**3. Management of NSAIDs therapy**

In order to reduce the incidence of GI complications among patients receiving chronic NSAIDs therapy, various management strategies were developed (prevention strategy, identify and treat modifiable risk factors, use of gastroprotective agents, use of "low-risk" NSAIDs )

#### *General prevention strategies*

Prevention strategies have to be followed by all patients receiving long-term NSAIDs therapy; crucial point is to stratify patient's risk (both gastrointestinal and cardiovascular).

Some general rules have to be kept in mind by physicians who prescribe NSAIDs: use the "safer" NSAID at the lowest effective dose and for the shortest period of time (see Table 1 for relative GI toxicity of NSAIDs); when possible, prescribe anti-dolorific drugs other than NSAIDs (i.e. acetaminophen, tramadol or codeine). Avoid concomitant therapy, when possible, with antiplatelet agents, anticoagulants or corticosteroids; suggest to the patients to avoid physical (and psycological) stress and reduce (or avoid) smoke and/or alcohol assumption (Lanza et al., 2009).

#### *Prescription of selective COX2 inhibitors*

The anti-dolorific, anti-inflammatory and chemo-preventive effects of NSAIDs are mediated by inhibition of COX. The development of an NSAID selectiveely inhibiting the COX-2 isoform was reached in order to avoid NSAID-related GI toxicity. Coxibs appear to be 200 to 300-fold more selective for COX-2 than COX-1.

The active effects of coxibs are similar to those observed with nsNSAIDs but with a better GI safety profile (based on the reduced inhibition on COX-1 dependent prostaglandins secretion in upper GI tract). However, these benefits are balanced with the well reported increased CV risk observed in long-term users; the registration trials of coxibs (rofecoxib and


Finally, the use of acetylsalicylic acid, even if prescribed at low doses, seems to abolish the GI safety profile of coxibs. Although the use of a COX-2 selective inhibitors could lead to a significant decrease in GI adverse events, when coxibs are prescribed together with aspirin the overall GI toxicity appear to be similar to that observed with standard NSAIDs

Although GI injury (peptic ulcers or erosive gastropathy) is the most frequently observed side effects in patients on chronic NSAIDs therapy, presence of *Hp* infection is the most common cause of peptic disease in patients not on NSAIDs therapy. It was estimated that chronic *Hp* infection was present in about 50% of the population worldwide; however, only a little amount of these patients (5-10%) will develop GI injuries. Risk factors for development of Hp-related peptic ulcers are not well understood; however, different histological pattern of gastritis, change in acid secretion, the presence of duodenal gastric metaplasia, ulcerogenic bacterial strains and host genetic factors are all involved. For example, the relative risk to present peptic ulceration is increased in patients infected by the CagA-positive bacterial strain (Pilotto, 1997; Covacci, 1993; Li, 1999; van Doorn, 1998; Garcia

In order to reduce the incidence of GI complications among patients receiving chronic NSAIDs therapy, various management strategies were developed (prevention strategy, identify and treat modifiable risk factors, use of gastroprotective agents, use of "low-risk"

Prevention strategies have to be followed by all patients receiving long-term NSAIDs therapy; crucial point is to stratify patient's risk (both gastrointestinal and cardiovascular). Some general rules have to be kept in mind by physicians who prescribe NSAIDs: use the "safer" NSAID at the lowest effective dose and for the shortest period of time (see Table 1 for relative GI toxicity of NSAIDs); when possible, prescribe anti-dolorific drugs other than NSAIDs (i.e. acetaminophen, tramadol or codeine). Avoid concomitant therapy, when possible, with antiplatelet agents, anticoagulants or corticosteroids; suggest to the patients to avoid physical (and psycological) stress and reduce (or avoid) smoke and/or alcohol

The anti-dolorific, anti-inflammatory and chemo-preventive effects of NSAIDs are mediated by inhibition of COX. The development of an NSAID selectiveely inhibiting the COX-2 isoform was reached in order to avoid NSAID-related GI toxicity. Coxibs appear to be 200 to

The active effects of coxibs are similar to those observed with nsNSAIDs but with a better GI safety profile (based on the reduced inhibition on COX-1 dependent prostaglandins secretion in upper GI tract). However, these benefits are balanced with the well reported increased CV risk observed in long-term users; the registration trials of coxibs (rofecoxib and

(Silverstein, 2000).

