SummaryBackgroundThe vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials.MethodsWe undertook meta-analyses of 280 trials of NSAIDs versus placebo (124 513 participants, 68 342 person-years) and 474 trials of one NSAID versus another NSAID (229 296 participants, 165 456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed).FindingsMajor vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14–1·66; p=0·0009) or diclofenac (1·41, 1·12–1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31–2·37; p=0·0001; diclofenac 1·70, 1·19–2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10–4·48; p=0·0253), but not major vascular events (1·44, 0·89–2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69–1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00–2·49; p=0·0103) and diclofenac (1·65, 0·95–2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56–6·41; p=0·17), but not by naproxen (1·08, 0·48–2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17–2·81, p=0·0070; diclofenac 1·89, 1·16–3·09, p=0·0106; ibuprofen 3·97, 2·22–7·10, p<0·0001; and naproxen 4·22, 2·71–6·56, p<0·0001).InterpretationThe vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making.FundingUK Medical Research Council and British Heart Foundation.

Preclinical studies of chemoprevention drugs given in combination at low doses show remarkable efficacy in preventing adenomas with little additional toxicities, suggesting a strategy to improve risk to benefit ratios for preventing recurrent adenomas. Three hundred seventy-five patients with history of resected (≥3 mm) adenomas were randomly assigned to receive oral difluoromethylornithine (DFMO) 500 mg and sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site. Follow-up colonoscopy was done 3 years after randomization or off-study. Colorectal adenoma recurrence was compared among the groups with log-binomial regression. Comparing the outcome in patients receiving placebos to those receiving active intervention, (a) the recurrence of one or more adenomas was 41.1% and 12.3% (risk ratio, 0.30; 95% confidence interval, 0.18-0.49; P < 0.001); (b) 8.5% had one or more advanced adenomas, compared with 0.7% of patients (risk ratio, 0.085; 95% confidence interval, 0.011-0.65; P < 0.001); and (c) 17 (13.2%) patients had multiple adenomas (>1) at the final colonoscopy, compared with 1 (0.7%; risk ratio, 0.055; 0.0074-0.41; P < 0.001). Serious adverse events (grade ≥3) occurred in 8.2% of patients in the placebo group, compared with 11% in the active intervention group (P = 0.35). There was no significant difference in the proportion of patients reporting hearing changes from baseline. Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects.More than 50,000 people in the United States will die in 2007 from colorectal cancer. In the United States, cancer is the leading cause of death in people under age 74 years (1), and colorectal cancer is the second most common cause of cancer deaths after lung cancer (2). Colorectal cancer may be prevented by removal of precursor adenomas found during screening sigmoidoscopy or colonoscopy (3), although rates are variable and range from 30% to 90% depending highly on reimbursement policies (4, 5).Diet and inflammation have been associated with risk of colorectal cancer (6), and a series of clinical trials have been conducted to test the efficacy of individual dietary supplements or anti-inflammatory agents to prevent the incidence or recurrence of colon polyps (7-14). Unfortunately, these trials have not translated into significant changes in medical practice for prevention or management of colon cancer for a variety of reasons, including lack of efficacy, unacceptable toxicities, and the availability of competing strategies for risk reduction (15).Studies in rodent models have shown that combination chemoprevention strategies are often more effective than those using individual agents (16,17). Difluoromethylornithine (DFMO) has been identified as a potent inhibitor of intestinal and colon carcinogenesis in animal models, especially in combination with nonsteroidal anti-inflammatory drugs (18)(19)(20). DFMO and the n...

Adopting a diet that is low in fat and high in fiber, fruits, and vegetables does not influence the risk of recurrence of colorectal adenomas.

Objective-Some individuals are diagnosed with colorectal cancer (CRC) despite recent colonoscopy. We examined individuals under colonoscopic surveillance for colonic adenomas to assess possible reasons for diagnosing cancer after a recent colonoscopy with complete removal of any identified polyps.Design-Primary data were pooled from eight large (>800 patients) North American studies in which participants with adenoma(s) had a baseline colonoscopy (with intent to remove all visualised lesions) and were followed with subsequent colonoscopy. We used an algorithm based on the time from previous colonoscopy and the presence, size and histology of adenomas detected at prior exam to assign interval cancers as likely being new, missed, incompletely resected (while previously an adenoma) or due to failed biopsy detection.Results-9167 participants (mean age 62) were included in the analyses, with a median followup of 47.2 months. Invasive cancer was diagnosed in 58 patients (0.6%) during follow-up (1.71 per 1000 person-years follow-up). Most cancers (78%) were early stage (I or II); however, 9 (16%) resulted in death from CRC. We classified 30 cancers (52%) as probable missed lesions, 11 (19%) as possibly related to incomplete resection of an earlier, non-invasive lesion and 14 (24%) as probable new lesions. The cancer diagnosis may have been delayed in three cases (5%) because of failed biopsy detection.Conclusions-Despite recent colonoscopy with intent to remove all neoplasia, CRC will occasionally be diagnosed. These cancers primarily seem to represent lesions that were missed or incompletely removed at the prior colonoscopy and might be avoided by increased emphasis on identifying and completely removing all neoplastic lesions at colonoscopy.

