASE, and

CINAHL databases (1990�2008) as well as in the

proceedings of the major digestive and rheumatology

meetings. The writing and references provided by

each contributor were collectively analyzed and

discussed by all authors during several meetings

until the final manuscript was agreed.

Results

Seven major ‘historical’ myths that may perpetuate

habits and beliefs in clinical practice were identified.

Each was thoroughly examined, drawing conclusions

relevant to clinical practice.

Myth 1: NSAIDS when given for short periods (days)

have a lower GI risk than when given in the longer term

(weeks/months)

It is widely believed that treating patients with

t-NSAIDs for short periods carries no, or very low,

GI risk. However, current evidence suggests that this

is not the case and that the risk may even be higher

during the initial treatment period. This evidence

comes both from randomized controlled trials and

observational studies.

Recent outcome trials (23�27) have shown that

upper GI complications and symptomatic ulcers

occur within the first month of therapy. Although

these trials have shown, in general, that COX-2-

selective inhibitors are associated with a clear risk

reduction for upper GI events compared with

t-NSAIDs, the question is whether severe upper

GI events can also occur in patients taking COX-2-

selective inhibitors early in the treatment period. The

data reported show a lower incidence of these events

in the initial treatment period and a less rapid increase

in the incidence of these events over time compared

with t-NSAIDs (23,24,27). The APPROVe trial,

which compared the efficacy of rofecoxib with pla-

cebo in preventing colon polyps, showed that patients

taking rofecoxib did have events early, particularly

within the first month of treatment (28).

Observational studies have either found a con-

stant GI risk over time for patients taking t-NSAIDs

or an increased relative risk during the first month

(short-term) of therapy (29). A well performed

cohort study (30) showed that admission to hospital

for upper gastrointestinal bleeding (UGIB) and

perforation remained constant over months of

NSAID exposure, i.e. long-term therapy (Figure 1)

and suggested a carry-over effect at the end of

prescribing. In a more recent investigation it was

found that the relative risk (RR) of ulcer bleeding for

coxib use was lower (neutral for celecoxib) com-

pared to t-NSAIDs. However, the RR was also

higher during the first month of t-NSAID or coxib

use compared to continuous use (31). A meta-

analysis of 18 observational studies reported a

constant RR of upper GI complications over time,

and that RR dropped quickly once treatment was

stopped. Traditional-NSAID use increased the

risk of UGIB among new users and among those

already on therapy for several months, at least

during the first year of treatment. However, the

pooled RR was greater for new users (RR 5.7; 95%

confidence interval (CI) 4.9�6.6). On average,

2 months after the end of therapy the risk had

returned to base-line incidence among subjects not

using t-NSAIDs (29).

A careful analysis of available studies suggests

that the reported higher risk of GI complications in

short-term t-NSAID users compared to those taking

long-term t-NSAIDs is likely due to the inclusion of

patients prone to develop complications (e.g. at-risk

patients carrying asymptomatic lesions or ulcers),

whereas estimates of RR in long-term users are

Myths and facts on NSAIDs and coxibs 425

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based on studies depleted of such susceptible

populations.

In summary, the evidence from both randomized

clinical trials (RCTs) and observational studies

indicates that the risk of GI complications is present

with both short-term and long-term use of

t-NSAIDs from the first dose. Thus, even a short

course of NSAID therapy (e.g. for postoperative

pain or acute musculoskeletal injury) carries a risk

equivalent to that of long-term treatment. As a

consequence, strategies to prevent GI complications

should be implemented regardless of the duration of

therapy, especially in patients with high GI risk.

Myth 2: Coxibs and t-NSAIDs are associated with

similar rates of dyspepsia

Upper GI symptoms (including dyspepsia, heart-

burn, abdominal bloating or cramping), associated

with t-NSAID use occur in up to 25% of patients

taking t-NSAIDs (32). These symptoms, which have

little relationship to erosions or ulceration seen

endoscopically, are sufficient to prompt a change in

therapy in 10% of patients. Dyspeptic symptoms are

the most prevalent and resource-consuming adverse

effects of t-NSAIDs and have important cost-effec-

tiveness implications when selecting between COX-

2-selective and non-selective t-NSAIDs (33).

Although dyspepsia has been estimated to occur

in 15%�60% of t-NSAID users (34), data from a

meta-analysis indicate that only 8%�12% of patients

receiving chronic high-dose t-NSAID therapy de-

velop recurrent dyspeptic symptoms (12). The in-

cidence of dyspepsia with coxib therapy has been

extensively studied. In the diclofenac protocol of

the CLASS study (23) dyspepsia was assessed by

the Severity of Dyspepsia Assessment (SODA)

questionnaire (35). SODA revealed that celecoxib,

at 2 to 4 times the recommended dose, had a

superior dyspepsia-related tolerability and patient

satisfaction compared with standard dose diclofenac

(35), and this held true for both younger and older

patients. A similar reduction in dyspeptic symptoms

was reported in two pooled analyses of rofecoxib

(36) and valdecoxib (37) trials, although in aspirin

users celecoxib was associated to a significantly lower

incidence of GI symptoms than rofecoxib (38).

