**5. Management of NSAID prescription and gastroprotective strategies in patients with both CV and GI risk factors**

The greatest intellectual and clinical challenge in the area of NSAID-induced GI injury is the management of patients with both gastrointestinal and cardiovascular disease; a tight correlation between GI bleeding and CV disease (and related treatment) is well recognized (Hallas et al., 2006). Most of these events appear to be related to antiplatelet and/or anticoagulant agents prescribed in those patients (Pearson et al., 2002; McQuaid and Laine, 2006; Derry and Loke, 2000; Peters et al., 2003). Even though, in epidemiologic studies, presence of CV disease appear to be an independent risk factor for ulcer bleeding, not related to aspirin and anticoagulant agents use (Weil et al., 2000).

For a complete discussion of the pathogenesis of NSAID-related (including aspirin) GI injury see specific section of this chapter. However, both NSAIDs and ASA through topic and systemic effects induce mucosal injury.

Clopidogrel, through a specific inhibition of platelet aggregation, play a pivotal role in impairment of ulcer healing process; in fact, platelet aggregation and angiogenesis are both critical for healing of GI injuries. Therefore, even if clopidogrel may not be the primary cause of gastroduodenal injury, its related impairment of mucosal healing and angiogenesis could lead to clinically significant ulceration in the presence of other co-factors (eg. excessive acid exposure, other drugs or *Hp*) (Ma et al., 2001).

Patients with CV co-morbidities, requiring NSAIDs for their anti-inflammatory or analgesic effects (i.e. rheumatoid arthritis, muscle-skeletal disease, etc.) present an increased GI risk and are exposed to an increased rate of systemic hypertension secondary to NSAIDs or coxibs use (Lanas et al., 2000; Antman, 2005). The management of these patients is based on the assessment of the risk/benefit ratio of every drug prescribed. In patients on secondary prophylaxis for myocardial infarction or cerebrovascular event, prescription of antiplatelet agents (aspirin or clopidogrel or both) is mandatory and also some high-risk CV patients would benefit from a low-dose aspirin prophylaxis; in such cases, especially in those with GI risk factors, the prescription of a gastroprotective agent appear to be useful and effective in reducing adverse events.

It has be kept in mind that, coxibs and nsNSAIDs might be associated with an increased risk of acute cardiovascular events, and that co-administration of an NSAID (ibuprofen) and aspirin reduce the antiplatelet effects and consequently the prophylactic efficacy. Data are lacking about the consequences of co-administration of coxibs and aspirin on cardioprotection.

Finally, in this setting, presence of CV co-morbidities or assumption of prophylactic lowdose aspirin should be considered a contraindication for NSAIDs prescription; in those case in which appear necessary, general prescription strategies designed to reduce the adverse events rate have to be kept in mind (see specific section in this chapter).

#### *Gastroprotective strategies in patients with CV disease*

When a physician approaches a patient who need NSAID therapy with CV and GI disease, there are some considerations to take in mind in order to reduce adverse events related to co-morbidities:


#### *Gastroprotective strategies in patients receiving clopidogrel*

160 New Advances in the Basic and Clinical Gastroenterology

The greatest intellectual and clinical challenge in the area of NSAID-induced GI injury is the management of patients with both gastrointestinal and cardiovascular disease; a tight correlation between GI bleeding and CV disease (and related treatment) is well recognized (Hallas et al., 2006). Most of these events appear to be related to antiplatelet and/or anticoagulant agents prescribed in those patients (Pearson et al., 2002; McQuaid and Laine, 2006; Derry and Loke, 2000; Peters et al., 2003). Even though, in epidemiologic studies, presence of CV disease appear to be an independent risk factor for ulcer bleeding, not

For a complete discussion of the pathogenesis of NSAID-related (including aspirin) GI injury see specific section of this chapter. However, both NSAIDs and ASA through topic

Clopidogrel, through a specific inhibition of platelet aggregation, play a pivotal role in impairment of ulcer healing process; in fact, platelet aggregation and angiogenesis are both critical for healing of GI injuries. Therefore, even if clopidogrel may not be the primary cause of gastroduodenal injury, its related impairment of mucosal healing and angiogenesis could lead to clinically significant ulceration in the presence of other co-factors (eg. excessive

