Byron Cryer

Clopidogrel with or without Omeprazole in Coronary Artery Disease

BACKGROUND Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel. METHODS We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing. RESULTS We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole. CONCLUSIONS Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.).

Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury in healthy humans☆

BACKGROUND & AIMS The safety of low-dose daily aspirin therapy in the gastrointestinal tract is uncertain. Our objectives were to evaluate the long-term effects of very low daily aspirin doses in the gastrointestinal tract and effects on platelet-derived serum thromboxane levels in volunteers. METHODS Subjects were randomized to receive 10 mg (n = 8), 81 mg (n = 11), or 325 mg (n = 10) aspirin daily for 3 months. Before administration of aspirin, all subjects underwent gastroduodenoscopy, and most underwent proctoscopy for assessment of mucosal injury and prostaglandin content. After 1.5 and 3 months, subjects again underwent gastroduodenoscopy and, at 3 months, another proctoscopy. RESULTS Each aspirin dose (even 10 mg) significantly reduced gastric mucosal prostaglandin levels, to approximately 40% of the baseline value. All three doses also induced significant gastric injury, and 325 mg caused duodenal injury. Three subjects developed gastric ulcers, 1 while taking 10 mg/day of aspirin. Furthermore, aspirin at 81 mg/day and 325 mg/day (but not 10 mg/day) significantly reduced duodenal mucosal prostaglandin levels to approximately 40% of the baseline value. Only 325 mg of aspirin per day significantly reduced rectal mucosal prostaglandin levels to approximately 60% of the baseline value. Serum thromboxane levels were inhibited 62%, 90%, and 98% with 10, 81, and 325 mg of aspirin. CONCLUSIONS The findings explain aspirins predominant gastric toxicity and question the safety of even 10 mg of aspirin daily.

Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison

BACKGROUND Upper gastrointestinal safety of cyclo-oxygenase (COX)-2 selective inhibitors versus traditional non-steroidal anti-inflammatory drugs (NSAIDs) has not been assessed in trials that simulate standard clinical practice. Our aim was to assess the effects of these drugs on gastrointestinal outcomes in a population that includes patients taking gastrointestinal protective therapy. METHODS A prespecified pooled intent-to-treat analysis of three double-blind randomised comparisons of etoricoxib (60 or 90 mg daily) and diclofenac (150 mg daily) in 34 701 patients with osteoarthritis or rheumatoid arthritis was done for upper gastrointestinal clinical events (bleeding, perforation, obstruction, or ulcer) and the subset of complicated events (perforation, obstruction, witnessed ulcer bleeding, or significant bleeding). We also assessed such outcomes in patients who were taking concomitant proton pump inhibitors (PPIs) or low-dose aspirin. These trials are registered with , with the numbers , , and . FINDINGS Overall upper gastrointestinal clinical events were significantly less common with etoricoxib than with diclofenac (hazard ratio [HR] 0.69, 95% CI 0.57-0.83; p=0.0001). There were significantly fewer uncomplicated gastrointestinal events with etoricoxib than there were with diclofenac (0.57, 0.45-0.74; p<0.0001); there was no difference in complicated events (0.91, 0.67-1.24; p=0.561). PPIs were used concomitantly for at least 75% of the study period by 13 862 (40%) and low-dose aspirin by 11 418 (33%) patients; treatment effects did not differ significantly in these individuals. INTERPRETATION There were significantly fewer upper gastrointestinal clinical events with the COX-2 selective inhibitor etoricoxib than with the traditional NSAID diclofenac due to a decrease in uncomplicated events, but not in the more serious complicated events. The reduction in uncomplicated events with etoricoxib is maintained in patients treated with PPIs and is also observed with regular low-dose aspirin use.

Duration of the interval between the completion of bowel preparation and the start of colonoscopy predicts bowel- preparation quality

