EDITORIALS

NSAIDs, Risks, and Gastroprotective Strategies: Current Statusand Future

See “The relative efficacies of gastroprotec-tive strategies in chronic users of nonsteroi-dal anti-inflammatory drugs,” by TargownikLE, Metge CJ, Leung S, et al, on page 937.

Nonsteroidal anti-inflammatory drugs (NSAIDs) areamong the most widely used drugs. Each year,

�111,000,000 prescriptions for NSAIDs were prescribed inthe United States at a cost of $5 billion. Furthermore, thereis an additional $2 billion spent on over-the-counter (OTC)NSAIDs.1 NSAIDs are primarily used for reducing the pain,disability, and reduced quality of life associated with painand inflammation.2,3 In addition, aspirin is used for preven-tion of cardiovascular events.4 Both NSAIDs and aspirin aredisproportionately used among the elderly and about onethird of individuals aged �65 years have been reported totake NSAIDs on a daily basis, and 70% use them at leastonce a week.5,6

NSAID use carries with it a risk of major gastrointestinal(GI) events, including symptomatic ulcers and ulcer com-plications (bleeding, perforation, and obstruction). For al-most 50 years, the pharmaceutical industry regularly intro-duced new compounds that were generally touted as moreeffective and/or safer, culminating in the discovery of thecyclo-oxygenase inhibitors (coxibs), which theoretically of-fered anti-inflammatory and analgesic effects with minimalor no serious GI side effects. Clinical experience showed thatthis promise of GI safety was only partially fulfilled and thatNSAID use, including coxibs, also increased the risk ofcardiovascular complications.

We have now entered a sorting out period that focuseson the differentiation of the relative benefits versus risksof individual drugs and drug combinations. In this issueof GASTROENTEROLOGY, Targownik et al7 report the resultsof a study using a population-based, administrativeclaims database to compare the relative efficacy of gas-troprotective strategies in decreasing the risk of upper GIcomplications among chronic NSAID users. When theanalyses were restricted to patients with complications ofpeptic ulcer, they found that the cyclo-oxygenase(COX)-2 inhibitor plus a proton pump inhibitor (PPI)was associated with the greatest degree of risk reduction.The gastroprotective strategies of nonselective NSAIDs(nsNSAIDs) with a PPI, COX-2 inhibitor alone, or

nsNSAID plus low dose misoprostol had similar relativerisk reductions in terms of admissions for complicationsof peptic ulcer disease. Neither cost-effectiveness nor car-diovascular risks versus GI benefits were evaluated.

Studies with very large sample sizes are underway tocompare the cardiovascular safety of coxibs and com-monly used NSAIDs. Similar trials with GI events as theprimary outcome have not been done because the overallrisk of major events (primarily upper GI bleeding) is low(typically �4 per 1,000 per year in low-risk patients),thereby requiring enormous trials to draw firm conclu-sions. Pharmaceutical companies are generally hesitantto undertake such trials unless the risks of failure are lowand a positive result is likely to lead to improved sales.PPI manufacturers are particularly vulnerable to classeffects, such that new indications are usually seen asgeneralizable to all PPIs. Pharmaceutical companies havetherefore shied away from undertaking the large trialsneeded to prove efficacy of various gastroprotectiveagents. Instead, they have focused on the “tried and truemarketing methods,” including funding and publishingmarketing-type studies using doses and surrogate end-points where the positive effect of their drugs are assured,as well as supporting speakers bureaus, guideline devel-opment, and consensus conferences to create a market.8

Although the effects of these efforts on drug sales areunknown, recent studies have confirmed that compliancewith “guidelines” for high-risk patients remains poor.9 –12

NSAID-induced GI complications have largely re-placed Helicobacter pylori–associated peptic ulcers as afrequent cause of hospitalization, morbidity, and mortal-ity. The fact that clinicians embraced coxibs suggests thatthe message was not unheeded. The evidence regardingcardiovascular events with coxibs aroused much concernand led to changes in practice. However, withdrawal ofmost of the available coxibs did not result in a majorincrease in the use of gastroprotectives,13 suggesting thatthe poor guideline compliance with regard to use ofgastroprotectives reflected a failure of the opinion-leader-intensive marketing approach to eliminate uncertaintywith regard to the importance of identifying and strati-fying patients in terms of risk for serious GI events andthe actual benefits that could be expected with the dif-ferent gastroprotective strategies. The approach may haveactually been successful in educating physicians to beable to identify those patients at high risk of complica-

GASTROENTEROLOGY 2008;134:1240–1257

tion in whom a gastroprotective strategy is warranted,but not convincing physicians and/or patients about theneed for a regimen that requires multiple medications (ie,coxibs allowed for gastroprotection and analgesia with asingle agent). Finally, better data about actual effective-ness of other gastroprotective strategies is only now be-coming widely available for prescribers.