Patients with CV co-morbidities, requiring NSAIDs for their anti-inflammatory or analgesic effects (i.e. rheumatoid arthritis, muscle-skeletal disease, etc.) present an increased GI risk and are exposed to an increased rate of systemic hypertension secondary to NSAIDs or coxibs use (Lanas et al., 2000; Antman, 2005). The management of these patients is based on the assessment of the risk/benefit ratio of every drug prescribed. In patients on secondary prophylaxis for myocardial infarction or cerebrovascular event, prescription of antiplatelet agents (aspirin or clopidogrel or both) is mandatory and also some high-risk CV patients would benefit from a low-dose aspirin prophylaxis; in such cases, especially in those with GI risk factors, the prescription of a gastroprotective agent appear to be useful and effective

It has be kept in mind that, coxibs and nsNSAIDs might be associated with an increased risk of acute cardiovascular events, and that co-administration of an NSAID (ibuprofen) and aspirin reduce the antiplatelet effects and consequently the prophylactic efficacy. Data are lacking about the consequences of co-administration of coxibs and aspirin on

Finally, in this setting, presence of CV co-morbidities or assumption of prophylactic lowdose aspirin should be considered a contraindication for NSAIDs prescription; in those case in which appear necessary, general prescription strategies designed to reduce the adverse

When a physician approaches a patient who need NSAID therapy with CV and GI disease, there are some considerations to take in mind in order to reduce adverse events related to

events rate have to be kept in mind (see specific section in this chapter).

*Gastroprotective strategies in patients with CV disease* 

**5. Management of NSAID prescription and gastroprotective strategies in** 

**patients with both CV and GI risk factors** 

and systemic effects induce mucosal injury.

acid exposure, other drugs or *Hp*) (Ma et al., 2001).

in reducing adverse events.

cardioprotection.

co-morbidities:

related to aspirin and anticoagulant agents use (Weil et al., 2000).

Dual anti-platelet therapy (low-dose aspirin plus clopidogrel), prescribed to patients for secondary prevention of acute coronary syndrome or undergoing coronary stent implantation, is effective in preventing stent thrombosis and reducing the risk of reinfarction, but significantly increase the risk of GI bleeding. The relative risk increase to about 2.5-fold in patients receiving clopidogrel or ASA, when compared to patients not on antiplatelet agents (Ibanez et al., 2006; van Hecken et al., 1998; Delaney et al., 2007). Use of clopidogrel in aspirin-taking patients synergistically increase the risk of bleeding (2- to 3 fold) and the mean blood loss in case of haemorrhage (Yusuf et al., 2001; Connoly et al., 2009). Dual antiplatelet agents are not indicated for CV primary prevention because of the observed low reduction in CV events and significant increase in severe GI bleeding.

Clopidogrel, as discussed above, does not induce ulceration of upper GI tract, but impairs natural healing process (through inhibition of platelet attivation and aggregation) and increases bleeding from preexisting lesions (induced by other causes). As in NSAID-related GI bleeding, acid suppression could favors the healing process and stabilization of thrombi thereby reducing the rate of complications from upper GI injury (Ma et al., 2001).

Acid suppressive therapy (both H2RAs and PPIs) demonstrated its efficacy in reduction of bleeding risk related to antiplatelet therapy. H2RAs appear to be able to reduce the rate of GI adverse events in patients receiving low-dose aspirin (3.8% in famotidine-receivers vs. 23.5% of placebo ones) (Taha et al., 2009) while no reduction was found in those treated with clopidogrel (Lanas et al., 2007). PPIs resulted to be more effective than H2RAs in reducing upper GI events in a cohort of patients receiving both aspirin and clopidogrel (OR:0.04 of PPI-receiving vs 0.43 of H2RA-receiving) (Ng et al., 2008).

After the evidence of the positive effects of PPI prescription in reducing GI adverse events among clopidogrel-receiving patients, some observational studies suggested the presence of a possible interaction between clopidogrel and PPI determining a reduced antiplatelet effect (Ho et al., 2009; Juurlink et al., 2009). Moreover, in vitro studies (assessing platelet

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

Until now, there is no clinical study evaluating different PPI doses.

*Keypoint II – Timing and dosing:* 

Mucosal Defense, Risk Factors for Complication Development and Clinical Management 163

Pharmacokinetic and pharmacodynamic properties of both these drug classes suggest a reduced interaction if the two administrations were separated from at least 12 hours (both PPI and clopidogrel present a plasma half-life of less than 2 hours). However, only a prospective trial tested this hypothesis, using a surrogate end-point (platelet aggregation). Further studies, evaluating the clinical outcome, are necessary to corroborate this result.