BACKGROUND Recent studies suggest that colonoscopies done in the morning have better-quality bowel preparations than those done in the afternoon. OBJECTIVE We aimed to determine how the duration of the interval between the end of the preparation and the start of the colonoscopy affects preparation quality. DESIGN We prospectively studied consecutive outpatients who had colonoscopies performed at our hospital within a 3-month period. The time of day when the colonoscopy started and the time interval from the last dose of preparation agent to the start of the colonoscopy were recorded. The endoscopist graded the quality of the preparation in the right side of the colon by using a 5-point visual scale. PATIENTS We studied 378 patients (96% men, mean age 62.2 years) who received preparations of polyethylene glycol electrolyte-based (PEG) and sodium phosphate (SP) solution (71%), oral PEG and magnesium citrate (23%), or SP alone (6%). RESULTS Compared with patients whose preparations were graded as 2/3/4 (fair/poor/inadequate), those whose preparations were graded as 0/1 (excellent/good) had a significantly shorter interval between the time of the last preparation agent dose and the start of the colonoscopy (P = .013). LIMITATIONS We used a nonvalidated scale to assess the quality of bowel preparation. CONCLUSIONS Bowel-preparation quality varies inversely with the duration of the interval between the last dose of the bowel-preparation agent and the start of colonoscopy. This interval appears to be a better predictor of bowel-preparation quality than the time of day when colonoscopy is performed.

Lower Gastrointestinal Events in a Double-Blind Trial of the Cyclo-Oxygenase-2 Selective Inhibitor Etoricoxib and the Traditional Nonsteroidal Anti-Inflammatory Drug Diclofenac

BACKGROUND & AIMS Nonsteroidal anti-inflammatory drugs (NSAIDs) cause lower gastrointestinal (GI) clinical events such as bleeding. Cyclo-oxygenase (COX)-2 selective inhibitors decrease upper GI events, but no prospective trial has prespecified assessment of lower GI clinical events. METHODS Patients >or=50 years old with osteoarthritis or rheumatoid arthritis were randomly assigned to etoricoxib (60 or 90 mg qd) or diclofenac (150 mg qd). Lower GI clinical events, confirmed by a blinded adjudication committee, included perforation or obstruction requiring hospitalization or bleeding (gross or occult rectal bleeding without upper GI cause associated with hypotension, orthostatic changes in heart rate [>20 beats per minute] or blood pressure [>20 mmHg systolic or >10 mmHg diastolic], hemoglobin drop >or=2 g/dl, or transfusion; or observed active bleeding or stigmata of hemorrhage). RESULTS We enrolled 34,701 patients with mean duration of therapy of 18 months. Rates were 0.32 and 0.38 lower GI clinical events per 100 patient-years for etoricoxib and diclofenac (hazard ratio [HR] = 0.84; 95% confidence interval [CI], 0.63-1.13). Bleeding was the most common event (rates of 0.19 and 0.23 per 100 patient-years, respectively). Multivariable analysis revealed significant risk factors to be prior lower GI event (HR = 4.06; 95% CI, 2.93-5.62) and age >or=65 years (HR = 1.98; 95% CI, 1.45-2.71). CONCLUSIONS A statistically significant decrease in lower GI clinical events was not seen with the COX-2 selective inhibitor etoricoxib versus the traditional NSAID diclofenac. The risk of a lower GI clinical event with NSAID use seems to be constant over time, and the major risk factors are a prior lower GI event and older age.