Randomized controlled trials providing hard numbers inrelation to risks and benefits of gastroprotective effects areneither available, nor on the horizon. However, as exempli-fied by the paper by Targownik et al,7 the data availablefrom case-control studies provide evidence that can be usedto define the best use of the different preventive strate-gies.14–20 Together, these studies provide a relatively consis-tent story and can be used to piece together what appears tobe a coherent strategy for physicians and to identify missinglinks that need further exploration.

Information Clinicians Require to MakeInformed DecisionsThe decision to use a therapy should be based on

an estimate of the benefits relative to the risks, in thisinstance of GI and cardiovascular complications. Becausethere is no evidence that putative surrogate markers suchas endoscopic ulcers reliably predict clinical outcomes,we will focus on potentially life-threatening complica-tions such as upper GI bleeding. There are also few dataregarding the natural history of NSAID-induced ulcers.We will nonetheless assume that when data are lacking,the natural history of NSAID- and H pylori–associatedulcers are similar in terms of recurrence and risk ofbleeding and of rebleeding. The proportion of patientswith H pylori–associated ulcers without H pylori eradica-tion or long-term anti-secretory therapy who experiencerebleeding has ranged from 6% to 33% (median, 28%),21

and the degree of protection from rebleeding amongthose with H pylori infection receiving long-term anti-secretory therapy was approximately 75%.22 Although the

background risk of severe upper GI events increasesmarkedly with age and is higher in populations where Hpylori is still prevalent, we will use population-based databecause they are equivalent, and do not attempt to sep-arate H pylori–infected from uninfected individuals. Ran-domized controlled trials controlling for H pylori statusare available for the highest risk population of patientsthat have recently bled from an NSAID-associated ulcerand we will extrapolate from those studies to providerecommendations regarding these highest risk pa-tients.23,24 We obtained data regarding low- and interme-diate-risk patients from recent population-based studiesand from large randomized controlled trials, especially inrelation to the use of coxibs to estimate the actual riskreduction associated with different protective strate-gies.7,11,14 –20,25–32 Most of the case-control studies havenot provided data regarding the doses used. Studies ofPPIs to prevent endoscopic ulcers have consistently failedto demonstrate a dose response relationship, suggestingthat once-daily regimens with the lowest dose availablewould be appropriate. However, it is generally believed,and the available data support the notion that ulcerhealing is directly correlated with the degree of acidsuppression such that twice daily dosing may be pre-ferred, especially for higher risk patients.33,34 The studyby Targownik et al7 showed a trend for increased protec-tion for those taking more than once daily dose, which isalso consistent with the studies showing that poor com-pliance was associated with reduced effectiveness.12,32,35

The risk of GI bleeding increases with age, but even theoldest age group is generally �2.5% (eg, 25 per 1000patient-years); it increases to approximately 5% for thosewith a history of peptic ulcers (Table 1). The relativeprotections from different protective strategies and indifferent risk groups show that PPI cotherapy is associ-ated with a 50%– 80% reduction in major events, primar-ily bleeding. Using these data, we have estimated the costof gastroprotective drug therapy per upper GI bleeding

Table 1. Annual Cost of Preventing 1 Event in Relation to Cost of Gastroprotective Therapy and Risk of a Serious GI Event

Events/1,000a NNT 60%/80%b

Cost � 1,000 events prevented

Age group (y)@ $10c @ $5 @ $1 @ $0.5

3.5 477/358 1741/1306 870/653 174/130 87/65 20–597.0 239/179 872/653 436/326 87/65 43/32 60–69

14 120/90 438/328 219/164 43/32 21/16 70–7925 67/50 244/182 144/91 24/18 12/9 �8050d 35/26 127/95 63/47 12/9 6/5

100 17/13 66/47 33/23 7/5 4/3

Calculations are not part of a formal cost-effectiveness analysis, but rather are restricted to gastroprotective drug costs based on the numberneeded to treat with 2 levels of protection and receiving the therapy daily for 1 year.aBleeding events per 1000 patients/year.bNumber needed to treat with the risk reduction associated with PPIs calculated at both 60% and at best case scenario 80%.cCost (�1000) calculated for different costs of gastroprotective therapy here ranging from $10/day, which is approximately equivalent totwice-a-day dosing, to $0.50 per day, which is approximately equal to over-the-counter 20 mg omeprazole.dThe proportion with bleeding among those with prior clinical peptic ulcers is approximately 5%, thus constituting a high-risk group.

