Clinica Pediatrica, Dipartimento dell’Età Evolutiva, Università di
Hallstrom M, Eerola E, Vuento R, Janas M, Tammela O. Eﬀ ects of mode of
delivery and necrotising enterocolitis on the intestinal microﬂ ora in preterm infants. Eur J Clin Microbiol Infect Dis 2004; 23: 463–70.
Manzoni P, Mostert M, Leonessa ML. Oral supplementation with Lactobacillus
CG declares that he has no conﬂ ict of interest. SB is on the advisory board of
casei subspecies rhamnosus prevents enteric colonization by Candida species
Eli Lilly’s GeNeSIS research programme and recevies honoraria.
in preterm neonates: a randomized study. Clin Infect Dis 2006; 42: 1735–42.
Mazmanian LK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory
Lin PW, Stoll BJ. Necrotising enterocolitis. Lancet 2006; 368: 1271–83.
molecule of symbiotic bacteria directs maturation of the host immune
Guillet R, Stoll BJ, Cotton CM, et al. Association of H2-blocker therapy and
system. Cell 2005; 122: 107–18.
higher incidence of necrotizing enterocolitis in very low birth weight infants.
Macpherson AJ, Uhr T. Induction of protective IgA by intestinal dendritic cells
Pediatrics 2006; 117: e137–42.
carrying commensal bacteria. Science 2004; 303: 1662–65.
Holman RC, Stoll BJ, Curns AT, et al. Necrotising enterocolitis hospitalisations
10 Deshpande G, Rao S, Patole S. Probiotics for prevention of necrotising
among neonates in the United States. Paediatr Pernat Epidemiol 2006; 20:
enterocolitis in preterm neonates with very low birthweight: a systematic
review of randomised controlled trials. Lancet 2007; 369: 1614–20.
Martin CR, Walker WA. Immune defences and the inﬂ ammatory
Kunz AN, Noel JN, Fairchok MP. Two cases of lactobacillus bacteremia during
response in necrotising enterocolitis. Semin Fetal Neonatal Med 2006; 11:
probiotic treatment of short gut syndrome. J Pediatr Gastroenterol Nutr 2004;
Kelly D, Campbell JI, King TP, et al. Commensal anaerobic gut bacteria
12 Munoz P, Bouza E, Cuenca Estrella M, et al. Saccharomyces cerevisiae fungemia:
attenuate inﬂ ammation by regulating nuclear-cytoplasmic shuttling of
an emerging infectious disease. Clin Infect Dis 2005; 40: 1625–34.
PPAR-gamma and RelA. Nat Immunol 2004; 5: 104–12. Summing the risk of NSAID therapy
See Articles page 1621
Reports concluding that chronic use of non-steroidal synthesis of the literature—not complete reliance on anti-inﬂ ammatory drugs (NSAIDs) increases the likelihood
single studies that address one outcome—is required to
of cardiovascular adverse events have led patients and inform decisionmaking. This stepwise approach is crucial, clinicians to reduce use. It is intriguing to recollect that the because appropriate selection of an NSAID should be cardiotoxicity of NSAIDs (both cyclo-oxygenase-2 [COX-2]
driven by assessment of an individual’s cardiovascular
selective inhibitors and non-selective dual inhibitors have and gastrointestinal risk, or both, rather than by a been implicated) would not have been revealed if not drug’s reported rate of adverse events in heterogeneous for the push to market novel drugs developed to reduce populations (table).1the well-documented gastrointestinal complications of
The importance of individualised risk assessment and
this widely used class. While weighing risks and beneﬁ ts its role on a single NSAID-related safety outcome is of interventions is an essential component of clinical exempliﬁ ed in the study by Frances Chan and colleagues in decisionmaking, it has become increasingly complex to today’s Lancet.3 They report that the twice-daily addition of decide in whom the use of any NSAID—with or without a a proton-pump inhibitor to twice daily celecoxib lowered gastroprotective agent, and with or without concomitant the 13-month recurrence of ulcer bleeding to 0% in the aspirin—is appropriate. In view of the multiplicity, and in combined treatment group compared with 8·9% with many cases rarity, of adverse events, it is unlikely that a celecoxib alone (95% CI for the diﬀ erence, 4·1–13·7). The single mega-trial will adequately address the numerous trial enrolled individuals at highest risk of a gastrointest-safety and eﬀ ectiveness issues. In the meantime, careful inal complication: those with previous gastrointestinal