Moreover, in an elderly population, upper GI

symptoms and prescription of gastroprotective drugs

were lower in COX-2-selective than t-NSAID users

(39). Furthermore, compared with those taking t-

NSAIDs, coxib users were less likely to switch

medications (40), and the ‘survival time’ on a coxib

was significantly greater than on t-NSAIDs, with a

median survival time of celecoxib (15 months)

significantly longer than that of rofecoxib (13

months) (41).

The impact of dyspepsia in t-NSAID and COX-

2-selective users was examined in a meta-analysis of

26 RCTs (42) (Figure 2). The study revealed a 12%

relative risk reduction in dyspeptic symptoms for

coxibs versus t-NSAIDs. Compared with a t-

NSAID, the number needed to treat (NNT) with a

coxib to prevent 1 patient from developing dyspeptic

symptoms was 27.

Dyspepsia reduction with coxib therapy may not

appear substantial, and patients on COX-2-selective

NSAIDs may need co-therapy with proton pump

inhibitors (PPIs) to obtain the same symptom

improvement observed in those taking t-NSAIDs

(43). Experience, however, indicates that*in the

individual patient*the lower dyspepsia rate of coxibs

compared with t-NSAIDs, while not large, could be

clinically relevant.

Although head-to-head data are limited, a t-

NSAID�PPI affords greater risk reduction for

dyspepsia than selective drugs when compared with

the common base-line of t-NSAIDs (42). Regardless

of the treatment pursued, patient reassurance is

important, as more than 50% of patients with

NSAID-associated dyspepsia may improve without

any intervention whatsoever (43).

Myth 3: A proton pump inhibitor and a traditional

NSAID achieves full GI protection

Although the upper GI toxicity of t-NSAIDs is well

documented, the appreciation that t-NSAID da-

mage extends beyond the duodenum is less well

recognized (44). Traditional-NSAID-associated

toxicity to the small and large bowel has several

different manifestations, including subclinical and

Figure 1. Relative risk (95% confidence intervals) for admission

for complicated upper gastrointestinal events during each time-

period of continuous exposure (mean value shown as upper dotted

line) and during each time period of subsequent continuous non-

exposure to non-steroidal anti-inflammatory drugs (NSAIDs)

(30).

426 R. H. Hunt et al.

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clinically evident damage. The prevalence of t-

NSAID-associated lower GI adverse effects may

exceed that detected in the upper GI tract, and the

frequency of life-threatening complications in the

lower GI tract represents about one-third of all

GI complications associated with the use of these

drugs (45).

Although inhibition of mucosal prostaglandin

(PG) synthesis during t-NSAID treatment occurs

along the entire digestive tract, there are significant

differences between the intestine and the stomach

and duodenum with regard to other pathogenic

factors that may add to damage. The absence of

acid (which plays a pivotal role in the pathogenesis of

upper GI damage) and the presence of bacteria and

bile in the intestine (46) (which may trigger specific

t-NSAID-related pathogenic mechanisms in the

distal GI tract) are the most important.

Co-administration of misoprostol (a synthetic

PGE1 analog) or proton pump inhibitors (PPIs)

currently represents the best available strategy to

prevent t-NSAID-associated upper GI symptoms

and mucosal damage in patients with GI risk factors

(32,47). However, t-NSAID-associated intestinal

damage is not a pH-dependent phenomenon, and

co-administration of antisecretory drugs is unable to

either prevent or treat lower GI mucosal lesions

beyond the proximal duodenum. Although recent

experimental evidence (48) suggests a protective

activity of PPIs on indomethacin-induced intestinal

damage acting through antioxidant and anti-inflam-

matory properties, video capsule studies have shown

that the combination of a PPI with a t-NSAID is not

capable of preventing the lower intestinal damage

associated with short-term administration of na-

proxen or ibuprofen (49,50).

COX-2-selective inhibitors may induce less or no

damage to the intact distal gastrointestinal tract

compared to t-NSAIDs. The lack of intestinal

damage with this class of drugs in animal experi-

ments has been confirmed in clinical studies (45).

Most patients taking either meloxicam (51) or

nimesulide (52), two preferential COX-2 inhibitors,

had normal intestinal permeability and no increase

in intestinal inflammation in comparison to control

patients not taking the drug. Conversely from t-

NSAIDs, neither rofecoxib (53) nor lumiracoxib

(54) affects intestinal permeability in humans. In

studies performed in healthy volunteers rofecoxib

(55) and etoricoxib (56) compared with ibuprofen

did not increase fecal blood loss. Similarly, the

incidence of anemia with celecoxib is significantly

lower than with t-NSAIDs (23,57). Although some

case reports of acute colitis or lower intestinal

complications have been reported with coxibs, data

from the VIGOR trial have shown that the benefits

of rofecoxib 50 mg/day compared with naproxen

(500 mg b.i.d.) were seen in both the upper and

Author

Benson [2002]Cannon [2000]Day [2000]Dougados [2001]Emery [1999]Geusens [2002]Goldstein [2001]Hawkey [2000]Hawkey [2003]Hawkey [2004]Izhar [2004]Kiviz [2001]Kiviz [2002]Kiviz [2004]Kiviz [2004]Leung [2002]Makarowski [2002]Matumoto [2002]McKenna [2001]Myllykangas [2002]Pavelka [2003]Saag [2000]Schnitzer [2002]Sikes [1999]Silverstein [2000]Simon [1998]