April 2008 EDITORIALS 1241

event prevented (Table 1). Importantly, we do not at-tempt to provide a formal cost-effectiveness analysis, butinstead compare the gastroprotective drug costs in termsof the number needed to treat for both a 60% and an 80%reduction in upper GI bleeding based on US dollars (in$1000s). As shown in Table 1, the cost of twice a daynon-OTC PPI therapy would exceed $1 million per eventprevented in low-risk groups. The fact that the cost toprevent an event in low-risk patients is excessive is con-sistent with guidelines suggesting no cotherapy for lowerrisk patients (eg, �60 or �65).36,37

The Red Book provides the average wholesale costs inthe United States of the drugs used in different protectivestrategies.38 The cost of gastroprotective drugs varieswidely around the world and is expected to decrease inthe United States as patents expire. For example, theaverage wholesale cost of rabeprazole 20 mg is $5.05 inthe United States versus $1.18 in Hong Kong. Omepra-zole 20 mg OTC costs approximately $0.50 in the UnitedStates versus $0.13 in Hong Kong.

The available data (discussed below) suggest that thedifferent gastroprotective strategies provide similar de-grees of protection. Modest differences in effectiveness,for example, twice-a-day versus once-a-day PPI therapy orbetween PPI and fixed dose misoprostol diclofenac com-bination therapy, could greatly affect the actual costeffectiveness. Here we assume that the different strategiesare similarly effective. Thus, the other costs and the costsassociated with an event would be constant and if thedrug costs were high, they would drive the final results.

When one considers long-term PPI use in low-riskgroups of chronic NSAID users where the numberneeded to treat is high (ie, most do not benefit), one mustalso consider potential complications of long-term PPIuse, including acceleration of the rate of corpus atrophyamong the H pylori infected39,40 and, possibly, their role

in hip fractures, community-acquired pneumonia, andpseudomembranous colitis.41– 46 Studies are needed toprovide estimates of each of these complications so thatrisk– benefit calculations can be made.

It is important to note that the direct and indirectcosts associated with hospitalization and care of an acuteupper GI bleeding event also vary greatly depending onthe patient’s age, presence of comorbid conditions, car-diovascular risks, and so on. In addition, our informalanalysis did not consider the effect of the intervention onlife expectancy. As such, the cost-effectiveness data pre-sented in this editorial should not be compared withstandard metrics such as cost per year of life saved.Rather, this commentary highlights that this topic is ripefor formal cost– benefit analyses.

Fixed Combinations of NSAIDs andGastroprotectivesSeveral studies have suggested that the threshold for

effective PPI protection requires that the patient take �80%of the prescribed PPI.12,32,35 van Soest et al12 report a 16%increase in NSAID-related upper GI complications withevery 10% decrease in adherence.12 The issue of complianceis eliminated by the use of combination therapy and thereare now 4 studies (including the current paper in GASTRO-ENTEROLOGY) showing that the fixed combination of miso-prostol and diclofenac (Arthrotec) seems to provide similarprotection to that achieved with the combination of a PPIand an nsNSAID.41–46 The cost of the fixed-dose misopros-tol combination use is relatively high; there is no costadvantage to its use. Although the data with the fixed-dosemisoprostol–diclofenac seem consistent, the benefits didnot seem to extend to instances where misoprostol wasgiven separately.47 These data suggest that the eliminationof compliance issues by using the fixed low-dose misopros-tol nsNSAID combination may be responsible for its appar-ent effectiveness. Many believe that the low-dose misopros-tol is less effective than PPI gastroprotective therapy.Although there are no direct comparative trials, in veryhigh-risk patients (see below) PPI cotherapy was partiallyeffective, whereas misoprostol seemed ineffective.

