efectos adversos en gi de aines 2010[1]

8/2/2019 Efectos Adversos en GI de Aines 2010[1]

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Adverse effects of non-steroidal anti-inflammatory drugs(NSAIDs, aspirin and coxibs) on upper gastrointestinal tract

Carlos Sostres, MD, Research Fellow a, Carla J. Gargallo, MD, Research Fellow a,

Maria T. Arroyo, MD, DSc, Permanet Staff Member a,

b,Angel Lanas, MD, DSc, Professor, Clinical Chiefa,b,c,*

a Service of Digestive Diseases, University Hospital Lozano Blesa, Zaragoza, Spainb CIBERehd, Aragon Health Sciences Institute, Zaragoza, Spainc University of Zaragoza, Spain

Keywords:

NSAIDs

coxibs

GI damageproton pump inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the

most widely prescribed medication in the world. Their main

benefit derives from their anti-inflammatory and analgesic effect,

but the use of these agents is not innocuous since they mainlyincrease the risk of gastrointestinal (GI) and cardiovascular

complications compared with non-NSAID users. NSAIDs injures

the upper and lower gut by depleting COX-1 derived prostaglan-

dins and causing topical injury to the mucosa. The risk of upper GI

complications varies, depending on the presence of one or more

risk factors. Among them, the three main risk factors are prior

history of peptic ulcer, the single most important risk factor, age,

the most common, and concomitant aspirin use, due to their GI

and cardiovascular implications. Those individuals at-risk should

be considered for alternatives to NSAID therapy and modifications

of risk factors. If NSAID therapy is required, patients at risk will

need prevention strategies including co-therapy of NSAID withgastroprotectants (PPI or misoprostol) or the prescription of COX-2

selective inhibitors. The probable introduction of NO-NSAIDs in the

market in the near future may open a new therapeutic option for

patients with hypertension who need NSAIDs.

2009 Elsevier Ltd. All rights reserved.

* Corresponding author. Servicio de Aparato Digestivo, Hospital Clnico Universitario Lozano Blesa, c/Domingo Miral s/n, 5009

Zaragoza, Spain.E-mail address: [email protected] (A. Lanas).

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Gastroenterology

1521-6918/$ see front matter 2009 Elsevier Ltd. All rights reserved.

doi:10.1016/j.bpg.2009.11.005

Best Practice & Research Clinical Gastroenterology 24 (2010) 121132
mailto:[email protected]://www.sciencedirect.com/science/journal/15216918http://www.sciencedirect.com/science/journal/15216918mailto:[email protected]


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Introduction

More than one hundred years have passed since Felix Hoffman in 1897 synthesised acetylsalicylic

acid (ASA) as the first non-steroidal anti-inflammatory drug. Approximately 40 years pass before

Douthwaite and Lintott provided endoscopic evidence that aspirin could cause gastrointestinal injury

and it is in the early 1970s when investigators began to understand how aspirin works by showing thatASA inhibits the production of prostaglandins, that are involved in inflammations.

Today, NSAIDs are among the most commonly used drugs in the world. In Europe, NSAIDs repre-

sents more than 7.7% of all prescriptions and it is probably that these figures are underestimated

because of over-the-counter use is not included [1]. In absolute terms, in the year 2004, a total of 111

million NSAID prescriptions were written in the United States [2], and it is expected that the use of

NSAIDs will increase because the incidence of rheumatic diseases also is increasing. Their use is more

frequent among women and increases with age, as does the incidence of rheumatic diseases. Indeed

more than 90% of prescriptions for NSAIDs are made to patients aged >65 years.

The major problem with the use of these drugs is that adverse events are common, especially

gastrointestinal morbidities, including complications in both upper and lower gastrointestinal tract.

Mechanisms of gastrointestinal (GI) injury

NSAIDs injure the gut by causing topical injury to the mucosa and a systemic effects associated with

mucosal prostaglandin depletion derived from COX-1. The systemic effects of NSAIDs appear to have

the predominant role. Because of that the use of enteric-coated aspirin preparations and parenteral or

rectal administration of NSAIDs in order to prevent topical mucosal injury has failed to prevent the

development of ulcers.

