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Will an aspirin a day keep the endoscope away?

2003; Elsevier BV; Volume: 125; Issue: 2 Linguagem: Inglês

10.1016/s0016-5085(03)00962-4

1528-0012

Raymond N. DuBois,

Helicobacter pylori-related gastroenterology studies

Benamouzig et al. report in this issue of gastroenterology that daily aspirin is associated with a significant reduction in the risk of recurrent adenomas 1 year after initiation of treatment.1Benamouzig R. Deyra J. Martin A. Girard B. Jullian E. Piednoir B. Couturier D. Coste T. Little J. Chaussade S. The Association Pour La Prévention Par L’aspirine Du Cancer Colorectal Study GroupDaily soluble aspirin and prevention of colorectal adenoma recurrence one-year results of the APACC trial.Gastroenterology. 2003; 125: 328-336Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar These results confirm two other recent reports indicating that an aspirin a day is associated with a significant reduction in the incidence of colorectal adenomas.2Baron J.A. Cole B.F. Sandler R.S. Haile R.W. Ahnen D. Bresalier R. McKeown-Eyssen G. Summers R.W. Rothstein R. Burke C.A. Snover D.C. Church T.R. Allen J.I. Beach M. Beck G.J. Bond J.H. Byers T. Greenberg E.R. Mandel J.S. Marcon N. Mott L.A. Pearson L. Saibil F. van Stolk R.U. A randomized trial of aspirin to prevent colorectal adenomas.N Engl J Med. 2003; 348: 891-899Crossref PubMed Scopus (1269) Google Scholar, 3Sandler R.S. Halabi S. Baron J.A. Budinger S. Paskett E. Keresztes R. Petrelli N. Pipas J.M. Karp D.D. Loprinzi C.L. Steinbach G. Schilsky R. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer.N Engl J Med. 2003; 348: 883-890Crossref PubMed Scopus (1025) Google ScholarAspirin, or acetylsalicylic acid (ASA), was first introduced to the public in 1899 by the German company now known as Bayer. Today Americans take over 80 million aspirin tablets each day. It has become one of the world’s most successful drugs because of its ability to relieve pain and reduce fever, with remarkably few side effects for the majority of patients. Aspirin’s potential use as a pharmaceutical continues to be evaluated. Based on recent research, scientists have reason to believe that this 100-year-old drug may have other health benefits, such as the prevention of colorectal cancer. How was this “wonder drug” developed? How does it work? Will “chemoprevention” using aspirin have any impact on current screening regimens for colorectal cancer?In 400 B.C., the Greek physician, Hippocrates, prescribed the bark and leaves of the willow tree (rich in a substance called salicin) to relieve pain and fever.4Mueller R.L. Scheidt S. History of drugs for thrombotic disease. Discovery, development, and directions for the future.Circulation. 1994; 89: 432-449Crossref PubMed Google Scholar In 1763, the first experiment with willow bark was reported by Rev. Edmund Stone to the Royal Society of London.5Stone E. An account of the success of the bark of the willow in the cure of agues.Philos Trans R Soc Lond. 1763; 53: 195-200Crossref Google Scholar Rev. Stone treated 50 parishioners who had rheumatic fever with ground up willow bark and found that it helped relieve their symptoms. It was not until 1828–1829, however, that a German chemist, Johann Buchner at the University of Munich, isolated a tiny amount of bitter tasting substance from willow bark which he called “salicin,” which was later used to create salicylic acid. In 1853, a French chemist, Charles Grederic Gerhardt, neutralized salicylic acid by buffering it with sodium (sodium salicylate) and acetyl chloride, creating acetyl salicylic acid (ASA), but this work was dropped and not pursued for another 44 years. Finally, in 1897, a German chemist at Bayer, Felix Hoffmann, rediscovered Gerhardt’s formula and chemically synthesized a stable form of ASA. Bayer came up with the name “aspirin,” in which “A” came from acetyl chloride, “spir” from spiraea ulmaria (the plant from which salicylic acid was derived), and “in” was a common ending for medicines of that era. Shortly following its launch in 1899, aspirin became the number one drug worldwide.Aspirin’s role in disease prevention did not become apparent for another 50 years.4Mueller R.L. Scheidt S. History of drugs for thrombotic disease. Discovery, development, and directions for the future.Circulation. 