Lansoprazole is also available as a dose pack (eg, Prevacid,NapraPAC) with 2 different doses of naproxen (375 or 500mg) along with 15 mg of lansoprazole to be given twice aday. The lansoprazole-naproxen formulation provides bothmedications and, depending on the pharmacy markup, maybe less expensive than providing the drugs separately (Table2). As noted, compliance appears to be a critical variable inPPI gastroprotective therapy.12,32,35 Compliance with regu-lar PPI use is not restricted to gastroprotective therapy as italso tends to be irregular even in those with gastroesopha-geal reflux disease (GERD).48 In fact, a study of �16,000 PPIusers in the Netherlands showed that half of the patientsused PPIs �50% of the time, independent of the indication,including erosive GERD.48 Overall, improved compliancemay be the critical issue with regard to the widespread and

Table 2. Average Wholesale Cost of One Dose of theCommonly Used Agents38

Agent $US

Omeprazole 20 mg OTC 0.50Omeprazole 20 mg generic 4.15Esomeprazole 20 mg 5.24Esomeprazole 40 mg 5.24Lansoprazole 15 mg 5.25Lansoprazole 30 mg 5.25Rabeprazole 20 mg 5.05Pantoprazole 40 mg 4.20Prevacid NapraPAC 375 1.52Prevacid NapraPAC 500 1.52Misoprostol 100 mcg 1.23Misoprostol 200 mcg 1.63Arthroteca 50/0.2 mg 2.14Arthrotec 75/0.2 mg 3.51Celecoxib 100 mg 2.14Celecoxib 200 mg 3.51

aFixed dose combination of diclofenac and misoprostol.

1242 EDITORIALS GASTROENTEROLOGY Vol. 134, No. 4

effective use of gastroprotection. Although, as noted, 2NSAID-gastroprotective combinations are available, neitherappears to be widely used. Clearly, studies where complianceis directly assessed and studies comparing combinationtherapy with separately prescribed therapy are needed. Theongoing PRECISION study should provide some objectivedata regarding compliance in relation to PPI.

Very High GI Risk Patients in WhomnsNSAIDs Are Best AvoidedVery high-risk patients are those who have bled

from an NSAID-associated ulcer (ie, NSAID users and Hpylori negative). To date, there are 3 randomized controltrials on very high-risk patients. After confirmed ulcerhealing, celecoxib, celecoxib plus PPI, or nsNSAID plusPPI were given. The reported annualized rebleeding rateswere 9.8%, 13%, and 8.9% with celecoxib23–25; 12.8% and13.6% with nsNSAID plus PPI23,24; and 0% with celecoxibplus PPI.25 The markedly reduced rate of rebleeding withthe combination of celecoxib and a PPI was also noted inrecent case-control studies.7,11,19 The rebleeding risk withplacebo is unclear. As noted, in H pylori ulcers the medianwas 28%.21 In Hong Kong, it was 37.6%,49 which is con-sistent with a 50%– 60% reduction. Importantly, the rateof recurrent bleeding was unacceptably high, suggestingthat nsNSAIDs should be avoided and that, if celecoxibwas given, it should be given with PPI cotherapy.50 Onesmall randomized controlled trial showed that low-dosemisoprostol was also ineffective in very high-risk patientswith an annualized rebleeding rate of �60%, making italso a poor choice.51 These data suggest that in veryhigh-risk patients the combination of celecoxib plus aPPI has the lowest risk of recurrent upper GI bleeding.

What Is the Place of Coxibs?Several meta-analyses of case-control studies and

randomized controlled trials have examined the relativecardiovascular risks of coxibs and nsNSAIDs.52–55 Cur-rent evidence suggests that both coxibs and nsNSAIDsincrease cardiovascular risk. Naproxen appears to be leastcardiotoxic,52–55 but it is associated with a relatively highGI risk.11,19,56 Compared with naproxen, diclofenac andibuprofen seem to have somewhat higher cardiovascularrisks,54 but lower GI toxicity.56,57 Among the coxibs, onlycelecoxib remains on the US market; the relative GI andcardiovascular safety of celecoxib versus commonly usednsNSAIDs must await the results of ongoing clinicaltrials in patients at higher risk for cardiovascular events.Currently, celecoxib and other nsNSAIDs such as diclofe-nac and ibuprofen should be used in patients with lowcardiovascular risk. It appears prudent to add low-doseaspirin to NSAID users who have cardiovascular riskfactors. However, 2 issues remain unresolved. First, thelow cardiotoxicity of naproxen was largely derived fromstudies in which very few patients used aspirin. If con-

comitant aspirin wipes out all platelet COX-1 activity, itis doubtful whether there will be any advantage ofnaproxen over other NSAIDs. Second, it is uncertainwhether low-dose aspirin can counteract the cardiovas-cular hazards of NSAIDs (including coxibs). It has beensuggested that concomitant administration of ibuprofenand aspirin is associated with attenuation of the anti-platelet effect of aspirin,58,59 and the concomitant use ofaspirin and ibuprofen was associated with an increase incardiovascular mortality by almost 2-fold.60 Patients re-ceiving prophylactic aspirin therefore should avoid usingibuprofen or the aspirin should be administered at least1 hour before the ibuprofen.