Overall (95% CI)

Relative Risk (95% CI)

0.77 (0.56, 1.05)1.00 (0.72, 1.40)0.90 (0.59, 1.38)0.88 (0.47, 1.64)0.69 (0.49, 0.96)0.55 (0.37, 0.81)0.85 (0.59, 1.23)0.56 (0.33, 0.94)0.97 (0.75, 1.24)0.84 (0.74, 0.96)0.33 (0.01, 7.55)0.76 (0.54, 1.06)1.66 (0.87, 3.16)0.83 (0.56, 1.22)0.82 (0.71, 0.96)0.63 (0.40, 0.99)0.73 (0.40, 1.31)0.82 (0.56, 1.21)0.77 (0.43, 1.39)0.47 (0.27, 0.81)0.75 (0.51, 1.10)0.81 (0.57, 1.14)0.91 (0.88, 0.95)0.87 0.57, 1.33)0.84 (0.78, 0.91)0.78 (0.41, 1.51)

0.88 (0.85, 0.91)

% Weight

1.10.90.60.31.10.80.80.51.33.30.00.90.20.72.80.70.40.70.40.60.80.963.30.716.00.3

-1 1 10Relative Risk

-0.1

Figure 2. Meta-analysis using the fixed-effects model of RCTs reporting dyspeptic symptoms in patients who received COX-2-selective

versus t-NSAIDs. Summary estimate is the relative risk with 95% confidence intervals (42).

Myths and facts on NSAIDs and coxibs 427

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lower GI tract, with risk reductions of 50% and

60%, respectively (24,58). Similarly, fewer lower GI

adverse events were reported in a large, long-term

RCT (MEDAL study) with etoricoxib (60 or 90 mg

daily), where a 24% risk reduction over diclofenac in

all investigator-reported events was observed (59).

Myth 4: Aspirin negates the GI benefits of a coxib

It is widely believed that co-prescription of aspirin

negates the benefit of a coxib and that this drug

combination should not be used. This has led to the

clinical dilemma of how to manage patients who

require an anti-inflammatory drug for arthritis but

are at GI risk, and who also need to take aspirin for

cardiovascular prophylaxis.

Since up to 45% of coxib users could be taking

low-dose aspirin (60), the question of COX-2-

selective inhibitor GI safety in the presence of aspirin

is of substantial clinical importance.

Overwhelming evidence from large randomized

trials (34,460 patients), meta-analyses of randomized

trials (52,474 patients), and large observational

studies (3,093 bleeding events) shows a better GI

safety of coxibs, with consistent reductions in serious

GI events of about 50% in comparison to t-NSAIDs

(61). However, subanalyses of aspirin users from two

large-scale outcome trials (CLASS (26) and TAR-

GET (27)) have demonstrated that, in the presence of

aspirin use, there was no significant difference in the

incidence of upper GI ulcer complications between

t-NSAID and the COX-2-selective inhibitor users

(i.e. celecoxib or lumiracoxib, respectively). The

more recent MEDAL study also showed that the

decrease in overall and uncomplicated GI events in

etoricoxib versus diclofenac users was smaller in

patients taking low-dose aspirin (62).

Thus, while coxibs present a better upper GI

safety profile than t-NSAIDs, aspirin use is a strong

effect modifier (63) so that the differences between

them tend to be reduced when combined with low-

dose aspirin (31). It is, however, worth mentioning

that neither of the above trials was specifically

powered to address the issue of ulcer complications

in aspirin users. As such, the generalizability of these

results is open to question. The clinical importance

of this issue needs to be addressed in adequately

powered long-term safety studies evaluating ulcer

complications. Until such time, the possibility re-

mains of a relative benefit of COX-2-selective

inhibitors compared with t-NSAIDs, also in aspirin

users. Interestingly enough, in the subpopulation of

aspirin users in the SUCCESS-I study the incidence

of ulcer complications was numerically lower in the

celecoxib group compared with the t-NSAIDs

group, although this difference was not statistically

significant (odds ratio 2.0; 95% CI 0.12�31.7) (64).

In contrast to the findings from these large trials,

endoscopic studies offer mixed results. Two separate

retrospective post hoc analyses of pooled endoscopic

trials, one with celecoxib and the second with

valdecoxib, demonstrated that the rate of endoscopic

ulcers was approximately 50% lower in aspirin users

(81�325 mg/day) receiving a COX-2-selective in-

hibitor compared with those randomized to a non-

selective NSAID plus aspirin (65,66). However, in

contrast to these results, a prospective analysis by

Laine et al. (67) demonstrated that the use of

rofecoxib (25 mg o.d.) with low-dose aspirin (81

mg o.d.) increased the incidence of endoscopic

ulcers (]3 mm in diameter) to a rate not signifi-

cantly different from that of ibuprofen alone. The

cumulative endoscopic ulcer incidence rate was 16%

in the group receiving aspirin plus rofecoxib com-

pared with 17% in the subjects receiving ibuprofen

(P�0.62) (67). However, this analysis did not

include a t-NSAID plus aspirin treatment arm.