1994; 89: 432-449Crossref PubMed Google Scholar In 1950, a California general practitioner, Dr. Lawrence Craven, recommended a daily dose of aspirin to reduce the risk of heart attack. Craven had experimented with the blood thinning effects of aspirin after observing that patients who chewed Aspergum for pain relief following tonsillectomy often had bleeding gums. He found that none of the 8000 male patients to whom he prescribed aspirin daily for 6 years had suffered a heart attack (however, the Food and Drug Administration did not approve the use of aspirin for this purpose until 1988). Despite the proliferation of aspirin in the marketplace, the precise mechanism of its action was not appreciated until the early 1970s when Sir John Vane found that it served a key role in blocking the production of proinflammatory prostaglandins,6Vane J.R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.Nature. 1971; 231: 232-235Crossref Scopus (7264) Google Scholar a discovery for which Vane and 2 Swedish scientists, Sune Bergstrom and Bengt Samuelsson, won the Nobel Prize in Medicine in 1982. Later, it was found that aspirin binds covalently and blocks the active site of the prostaglandin-endoperoxide synthase-1 enzyme (often referred to as cyclooxygenase [COX]-1). A second, inducible form of prostaglandin-endoperoxide synthase (referred to as COX-2) was subsequently cloned and the complementary DNA sequence reported by several groups.7Kujubu D.A. Fletcher B.S. Varnum B.C. Lim R.W. Herschman H.R. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue.J Biol Chem. 1991; 266: 12866-12872Abstract Full Text PDF PubMed Google Scholar, 8Xie W. Chipman J. Robertson D. Erikson R. Simmons D. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing.Proc Natl Acad Sci U S A. 1991; 88: 2692-2696Crossref PubMed Scopus (1677) Google Scholar, 9O’Banion M.K. Sadowski H.B. Winn V. Young D.A. A serum- and glucocorticoid-regulated 4-kilobase mRNA encodes a cyclooxygenase-related protein.J Biol Chem. 1991; 266: 23261-23267PubMed Google ScholarAspirin belongs to a class of agents known as nonsteroidal anti-inflammatory drugs (NSAIDs). A surgeon at the University of Colorado, Dr. William Waddell, was one of the first physicians to observe a connection between the use of NSAIDs and a reduction in colonic polyps in humans with familial polyposis (FAP).10Waddell W.R. Loughry R.W. Sulindac for polyposis of the colon.J Surg Oncol. 1983; 24: 83-87Crossref PubMed Scopus (480) Google Scholar He astutely observed a reduction in polyp number in his FAP patients after their use of NSAIDs for pain relief. This observation was followed by several studies that clearly documented a decrease in polyp burden in patients treated with sulindac, or in rodents treated with other NSAIDs.11Smalley W. DuBois R.N. Colorectal cancer and nonsteroidal anti-inflammatory drugs.Adv Pharmacol. 1997; 39: 1-20Crossref PubMed Scopus (340) Google Scholar A number of observational studies have been reported which show a reduction in risk and/or mortality from colorectal cancer in people who take aspirin or other NSAIDs on a regular basis.12Giardiello F.M. Offerhaus G.J.A. DuBois R.N. The role of nonsteroidal anti-inflammatory drugs in colorectal cancer prevention.Eur J Cancer. 1995; 31A: 1071-1076Abstract Full Text PDF PubMed Scopus (172) Google Scholar This work led many groups to study the potential role of NSAIDs and COX enzymes in colorectal carcinogenesis. The first report of COX expression in colorectal cancers appeared in gastroenterology in 1994.13Eberhart C.E. Coffey R.J. Radhika A. Giardiello F.M. Ferrenbach S. DuBois R.N. Up-regulation of cyclooxygenase-2 gene expression in human colorectal adenomas and adenocarcinomas.Gastroenterology. 