Dose Effects of Aspirin on Gastric Prostaglandins and Stomach Mucosal Injury

Aspirin is almost certainly the most widely used drug in the world. It is used both therapeutically (to reduce pain, inflammation, and fever) and prophylactically (to prevent thrombotic events). Although prophylactic, antithrombotic doses of aspirin are generally lower than therapeutic doses, epidemiologic studies suggest that such doses may still be associated with gastrointestinal damage [1-3]. In a long-term, placebo-controlled study evaluating aspirin for secondary prevention of myocardial infarction, a daily dose of 1000 mg increased the risk for hospitalization for gastric and duodenal ulcers by about eightfold [1]. In another long-term, placebo-controlled study evaluating aspirin for stroke prevention in patients with transient ischemic attacks, the rate of hospitalization for serious gastrointestinal bleeding was increased approximately threefold with 1200 mg of aspirin per day and twofold with just 300 mg of aspirin per day [2]. In another long-term study for primary prevention of cardiovascular diseases, an aspirin dose of 325 mg given every other day was associated with a significantly greater risk for duodenal ulcer when compared with placebo [3]. Few experimental data exist on the risk for gastroduodenal mucosal injury as a function of aspirin dose, and it is not known whether any clinically used dose of aspirin is free of risk for gastroduodenal mucosal damage. In a recent endoscopic study of patients with coronary artery disease, most of whom were receiving only 100 mg of aspirin per day, the prevalence of gastric erosions was higher than the prevalence of erosions in a historical control group [4]. The literature contains little information on the relation between aspirin dosage and suppression of gastroduodenal mucosal prostaglandin synthesis in humans. Because suppression of gastroduodenal mucosal prostaglandin synthesis appears to be one of the important mechanisms for mucosal damage by aspirin [5, 6], it would be useful to determine the threshold dose for gastroduodenal mucosal prostaglandin inhibition in humans because aspirin doses below this threshold may not damage the gastroduodenal mucosa. Our goal was to determine the effects of a wide range of doses of aspirin (3 mg/d to 2600 mg/d) on gastric juice prostaglandins (PGE2 and PGF2 ) and on stomach mucosal injury as reflected by gastric juice hemoglobin and DNA, both of which are sensitive indicators of mucosal injury [7, 8]. Effects of various doses of aspirin were also related to their effects on gastric acid secretion and serum thromboxane B2. Methods Healthy volunteers between the ages of 18 and 75 years were solicited through advertisement. All respondents had a screening history, physical examination, complete blood count, and serum electrolyte, creatinine, bilirubin, and liver chemistry tests. Volunteers were excluded for heartburn; abdominal pain; indigestion; bloating; fullness; nausea and vomiting; use (within the previous 2 weeks) of aspirin, nonsteroidal anti-inflammatory drugs, glucocorticoids, histamine-2-receptor antagonists, sucralfate, misoprostol, omeprazole, antacids, or Pepto-Bismol (Procter and Gamble, Cincinnati, Ohio); history of allergy to aspirin or topical tetracaine; a positive urine pregnancy test; history of gastric surgery, peptic ulcer, or other gastrointestinal disease; history of liver disease (including currently elevated liver chemistry tests); or history or presence of anemia, thrombocytopenia, leukopenia, gout, coagulation disorder, or renal insufficiency. Sixteen people (5 men and 11 women) met all entry criteria and gave written consent to participate as paid volunteers. Use of any medication other than study medication was not allowed during the study. The study was approved by the Human Studies Subcommittee at the Department of Veterans Affairs Medical Center, Dallas, Texas. Part 1 Ten volunteers (four men and six women; mean age, 44.2 years; range, 19 to 73 years) were enrolled in part 1 of the study. One man was excluded for noncompliance. On 4 separate days at least 1 week apart, each of the other nine participants received placebo (calcium sulfate, 222 mg; cellulose, 97 mg); aspirin, 81 mg (Bayer Childrens Aspirin, Glenbrook Laboratories; New York, New York); aspirin, 325 mg (one tablet); or aspirin, 650 mg (two 325-mg tablets). Medication was taken with each of three meals and at bedtime on the day before the study and at 0700 h on the study day. During the course of four visits, each of the nine volunteers took each of the four drug regimens in random order. Medications were dispensed by a research pharmacist so that the investigators were blinded to the study regimens. Although the medications differed in appearance, volunteers were blinded to exact ingredients of the medications and were instructed to refrain from discussing their study regimens with the investigators and technical assistants. We used the dosing schedule of the highest dose of aspirin (650 mg four times a day) in a previous study, which resulted in significant inhibition of gastric mucosal PGE2 and PGF2 concentrations [9]. Each volunteer was instructed to report to the research laboratory on the study day after an overnight fast. At 0800 h (1 hour after the fifth and final dose of medication), a venous blood sample was taken for determination of serum salicylate concentration. Then, a nasogastric tube was positioned fluoroscopically in the dependent portion of the gastric antrum. Volunteers were trained not to swallow their saliva and to collect saliva through dental suction catheters. Residual gastric secretion was aspirated with the volunteer in the supine position and the fluid was discarded. Beginning at 0830 h, gastric juice was collected by intermittent suction pump aspiration, and the samples collected were divided into aliquots and placed in separate containers every 15 minutes for the next 2 hours. In our laboratory, typical recovery of gastric juice with a nasogastric tube positioned fluoroscopically is greater than 90% [10]. Part 2 Eleven volunteers (three men and eight women; mean age, 45.2 years; range, 25 to 73 years) were enrolled in part 2 of the study. Two men were excluded for noncompliance. Four of the remaining nine volunteers (one man and three women) had participated in part 1 of the study. On five separate occasions at least 14 days apart, each volunteer received placebo (calcium sulfate, 222 mg; cellulose, 97 mg); aspirin, 3 mg; aspirin, 10 mg; aspirin, 30 mg; or aspirin, 81 mg for 8 days. Medications were prepared and packaged in identical green opaque gelatin capsules by the Pharmacy Service at Dallas Veterans Affairs Medical Center. Medications were dispensed by a research pharmacist so that the study was double-blinded. Volunteers were instructed to take the medication with breakfast for 7 days before the study and at 0600 h on the study day. During the course of five visits, each volunteer received each of the five drug regimens in random order. Each volunteer was instructed to report to the research laboratory after an overnight fast. At 0700 h (1 hour after the last dose of medication), venous blood samples were drawn for serum salicylate and serum thromboxane B2 determinations. We chose to monitor serum thromboxane B2 concentrations in part 2 because data from part 1 suggested that aspirin doses of 324 mg/d or less would not result in any detectable serum salicylate level and because the serum thromboxane B2 level has been shown to be a clinically relevant and reliable marker of low-dose aspirin therapy [11]. After venipuncture, a nasogastric tube was positioned fluoroscopically in the gastric antrum, as described above. Beginning at 0730 h, gastric juice was collected by intermittent suction pump aspiration and samples collected were divided into aliquots and placed in separate containers every 15 minutes for the next 60 minutes. We chose to do this study for 60 minutes because results from part 1 indicated that no substantial fluctuations in gastric juice prostaglandin, hemoglobin, and DNA, or gastric acid outputs occurred throughout the 2-hour study period. The aspirin dosing schedule was chosen based on the following observations: 1) Thirty mg of aspirin daily has recently been shown to be as effective as 283 mg daily in the prevention of cerebrovascular events in patients with a transient ischemic attack or minor stroke [12]; 2) reduction of serum thromboxane B2 by low-dose aspirin is cumulative on repeated daily dosing and has been shown to reach a steady state after 7 days [13]; and 3) serum thromboxane B2 generally returns to normal by 14 days after cessation of aspirin therapy [13, 14]. Processing of Gastric Juice Samples and Determination of Gastric Acid Output The volume of each 15-minute gastric juice sample was recorded to the nearest 0.2 mL, and indomethacin was added immediately to the sample after collection (final indomethacin concentration, 50 M) to prevent further prostaglandin synthesis. The pH of each sample was determined by glass electrode. Acidity was derived from the pH [15] and expressed as mmol/L. Acid output was calculated by multiplying volume by acidity, expressed as mmol/h. To stabilize prostaglandins in the specimen, the sample was then titrated to pH 7.0 with 0.2-N NaOH and kept at 4 C. Samples were processed the same day that they were collected and used in subsequent determinations of PGE2, PGF2 , hemoglobin, and DNA concentrations. Determination of Gastric Juice PGE2 and PGF2 Output Extraction of prostaglandins from gastric juice samples was done according to the method of Peskar and colleagues [16]. Aliquots of gastric juice that had been titrated to pH 7.0 were homogenized and centrifuged. The resultant supernatant was titrated to pH 3.0 with acetic acid. The acidified supernatant was extracted twice with four volumes of ethyl acetate. The organic extracts were pooled and stored at 70C until radioimmunoassay. Before the assay, organic extracts were ev