In conclusion, even if some observational retrospective studies suggested a small increase (relative risk <2) in CV adverse events, large, prospective, controlled trial are necessary to validate this finding. Finally, although interrupted before the designed conclusion of enrollment and follow-up, the only prospective RCT available suggest a non-increased CV risk in patients receiving omeprazole plus dual antiplatelet therapy (Bhatt et al., 2010).

In all patients, especially in those with both CV and GI risk factors, prescription of NSAIDs, antiplatelet agents and gastroprotection must be based on an accurate risk/benefit analysis. Antiplatelet agents are necessary in patients with CV co-morbidities, specially in those with prior acute coronary syndrome or with a recent stent placement; however, prescription of

Fig. 1. Suggested management strategy in order to minimize upper GI adverse events in

patients receiving chronic NSAIDs therapy.

aspirin, clopidogrel or both is associated with an increased risk of GI bleeding.

activation/activity as a surrogate marker of antiplatelet effect) confirmed this hypothesis of interaction.

Clopidogrel and PPIs (mostly omeprazole) share a common metabolic pathway: clopidogrel is a pro-drug, whose bioavailability is dependent from intestinal absorption (ABCB1 dependent) and liver metabolism (through cytochrome P-450 pathway). Clopidogrel 2-step activation in the liver is secondary to CYP2C19 and CYP3A activity. Most of the PPIs available (omeprazole, lansoprazole and rabeprazole) share the same hepatic pathway through CYP2C19 (Li et al., 2004). Among PPIs, pantoprazole is the only that do not significantly inhibit hepatic CYP2C19 at therapeutic doses, because it is mostly metabolized through CYP3A4 pathway, while the other PPIs available present a lower interaction with this isoenzyme (Ishizaki and Horay, 1999).

Co-prescription of clopidogrel and PPIs may result in a competition of CYP2C19 metabolism, with reduced transformation of clopidogrel in its active form (Roden and Stein, 2009). This hypothesized impairment was additionally supported by the finding of genetic polymorphisms associated in CYP2C19 activity (Mega et al., 2009; Singh et al. 2010; Ma et al., 2010; Tiroch et al., 2010) and with a reduced antiplatelet activity and a worse clinical outcome (CV adverse events and re-infarction). Early clinical prospective studies in humans demonstrated a negative effect of omeprazole on surrogate clinical endpoints (ex vivo platelet assay, vasodilatator-stimulated phosphoprotein VASP) while other PPIs (pantoprazole and esomeprazole) did not (Gilard et al., 2008; Cuisset et al., 2009; O'Donoghue et al., 2009; Siller-Matula et al., 2009).

Based on conflicting data emerging from observational studies biased by non uniform prescription behaviours (eg. PPIs could be prescribed mainly to high-risk patients), a randomized controlled trial was designed enrolling patients receiving both aspirin and clopidogrel in order to evaluate the CV safety profile of omeprazole, the COGENT study (Bhatt et al., 2010). The results of this trial, enrolling 3761 patients who had acute coronary syndrome or underwent coronary stent placement, did not found any different CV outcome (myocardial infarction, stroke, coronary artery bypass graft or CV death) in patients receiving omeprazole when compared to those receiving placebo (Hazard Risk: 0.99), while confirming a reduced risk of GI adverse events (Hazard risk: 0.34). However, this strong evidence is limited by the premature closure of this trial (both enrollment and follow-up) due to bankrupt of the sponsorship, significantly limiting the power of the conclusion.

#### *Keypoint I - Difference between PPIs in clopidogrel-receiving patients:*

Retrospective studies showed, in some cases, an overall increased CV toxicity (Rassen et al., 2009; Ho et al., 2009; Laine and Hennekens, 2010; Ray, 2010) while others identified specific molecule-related effects (i.e. an increased risk for pantoprazole in nested case-control retrospective study of Stockl et al., 2010). On the opposite, a population-based study (Juurlink et al., 2009) identified an increased CV risk for all patients receiving PPIs other than pantoprazole. Finally, the only prospective evidence available did not identify an increased risk for omeprazole (Bhatt et al., 2010). However, no prospective trial (either published or ongoing) compared the clinical events related to different PPIs in patients receiving dual antiplatelet therapy. Therefore, guidelines do not suggest any recommendation for a specific molecule (Abraham et al., 2010).