bleeding. While the complete absence of recurrent events
No or low NSAID NSAID gastrointestinal risk gastrointestinal risk
for those on combination therapy, even in the face of aspirin therapy, is surprising, the ﬁ nding provides clear
COX-2 selective inhibitor or non-selective
guidance for those individuals at greatest gastrointestinal
COX-2 selective inhibitor+proton-pump inhibitor for those with prior gastrointestinal bleeding
risk who require an NSAID. The incremental risk-reduction
Proton-pump inhibitor irrespective of NSAID
of a proton-pump inhibitor in the setting of aspirin and
Naproxen if CV risk outweighs gastrointestinal risk
a COX-2 inhibitor is consistent with the trials comparing
inhibitor if gastrointestinal risk COX-2 selective inhibitor+proton-pump inhibitor of aspirin/NSAID combination
for those with previous gastrointestinal bleeding
etoricoxib and diclofenac.4 The MEDAL programme
combined data from three trials and the ﬁ ndings contrast
*Non-selective or selective (low-dose) inhibitor without established aspirin interaction if naproxen is ineﬀ ective.2
with those from several studies showing no signiﬁ cant
Misoprostol at full dose (200 μg four times a day) may be substituted for proton-pump inhibitor. Adapted from reference 1.
gastrointestinal safety beneﬁ t of COX-2 inhibitors plus
Table: Clinicians guide to anti-inﬂ ammatory therapy in 2007
aspirin over a traditional NSAID-aspirin combination.5,6
www.thelancet.comVol 369 May 12, 2007
This new information supporting the gastrointestinal questions. As important pieces are added to the puzzle,
advantage of a combination of a COX-2 and proton-pump
it remains critical to sum the risks using all the parts.
inhibitor should not to be interpreted without careful consideration of competing risks from the cardiovascular *James M Scheiman, A Mark Fendrickperspective. For individuals with documented cardio-
Division of Gastroenterology, Department of Internal Medicine,
vascular risks, the selection of an NSAID is not University of Michigan School of Medicine, Ann Arbor, MI 48109,
USA (JMS); and Departments of Internal Medicine and Health
straightforward. Recent position statements,7 supported Management & Policy, University of Michigan Schools of Medicine
by collective but not conclusive data,8 suggest that and Public Health, Ann Arbor, Michigan, USA (AMF) naproxen is diﬀ erentiated from other selective and [email protected] agents that may increase cardiovascular JS is a consultant for AstraZeneca, Merck, Novartis, Pﬁ zer, Pozen, Bayer, GSK, PLx risk. For those with competing cardiovascular and Pharma, NiCox, Horizon Therapeutics, and TAP Pharmaceuticals, and has received
speaker’s honoraria from AstraZeneca, Takeda, Santarus, and TAP Pharmaceuticals;
gastrointestinal risks, the tradeoﬀ s between reducing MF receives research support from Amgen, Merck and Co, Pﬁ zer Inc, Johnson and gastrointestinal adverse events (COX-2 inhibitor instead of
Johnson, Sanoﬁ , and Aventis Pharmaceuticals, is on a speakers bureau for Pﬁ zer, AstraZeneca, and TAP, and is a consultant for ActiveHealth Management,
a non-selective NSAID) must be explicitly weighed against AstraZeneca Pharmaceuticals, Eli Lilly and Co, GlaxoSmithKline, MedImpact
HealthCare Systems Inc, Merck and Co, Pﬁ zer Inc, Johnson and Johnson,
vascular side-eﬀ ects (naproxen Sanoﬁ -Aventis Pharmaceuticals, TAP Pharmaceuticals, and Value Based Beneﬁ ts Inc.