1994; 107: 1183-1188Abstract PubMed Google Scholar It was found that COX-2 was overexpressed in the majority of colorectal cancers and adenomas. This led to a number of studies evaluating the role of COX-2 in cancer, and much of this work has been reviewed recently.14Gupta R.A. DuBois R.N. Colorectal cancer and the cyclooxygenase pathway.Nat Rev Cancer. 2001; 1: 11-21Crossref PubMed Scopus (945) Google Scholar The most direct and compelling evidence implicating a role for COX-2 in colorectal cancer has come from genetic studies in mice. Oshima et al. determined intestinal polyp number in ApcΔ716 mice (a mouse model similar to the APCMin but in which there is a targeted truncation in the APC gene) in both wild-type and homozygous null COX-2 genetic backgrounds.15Oshima M. Dinchuk J.E. Kargman S.L. Oshima H. Hancock B. Kwong E. Trzaskos J.M. Evans J.F. Taketo M.M. Suppression of intestinal polyposis in APCΔ716 knockout mice by inhibition of prostaglandin endoperoxide synthase-2 (COX-2).Cell. 1996; 87: 803-809Abstract Full Text Full Text PDF PubMed Scopus (2271) Google Scholar The number and size of polyps was reduced in the COX-2 null mice compared with COX-2 wild-type mice. Treatment of the ApcΔ716 COX-2 wild-type mice with a novel COX-2 inhibitor or the NSAID sulindac also reduced polyp number. A clinical trial also has shown a reduction in polyp burden in humans with FAP following treatment with the selective COX-2 inhibitor celecoxib.16Steinbach G. Lynch P.M. Phillips R.K.S. Wallace M.H. Hawk E. Gordon G.B. Wakabayashi N. Saunders B. Shen Y. Fujimura T. Su L.K. Levin B. Godio L. Patterson S. Rodriguez-Bigas M.A. Jester S.L. King K.L. Schumacher M. Abbruzzese J. DuBois R.N. Hittelman W.N. Zimmerman S. Sherman J.W. Kelloff G. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis.N Engl J Med. 2000; 342: 1946-1952Crossref PubMed Scopus (2264) Google ScholarPrior to the current Benamouzig study reported in this issue of gastroenterology, there have been at least 3 prospective randomized trials undertaken that have evaluated the role of aspirin for prevention of colorectal polyps. The first trial, which evaluated healthy male physicians treated with 325 mg of aspirin every other day vs. placebo, showed no treatment effect.17Gann P.H. Manson J.E. Glynn R.J. Buring J.E. Hennekens C.H. Low-dose aspirin and incidence of colorectal tumors in a randomized trial.J Natl Cancer Inst. 1993; 85: 1220-1224Crossref PubMed Scopus (402) Google Scholar However, this trial was not originally designed to look at these endpoints and had limited statistical power to evaluate neoplasia as an outcome. A recent trial by Sandler et al. evaluated 325 mg of aspirin daily vs. placebo in patients with a history of colorectal cancer and found a statistically significant reduction in polyp incidence.3Sandler R.S. Halabi S. Baron J.A. Budinger S. Paskett E. Keresztes R. Petrelli N. Pipas J.M. Karp D.D. Loprinzi C.L. Steinbach G. Schilsky R. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer.N Engl J Med. 2003; 348: 883-890Crossref PubMed Scopus (1025) Google Scholar Another trial, published in the same issue of the New England Journal of Medicine by Baron et al. also found a reduction in the risk of recurrent adenomas in one of the aspirin treatment arms compared with placebo.2Baron J.A. Cole B.F. Sandler R.S. Haile R.W. Ahnen D. Bresalier R. McKeown-Eyssen G. Summers R.W. Rothstein R. Burke C.A. Snover D.C. Church T.R. Allen J.I. Beach M. Beck G.J. Bond J.H. Byers T. Greenberg E.R. Mandel J.S. Marcon N. Mott L.A. Pearson L. Saibil F. van Stolk R.U. A randomized trial of aspirin to prevent colorectal adenomas.N Engl J Med. 2003; 348: 891-899Crossref PubMed Scopus (1269) Google Scholar The Baron study examined patients with a history of one or more colorectal adenomas and, surprisingly, found that only the lower dose of aspirin (81 mg daily) had a significant effect. Benamouzig et al. evaluated 238 patients with a history of colorectal adenomas following 1 year of treatment with 160 or 300 mg/day of lysine acetylsalicylate vs. placebo. The relative risks for recurrent adenomas for the 300 mg vs. placebo and 160 mg vs. placebo, respectively, were 