Two meta-analyses of celecoxib plus ASA found

50% fewer endoscopic ulcers than in those taking

t-NSAIDs and ASA (68,69). The study by Moore

and colleagues (68) showed that in patients not

taking ASA, the relative risk (RR) of celecoxib at any

dose versus a t-NSAID was 0.28 (95% CI 0.22�0.36); with ASA, the RR for any dose of celecoxib

versus a t-NSAID was 0.48 (95% CI 0.28�0.83),

suggesting the protective advantage of the coxib was

preserved but was smaller when ASA was also used

(69). In line with these findings, a recent endoscopic

study (70) found, in subjects receiving celecoxib plus

aspirin, an incidence of gastroduodenal ulcers sig-

nificantly lower than for naproxen plus aspirin (7%

versus 25.3%; RR 0.28 (95% CI 0.17�0.45); PB

0.001), but significantly higher than placebo plus

aspirin (7% versus 1.6%; RR 4.78 (95% CI 1.12�20.32); P�0.016).

While these endoscopic findings are important,

they do not provide definitive guidance for making

therapeutic decisions in patients requiring anti-

inflammatory therapy for pain and low-dose aspirin

for cardiovascular prophylaxis. Endoscopic ulcer

rates are indeed surrogate markers for ulcer compli-

cations. However, data concerning hospital admis-

sions for upper GI bleeding do confirm an advantage

of coxibs over t-NSAIDs in low-dose aspirin users. A

cohort study (71) using a Quebec health insurance

database showed that, in elderly patients, coxibs

(namely celecoxib and rofecoxib) and ASA were less

likely to be associated with GI hospitalization than a

t-NSAID and ASA (Table I) (HR 0.53, 95% CI

0.34�0.83). All these data, taken together, suggest

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that in patients receiving cardiovascular protection

with ASA and pain control with anti-inflammatory

drugs, celecoxib (and likely other coxibs) may be

safer with regards to GI toxicity compared to t-

NSAIDs.

New data further show that concomitant t-

NSAID use can attenuate the benefits of ASA

therapy. Ibuprofen associated with the COX-1 bind-

ing site blocks access of ASA to the serine binding site

in the apex of the COX-1 pocket, which has im-

portant clinical implications (72,73) for the cardio-

vascular protective effect of ASA. Compared with

those who used aspirin alone, it has been shown that

patients taking aspirin plus ibuprofen had an in-

creased risk of all-cause mortality (adjusted hazard

ratio 1.93, 95% CI 1.30�2.87; P�0.0011) and

cardiovascular mortality (1.73, 1.05�2.84; P�0.0305) (73). Co-administration of placebo or cel-

ecoxib, however, did not adversely influence aspirin-

related inhibition of platelet COX-1 activity (74).

In summary, in all available large coxib GI

outcome studies, when aspirin was permitted, a

coxib plus aspirin is associated with a non-signifi-

cantly lower ulcer rate and lower ulcer complication

rate when compared with t-NSAIDs alone. More-

over, a coxib plus low-dose aspirin is associated with

lower GI risk than a t-NSAID plus low-dose aspirin.

Thus, combination of aspirin plus a coxib is the

preferred option compared with aspirin plus a t-

NSAID, for patients at high GI risk who require

aspirin for CV prophylaxis. Future RCTs specifically

designed to compare the GI and CV safety of a coxib

plus aspirin and a t-NSAID plus aspirin are needed

to confirm these conclusions.

Myth 5: Coxibs increase the risk of renovascular events

compared to traditional NSAIDs

In the human kidney prostaglandin E2 and prosta-

cyclin are the predominant prostanoids, which play

an important role in maintenance of renal blood flow

and glomerular filtration rate (GFR), inhibition of

tubular sodium reabsorption, antagonism of anti-

diuretic hormone, and regulation of renin secretion

(75). As regards the involvement of COX isoen-

zymes in kidney physiology, clinical studies with

selective COX-2 inhibitors found that COX-2 is the

critical enzyme for sodium excretion and renin

release (76). For renal hemodynamics the evidence

points to COX-1 as the predominant enzyme (75).

Thus, from a pharmacological standpoint there is no

special risk of selective COX-2 inhibition as com-

pared with inhibition of both COX isoenzymes by t-

NSAIDs (75). All t-NSAIDs and coxibs may affect

renal function leading to edema, hypertension,

hyperkalemia, water intoxication, decreased GFR,

and acute renal failure (75). In patients without

renal risk factors (Table II) the renal adverse effects

of t-NSAIDs are rarely seen (77). However, the

incidence of t-NSAID-induced renal side-effects can

be as high as 20% in at-risk patients (78).