Topical injury

The acidic properties of most NSAIDs (included ASA) initiate mucosal damage. These weak acidsremain in their nonionised lipophilic form in the highly acidic gastric environment. These conditions

favour migration into surface epithelial cell, where NSAIDs are dissociated into the ionised form that

trap hydrogen ions, inducing mucosal injury [3].

Systemic effects

NSAIDs inhibit cyclooxygenase (COX), a key in the biosynthesis of prostaglandins. There are two iso-

forms, COX 1 and COX 2. Traditional NSAIDs (tNSAIDs) and ASA inhibit both isoforms. Selective NSAIDs

(COXIBs) spare COX 1 and primarily inhibit COX 2. COX 1 isoform is expressed in most tissues, producing

prostaglandins thatplay an important protective role in the gut by stimulating the synthesis and secretion

of mucus and bicarbonate, increasing mucosal blood flow and promoting epithelial proliferation. WhenNSAIDs inhibit this enzyme create a gastric environment that is more susceptible to topical attack by

endogenous [4] and exogenous factors. Besides, the inhibition of the COX 1 blocks platelet production of

thromboxane, which increases bleeding when an active GI bleeding site is present [5]. On the other hand,

COX 2 isoform is induced in most tissuesin response to inflammatorystimuli. Prostaglandins derived from

COX-2 can be generated at the ulcer margin and appear to play an important role in ulcer healing through

triggering the cell proliferation, promotion of angiogenesis and restoration of mucosal integrity [6]. This

isoform is the primary target for anti-inflammatory drugs. Therefore selective COX-2 NSAIDs while having

littleto no effecton COX-1, should result in effective painrelief with reduced adverse GI effects. This COX2

hypothesis has been challenged by data from animal studies. Wallace et al [7] reported that inhibition of

both COX-1 and COX-2 is required for NSAID-induced gastric injury in the rat.

Upper gastrointestinal effects of NSAIDs

NSAIDs can adversely affect both the upper and lower gastrointestinal tract. The clinical significance

and frequency of adverse events with NSAIDs in the lower GI tract have been increasingly reported, but

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are less characterised than those from the upper GI tract. A recent study from Lanas et al [8] have shown

that the frequency of hospitalisations due to upper GI complications decreasing for the last 10 years,

whereas those from the lower GI tract are increasing. In this article, we will focus on the upper GI events.

From a clinical point of view, upper GI adverse events of NSAIDs can be categorised in different types:

Symptoms like dyspepsia, nausea, vomiting, abdominal pain and heartburn. They are the most usualadverse GI effects linked to NSAID use, and can be present in up 40% of NSAIDs users [9]. Sadly, the

occurrence of these symptoms are not clearly predictive of the appearance of GI complications, about

5060% of patients with complications will not have warming signs or symptoms [10] and conversely,

as many as 50% of patients with dyspepsia have normal-appearing mucosa [11]. About 10% of long-

term NSAIDs users stop NSAID treatment because of these adverse GI effects [9].

NSAIDS Related Gastroduodenal Injury With Unclear Clinical Significance. This injury includes

a combination of subepithelial haemorrhages, erosions, and ulcerations. This damage happens in 30

50% of patients taking NSAIDs but most lesions are asymptomatic, trifling, and disappear or reduce in

number with continued use thanks probably due to the mucosal adaptation process [12]. Only 15

30% of NSAIDs users have endoscopically confirmed GI ulcers [11,12]. The gastric antrum is the most

frequently affected location, but the rest of GI tract can also be affected. Symptomatic Ulcers And Gi Complications (Gi Bleeding, Ulcer Perforation And Obstruction). GI compli-

cations occur in approximately 11.5% of patients in the first year of treatment with traditional

NSAIDs (tNSAIDs) [1316] and when symptomatic ulcers are included this figure rises up to 45%

[17]. The average relative risk of developing a serious GI complications is 3- to 5-fold greater among

NSAIDs users than among non-users. Some studies have suggested that the first 2 months of treat-

ment is the period of greater risk for complications with a relative risk of 4.5% (95% confidence

interval: 2.97) [18,19], but the risk remains constant after that and for the period of NSAID treat-

ment. The most important risk factor among patients with bleeding ulcers was NSAIDs or ASA use, it

is found in 53% in 1 study, overcoming bleeding ulcers due to Helicobacter pylori infection [20].