Aspirin absorption rates and platelet inhibition times with 325-mg buffered aspirin tablets (chewed or swallowed intact) and with buffered aspirin solution

Large clinical trials such as the second International Study of Infarct Survival routinely gave patients with myocardial infarction a chewed aspirin, yet there are no data to show whether chewing of aspirin is better, or worse, than swallowing a whole tablet. We performed a randomized, placebo-controlled study to determine whether chewing aspirin or administering it in solution accelerates its absorption and antiplatelet activity. On separate days, 12 fasting volunteers ingested 325 mg of buffered aspirin, either by chewing a tablet for 30 seconds before swallowing it with 4 ounces of water, swallowing a whole tablet with 4 ounces of water, or drinking 4 ounces of Alka Seltzer. Frequent blood samples were obtained for serum aspirin, salicylate, and thromboxane B2 (TxB2) concentrations. With all formulations of aspirin, serum TxB2 decreased 50% when the plasma aspirin concentration reached approximately 1,000 ng/ml. A 50% and 90% decrease in serum TxB2 occurred more quickly after chewing a tablet than after a tablet was swallowed whole. For example, the t 50% for serum TxB2 inhibition was 5.0 +/- 0.6 minutes with the chewed tablet versus 12.0 +/- 2.3 minutes when the tablet was swallowed (p = 0.01). A 50% decrease in serum TxB2 occurred 7.6 +/- 1.2 minutes after Alka Seltzer solution (p = 0.04 vs chewing a tablet; p = 0.13 vs swallowing a whole tablet). Chewing an aspirin tablet is the most effective way of accelerating absorption of aspirin into the blood and shortening the time required for an antiplatelet effect.