The Effect of H pylori InfectionThe issues here include the fact that antisecretory

therapy is more effective in H pylori than in NSAID-associated diseases. Thus, the results of studies con-ducted among populations with high H pylori prevalenceprobably overestimate the effectiveness of antisecretorydrugs.14 In addition, the inclusion of H pylori–infectedand H pylori ulcer patients in the endoscopic ulcer pre-vention studies with coxibs, and antisecretory drugs sig-nificantly confounded the interpretation. However, sev-eral meta-analyses have repeatedly shown that H pyloriincreases the risk of ulcer complications among NSAIDusers61– 63; because H pylori is the only treatable GI riskfactor, we recommend test-and-treat H pylori infection inpatients who require long-term NSAIDs.

Future StudiesStudies in the very high-risk groups designed to

prevent rebleeding provide valuable information for thatsubpopulation and have shown that celecoxib plus a PPIappears most effective. Studies on traditional high-riskpatients (eg, the elderly NSAID and aspirin user) areunlikely to be done soon given the large sample sizesrequired to show even relatively large differences. Theongoing PRECISION study comparing celecoxib,naproxen, and ibuprofen for cardiovascular events inhigher cardiovascular risk patients should provide someuseful information; most patients are also receiving as-pirin and a PPI. That study should allow a better com-parison of coxibs and nsNSAIDs as well as the effect ofcompliance on major upper GI complications. Well-de-signed observational studies can also provide much use-ful new information. One hopes that future studies canbe designed to address remaining questions stratified forH pylori status, drug and dose, and compliance.

RecommendationsThe presence of an H pylori infection approxi-

mately doubles the risk of a major GI event amongNSAID users.61 We therefore recommend H pylori testingfor those in whom chronic NSAID use is contemplated.

April 2008 EDITORIALS 1243

The choice of NSAIDs is now complicated by uncertaintyregarding relative cardiovascular risks of the differentNSAIDs. Nonetheless, the old rule to prescribe the lowestdose for the shortest time still applies; risk increases withdose and varies depending on the NSAID chosen. Ratio-nal decision making depends on assessment of individualpatients’ GI and cardiovascular risks (Table 3) and selec-tion of cost-effective gastroprotectives or coxibs (Tables 1and 2). In patients with low GI and low cardiovascularrisk, nsNSAIDs are the preferred treatment. We recom-mend a coxib or cotherapy with a PPI or misoprostol inpatients with high GI risk. A coxib or fixed-dose combi-nations of misoprostol-diclofenac or PPI-nsNSAID mayimprove drug compliance and thus effectiveness. A coxibplus a PPI or not to use NSAIDs are the treatmentoptions if the patient has prior ulcer bleeding. In patientswith high cardiovascular risk, naproxen is the preferredNSAID. We recommend cotherapy with a PPI or miso-prostol in patients receiving concomitant nsNSAID andlow-dose aspirin. Finally, the data are consistent with thenotion that no form of NSAID therapy should be used inpatients with high GI and high cardiovascular risk.

DAVID Y. GRAHAMDepartment of MedicineMichael E. DeBakey VAMC andBaylor College of MedicineHouston, Texas

FRANCIS K. L. CHANDepartment of Medicine & TherapeuticsThe Chinese University of Hong KongHong Kong

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Table 3. Risk Groups and Recommendations

Low GI riska High GI riska Very high GI riska

Low CV risk (not on aspirin) Nonselective NSAID alone Nonselective NSAID � PPI/misoprostol Coxib � PPI/misoprostolHigh CV riskb (on aspirin) Naproxen � PPI/misoprostol Naproxen � PPI/misoprostol Avoid NSAIDs or coxibs if possible

Coxib, cyclo-oxygenase inhibitor; CV, cardiovascular; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump inhibitor.aGI risk is arbitrarily classified as low, high, and very high if the annualized ulcer complication rates are �1% (eg, age 20–64), 1–5% (eg, olderages), and �5% (eg, multiple risk factors, prior ulcer bleeding), respectively.bHigh CV risk is defined as any CV disease that requires prophylactic low-dose aspirin.