MORTALITY. The worst outcome of GI complications is death, but mortality data associated with

NSAIDs treatment are scant [21]. In the United States, a report from early 1990s estimated deaths at16,500 per year. However, this may represent an overestimate because these data were extrapolated

from a relatively small rheumatoid arthritis population to the general population [22]. In Spain, in the

year 2001, 50114 GI bleeding events were reported with 18,191 GI complications and 1022 death

attributed to aspirin or other NSAIDs use. The mortality rate in this study was estimated as 15.3

deaths/100,000 NSAID/aspirin users. Up to one-third of all NSAID/aspirin deaths can be attributed to

low-dose aspirin use. However, this lower rate estimate could be due to fact that both NSAIDs

associated GI complications and death have been decreasing in recent years.

Fries et al [23] reported that GI hospitalisation rates linked to NSAID first rose from 0.6% in 1981 to

a peak of 1.5% in 1992, and then markedly declined to 0.5% in 2000. This decrease was attributed to

several factors: use of lower doses of NSAIDs, less use of more toxic NSAIDs, increased use of saferNSAIDs, increased use of proton pump inhibitors (PPIs) and decreasing prevalence of H. Pylori.

Several studies have reported time trends for ulcer incidence or hospitalisations due to upper ulcer

gastrointestinal complications (overall and not only NSAIDs associated upper GI events). Some of these

studies have shown a decreasing trend in the rate of hospitalisations because of ulcer complications GI

events [24,25] which parallelled a simultaneous increased of PPI prescription rate and H. pylori

infection decline in the population [26,27], but this was not confirmed by others [28,29]. More recent

data from Spain have shown that hospitalisations due to upper GI complications fell from 87/100,000

persons in 1996 to 47/100,000 persons in 2005 with clear decrease in overall mortality rates. This

tendency contrasted with a mild but progressive and statistically significant increase in the rate of

lower GI complications [8]. These trends have been also seen in the USA [30].

The role of cyclooxygenase 2 inhibitors

The identification of the COX-2 isoenzyme opened the door to development of NSAIDs which

selectively inhibit COX-2. The main goal of which was to decrease the GI toxicity. Coxib spare COX-1 and

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primarily inhibit COX-2 function therefore decrease but do not eliminate NSAIDs associated GI toxicity

and are efficacious as tNSAIDs in relieving pain [15].

Data from large GI outcomes studies have characterised the GI effects of coxib. The Celecoxib Long-

term Arthritis Safety Study (CLASS Study) that compared high dose Celecoxib (400 mg bid), diclofenac

(75 mg bid), and ibuprofen (800 mg 3 times daily) showed that symptomatic ulcers were significantly

less common among celecoxib users than tNSAIDs users; however ulcer complication rates were notsignificantly different (which was probably due to the confounding factor of concomitant low-dose

aspirin use which was present in 22% of patients) [15]. However, a recent meta-analysis of available

trials of the Cochrane collaboration confirms that celecoxib at any dose was associated with statistically

less GI events [31]. Moreover, the results of another large outcomes study, celecoxib vs naproxen and

diclofenac in osteoarthritis patients (SUCCESS I Study), confirmed the significantly better safety profile

of celecoxib compared with tNSAIDs [32]. The Vioxx Gastrointestinal Safety of Rofecoxib trial (VIGOR

Study) concluded that rofecoxib users had 50% fewer GI events compared with naproxen users [14].

Later, in the comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis

Research and Gastrointestinal Event Trial (TARGET), showed a 75% decrease in adverse GI events with

the coxib [16]. It is important to emphasise that although the incidence of adverse GI events increased

in relation to the presence of GI risk factors, the differences from NSAIDs were maintained in subgroupsof patients with and without risk factors [33].

Notwithstanding, it is important to note that 3 of the above commented outcome studies (CLASS,

TARGET and SUCCESS studies) [15,16,32], one endoscopy study [38] and several epidemiological studies

[35,36] have shown that the concomitant use of low-dose aspirin and coxib or tNSAIDs increases further

therisk of upper GI bleeding in NSAIDs users andattenuates theGI advantage of a coxib over an tNSAID. A

recent meta-analysis of RCTs has shown that coxib plus low-dose ASA use was associated with a lower

risk of upper GI complications when compared to non-selective NSAID plus low-dose ASA [39].