#### *Keypoint II – Timing and dosing:*

162 New Advances in the Basic and Clinical Gastroenterology

activation/activity as a surrogate marker of antiplatelet effect) confirmed this hypothesis of

Clopidogrel and PPIs (mostly omeprazole) share a common metabolic pathway: clopidogrel is a pro-drug, whose bioavailability is dependent from intestinal absorption (ABCB1 dependent) and liver metabolism (through cytochrome P-450 pathway). Clopidogrel 2-step activation in the liver is secondary to CYP2C19 and CYP3A activity. Most of the PPIs available (omeprazole, lansoprazole and rabeprazole) share the same hepatic pathway through CYP2C19 (Li et al., 2004). Among PPIs, pantoprazole is the only that do not significantly inhibit hepatic CYP2C19 at therapeutic doses, because it is mostly metabolized through CYP3A4 pathway, while the other PPIs available present a lower interaction with

Co-prescription of clopidogrel and PPIs may result in a competition of CYP2C19 metabolism, with reduced transformation of clopidogrel in its active form (Roden and Stein, 2009). This hypothesized impairment was additionally supported by the finding of genetic polymorphisms associated in CYP2C19 activity (Mega et al., 2009; Singh et al. 2010; Ma et al., 2010; Tiroch et al., 2010) and with a reduced antiplatelet activity and a worse clinical outcome (CV adverse events and re-infarction). Early clinical prospective studies in humans demonstrated a negative effect of omeprazole on surrogate clinical endpoints (ex vivo platelet assay, vasodilatator-stimulated phosphoprotein VASP) while other PPIs (pantoprazole and esomeprazole) did not (Gilard et al., 2008; Cuisset et al., 2009;

Based on conflicting data emerging from observational studies biased by non uniform prescription behaviours (eg. PPIs could be prescribed mainly to high-risk patients), a randomized controlled trial was designed enrolling patients receiving both aspirin and clopidogrel in order to evaluate the CV safety profile of omeprazole, the COGENT study (Bhatt et al., 2010). The results of this trial, enrolling 3761 patients who had acute coronary syndrome or underwent coronary stent placement, did not found any different CV outcome (myocardial infarction, stroke, coronary artery bypass graft or CV death) in patients receiving omeprazole when compared to those receiving placebo (Hazard Risk: 0.99), while confirming a reduced risk of GI adverse events (Hazard risk: 0.34). However, this strong evidence is limited by the premature closure of this trial (both enrollment and follow-up) due to bankrupt of the sponsorship, significantly limiting the power of the

Retrospective studies showed, in some cases, an overall increased CV toxicity (Rassen et al., 2009; Ho et al., 2009; Laine and Hennekens, 2010; Ray, 2010) while others identified specific molecule-related effects (i.e. an increased risk for pantoprazole in nested case-control retrospective study of Stockl et al., 2010). On the opposite, a population-based study (Juurlink et al., 2009) identified an increased CV risk for all patients receiving PPIs other than pantoprazole. Finally, the only prospective evidence available did not identify an increased risk for omeprazole (Bhatt et al., 2010). However, no prospective trial (either published or ongoing) compared the clinical events related to different PPIs in patients receiving dual antiplatelet therapy. Therefore, guidelines do not suggest any

interaction.

conclusion.

this isoenzyme (Ishizaki and Horay, 1999).

O'Donoghue et al., 2009; Siller-Matula et al., 2009).

*Keypoint I - Difference between PPIs in clopidogrel-receiving patients:* 

recommendation for a specific molecule (Abraham et al., 2010).

Pharmacokinetic and pharmacodynamic properties of both these drug classes suggest a reduced interaction if the two administrations were separated from at least 12 hours (both PPI and clopidogrel present a plasma half-life of less than 2 hours). However, only a prospective trial tested this hypothesis, using a surrogate end-point (platelet aggregation). Further studies, evaluating the clinical outcome, are necessary to corroborate this result. Until now, there is no clinical study evaluating different PPI doses.

In conclusion, even if some observational retrospective studies suggested a small increase (relative risk <2) in CV adverse events, large, prospective, controlled trial are necessary to validate this finding. Finally, although interrupted before the designed conclusion of enrollment and follow-up, the only prospective RCT available suggest a non-increased CV risk in patients receiving omeprazole plus dual antiplatelet therapy (Bhatt et al., 2010).