0.63 (CI 95%, 0.46–0.84; P = 0.002) and 0.66 (CI 95%, 0.46–0.95; P = 0.02). Whereas the Baron study showed that only the group treated with 81 mg of aspirin had a statistically significant reduction in adenomas, this study showed equivalent effects in both the 160 mg– and 300 mg-treated groups. The Sandler study only evaluated 1 daily dose of aspirin (325 mg), but the magnitude of reduction in risk of recurrent adenomas was similar to that seen with both doses of aspirin in the Benamouzig study. It is difficult to understand why the 325 mg-treated group in the Baron study did not respond. The patients in the Benamouzig study seemed to be at somewhat higher risk for recurrent adenomas than those recruited to the Baron study, but this still does not explain why the lower dose of aspirin was more effective in the Baron trial.The most important conclusion that can be drawn from these 3 studies is that aspirin does seem to cause a measurable decrease in the recurrence of adenomas in higher risk patients. Does this actually lower the patient’s risk for developing colorectal carcinoma? Are these benefits of the magnitude required to delay follow-up screening for polyp recurrence? The answers to these questions are not yet known, hence endoscopic screening for recurrent adenomas remains the recommendation of choice. Because we do not know whether those adenomas sensitive to aspirin or those resistant to aspirin treatment will progress to a carcinoma, more studies will be required before we understand the precise indications for aspirin or fully understand its role in colorectal cancer prevention. The ancient healers knew that salicin-laden willow bark was beneficial in relieving their patients’ pain, inflammation, and fever. Over 2000 years later, we are still pondering the effects of derivatives of this anti-inflammatory medication on humans. Unfortunately, we do not yet have all the answers nor do we have enough information to make any definite recommendations to our patients. We can tell our patients who take daily aspirin for cardiovascular indications that they may gain additional benefits with regard to reduction in polyp recurrence. Benamouzig et al. report in this issue of gastroenterology that daily aspirin is associated with a significant reduction in the risk of recurrent adenomas 1 year after initiation of treatment.1Benamouzig R. Deyra J. Martin A. Girard B. Jullian E. Piednoir B. Couturier D. Coste T. Little J. Chaussade S. The Association Pour La Prévention Par L’aspirine Du Cancer Colorectal Study GroupDaily soluble aspirin and prevention of colorectal adenoma recurrence one-year results of the APACC trial.Gastroenterology. 2003; 125: 328-336Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar These results confirm two other recent reports indicating that an aspirin a day is associated with a significant reduction in the incidence of colorectal adenomas.2Baron J.A. Cole B.F. Sandler R.S. Haile R.W. Ahnen D. Bresalier R. McKeown-Eyssen G. Summers R.W. Rothstein R. Burke C.A. Snover D.C. Church T.R. Allen J.I. Beach M. Beck G.J. Bond J.H. Byers T. Greenberg E.R. Mandel J.S. Marcon N. Mott L.A. Pearson L. Saibil F. van Stolk R.U. A randomized trial of aspirin to prevent colorectal adenomas.N Engl J Med. 2003; 348: 891-899Crossref PubMed Scopus (1269) Google Scholar, 3Sandler R.S. Halabi S. Baron J.A. Budinger S. Paskett E. Keresztes R. Petrelli N. Pipas J.M. Karp D.D. Loprinzi C.L. Steinbach G. Schilsky R. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer.N Engl J Med. 2003; 348: 883-890Crossref PubMed Scopus (1025) Google Scholar Aspirin, or acetylsalicylic acid (ASA), was first introduced to the public in 1899 by the German company now known as Bayer. Today Americans take over 80 million aspirin tablets each day. It has become one of the world’s most successful drugs because of its ability to relieve pain and reduce fever, with remarkably few side effects for the majority of patients. Aspirin’s potential use as a pharmaceutical continues to be evaluated. Based on recent research, scientists have reason to believe that this 100-year-old drug may have other health benefits, such as the prevention of colorectal cancer. How was this “wonder drug” developed? How does it work? Will “chemoprevention” using aspirin have any impact on current screening regimens for colorectal cancer? In 400 B.C., the Greek physician, Hippocrates, prescribed the bark and leaves of the willow tree (rich in a substance called salicin) to relieve pain and fever.4Mueller R.L. Scheidt S. History of drugs for thrombotic disease. Discovery, development, and directions for the future.Circulation. 