Role of *Helicobacter pylori* infection

Rodriguez, 1994; Huang, 2002).

*General prevention strategies* 

assumption (Lanza et al., 2009).

*Prescription of selective COX2 inhibitors* 

300-fold more selective for COX-2 than COX-1.

NSAIDs )

**3. Management of NSAIDs therapy** 


Table 1. Dose-dependent risk for Upper GI bleeding (Acetaminophen and ns-NSAIDs) Dose-dependent risk for Upper GI bleeding (Acetaminophen and ns-NSAIDs)

subsequently valdecoxib) reported an alarming increase of CV events (congestive heart failure, polmunary edema and myocardial infarction), leading to withdrawal from market of both drugs (Juni et al., 2004; Abraham et al., 2007).

Currently, this new drug generation accounts for about 33% prescription (60% of the relative healthcare expenditure). Initially, a completely safe profile of coxibs was speculated based on preclinical and clinical trial, even for high risk patients (Skelly and Hawkey, 2002). However, these benefit effects were initially demonstrated only in patients without GI risk factors. The incidence of GI events in patients with one or more risk factors was similar in those receiving coxibs or nsNSAIDs (Silverstein et al., 2000; Bombardier et al., 2000; Skelly and Hawkey, 2002; Farkouh et al., 2004).

Clinical trials demonstrated that coxibs have a reduced relative risk of development of peptic ulcers and other GI complications (Hooper et al.,2004); in fact, a significant reduction in ulcers found on endoscopy studies (about 4-fold reduction) was observed (FitzGerald and Patrono, 2001),. High doses of coxibs (rofecocix or celecoxib) allow an approximately 50% reduction in the incidence of GI injury when compared to nsNSAIDs (Bombardier et al., 2000). Coxibs present a reduced but not abolished GI toxicity when compared to nsNSAIDs. For example, patients receiving Rofecoxib present an increased risk for peptic ulcer bleeding when compared to patients receiving placebo (0.88 vs. 0.18 clinically significant events registered/year; relative risk 4.9) (Lanas et al., 2007).

Moreover, coxibs do not show advantages over nsNSAIDs in healing ulcers in patients with recent bleeding, because they inhibit the natural healing process of peptic ulcers (Perini et al., 2003).

In addition, clinical evidences showed that all GI benefits of coxibs disappear in patients receiving also low-dose aspirin (i.e. for CV primary prevention) (Schnitzer et al., 2004; Farkouh et al., 2004). Moreover, when coxibs are used in combination to antiplatelet agents

Chronic NSAIDs Therapy and Upper Gastrointestinal Tract – Mechanism of Injury,

increased to 800mcg/day.

may be needed.

Evidences on PPI gastroprotection



Table 2. Evidences on PPI gastroprotection

**4. Management of specific populations** 


Mucosal Defense, Risk Factors for Complication Development and Clinical Management 157

effects, misoprostol should be started at the lowest dose (100 mcg x 3 daily) and, if tolerated,

*H2RAs* (i.e. ranitidine, cimetidine) induce acid suppression through the blockade of histamine H2 receptors in gastric parietal cells, while *PPIs* (i.e. omeprazole, lansoprazole, esomeprazole, pantoprazole and rabeprazole) act on the H+/K+ ATPase pump, localized on

PPIs appear to be more effective in preventing and healing NSAID-related ulcers (better duodenal than gastric ones) than high-doses of H2RAs because of the long-lasting inhibition of parietal cells acid secretion (standard H2RA doses are not effective in preventing GI injury) (Taha et al., 1996). Moreover, H2RA treatment could be "complicated" by phenomenon of tolerance which is not always observed, but could significantly reduce H2RA-induced acid suppression. Although the tolerance phenomenon is not observed in patients receiving PPIs, a rapid metabolization in some patients (rapid acetylators) may reduce PPI efficacy. Therefore, standard PPI therapy may sometimes not be sufficient to heal ulcers or treat NSAID-relate dyspepsia and in those cases an higher dose or a different PPI

Finally, on the basis of the incomplete gastroprotective effect of H2RAs and the significant reduction in PPIs' cost, there is no reason to prescribe H2RAs for gastroprotection in patients receiving chronic NSAID therapy; since H2RAs could mask warning symptoms of peptic ulcer disease (Singh and Rosen Ramey, 1998) their use should be limited to patients with NSAID-related dyspepsia unresponsive to PPI and with a negative upper GI endoscopy.