Scheiman, JM., Fendrick AM. Practical approaches to minimizing
In addition to individual patients’ characteristics,
gastrointestinal and cardiovascular safety concerns with COX-2 inhibitors and NSAIDs. Arthritis Res Ther 2005; 7 (suppl 4): S23–29.
attention to dose, administration, and duration of NSAID 2
Grosser T, Fries S, Fitzgerald GA. Biological basis for the cardiovascular
use should also be considered. Chan and colleagues used
consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Cllin Invest 2006; 116: 4–15.
celecoxib 200 mg twice daily, a dose with established 3
Chan FKL, Wong VWS, Suen BY, et al. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer
cardiovascular risk.9 There is no published evidence that
bleeding in patients at very high risk: a double-blind, randomised trial.
concomitant aspirin lessens the increased cardiovascular
Lancet 2007; 369: 1621–26.
Laine L, Curtis SP, Cryer B, for the MEDAL Steering Committee. Assessment of
risk observed with COX-2 selective inhibitors,9,10 A once
upper gastrointestinal safety of etoricoxib and diclofenac in patients with
daily 400 mg and 200 mg dose of celecoxib seems to
osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised
not share this hazard,11,12 at least in patients with average
comparison. Lancet 2007; 369: 465–73.
Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with
cardiovascular risk. On examination of the existing data,
celecoxib vs nonsteroidal anti-inﬂ ammatory drugs for osteoarthritis and
NSAID adverse eﬀ ects should not be attributed simply by
rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000; 284: 1247–55.
drug classiﬁ cation (ie, COX-2 selective inhibitor or non-
Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib with
selective inhibitors), but instead by the dose and dura tion
naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications:
of COX-2 inhibition. While the ongoing PRECISION trial,
randomised controlled trial. Lancet 2004; 364: 665–74.
Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts H, Taubert KAA. Use
in which naproxen, ibuprofen, and celecoxib are being
of nonsteroidal antiinﬂ ammatory drugs: an update for clinicians: a scientiﬁ c
compared, will be informative, the lack of a placebo control
statement from the American Heart Association. Circulation 2007; published online Feb 26. DOI:10.1161/CIRCULATIONAHA.106.181424.
arm and the years of data collection necessary require 8 Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do timely decisions be made with available data.13
selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal antiinﬂ ammatory drugs increase the risk of atherothrombosis? Meta-analysis
Comment about costs is warranted, because it may not
of randomised trials. BMJ 2006; 332: 1302–08.
Solomon SD, McMurray JJ, Pfeﬀ er MA, et al. Cardiovascular risk associated
be feasible to recommend the “safest” regimen in every
with celecoxib in a clinical trial for colorectal adenoma prevention.
circumstance. The cost-eﬀ ectiveness of risk-reducing
N Engl J Med 2005; 352: 1071–80.
10 Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with
therapies is intimately related to the patients’ underlying
rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;
14 For those at highest gastrointestinal risk, the use of 11 Arber N, Eagle CJ, Spicak J, for the PreSAP Trial Investigators. Celecoxib for the
a proton-pump inhibitor and a low-dose COX-2 inhibitor
prevention of colorectal adenomatous polyps. N Engl J Med 2006; 355: 885–95.
seems cost eﬀ ective for those without high cardiovascular 12 ADAPT Research Group. Cardiovascular and cerebrovascular events in the
randomized, controlled Alzheimer’s Disease Anti-inﬂ ammatory Prevention
risk. In those patients in whom the cardiovascular risk
Trial (ADAPT). PLoS Clin Trials 2006; 1: e33. http://dx.doi.org/10.1371/journal. pctr.0010033 (accessed April 19, 2007).
parallels or exceeds gastrointestinal concerns, naproxen 13 PRECISION: Prospective Randomized Evaluation of Celecoxib Integrated with a proton-pump inhibitor is recommended when
Safety vs Ibuprofen Or Naproxen. ClinicalTrials.gov Identiﬁ er: NCT00346216. http://clinicaltrials.gov/ct/show/NCT00346216;jsessionid=D55628B7B188
792A5D69CD83784575F1?order=10 (accessed April 25, 2007).
14 Fendrick AM, Bandekar RR, Chernew ME, Scheiman JM. Role of initial NSAID
The choice of NSAID remains confusing and contro-
choice and patient risk factors in the prevention of NSAID gastropathy:
versial in a setting of several important unanswered
a decision analysis. Arthritis Rheum 2002; 47: 36–43.
www.thelancet.comVol 369 May 12, 2007
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