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46. Yang YX, Lewis JD, Epstein S, et al. Long-term proton pump inhibitortherapy and risk of hip fracture. JAMA 2006;296:2947–2953.

47. Ashworth NL, Peloso PM, Muhajarine N, et al. A population basedhistorical cohort study of the mortality associated with nabum-etone, Arthrotec, diclofenac, and naproxen. J Rheumatol 2004;31:951–956.

48. Van Soest EM, Siersema PD, Dieleman JP, et al. Persistence andadherence to proton pump inhibitors in daily clinical practice.Aliment Pharmacol Ther 2006;24:377–385.

49. Chan FK, Chung SC, Suen BY, et al. Preventing recurrent uppergastrointestinal bleeding in patients with Helicobacter pylori in-fection who are taking low-dose aspirin or naproxen. N Engl J Med2001;344:967–973.

50. Graham DY. NSAIDs, Helicobacter pylori, and Pandora’s box.N Engl J Med 2002;347:2162–2164.

51. Chan FK, Sung JJ, Ching JY, et al. Randomized trial of low-dosemisoprostol and naproxen vs. nabumetone to prevent recurrentupper gastrointestinal haemorrhage in users of non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther 2001;15:19–24.

52. Kearney PM, Baigent C, Godwin J, et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflam-matory drugs increase the risk of atherothrombosis? Meta-anal-ysis of randomised trials. BMJ 2006;332:1302–1308.

53. Juni P, Nartey L, Reichenbach S, et al. Risk of cardiovascularevents and rofecoxib: cumulative meta-analysis. Lancet 2004;364:2021–2029.

54. McGettigan P, Henry D. Cardiovascular risk and inhibition ofcyclooxygenase: a systematic review of the observational studiesof selective and nonselective inhibitors of cyclooxygenase 2.JAMA 2006;296:1633–1644.

55. Abraham NS, El-Serag HB, Hartman C, et al. Cyclooxygenase-2selectivity of non-steroidal anti-inflammatory drugs and the risk ofmyocardial infarction and cerebrovascular accident. Aliment Phar-macol Ther 2007;25:913–924.

56. Langman MJ, Weil J, Wainwright P, et al. Risks of bleeding pepticulcer associated with individual non-steroidal anti-inflammatorydrugs. Lancet 1994;343:1075–1078.

57. McKellar G, Madhok R, Singh G. The problem with NSAIDs: whatdata to believe? Curr Pain Headache Rep 2007;11:423–427.

58. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenaseinhibitors and the antiplatelet effects of aspirin. N Engl J Med2001;345:1809–1817.

59. MacDonald TM, Wei L. Is there an interaction between the car-diovascular protective effects of low-dose aspirin and ibuprofen?Basic Clin Pharmacol Toxicol 2006;98:275–280.

60. MacDonald TM, Wei L. Effect of ibuprofen on cardioprotectiveeffect of aspirin. Lancet 2003;361:573–574.

61. Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infec-tion and non-steroidal anti-inflammatory drugs in peptic-ulcer dis-ease: a meta-analysis. Lancet 2002;359:14–22.

62. Papatheodoridis GV, Sougioultzis S, Archimandritis AJ. Effects ofHelicobacter pylori and nonsteroidal anti-inflammatory drugs on

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peptic ulcer disease: a systematic review. Clin GastroenterolHepatol 2006;4:130–142.

63. Vergara M, Catalan M, Gisbert JP, et al. Meta-analysis: role ofHelicobacter pylori eradication in the prevention of peptic ulcer inNSAID users. Aliment Pharmacol Ther 2005;21:1411–1418.

Address requests for reprints to: David Y. Graham, MD, Michael E.DeBakey Veterans Affairs Medical Center, RM 3A-320 (111D), 2002Holcombe Boulevard, Houston, Texas 77030. e-mail: dgraham@bcm.tmc.edu; fax: (713) 790-1040.