These gastrointestinal benefits have to be balanced against the known cardiovascular risks, partic-

ularly with long-term use. The VIGOR and Adenomatous Polyp Prevention on Vioxx Trial Investigators

(APPROVe) studies showed that rofecoxib were associated with increased risk of cardiovascular events

after 12 and36 monthsof treatmentwhen compared to naproxen (VIGOR) or placebo (APPROVe) [14,37].Other outcome studies have shown also that celecoxib at doses of 400 mg bid or 200 mg bid [34],butnot

400 mg once a day [40] is associated with increased risk of cardiovascular events. Observational studies

have shown, however, that celecoxib at 200 mg/day dose was not associated with increased risk of

cardiovascular events[14,15]. Recentobservational studies have shown that alsomost NSAIDs (including

nonselective) may be associated with increased cardiovascular risk and this may be different for the

different compounds, dose and length of treatment [21,41,42]. Of all traditional NSAIDs, diclofenac have

been found to be the one increasing the CV risk the most [43]. In the MEDAL program etoricoxib at the

dose of 6090 mg/day was found to be not different to diclofenac in the incidence of CV events [44]. The

study also showed no differences in the incidence of upper GI complications between these 2

compounds, although the total number of events (symptomatic ulcers and complications) was statis-

ticallylower in etoricoxib users [45]. Lastly, both tNSAIDs andcoxib mayalsoincreaseblood pressureandreduce kidney function. A new class of drugs, the CINOD, have shown to have reduced upper GI toxicity

anda better profile on blood pressure than tNSAIDs [4648] andcould be a therapeuticoption in patients

with increased blood pressure than need NSAIDs, when they were available in the market [49].

Risk factors for gastrointestinal complications

Dyspeptic symptoms are not a trustworthy warming sign; because of that it is important to identify

factors that increase the risk of GI events in NSAIDs users. Several studies have demonstrated which are

the major risk factors for GI event associated with NSAID therapy. ( Table 1) [5052,23].

Among them, the two main are prior history of complicated ulcers, the most important one, and

age. Older age is the most common in NSAIDs users and those age>

70 years are considered to carrya risk similar to those with history of peptic ulcer. Advancing age increases risk by about 4% per year,

probably because of the presence of other associated risk factors [51].

The role ofH. pylori in patients taking NSAIDs and the potential effect of its eradication on the risk of

upper GI events in infected NSAIDs users has been controversial. A meta-analysis of case-control



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studies showed synergism for the development of complicated and uncomplicated ulcer between

H. pylori infection and NSAIDs [53]. H. pylori is also a risk factor in low-dose aspirin users [50,54] and

even a post hoc analysis of the VIGOR trial suggested that the GI benefits of coxib is lower in coxib users

with the infection than in those without the infection [51].

Concomitant ASA use is another factor which increases the GI risk. It is important to note that more

than 20% patients who need NSAIDs also take low-dose aspirin (LD-ASA). The addition of LD-ASA tot-NSAIDs or coxibs increases the risk of GI events (estimated annual GI risk is 5.67.5% GI events/year)

[55]. Because of that, patients who combine an NSAID with LD-ASA are another high-risk group.

Evidence from observational studies and randomised trials showed that the risk of coxib plus ASA is

lower than NSAIDs plus ASA, but both were increased by ASA [23,56].

Management

The main goal in the management of patients receiving NSAIDS is the prevention of GI complica-

tions. Other objectives are the treatment of GI mucosal lesions and the treatment and prevention of

NSAID-induced dyspepsia. Finally, due to the association of NSAID and coxib use with CV risk, this

factor should also be taken into account in the management of patients who need NSAIDs.

Prevention strategies

Under a cost-effective perspective patients with one or more risk factors should receive prevention

strategies. In order to achieve this objective, there are several options (Table 2).

Targeting modifiable risk factors

There are some risk factors (e.g. age) that cannot be modified. But most risk factors can be modified.