UDCA treatment was associated with a non-statistically significant reduction in total colorectal adenoma recurrence but with a statistically significant 39% reduction in recurrence of adenomas with high-grade dysplasia. Because severely dysplastic lesions have a high risk of progression to invasive colorectal carcinoma, this finding indicates that future chemoprevention trials of UDCA in individuals with such lesions should be considered.

Background-Observational studies and randomized trials have reported increased cardiovascular risk associated with cyclooxygenase-2 inhibitors. Prior placebo-controlled randomized studies had limited ability to assess the relationship of either celecoxib dose or pretreatment cardiovascular status to risk associated with celecoxib. Our aim was to assess the cardiovascular risk associated with celecoxib in 3 dose regimens and to assess the relationship between baseline cardiovascular risk and effect of celecoxib on cardiovascular events. Methods and Results-We performed a patient-level pooled analysis of adjudicated data from 7950 patients in 6 placebo-controlled trials comparing celecoxib with placebo for conditions other than arthritis with a planned follow-up of at least 3 years. Patients were administered celecoxib in 3 dose regimens: 400 mg QD, 200 mg BID, or 400 mg BID.From the pooled data, we calculated a hazard ratio for all dose regimens combined and individual hazard ratios for each dose regimen and examined whether celecoxib-related risk was associated with baseline cardiovascular risk. The primary end point was the combination of cardiovascular death, myocardial infarction, stroke, heart failure, or thromboembolic event. With 16 070 patient-years of follow-up, the hazard ratio for the composite end point combining the tested doses was 1.6 (95% CI, 1.1 to 2.3). The risk, which increased with dose regimen (Pϭ0.0005), was lowest for the 400-mg-QD dose (hazard ratio, 1.1; 95% CI, 0.6 to 2.0), intermediate for the 200-mg-BID dose (hazard ratio, 1.8; 95% CI, 1.1 to 3.1), and highest for the 400-mg-BID dose (hazard ratio, 3.1; 95% CI, 1.5 to 6.1). Patients at highest baseline risk demonstrated disproportionately greater risk of celecoxib-related adverse events (P for interactionϭ0.034). Conclusions-We observed evidence of differential cardiovascular risk as a function of celecoxib dose regimen and baseline cardiovascular risk. By further clarifying the extent of celecoxib-related cardiovascular risk, these findings may help guide treatment decisions for patients who derive clinical benefit from selective cyclooxygenase-2 inhibition.

Motivated, free-living individuals, given appropriate support, can make and sustain major dietary changes over a 4-y period.

Background Adenomatous polyps are the most common precursor to colorectal cancer (CRC), the second leading cause of cancer death in the United States. We sought to learn more about early events of carcinogenesis by investigating shifts in the gut microbiota of patients with adenomas. Methods We analyzed 16S rRNA gene sequences from the fecal microbiota of patients with adenomas (n=233) and without (n=547). Results Multiple taxa were significantly more abundant in patients with adenomas, including Bilophila, Desulfovibrio, pro-inflammatory bacteria in the genus Mogibacterium, and multiple Bacteroidetes species. Patients without adenomas had greater abundances of Veillonella, Firmicutes (Order Clostridia), and Actinobacteria (family Bifidobacteriales). Our findings were consistent with previously reported shifts in the gut microbiota of CRC patients. Importantly, the altered adenoma profile is predicted to increase primary and secondary bile acid production, as well as starch, sucrose, lipid, and phenylpropanoid metabolism. Conclusions These data hint that increased sugar, protein, and lipid metabolism along with increased bile acid production could promote a colonic environment that supports the growth of bile-tolerant microbes such as Bilophilia and Desulfovibrio. In turn, these microbes may produce genotoxic or inflammatory metabolites such as H2S and secondary bile acids, which could play a role in catalyzing adenoma development and eventually CRC. Impact This study suggests a plausible biological mechanism to explain the links between shifts in the microbiota and CRC. This represents a first step toward resolving the complex interactions that shape the adenoma-carcinoma sequence of CRC and may facilitate personalized therapeutics focused on the microbiota.