The renovascular risk of t-NSAIDs was seldom

described until clinical trials with coxibs. In the

study by Chan et al. (79) diclofenac 150 mg/d

caused hypertension, edema, and acute renal failure

in 18.9%, 5.6%, and 6.3% of patients, respectively,

in a group of 143 patients with at least one renal risk

factor; the corresponding figures for celecoxib 200

mg b.i.d. were 13.9%, 4.9%, and 5.6%, respectively.

A meta-analysis of 19 RCTs with a total of 45,451

patients found a relative risk (RR) of developing

hypertension with rofecoxib compared to t-NSAIDs

of 1.8 (95% CI 1.2�2.7), while with celecoxib versus

t-NSAIDs a trend for a lower RR was observed (RR

0.8; 95% CI 0.7�1.0) (80). Similar findings were

reported in a retrospective case-control study invol-

ving 17,844 patients aged over 65 years (81). The

prospective, randomized MEDAL program, which

included 34,701 patients with OA or rheumatoid

arthritis, showed that etoricoxib 90 mg/d was

associated with discontinuations due to edema

more frequently than diclofenac 150 mg/d; the

same held true for hypertension (62). The higher

risk for edema and hypertension with rofecoxib and

etoricoxib in comparison to celecoxib and t-NSAIDs

Table I. Risk for GI hospitalization amongst a cohort of elderly

patients taking t-NSAIDs or coxibs and requiring CV protection

with low-dose aspirin (71).

Treatment Hazard ratio (95% CI)

t-NSAIDs only (reference) 1

t-NSAIDs�aspirin 1.61 (1.02�2.56)

Coxibs 0.62 (0.45�0.81)

Coxibs�aspirin 0.86 (0.63�1.17)

Coxibs�aspirin versus t-NSAIDs�aspirin

0.53 (0.34�0.83)

Table II. Risk factors for renal side-effects of NSAIDs (75).

Risk factor

Pre-existing renal impairment

Dehydration

Sodium depletion by diet or diuretics

Congestive heart failure

Liver cirrhosis with ascites

Lupus nephritis

Postsurgical status

Co-medication with nephrotoxic drugs (e.g. aminoglycosides,

cyclosporine)

Co-medication with ACE inhibitors, angiotensin type 1 (AT1)

receptor antagonists

Co-medication with potassium-sparing diuretics

Myths and facts on NSAIDs and coxibs 429

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is currently not well understood. The most plausible

explanation is the long plasma half-life and sustained

inhibition of COX-2 by rofecoxib and etoricoxib

(15,77) as well as their greater renal excretion

compared to celecoxib (15).

The new-onset or exacerbation of edema and

hypertension can precipitate congestive heart failure

(CHF) (82). Recent studies have focused on the risk

of CHF associated with COX-2-selective inhibitors

or t-NSAIDs. The population-based cohort study

reported by Hudson and colleagues assessed the risk

for recurrent CHF or death in elderly patients

prescribed celecoxib, rofecoxib, or t-NSAIDs (83).

This risk, whether combined or separate, was higher

in patients prescribed t-NSAIDs or rofecoxib than in

those prescribed celecoxib (Figure 3). A similar

conclusion can be derived from the epidemiological

study by Mamdani and colleagues (84), which

compared rates of admission for CHF in elderly

patients who were newly dispensed COX-2 inhibi-

tors (rofecoxib n�14,583; celecoxib n�18,908), or

t-NSAIDs (n�5,391), and randomly selected non-

t-NSAID users as controls (n�100,000). Relative to

non-t-NSAID users, patients taking rofecoxib and t-

NSAIDs had an increased risk for admission for

CHF (adjusted rate ratio 1.8, 95% CI 1.5�2.2; and

1.4, 1.0�1.9, respectively), but not celecoxib (1.0,

0.8�1.3). In the MEDAL study, a higher rate of

congestive heart failure was seen with etoricoxib 90

mg than with diclofenac, but this difference fell short

of statistical significance; no difference was seen with

etoricoxib 60 mg (62).

In summary, the renovascular effects of

t-NSAIDs and coxibs are similar with molecule-

specific quantitative differences between the various

drugs. Blood pressure should be monitored and

managed appropriately in patients on t-NSAIDs

and coxibs. In patients with severe congestive heart

failure, however, these drugs should be avoided.

Myth 6: Non-selective NSAIDs are not associated with

increased CV risk

Several publications have raised concerns that coxibs

may be prothrombotic and increase the risk of acute

myocardial infarction (AMI). This has arisen because

of a theoretical possibility that selective COX-2

inhibitors may affect the balance between prothrom-

botic and antithrombotic prostanoids (72,85). The

possibility of a cardiovascular (CV) hazard of COX-2

inhibitors was first hypothesized during late-stage

clinical development, when a marked depression of

prostacyclin I2 (PGI2) biosynthesis (similar to that

achieved by t-NSAIDs) was observed in healthy

volunteers. Unlike ibuprofen and indomethacin,

neither celecoxib nor rofecoxib inhibited COX-1-

derived thromboxane A2 (TXA2) and thus did not

affect platelet aggregation. Because of this, it was

suggested that COX-2-selective inhibition could be

prothrombotic in patients with vascular disease (86).