In the last 3 years, Dr Graham has received small amounts of grantsupport and/or free drugs or urea breath tests from Meretek, Jannsen/Eisai, and TAP, and BioHit for investigator-initiated and completelyinvestigator-controlled research. Dr Graham is a consultant for Novar-

tis in relation to vaccine development for treatment or prevention of Hpylori infection and a paid consultant for Otsuka Pharmaceuticals,manufacturer of the 13C-urea breath test. Dr Graham also receivesroyalties on the Baylor College of Medicine patent covering the sero-logic test, HM-CAP. Dr Graham is also an unpaid member of theexecutive committee of the PRECISION trial, which is supported byPfizer and is designed to compare the cardiovascular safety of cele-coxib, naproxen, and ibuprofen in higher cardiovascular risk patients.Francis K. L. Chan reports having received an independent researchgrant and a consulting fee from Pfizer and paid lecture fees from TAPPharmaceuticals, Takeda, and AstraZeneca. He also chairs the Steer-ing Committee of the Pfizer-sponsored CONDOR study.

© 2008 by the AGA Institute0016-5085/08/$34.00

doi:10.1053/j.gastro.2008.02.007

Immunology and the Lynch Syndrome

See “Immune response against frameshift-induced neopeptides in HNPCC patients andhealthy HNPCC mutation carriers,” by Schwi-talle Y, Kloor M, Eiermann S, et al, on page988.

Colorectal cancer (CRC) in Lynch syndrome differsfrom its sporadic counterpart by virtue of certain

clinicopathologic features, namely its poor differentia-tion with mucoid features and signet cell excess, peritu-moral lymphocytic infiltration, Crohn’s-like reaction, andan excess of tumor-infiltrating lymphocytes.1– 4 At themolecular level, most Lynch syndrome–associated CRCsare microsatellite instability–high (MSI-H). A centralquestion regarding CRC patients with Lynch syndromethat puzzles both clinicians and basic scientists is whythese patients do relatively well compared with individ-uals with sporadic cases of CRC, a fact empirically ob-served before the identification of mismatch repair genesin 1993.5,6 Anecdotally, patients belonging to Lynch syn-drome families were known to have survived multipleprimary cancers.7–9 The identification of germline muta-tions in the mismatch repair genes as being characteristicof Lynch syndrome permitted further refinement in iden-tifying these patients and multiple studies have demon-strated a better prognosis in the Lynch syndrome pa-tients compared with age- and stage-matched “sporadic”colon cancer patients.10 –15

Watson et al13 compared Lynch syndrome cases bystage and survival in a retrospective cohort of familymembers who developed CRC with the same factors in anunselected hospital series of patients with sporadic CRC.Therein, Lynch syndrome cases had lower stage disease (P� .001) and fewer distant metastases at diagnosis (P �

.001 in an analysis stratified by T classification). Impor-tantly, “In stage-stratified survival analysis, the [heredi-tary nonpolyposis colorectal cancer (HNPCC)] cases hada significant overall survival advantage regardless of ad-justment for their younger age. A conservative estimate ofthe hazard ratio (of HNPCC cases to the unselectedseries) was 0.67 (P � .0012).”13 It was concluded that theLynch syndrome patients showed lower stage at diagno-sis when compared to the unselected CRC cases, whichwas mainly attributable to rarer distant metastases atdiagnosis. Furthermore, Lynch syndrome patients sur-vived longer in cases with tumors of the same stage.Finally, the estimated death rate for the Lynch syndromecases, when adjusted for stage and age differences, was atmost only two thirds of the rate for the hospital series.The improved prognosis observed for Lynch syndromepatients was also observed in patients with the subtype ofsporadic CRC characterized by hypermethylation of theMLH1 promoter and associated with MSI.16 –19

Although these studies were interesting from a scientificviewpoint, much interest was aroused by the tentative ob-servation that 5-fluorouracil (5-FU)–based chemotherapymight not be beneficial to patients with microsatellite un-stable tumors.20,21 Suddenly, the phenomenon of MSI be-came of great interest to surgeons, gastroenterologists, andoncologists in that MSI could not only be used as a prog-nostic marker, but also may be important in guiding betterpatient treatment. Because approximately 15% of all CRCpatients have MSI, it is critical to conduct large prospectivestudies to definitively prove whether 5-FU really does notprovide a benefit, or might even be harmful, in this subsetof CRC patients. To date, the issue regarding the suitabilityof 5-FU treatment for MSI-H individuals has not yet beenresolved.

1246 EDITORIALS GASTROENTEROLOGY Vol. 134, No. 4