Table 2 summarizes key-points regarding PPI gastroprotective effects.


injury; *bismuth salts* act through the inhibition of peptic activity.



*Antacids* (containing aluminium or magnesium) are not clearly effective in preventing or healing NSAID-related ulcers and their potential healing mechanism appear to be unrelated to acid inhibition (i.e. promotion of angiogenesis, binding bile acids, suppressing *Hp* growth): *sucralfate* increase angiogenesis and tissue repair leading to prevention of mucosal

Management strategies are designed to reduce the incidence of GI complications and take into account patient's overall risk and specific NSAID-related risk factors. Most guidelines

parietal cell lumen inducing an irreversible inhibition (Kitchingman et al., 1989).

other than low-dose aspirin (i.e. clopidogrel and ticlopidine), the relative risk of upper GI bleeding was similar to patients receving aspirin alone or nsNSAIDs. Finally, the combination of coxibs to low dose aspirin appears to attenuate its CV protective effects.

Recently, a large prospective trial, was conducted in order to assess the safety profile of celecoxib compared to a combination regimen of a non-selective NSAID plus PPI (omeprazole plus diclofenac) (Chan et al., 2010); results of this randomized controlled trial, enrolling more than 4400 patients, demonstrated a reduced risk of GI adverse events of COX-2 selective treatment when compared to a nsNSAID plus a PPI regimen.

Based on clinical trial experience (Chan et al., 2007), co-therapy with coxibs plus PPIs could be considered in those patients with exceptionally high risk of peptic ulcer disease (eg recent NSAID-related ulcer bleeding) in order to significantly reduce the risk of development of GI injury or re-bleeding.

In conclusion, use of coxibs is a valuable strategy to minimize upper GI events; however, because of the increased CV risk and the reduced GI benefit in patients receiving antiplatelet agents, the use of these drugs have to be carefully evaluated in some high-risk categories of patients (i.e. older patients on low-dose aspirin regimen for primary CV prevention, patients with previous CV events or with CV risk factors, etc.); for a detailed discussion, see the specific section in this chapter.

Clear indications for COX-2 selective inhibitors prescription are (Lanza et al., 2009; Jawad, 2001):


#### *Prescription of gastroprotective agents*

The understanding of mechanisms underlying the pathogenesis of peptic ulcer disease lead, in the last decades, to significant development in gastroprotective treatments:


*Prostaglandins* (PG) inhibit histamine-induced cAMP generation in parietal cells, leading to a significant reduction in acid secretion. Prostaglandin analogues are indicated mostly for the prevention of NSAID-related GI injury because there are no clearly demonstrated effect on ulcer healing. The only available PG analogue registered for NSAID-related peptic ulcer disease is misoprostol (Donnely et al., 2000; Silverstein et al., 2005). However, the use of misoprostol is limited by its low tolerability. PG analogues, in a dose-dependent manner, induce diarrhea associated to abdominal pain and bloating; in order to minimize these side effects, misoprostol should be started at the lowest dose (100 mcg x 3 daily) and, if tolerated, increased to 800mcg/day.

*H2RAs* (i.e. ranitidine, cimetidine) induce acid suppression through the blockade of histamine H2 receptors in gastric parietal cells, while *PPIs* (i.e. omeprazole, lansoprazole, esomeprazole, pantoprazole and rabeprazole) act on the H+/K+ ATPase pump, localized on parietal cell lumen inducing an irreversible inhibition (Kitchingman et al., 1989).