The patient population most likely to use chronic

anti-inflammatory therapy, the elderly, is also at

highest risk for atherosclerotic disease. In these

patients, COX-2-specific inhibitors might lead to

loss of the homeostatic platelet inhibition normally

induced by PGI2 and consequently promote

or enhance platelet activation. Conventional

t-NSAIDs, which inhibit the synthesis of both PGI2

and TXA2, should not pose this theoretical risk.

The first clinical signal of a CV hazard arose from

a subanalysis of the VIGOR trial (24), which

demonstrated a significant increase in the risk of

AMI for rofecoxib relative to naproxen. The absence

of a placebo group in this trial and the low event rate

Figure 3. Adjusted hazard ratios (95% confidence intervals) for death and recurrent congestive heart failure (combined and alone) in

patients taking NSAIDs or coxibs, according to exposure group (83).

430 R. H. Hunt et al.

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in this subgroup analysis make interpretation of these

findings difficult. Moreover, rofecoxib was given at

twice the recommended dose, and the population

included rheumatoid arthritis (RA) patients (none of

whom took low-dose aspirin for CV protection).

Possible explanations include an increased risk of

AMI for rofecoxib, a cardioprotective effect of

naproxen, or a combination of both. Alternatively,

the findings of the VIGOR trial with respect to AMI

may have simply occurred by chance and neither

rofecoxib nor naproxen truly affects the risk of‘ AMI.

A thoughtful review to which the reader is referred

discusses these issues in detail (87).

Subsequent to the publication of VIGOR results,

Mukherjee and colleagues (88) extended the CV

safety concerns to celecoxib and potentially all

selective COX-2 inhibitors. After this report, several

analyses or meta-analyses (for review see (89,90))

provided evidence for or against an increased CV

risk during selective COX-2 inhibitor therapy. The

results of three different studies (10,11,91) docu-

menting an increase in AMI risk after rofecoxib,

celecoxib, and parecoxib/valdecoxib confirmed that

CV adverse events with these drugs is a class- rather

than a molecule-dependent effect, and that the risks

may be dose-related. Meanwhile the National In-

stitutes of Health decided to stop the ADAPT trial

because of an increased incidence of AMI in patients

treated with naproxen (92). These results, unex-

pected in the light of the platelet antiaggregant effect

of naproxen (93), suggested that the CV risks of

coxibs are similar to those seen with t-NSAIDs.

Indeed, five subsequent observational studies

(83,94�97), two systematic reviews of observational

studies (98,99), and a meta-analysis of randomized

trials (12) concluded that both t-NSAIDs and COX-

selective NSAIDs share the same CV risks, i.e. an

increase in AMI, CHF, and risk of sudden death.

The lack of cardioprotective effect of naproxen and

the inability of low-dose ASA to counterbalance the

CV effects of coxibs, pointed out in the Hippisley-

Cox study (94), challenged the hypothesis that the

increase in CV risk of selective COX-2 inhibitors

could be due to their ‘prothrombotic’ activity.

However, a recent large (1.9 million patients)

inception cohort study (100) reported that conco-

mitant use of aspirin reduced the risk of CV events

when given with rofecoxib, celecoxib, sulindac,

meloxicam, and indomethacin, but not when given

with ibuprofen. If confirmed by additional studies,

these findings suggest that COX-selective NSAIDs

are preferable to t-NSAIDs in rheumatic patients

with CV risk who require low-dose aspirin (101).

Although the combined clinical experience is

suggestive of an increased CV risk with coxibs in

situations of elevated thrombotic risk (102) and a

gradual increase of risk over extended periods of

exposure (103), the speculative thrombogenicity of

selective COX-2 inhibitors has not been documen-

ted in clinical trials to date. Indeed, studies showing

an increased AMI risk should be interpreted with

caution, because affected patients had multiple risk

factors for hypercoagulability, and the association

between coxib treatment and thrombotic episodes

could have been only temporal rather than causal in

nature. The importance of underlying risk factors

has been clearly emphasized by the Nurses’ Health

Study, which examined the influence of t-NSAIDs

on the risk of major CV events (non-fatal AMI, fatal

coronary heart disease (CHD), non-fatal and fatal

stroke) (96). While confirming the elevated CV risk

of frequent (�22 days per month) t-NSAID use, the

study revealed that the risk was particularly evident

among current smokers (in whom endothelial dys-

function triggers platelet adhesiveness and aggrega-

tion (104)) and was absent among those who had

never smoked (Table III). Patients with pre-existing

CV disease are obviously at the highest risk, but a

randomized controlled trial has not been conducted

in this population. However, a recent cohort study

(105) confirmed that both rofecoxib and celecoxib

are associated with an excess risk of AMI for current

users with a history of myocardial infarction. Inter-

estingly, in this study only rofecoxib was associated

with increased AMI risk in patients without a

previous event.

The clinician should therefore not forget that

poor long-term control of CV risk factors, such as

hypertension, dyslipidemia, diabetes, smoking, and

obesity, is more deleterious in terms of CV mortality

than the administration of a t-NSAID. Both COX-

selective and t-NSAIDs should be used with caution

in patients with underlying prothrombotic states (in

whom low-dose aspirin or appropriate anticoagulant

Table III. CV risk in t-NSAID users: effect of smoking and

frequency of drug intake (96).