The best way to prevent mucosal injury is to avoid the use of NSAIDS and to substitute an agent less

toxic to the gastroduodenal mucosa such acetaminophen. If NSAID is necessary, it is important to be

aware that the risk increases with the dose. We should look for the lowest effective dose and patientsshould take the medication the shortest period of time. As much as possible, only a single NSAID should

be prescribed. Safer NSAID should be preferred. Although many of the differences of GI risk observed

among the different NSAIDS are driven by the dose used in the clinical practise, there is agreement that

ibuprofen, diclofenac and aceclofenac are associated with the lowest relative risk of GI bleeding [4.1

(3.15.3) and 2.1 (1.62.7) respectively] [24]. The use of concomitant therapy with low-dose aspirin,

corticosteroids, anticoagulants or even non-aspirin antiplatelet therapy should be avoided, since all

they have shown to increase further the risk of bleeding [15,16,46]. H. pylori infection eradication will

reduce the incidence of peptic ulcers in, at least, a subset of NSAIDS users.

Addition of gastroprotectants to NSAIDS

Patients with risk factors requiring anti-inflammatory drugs may be prescribed witha gastroprotectant.

Misoprostol. Several clinical trials have shown that the incidence of endoscopically visible erosions and

ulcers associated with NSAID use can be reduced by co-therapy with misoprostol [57]. It is the only

Table 1

Risk factors for gastrointestinal complications in NSAIDs users, ranked in terms of importance (highest risk at the top).

Prior history of complicated ulcers

Concomitant use of anticoagulants

Multiple NSAID use, including low-dose aspirin

Prior history of uncomplicated ulcer

High NSAID dose (or use of piroxicam or ketorolac)Age> 60 years

Severe illness

Helicobacter pylori infection

Concomitant use of corticosteroids



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gastroprotective agent evaluated in a large outcome trial for the prevention of NSAID-induced upper GI

complications. A 6-month, randomised, double blind, placebo-controlled trial involving rheumatoid

arthritis patients receiving NSAIDs demonstrated the effect of misoprostol on clinically evident GI

events [32]. Known as the Misoprostol Ulcer Complications Outcomes Safety Assessment (MUCOSA)

trial, the study showed that misoprostol 200 mcg qid significantly reduced symptomatic ulcers

(adjusted RR; 0.36 [0.200.67]) and serious GI complications (adjusted RR; 0.57 [0.360.91]). However,

misoprostol is limited by its poor tolerability. It has high frequency of symptomatic adverse GI events

such diarrhoea and abdominal pain.

H2-receptor antagonist. When compared to placebo different endoscopic studies have shown that raniti-

dine and famotidine reduce the incidence of duodenal ulcers, but not gastric ulcers. A meta-analysisshowed that H2-receptor antagonist did not significantly reduce the risk of symptomatic ulcers among

patients receiving NSAID (adjusted RR; 1.46 [0.0635.3]) [58]. However, a recent study shows that famo-

tidine is effective in the prevention of gastric and duodenal ulcers in patients taking low-dose aspirin [59].

Proton pump inhibitors. These drugs are significantly more effective than H2-receptor inhibitors for the

treatment and prevention of acid related diseases [60]. PPIs significantly reduced symptomatic ulcers in

patients by 91% (95% CI; 5398%) [58]. The increasing useof PPIs is associated with a 41.125.4% decrease

in the incidence of peptic ulcers and ulcer complications [24]. One of the studies included in the above

meta-analysis directly compared misoprostol and lansoprazole in patients on long-term NSAID use [61]

and it showed that each active treatment had an equivalent success rate of 69%. Other studies have

confirmed that omeprazole 20 mg/day was more effective than H. pylori eradication in the prevention ofulcer bleeding recurrence in patients receiving naproxen for 6 months [54]. In high-risk patients who

underwent H. pylori eradication, lansoprazole was more effective than placebo in the prevention of ulcer

bleeding recurrence in patients who receive low-dose aspirin for 12 months [62]. In another study,

esomeprazole associated with low-dose aspirin was also associated with a very low recurrence rate of

ulcer rebleeding when compared to clopidogrel alone [63]. In a recent case-control study by Lanas et al,

PPIs reduced the risk of upper GI complications. PPI use was associated with risk reduction among both

tNSAID and low-dose aspirin users and among patients taking NSAIDs and clopidogrel [64].