In all patients, especially in those with both CV and GI risk factors, prescription of NSAIDs, antiplatelet agents and gastroprotection must be based on an accurate risk/benefit analysis. Antiplatelet agents are necessary in patients with CV co-morbidities, specially in those with prior acute coronary syndrome or with a recent stent placement; however, prescription of aspirin, clopidogrel or both is associated with an increased risk of GI bleeding.

Fig. 1. Suggested management strategy in order to minimize upper GI adverse events in patients receiving chronic NSAIDs therapy.

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

*Gastroenterology.* 1999;116:1305–1309.

Acid.

**7. References** 

Mucosal Defense, Risk Factors for Complication Development and Clinical Management 165

Hydrochloric Acid; PG, Prostaglandin; nsNSAID, non-selective NSAID; NO, Nitric Oxide; TxA2, Thrombooxane A2; CINOD, COX-inhibiting NO-donating drug; ASA, Acetylsalicylic

Aalykke C, Lauritsen JM, Hallas J, et al. *Helicobacter pylori* and risk of ulcer bleeding among

Abraham NS, El-Serag HB, Johnson ML, Hartman C, Richardson P, Ray WA, Smalley

Consensus Documents. Circulation. 2010 Dec 14;122(24):2619-33.

Study Group*. Arch Intern Med* 2000;160:1455–61

Guidelines. Arthritis Rheum 2000;43:1905-15.

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*Am J Med.* 1998;105(suppl):22S–27S.

28;118(18):1894-909.

analysis of 25,307 patients. Eur Heart J. 2006;27:519 –26

Agrawal NM, Campbell DR, Safdi MA, *et al.* Superiority of lansoprazole vs ranitidine in

Andreotti F, Testa L, Biondi-Zoccai GG, Crea F. Aspirin plus warfarin compared to aspirin

Anon. Recommendations for the medical management of osteoarthritis of the hip and knee:

Antman EM, DeMets D, Loscalzo J. Cyclooxygenase inhibition and cardiovascular risk.

Barkin J. The relation between *Helicobacter pylori* and nonsteroidal anti-inflammatory drugs.

Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FK, Furberg CD, Johnson DA,

users of nonsteroidal anti-inflammatory drugs: a case-control study.

W.National adherence to evidence-based guidelines for the prescription of nonsteroidal anti-inflammatory drugs. Gastroenterology. 2005 Oct;129(4):1171-8. Abraham NS, El-Serag HB, Hartman C, Richardson P, Deswal A. Cyclooxygenase-2

selectivity of non-steroidal anti-inflammatory drugs and the risk of myocardial infarction and cerebrovascular accident. Aliment Pharmacol Ther. 2007;25:913–24. Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB, Furberg CD,

Johnson DA, Kahi CJ, Laine L, Mahaffey KW, Quigley EM, Scheiman J, Sperling LS, Tomaselli GF; ACCF/ACG/AHA. ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert

healing nonsteroidal anti-inflammatory drug-associated gastric ulcers: results of a double-blind, randomized, multicenter study. NSAID-Associated Gastric Ulcer

alone after acute coronary syndromes: an updated and comprehensive meta-

2000 update. American College of Rheumatology Subcommittee on Osteoarthritis

Mahaffey KW, Quigley EM; American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. 2008 Oct

Fig. 2. Suggested management strategy in order to minimize upper GI adverse events in patients receiving antiplatelet agents.

The need of a gastroprotection must be evaluated on the basis of GI risk factors. High risk patients require gastroprotection with PPIs, while low risk population receives only a small benefit from PPIs prescription; in this setting, the increased risk of CV adverse events, related to the possible interaction between PPI and clopidogrel, suggest the use of antiplatelet therapy without gastroprotection.

PPIs are demonstrated to be more effective than H2RAs (Ng et al., 2010); however, although to a minor extent, H2RAs (other than cimetidine, because of its hepatic metabolism through CYP2C19) appear to be an alternative option in decreasing risk of gastric and duodenal ulcers (also among antiplatelet-receiving patients) (Lin et al., 2011). H2RAs, because of the low cost and low interaction, could be a good choice in patients with low risk for GI bleeding presenting peptic symptoms or NSAID-related dyspepsia.