Relative risk

95% Confidence

intervals

t-NSAIDs 1.44 1.27�1.65

Current smoker 1.82 1.38�2.42

Past smoker 1.58 1.28�19.5

Never smoked 1.11 0.88�1.41

�15 packets/week 1.86 1.27�2.73

Myths and facts on NSAIDs and coxibs 431

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treatment should be used as clinically indicated)

and/or concomitant risk factors.

Myth 7: Corticosteroids or anticoagulants increase GI

risk in combination with NSAIDs, but it is safe to co-

prescribe NSAIDs with other medications

The interactions of NSAIDs with angiotensin-con-

verting enzyme (ACE) inhibitors, angiotensin type 1

(AT1) receptor antagonists, diuretics, and selective

serotonin reuptake inhibitors (SSRIs) are widely

underappreciated. Apart from the attenuation of

the effects of antihypertensive drugs, coxibs and t-

NSAIDs increase the risk of renal impairment when

given concomitantly with ACE inhibitors/AT1 re-

ceptor antagonists and diuretics (106).

Selective serotonin reuptake inhibitors (SSRIs)

are associated with an increased risk of bleeding

(22,107), leading to hospital admission (108). Gas-

trointestinal bleeding may be generalized (109) or

localized to the upper gastrointestinal tract (110�112). Other studies, however, did not find particular

association with bleeding (113,114).

SSRIs may impair platelet aggregation, and

depletion of serotonin is postulated as the most

likely mechanism (115). The risk of bleeding is

further increased when SSRIs are taken concomi-

tantly with t-NSAIDs or aspirin. Observational

studies show a RR for UGIB ranging from 1.3 to

3.6 for SSRIs alone, RR 12.2 to 15.6 for users of

SSRIs and t-NSAIDs together, and RR 5.2 to 7.2 for

SSRIs and aspirin users (22). Furthermore, the risk

ratio for gastrointestinal adverse effects overall was

12.4 (116). A recent meta-analysis of 4 observational

studies (117) involving 153,000 patients showed an

OR of 2.36 (95% CI 1.44�3.85) for SSRI-associated

UGIB, which increased to 6.33 (95% CI 3.40�11.8)

with concomitant t-NSAIDs use. In patients aged

over 50 years with no UGIB risk factors, the NNH

per year is 411 for SSRIs alone, and 106 with

concomitant t-NSAIDs use. Analysis of 101 sponta-

neous reports shows that UGIB occurred after a

median of 25 weeks with SSRIs; �67% of these

patients were on t-NSAIDs (117).

Although bleeding with SSRIs is rare, it is

increasing and estimated to occur at a frequency of

1 in 100 to 1 in 1,000 patient-years of exposure to

SSRIs, with the elderly in the higher range (115).

SSRIs are the most commonly prescribed antide-

pressants, and excess GI bleeding attributable to

SSRI use was assumed to be 3.1 per 1000 treatment

years, increasing to 4.1 per 1000 treatment years

among octogenarians and to 11.7 per 1000 treat-

ment years among those with prior UGIB (118).

The association has been an increasing concern

since these agents are widely used*especially in

the elderly (119), where NSAIDs already carry a

considerable GI risk.

Physicians should be aware of SSRI-induced

bleeding, and a preventive strategy should be con-

sidered in SSRI users at risk, especially the elderly or

those with a history of GI bleeding, and those taking

t-NSAIDs or aspirin and/or clopidogrel (22).

Although concomitant SSRIs and t-NSAIDs

strongly increase the risk of gastrointestinal events

and should be avoided (120), no study has investi-

gated whether patients already on a SSRI or other

anti-depressant and requiring an anti-inflammatory

drug should be prescribed a t-NSAID or a coxib.

The role of gastric mucosal protection with a PPI has

similarly not been explored in patients taking SSRIs.

However, a recent nation-wide, register-based,

matched, case-control study in Finland found that

the adjusted odds ratio (AOR) for GI bleeding

decreased with the type of concomitant NSAID,

with AOR 4.66 (3.48�6.24) for concurrent use of

SSRIs with t-NSAIDs, 4.17 (2.44�7.12) for SSRI

and semi-selective NSAIDs (nimesulide, nabume-

tone, meloxicam, and etodolac), and 2.56 (1.37�4.76) for COX-selective NSAIDs (121). This

suggests that a coxib rather than a t-NSAID may

decrease the bleeding risk in SSRI users.

Risk assessment should be based on the indivi-

dual patient, and physicians should consider any

concomitant drug use in current SSRI or t-NSAID

users. They must judge both risks and benefits in

relation to CV, GI, and neuropsychiatric issues.

SSRI-associated bleeding risk will probably be

decreased, but not abolished, with acid suppression,

but the evidence is lacking. Moreover, aspirin or

clopidogrel are also commonly prescribed in the

elderly, and concomitant SSRIs with aspirin are a

concern; close monitoring is needed, and a PPI may

be required. Prospective studies are needed to

determine whether SSRIs increase bleeding risks

when used long-term concomitantly with aspirin/

clopidogrel, and whether co-prescribed PPIs de-

crease risk in high-risk patients.