This drug is one of the safest in the market, but PPI use is also associated with adverse effects. Recent

data suggest that intestinal infection and pneumonia risk may be increased in patients taking these

drugs [65]. Interestingly, in a recent study from Ho PM et al in JAMA 2009 [66] found that concomitant

use of clopidogrel and PPI after hospital discharge for acute coronary syndrome (ACS) was associatedwith an increased risk of cardiovascular adverse outcomes than use of clopidogrel without PPI, sug-

gesting that use of PPI may be associated with attenuation of benefits of clopidogrel after ACS. Whereas

this is now a hot topic, we believe that the evidence still is weak and more data are need before firm

recommendations can be made, and patients with a clear increased risk of upper GI bleeding requiring

Table 2

PREVENTION STRATEGIES in patients with gastrointestinal risk factors who need NSAIDs.

General Rules

Use safer NSAIDs (coxibs, diclofenac, aceclofenac, ibuprofen.).

Use lowest effective dose for shortest period of time.

Less use of NSAIDs with highest gastrointestinal toxicity (ketorolac, piroxicam, ketoprofen).Avoid concomitant therapy with anticoagulants, corticosteroids, low-dose aspirin or antiplatelet agents.

Eradicate Helicobacter pylori infection in patients with prior ulcer history.

Use of Prevention Strategies

No Cardiovascular Risk Factors:

NO gastrointestinal risk factor: use tNSAID (no need for prevention strategies).

Presence of ONE or MORE gastrointestinal risk factors: coxib (standard dose) alone or tNSAID PPI or misoprostol.

History or ulcer bleeding: Avoid tNSAIDs. Coxib PPI. Eradicate Helicobacter pylori infection.

History of Cardiovascular Events or Risk for Cardiovascular Events >10% in 10 years (Treatment with Low-Dose Aspirin):

Presence of ONE or MORE gastrointestinal risk factors: low-dose tNSAID or coxib PPI. In Europe, if previous

cardiovascular event the EMEA contraindicates the use of coxibs.

History of ulcer bleeding: Avoid tNSAID or coxib. If necessary, coxib PPI. Eradicate Helicobacter pylori infection.



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double antiplatelet aggregation with clopidogrel and aspirin should not be privated of gastroprotection

with PPI. It is unclear whether some of the available PPI have a better or worst profile. Observed

differences may be due to differences in the magnitude of their use in clinical practise. In fact, a recent

study (the Cogentus Trial), still unpublished (Batt D, et al personal communication 2009), have shown

that patients taking a combined compound of clopidogrelomeprazole and aspirin vs clopidogrel plus

aspirin have shown no differences in the rate of cardiovascular events. Recent studies have reportedincreased hip fracture rates with long-term and high dose PPI use but there is not enough evidence to

confirm this finding [67].

COX-2 selective inhibitors. A meta-analysis revealed that the risk of symptomatic ulcers and serious

upper GI complications associated with coxibs were lower than that of nonspecific NSAIDS (adjusted

RR; 0.49 [0.380.62] and 0.55 [0.380.80], respectively) [58]. Data from the newest coxibs (lumiracoxib

and etoricoxib) confirm this safety profile in the GI tract [16,68]. In the CLASS study patients treated

with celecoxib 400 mg bid had significantly fewer upper GI ulcer complications than those treated

with nonselective NSAIDs (0.44% vs 1.27%; p 0.04) [15] in patients not taking aspirin. However, the GI

benefits of celecoxib was lost with the addition of LD-ASA, as the annualised incidence rates of upper GI

ulcer complications were 2.01% and 2.12%, respectively (p 0.92) with aspirin use. In TARGET, lumi-racoxib was not different to traditional NSAIDs in patients taking low-dose aspirin, but it was much less

toxic to the GI tract in patients not taking aspirin [16].

When prescribing all these agents, caution should be focussed in patients with cardiovascular

diseases. In Europe coxibs are contraindicated in patients with previous cardiovascular events or

uncontrolled hypertension. Whether this population may benefit from the potential introduction of

NO-naproxen into the market in the near future remains to be seen. Nevertheless, this compound

seems to have a favourable profile in patients with hypertension and to induce less gastroduodenal and

intestinal mucosal damage than naproxen [4648].