A randomized study of lubiprostone for opioid-induced constipation in patients with chronic noncancer pain.

Objective To evaluate the efficacy and safety of oral lubiprostone for relieving symptoms of opioid-induced constipation (OIC) in patients with chronic noncancer pain. Design Prospective, randomized, double-blind, placebo-controlled trial. Setting Seventy-nine US and Canadian centers. Subjects Patients aged ≥18 years with OIC, defined as <3 spontaneous bowel movements (SBMs) per week. Methods Patients received lubiprostone 24 mcg or placebo twice daily for 12 weeks. The primary endpoint was change from baseline in SBM frequency at week 8. Results Among randomized patients (N = 418; lubiprostone, N = 210; placebo, N = 208), most completed the study (lubiprostone, 67.1%; placebo, 69.7%). The safety and efficacy (intent-to-treat) populations included 414 (lubiprostone, N = 208; placebo, N = 206) and 413 (lubiprostone, N = 209; placebo, N = 204) patients, respectively. The mean (standard deviation) age was 50.4 (10.9) years; most patients were female (64.4%) and white (77.7%). Changes from baseline in SBM frequency rates were significantly higher at week 8 (P = 0.005) and overall (P = 0.004) in patients treated with lubiprostone compared with placebo. Pairwise comparisons showed significantly greater overall improvement for abdominal discomfort (P = 0.047), straining (P < 0.001), constipation severity (P = 0.007), and stool consistency (P < 0.001) with lubiprostone compared with placebo. Moreover, patients rated the effectiveness of lubiprostone as significantly (P < 0.05) better than placebo for 11 of 12 weeks. The most common treatment-related adverse events (AEs) with lubiprostone and placebo were nausea (16.8% vs 5.8%, respectively), diarrhea (9.6% vs 2.9%), and abdominal distention (8.2% vs 2.4%). No lubiprostone-related serious AEs occurred. Conclusion Lubiprostone effectively relieved OIC and associated signs and symptoms and was well tolerated in patients with chronic noncancer pain (http://clinicaltrials.gov/ct2/show/NCT00595946).

A Novel Composite Endpoint to Evaluate the Gastrointestinal (GI) Effects of Nonsteroidal Antiinflammatory Drugs Through the Entire GI Tract

Objective. Nonsteroidal antiinflammatory drugs (NSAID) not only cause damage to the upper gastrointestinal (GI) tract but also affect the lower GI tract. To date, there is no endpoint that evaluates serious GI events in the entire GI tract. The objective of this report is to introduce a novel composite endpoint that measures damage to the entire GI tract — clinically significant upper and lower GI events (CSULGIE) — in patients with NSAID-induced GI damage. Methods. We reviewed the data from largescale, multicenter, randomized, clinical trials on lower GI toxicity associated with NSAID use. The rationale for using CSULGIE as a primary endpoint in 2 ongoing trials — the Celecoxib vs Omeprazole and Diclofenac for At-risk Osteoarthritis (OA) and Rheumatoid Arthritis (RA) Patients (CONDOR) trial and the Gastrointestinal Randomized Events and Safety Open-Label NSAID Study (GI-REASONS) — is also discussed. Results. Previous randomized trials focused primarily on damage to the upper GI tract and often neglected the lower GI tract. The CSULGIE endpoint extends the traditional “perforation, obstruction, and bleeding” assessment of upper GI complications by including events in the lower GI tract (small/large bowel) such as perforation, bleeding, and clinically significant anemia. Conclusion. By providing clinicians with a new, descriptive language for adverse events through the entire GI tract, the CSULGIE endpoint has the potential to become a standard tool for evaluating the GI effects of a range of therapies.

MUCOSAL DEFENSE AND REPAIR: Role of Prostaglandins in the Stomach and Duodenum

When considering the diseases of the stomach and duodenum, peptic ulcer disease has been the one of greatest clinical impact. Although there are several components that contribute mechanistically to ulcer disease, it is recognized that gastroduodenal mucosal prostaglandins play a central pathogenic role, especially in ulcers related to the use of NSAIDs. As a result of understanding the mechanisms of NSAID-induced ulceration, the crucial function that gastroduodenal mucosal prostaglandins have in mucosal defense and repair is appreciated. It now is held widely that mucosal prostaglandin deficiency increases susceptibility to ulcer formation and that exogenous administration of supplemental prostaglandins reduces ulcer risk. This article reviews the role that mucosal prostaglandins play in defense of the gastric and duodenal mucosa against injury and ulceration.