Conclusions

The rapid growth of information concerning the

effects of COX inhibitors in the different organ

systems has increased the complexity of clinical

management of patients who need NSAIDs. Current

evidence often challenges historical myths that may

perpetuate habits and ‘beliefs’ in clinical practice.

We have reviewed some of these ‘myths’ and drawn

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the following evidence-based conclusions that

should help guide physicians who manage patients

with pain:

. The evidence from both RCTs and observa-

tional studies indicates that the risk of GI

complications is present with both short-term

and long-term use of t-NSAIDs from the very

first dose. Therefore, current strategies to

prevent GI complications should be imple-

mented regardless of the duration of therapy.

. The most frequent GI adverse effect of t-

NSAID therapy is abdominal pain or dyspep-

sia, which often leads to interruption of

treatment and serious worsening of the quality

of life. Current evidence indicates that coxibs

are associated with a lower incidence of this

adverse effect than t-NSAIDs. Albeit not

overwhelming, this advantage could be clini-

cally relevant in the individual patient.

. Traditional-NSAIDs induce damage in the

upper GI tract. The growing evidence indi-

cates that they also induce a wide range of

lesions, damage, and complications in the

small and large bowel. Whereas PPIs com-

bined with t-NSAIDs and coxibs are asso-

ciated with a decreased risk of upper GI

toxicity, the strategies to reduce NSAID

damage in the lower GI tract have not been

defined. Current evidence suggests that coxib

therapy may be the preferred option, but

further studies are needed.

. A substantial number of patients who need

NSAIDs are also taking low-dose aspirin for

cardiovascular prophylaxis. Aspirin increases

the risk of upper gastrointestinal complica-

tions when taken concomitantly with either

t-NSAIDs or COX-2-selective inhibitors. The

current challenging question is whether the

combination of low-dose aspirin and COX-

2-selective inhibitors is a better therapeutic

option than the combination of a t-NSAID

with low-dose aspirin. While there are no

clinical trials that have specifically addressed

this question, available large GI outcome

studies have shown that when aspirin was

allowed, a coxib plus aspirin was associated

with a non-significantly lower ulcer rate and

lower ulcer complications rate when com-

pared with t-NSAIDs. Moreover, some, but

not all, observational studies have shown that

a coxib plus low-dose aspirin was associated

with lower GI risk than a t-NSAID plus low-

dose aspirin. Thus, from a GI perspective, the

combination of aspirin plus a coxib seems the

preferred option compared with aspirin plus a

t-NSAID, for patients at high GI risk who

require aspirin for CV prophylaxis. Future

RCTs specifically designed to compare the GI

and CV safety of a coxib plus aspirin and a t-

NSAID plus aspirin are awaited to confirm

these conclusions.

. The renovascular effects of NSAIDs are well

known. Current evidence suggests that t-

NSAIDs and coxibs have a similar incidence

of these adverse effects, but with molecule-

specific quantitative differences between the

various drugs. Blood pressure should be

monitored and managed appropriately in

patients on NSAIDs. In patients with severe

congestive heart failure NSAIDs should be

avoided.

. The increased cardiovascular risk of COX-2-

selective inhibitors has been well documented

in RCTs and observational studies. Whereas

this risk may be different according to dose

and patient base-line cardiovascular risk,

more recent evidence points out that at least

some, if not all, t-NSAIDs may also increase

that risk. COX-selective and non-selective

t-NSAIDs should be used with caution in

patients with underlying prothrombotic states

and/or concomitant cardiovascular risk fac-

tors.

. In t-NSAID users great attention should be

paid to drug-to-drug interactions, especially

with ACE inhibitors, AT1 receptor antago-

nists, and SSRIs. Since these last drugs are

associated with an increased risk of UGIB,

their combination with t-NSAIDs is of parti-

cular concern, and close follow-up is needed.

Limited evidence suggests that co-administra-

tion of a PPI may be required and that a

coxib could represent a safer alternative to

t-NSAIDs.

Acknowledgements

This work was carried out thanks to an unrestrictededucational grant from Pfizer Europe, who supportedthe meetings amongst the authors. The Company didnot have any role in design, planning, or execution ofthe review, or in writing the manuscript. The terms ofthe financial support from Pfizer included freedomfor the authors to reach their own conclusions and anabsolute right to publish the results of their work,irrespective of any conclusions reached.

CS and AL were involved with the originalconcept and planning of the review. Each authorperformed searches and led on data extraction,analysis, and preparation of a given section of themanuscript. RH and CS co-ordinated the writing andprepared the first and subsequent versions of the

Myths and facts on NSAIDs and coxibs 433

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whole paper. All authors read and approved the finalmanuscript.

Declaration of interest: The authors have received

consulting and/or lecture fees from pharmaceutical

companies and other organizations. The authors have

received research support from charities and govern-

ment sources at various times. No author has any

direct stockholding in any pharmaceutical company.

The authors report no conflicts of interest. The

authors alone are responsible for the content and

writing of the paper.

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