Combination of PPI plus COX-2 selective inhibitors. In clinical practise, the available evidence indicates that

patients with previous ulcer bleeding who take either a ns-NSAIDs PPI or a coxib still have a high rateof bleeding after 6 months of therapy and that both types of therapy are equally effective [69,70]. In one

study [69] involving 287 patients receiving NSAIDs and presenting with ulcer bleeding compared

switching to celecoxib with co-therapy consisting of a PPI and a nonspecific NSAID. After 6 months, the

coxib arm had a 4.9% probability of recurrent ulcer bleeding, whereas patients on PPI co-therapy

showed a 6.4% probability of recurrence (pns). As shown recently, the combination of a PPI coxib

provides the safest option in patients at the highest risk of developing a GI complication [71]. This

combination is cost-effective [72], providing a 50% additional reduction in the incidence of upper GI

complications already obtained with any of these strategies (NSAIDS PPI vs coxib) alone. This suggests

that concomitant coxib and PPI therapy may be beneficial for GI bleeding patients, but further studies

are required to establish this recommendation. A recent small, randomised controlled trial has evalu-

ated the combination of a coxib PPI to prevent GI events in high-risk patients with previous ulcerstory. After 12 months of therapy, patients taking celecoxib 200 mg twice a day plus esomeprazole

20 mg/day had no recurrent ulcer bleeding events whereas 8.9% (p< 0.001) of patients taking the same

of dose of celecoxib and placebo had a recurrence ulcer bleeding event [73]. A recent study by Latimer

showed that prescribing a PPI for people with osteoarthritis who are taking either a tNSAID or coxibs is

cost-effective [74].

Adherence to the prescribed preventive therapy is an additional problem. A study by Sturkenboom

etal [75] showed that over 30% of patients were non-adherent and thelowest rate of non-adherencewas

associated with the first NSAID prescription (9%), increasing to 61% for patients with 3 or more

prescriptions. Non-adherence patients had higher risk of GI events compared with those who are fully

adherent. Another study by Van Soest showed that the risk of GI complications in NSAID users increased

16% for every 10% decrease in adherence. Patients with proportion of NSAIDs treatment days covered bygastroprotective agents of 2080% and 80% of days covered: 4.0-fold (95% CI: 1.213) respectively 2.5-fold (95% CI: 1.06.7) [76]. Predictors of

nonadherence include a high average daily dose of NSAIDs and long-term use of NSAIDs (90 days).

Predictors of adherence include a use of LD-ASA, anticoagulant use, history of upper GI events, among



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others [77]. Based on these relevant aspects, new formulations containing a NSAID and a antisecretory

drug (either a PPI or famotidine) are now being developed and may see the market soon.

Eradication of H. pylori

Eradication therapy is one of the mainstays of treatment in ulcer patients with H. pylori infection. A

meta-analysis of observational studies [53] showed synergism for the development of peptic ulcer andulcer bleeding between H. pylori infection and NSAID use. Randomised controlled trials have shown that

H. pylori eradication in naive NSAID users is associated with a significant reduction of the incidence of

endoscopic ulcers in patients starting NSAIDs [78,79]. However, the benefit is less evident in patients

already on long-term NSAIDs or in those who had an ulcer history or history of ulcer complications,

where co-therapy with a PPI seems necessary [54]. Among those taking low-dose aspirin, one study

reportedthat [54] therisk of recurrentulcerbleeding in PPI-treatedpatientswas at least similar to that of

patients receiving eradication therapy composed of bismuth subcitrate, tetracycline and metronidazole

(0.9% vs 1.9%;p ns). Among users of other NSAIDs, the respective rates were 4.4% vs 18.8% (p 0.005),

showing a clear advantage of PPIs over eradication therapy. Patients receiving long-termNSAIDs or low-

dose aspirin may also use PPIs after eradication treatment to prevent ulcer recurrence [62]. Testing for

and eradicating H. pylori in patients with a history of ulcer disease is recommend before starting chronic

antiplatelettherapy. Post-hoc analysisof the VIGOR study suggested that theGI benefits of coxib therapy

are greater in patients without H. pylori infection than those with the infection [51]. It is unclear that the

strategy ofH. pylori eradication will be cost-effective in all infected patients who start NSAID therapy.

Treatment

NSAID-induced dyspepsia: (Fig. 1) patients receiving NSAIDS frequently complain of GI symptoms in

the absence of ulcers. NSAID-associated dyspepsia is frequent and has been reported in up to 2550% of

patients [80,81]. However, the presence of dyspepsia does not predict the presence of mucosal lesions

in patients taking NSAIDS [80]. Since up to 40% of persons with endoscopic evidence of erosive gastritis

are asymptomatic and conversely, as many as 50% of patients with dyspepsia have normal-appearingmucosa. Antisecretory drugs, specially PPIs, reduce the incidence of dyspepsia [81,82], although up to

10% of patients with NSAID-induced dyspepsia will not obtain relief with antisecretory therapy [83].