PPIs appear to be more effective in preventing and healing NSAID-related ulcers (better duodenal than gastric ones) than high-doses of H2RAs because of the long-lasting inhibition of parietal cells acid secretion (standard H2RA doses are not effective in preventing GI injury) (Taha et al., 1996). Moreover, H2RA treatment could be "complicated" by phenomenon of tolerance which is not always observed, but could significantly reduce H2RA-induced acid suppression. Although the tolerance phenomenon is not observed in patients receiving PPIs, a rapid metabolization in some patients (rapid acetylators) may reduce PPI efficacy. Therefore, standard PPI therapy may sometimes not be sufficient to heal ulcers or treat NSAID-relate dyspepsia and in those cases an higher dose or a different PPI may be needed.

Finally, on the basis of the incomplete gastroprotective effect of H2RAs and the significant reduction in PPIs' cost, there is no reason to prescribe H2RAs for gastroprotection in patients receiving chronic NSAID therapy; since H2RAs could mask warning symptoms of peptic ulcer disease (Singh and Rosen Ramey, 1998) their use should be limited to patients with NSAID-related dyspepsia unresponsive to PPI and with a negative upper GI endoscopy.

Table 2 summarizes key-points regarding PPI gastroprotective effects.

Evidences on PPI gastroprotection

156 New Advances in the Basic and Clinical Gastroenterology

other than low-dose aspirin (i.e. clopidogrel and ticlopidine), the relative risk of upper GI bleeding was similar to patients receving aspirin alone or nsNSAIDs. Finally, the combination of coxibs to low dose aspirin appears to attenuate its CV protective effects.

Recently, a large prospective trial, was conducted in order to assess the safety profile of celecoxib compared to a combination regimen of a non-selective NSAID plus PPI (omeprazole plus diclofenac) (Chan et al., 2010); results of this randomized controlled trial, enrolling more than 4400 patients, demonstrated a reduced risk of GI adverse events of

Based on clinical trial experience (Chan et al., 2007), co-therapy with coxibs plus PPIs could be considered in those patients with exceptionally high risk of peptic ulcer disease (eg recent NSAID-related ulcer bleeding) in order to significantly reduce the risk of development of GI

In conclusion, use of coxibs is a valuable strategy to minimize upper GI events; however, because of the increased CV risk and the reduced GI benefit in patients receiving antiplatelet agents, the use of these drugs have to be carefully evaluated in some high-risk categories of patients (i.e. older patients on low-dose aspirin regimen for primary CV prevention, patients with previous CV events or with CV risk factors, etc.); for a detailed discussion, see the

Clear indications for COX-2 selective inhibitors prescription are (Lanza et al., 2009; Jawad,

The understanding of mechanisms underlying the pathogenesis of peptic ulcer disease lead,





*Prostaglandins* (PG) inhibit histamine-induced cAMP generation in parietal cells, leading to a significant reduction in acid secretion. Prostaglandin analogues are indicated mostly for the prevention of NSAID-related GI injury because there are no clearly demonstrated effect on ulcer healing. The only available PG analogue registered for NSAID-related peptic ulcer disease is misoprostol (Donnely et al., 2000; Silverstein et al., 2005). However, the use of misoprostol is limited by its low tolerability. PG analogues, in a dose-dependent manner, induce diarrhea associated to abdominal pain and bloating; in order to minimize these side

in the last decades, to significant development in gastroprotective treatments:

patients with HP-positive ulcer disease (even if related to NSAIDs)

disease preventing, healing and maintaining of remission

NSAID-induced ulcers (while no role in healing ulcers was demonstrated)

COX-2 selective treatment when compared to a nsNSAID plus a PPI regimen.

injury or re-bleeding.

Age > 65 years

2001):

specific section in this chapter.

Prolonged use of nsNSAIDs at the highest dose

Co-treatment with corticosteroids or anticoagulants

Previous history of peptic ulcer disease

*Prescription of gastroprotective agents* 

related peptic ulcer



Table 2. Evidences on PPI gastroprotection

*Antacids* (containing aluminium or magnesium) are not clearly effective in preventing or healing NSAID-related ulcers and their potential healing mechanism appear to be unrelated to acid inhibition (i.e. promotion of angiogenesis, binding bile acids, suppressing *Hp* growth): *sucralfate* increase angiogenesis and tissue repair leading to prevention of mucosal injury; *bismuth salts* act through the inhibition of peptic activity.