1994; 89: 432-449Crossref PubMed Google Scholar In 1763, the first experiment with willow bark was reported by Rev. Edmund Stone to the Royal Society of London.5Stone E. An account of the success of the bark of the willow in the cure of agues.Philos Trans R Soc Lond. 1763; 53: 195-200Crossref Google Scholar Rev. Stone treated 50 parishioners who had rheumatic fever with ground up willow bark and found that it helped relieve their symptoms. It was not until 1828–1829, however, that a German chemist, Johann Buchner at the University of Munich, isolated a tiny amount of bitter tasting substance from willow bark which he called “salicin,” which was later used to create salicylic acid. In 1853, a French chemist, Charles Grederic Gerhardt, neutralized salicylic acid by buffering it with sodium (sodium salicylate) and acetyl chloride, creating acetyl salicylic acid (ASA), but this work was dropped and not pursued for another 44 years. Finally, in 1897, a German chemist at Bayer, Felix Hoffmann, rediscovered Gerhardt’s formula and chemically synthesized a stable form of ASA. Bayer came up with the name “aspirin,” in which “A” came from acetyl chloride, “spir” from spiraea ulmaria (the plant from which salicylic acid was derived), and “in” was a common ending for medicines of that era. Shortly following its launch in 1899, aspirin became the number one drug worldwide. Aspirin’s role in disease prevention did not become apparent for another 50 years.4Mueller R.L. Scheidt S. History of drugs for thrombotic disease. Discovery, development, and directions for the future.Circulation. 1994; 89: 432-449Crossref PubMed Google Scholar In 1950, a California general practitioner, Dr. Lawrence Craven, recommended a daily dose of aspirin to reduce the risk of heart attack. Craven had experimented with the blood thinning effects of aspirin after observing that patients who chewed Aspergum for pain relief following tonsillectomy often had bleeding gums. He found that none of the 8000 male patients to whom he prescribed aspirin daily for 6 years had suffered a heart attack (however, the Food and Drug Administration did not approve the use of aspirin for this purpose until 1988). Despite the proliferation of aspirin in the marketplace, the precise mechanism of its action was not appreciated until the early 1970s when Sir John Vane found that it served a key role in blocking the production of proinflammatory prostaglandins,6Vane J.R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.Nature. 1971; 231: 232-235Crossref Scopus (7264) Google Scholar a discovery for which Vane and 2 Swedish scientists, Sune Bergstrom and Bengt Samuelsson, won the Nobel Prize in Medicine in 1982. Later, it was found that aspirin binds covalently and blocks the active site of the prostaglandin-endoperoxide synthase-1 enzyme (often referred to as cyclooxygenase [COX]-1). A second, inducible form of prostaglandin-endoperoxide synthase (referred to as COX-2) was subsequently cloned and the complementary DNA sequence reported by several groups.7Kujubu D.A. Fletcher B.S. Varnum B.C. Lim R.W. Herschman H.R. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue.J Biol Chem. 1991; 266: 12866-12872Abstract Full Text PDF PubMed Google Scholar, 8Xie W. Chipman J. Robertson D. Erikson R. Simmons D. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing.Proc Natl Acad Sci U S A. 1991; 88: 2692-2696Crossref PubMed Scopus (1677) Google Scholar, 9O’Banion M.K. Sadowski H.B. Winn V. Young D.A. A serum- and glucocorticoid-regulated 4-kilobase mRNA encodes a cyclooxygenase-related protein.J Biol Chem. 1991; 266: 23261-23267PubMed Google Scholar Aspirin belongs to a class of agents known as nonsteroidal anti-inflammatory drugs (NSAIDs). A surgeon at the University of Colorado, Dr. William Waddell, was one of the first physicians to observe a connection between the use of NSAIDs and a reduction in colonic polyps in humans with familial polyposis (FAP).10Waddell W.R. Loughry R.W. Sulindac for polyposis of the colon.J Surg Oncol. 1983; 24: 83-87Crossref PubMed Scopus (480) Google Scholar He astutely observed a reduction in polyp number in his FAP patients after their use of NSAIDs for pain relief. This observation was followed by several studies that clearly documented a decrease in polyp burden in patients treated with sulindac, or in rodents treated with other NSAIDs.11Smalley W. DuBois R.N. Colorectal cancer and nonsteroidal anti-inflammatory drugs.Adv Pharmacol. 1997; 39: 1-20Crossref PubMed Scopus (340) Google Scholar A number of observational studies have been reported which show a reduction in risk and/or mortality from colorectal cancer in people who take aspirin or other NSAIDs on a regular basis.12Giardiello F.M. Offerhaus G.J.A. DuBois R.N. The role of nonsteroidal anti-inflammatory drugs in colorectal cancer prevention.Eur J Cancer. 1995; 31A: 1071-1076Abstract Full Text PDF PubMed Scopus (172) Google Scholar This work led many groups to study the potential role of NSAIDs and COX enzymes in colorectal carcinogenesis. The first report of COX expression in colorectal cancers appeared in gastroenterology in 1994.13Eberhart C.E. Coffey R.J. Radhika A. Giardiello F.M. Ferrenbach S. DuBois R.N. Up-regulation of cyclooxygenase-2 gene expression in human colorectal adenomas and adenocarcinomas.Gastroenterology. 1994; 107: 1183-1188Abstract PubMed Google Scholar It was found that COX-2 was overexpressed in the majority of colorectal cancers and adenomas. This led to a number of studies evaluating the role of COX-2 in cancer, and much of this work has been reviewed recently.14Gupta R.A. DuBois R.N. Colorectal cancer and the cyclooxygenase pathway.Nat Rev Cancer. 2001; 1: 11-21Crossref PubMed Scopus (945) Google Scholar The most direct and compelling evidence implicating a role for COX-2 in colorectal cancer has come from genetic studies in mice. Oshima et al. determined intestinal polyp number in ApcΔ716 mice (a mouse model similar to the APCMin but in which there is a targeted truncation in the APC gene) in both wild-type and homozygous null COX-2 genetic backgrounds.15Oshima M. Dinchuk J.E. Kargman S.L. Oshima H. Hancock B. Kwong E. Trzaskos J.M. Evans J.F. Taketo M.M. Suppression of intestinal polyposis in APCΔ716 knockout mice by inhibition of prostaglandin endoperoxide synthase-2 (COX-2).Cell. 1996; 87: 803-809Abstract Full Text Full Text PDF PubMed Scopus (2271) Google Scholar The number and size of polyps was reduced in the COX-2 null mice compared with COX-2 wild-type mice. Treatment of the ApcΔ716 COX-2 wild-type mice with a novel COX-2 inhibitor or the NSAID sulindac also reduced polyp number. A clinical trial also has shown a reduction in polyp burden in humans with FAP following treatment with the selective COX-2 inhibitor celecoxib.16Steinbach G. Lynch P.M. Phillips R.K.S. Wallace M.H. Hawk E. Gordon G.B. Wakabayashi N. Saunders B. Shen Y. Fujimura T. Su L.K. Levin B. Godio L. Patterson S. Rodriguez-Bigas M.A. Jester S.L. King K.L. Schumacher M. Abbruzzese J. DuBois R.N. Hittelman W.N. Zimmerman S. Sherman J.W. Kelloff G. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis.N Engl J Med. 2000; 342: 1946-1952Crossref PubMed Scopus (2264) Google Scholar Prior to the current Benamouzig study reported in this issue of gastroenterology, there have been at least 3 prospective randomized trials undertaken that have evaluated the role of aspirin for prevention of colorectal polyps. The first trial, which evaluated healthy male physicians treated with 325 mg of aspirin every other day vs. placebo, showed no treatment effect.17Gann P.H. Manson J.E. Glynn R.J. Buring J.E. Hennekens C.H. Low-dose aspirin and incidence of colorectal tumors in a randomized trial.J Natl Cancer Inst. 1993; 85: 1220-1224Crossref PubMed Scopus (402) Google Scholar However, this trial was not originally designed to look at these endpoints and had limited statistical power to evaluate neoplasia as an outcome. A recent trial by Sandler et al. evaluated 325 mg of aspirin daily vs. placebo in patients with a history of colorectal cancer and found a statistically significant reduction in polyp incidence.3Sandler R.S. Halabi S. Baron J.A. Budinger S. Paskett E. Keresztes R. Petrelli N. Pipas J.M. Karp D.D. Loprinzi C.L. Steinbach G. Schilsky R. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer.N Engl J Med. 2003; 348: 883-890Crossref PubMed Scopus (1025) Google Scholar Another trial, published in the same issue of the New England Journal of Medicine by Baron et al. also found a reduction in the risk of recurrent adenomas in one of the aspirin treatment arms compared with placebo.2Baron J.A. Cole B.F. Sandler R.S. Haile R.W. Ahnen D. Bresalier R. McKeown-Eyssen G. Summers R.W. Rothstein R. Burke C.A. Snover D.C. Church T.R. Allen J.I. Beach M. Beck G.J. Bond J.H. Byers T. Greenberg E.R. Mandel J.S. Marcon N. Mott L.A. Pearson L. Saibil F. van Stolk R.U. A randomized trial of aspirin to prevent colorectal adenomas.N Engl J Med. 2003; 348: 891-899Crossref PubMed Scopus (1269) Google Scholar The Baron study examined patients with a history of one or more colorectal adenomas and, surprisingly, found that only the lower dose of aspirin (81 mg daily) had a significant effect. Benamouzig et al. evaluated 238 patients with a history of colorectal adenomas following 1 year of treatment with 160 or 300 mg/day of lysine acetylsalicylate vs. placebo. The relative risks for recurrent adenomas for the 300 mg vs. placebo and 160 mg vs. placebo, respectively, were 0.63 (CI 95%, 0.46–0.84; P = 0.002) and 0.66 (CI 95%, 0.46–0.95; P = 0.02). Whereas the Baron study showed that only the group treated with 81 mg of aspirin had a statistically significant reduction in adenomas, this study showed equivalent effects in both the 160 mg– and 300 mg-treated groups. The Sandler study only evaluated 1 daily dose of aspirin (325 mg), but the magnitude of reduction in risk of recurrent adenomas was similar to that seen with both doses of aspirin in the Benamouzig study. It is difficult to understand why the 325 mg-treated group in the Baron study did not respond. The patients in the Benamouzig study seemed to be at somewhat higher risk for recurrent adenomas than those recruited to the Baron study, but this still does not explain why the lower dose of aspirin was more effective in the Baron trial. The most important conclusion that can be drawn from these 3 studies is that aspirin does seem to cause a measurable decrease in the recurrence of adenomas in higher risk patients. Does this actually lower the patient’s risk for developing colorectal carcinoma? Are these benefits of the magnitude required to delay follow-up screening for polyp recurrence? The answers to these questions are not yet known, hence endoscopic screening for recurrent adenomas remains the recommendation of choice. Because we do not know whether those adenomas sensitive to aspirin or those resistant to aspirin treatment will progress to a carcinoma, more studies will be required before we understand the precise indications for aspirin or fully understand its role in colorectal cancer prevention. The ancient healers knew that salicin-laden willow bark was beneficial in relieving their patients’ pain, inflammation, and fever. Over 2000 years later, we are still pondering the effects of derivatives of this anti-inflammatory medication on humans. Unfortunately, we do not yet have all the answers nor do we have enough information to make any definite recommendations to our patients. We can tell our patients who take daily aspirin for cardiovascular indications that they may gain additional benefits with regard to reduction in polyp recurrence.