When compared with placebo, esomeprazole, 20 and 40 g/day, is effective en the prevention and

treatment of dyspepsia in patients on NSAID or coxib therapy without gastroduodenal mucosal lesions

Coxib

Dyspepsia?

Coxib + PPI

Dyspepsia?

Try low-dose NSAID/coxib

No NSAID/coxib

NSAID + PPI

Dyspepsia?

Coxib + PPI

Dyspepsia?

Fig. 1. Management of dyspepsia in NSAID users.



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in studies that were specifically designed to evaluate this side effect [80]. Coxibs have better GI

tolerability and lower incidence of dyspepsia than nonselective NSAIDS [31]. A recent study has shown

that in patients without ulcer lesions, rofecoxib had a similar incidence of dyspeptic symptoms

compared with those treated with diclofenac. In contrast, the addition of lansoprazole to diclofenac

significantly reduce the incidence of NSAID-induced dyspepsia [84].

NSAID-related gastroduodenal ulcers: Because of the prevalence and severity of NSAID-related GIcomplications, recent efforts have been directed at the prevention of mucosal injury induced by

NSAIDs. NSAID and coxib therapy delay the healing of active peptic ulcers. The best way to prevent

mucosal injury is to avoid the use of NSAIDs and substitute an agent less toxic to the gastroduodenal

mucosa. In patients who develop a peptic ulcer during NSAID or coxib treatment, the drug should be

stopped, patients treated with PPI therapy and H. pylori eradication if the infection is present. If patients

are unable to discontinue NSAID therapy, can be maintained and patients need to be treated with twice

a day PPI co-therapy until the ulcer is healed, which must be confirmed by endoscopy [85].

Practice points

NSAIDs use is associated with increased risk of GI mucosal injury and deaths from both the

upper and the lower GI tract.

The presence of dyspepsia is not clearly predictive of the appearance of GI complications,

more than a half of patients with GI complications will not have warming signs or symptoms,

and conversely, as many as 50% of patients with dyspepsia have normal-appearing mucosa.

The risk of GI complications varies, depending on the presence of upper GI risk factors. The

most relevant risk factors are previous history of peptic ulcer, advanced age and concomitant

low-dose aspirin use.

Coxibs are associated with reduced GI toxicity when compared with traditional NSAID. The

main side effect of coxibs is the increased risk of cardiovascular events but most traditional

NSAIDs (specially diclofenac) may also increase this risk. Dose and duration of use should be

considered.

Patients without GI risk factors should receive traditional NSAIDs. Those at risk may receive

either co-therapy with a PPI or misoprostol or a coxib alone. Patients with a previous ulcer

bleed or concomitant anticoagulant therapy who need NSAIDs should receive the combi-

nation of a coxib plus a PPI and H. pylori should be tested for and treated if present.

Patients with high GI and CV risk should be considered for alternative therapies to traditional

NSAIDs or coxibs

Research agenda

The COX-2 hypothesis has been challenged, COX 1 and COX 2 must be inhibited for gastric

ulceration to occur. It is unclear whether selective COX-1 inhibition in H. pylori negative

patients is associated with gastroduodenal damage.

It is unclear whether eradication of H. pylori is cost-effective for at-risk patients starting

NSAIDs therapy.

The effect ofH. pylori eradication on major upper GI complications in standard or at moderate

risk patients who start aspirin therapy is unknown.

The GI and CV profile of patients currently treated with NSAIDs in clinical practise and the

potential impact of current management recommendation on GI and CV outcomes isunknown.

The impact of the CINOD compounds, which may be available in the market in the near

futures, on GI and CV outcomes remains to be investigated.



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Conflict of interest

Dr Angel Lanas is consultant or has received research grants from AstraZeneca, Pfizer, Bayer and

Nicox. Dr Carlos Sostres, Dr Carla J. Gargallo and Dr Mara T. Arroyo reports no conflict of interest.

Acknowledgements

This study was funded by grants from the Carlos III, FIS PI08/1301 and Gobierno de Aragon. B01

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