Ignite Creation Date:
2024-05-05 @ 5:15 PM
Last Modification Date:
2024-10-26 @ 9:29 AM
Study NCT ID:
NCT00413309
Status:
COMPLETED
Last Update Posted:
2009-02-04
First Post:
2006-12-15
Brief Title:
Gastrointestinal Ulceration in Patients on Dual Antiplatelet Therapy After Percutaneous Coronary Intervention
Sponsor:
Brigham and Womens Hospital
Organization:
Brigham and Womens Hospital
Study Overview
Official Title:
Gastrointestinal Ulceration in Patients on Dual Antiplatelet Therapy After Percutaneous Coronary Intervention
Status:
COMPLETED
Status Verified Date:
2009-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
To determine the rate of symptomatic and asymptomatic gastrointestinal erosions and ulcerations in patients on dual antiplatelet aspirin and clopidogrel therapy after percutaneous coronary intervention PCI
Detailed Description:
Background and Significance
Percutaneous coronary intervention PCI is the standard of care for patients with acute coronary syndrome ACS Approximately 1200000 PCIs were performed in 2002 in the United States Drug-eluting coronary stents have nearly abolished the clinical problem of in-stent restenosis at a cost of increased susceptibility to in-stent thrombosis a catastrophic event associated with a 6-month mortality rate of 89 and a myocardial infarction rate that exceeds 50
To prevent in-stent thrombosis PCI patients receive aspirin 325 mg and a minimum loading dose of clopidogrel 300 mg prior to stent deployment In actual practice many patients are now receiving a clopidogrel loading dose of 600 mg to ensure adequate platelet inhibition Muller et al showed that administration of a higher loading dose 600mg of clopidogrel to patients undergoing PCI accelerates suppression of platelet aggregation when evaluated by aggregometry When patients were given a higher loading dose 600mg of clopidogrel as opposed to the conventional loading dose 300mg there was a 50 reduction in myocardial infarction after PCI in patients who received the higher dose If a 600 mg loading dose of clopidogrel is adopted as routine practice there may be a further increase in the risk of major gastrointestinal GI ulceration
In multivariable analysis the strongest predictor of stent thrombosis is premature discontinuation of dual antiplatelet therapy exceeding other independent predictors such as renal failure bifurcation lesions diabetes and low ejection fraction Hence following PCI with drug-eluting stents dual antiplatelet therapy with aspirin 75 to 162 mg lifelong in combination with clopidogrel 75 mg for at least 3 months is prescribed
The risk of overt GI bleeding with dual antiplatelet therapy can be as high as 13 within the first 30 days of therapy Weil et al found that all doses of aspirin were associated with an increased risk of GI bleeding and that the risk of GI bleeding due to low-dose aspirin was dose-related odds ratio 23 for 75 mg day 32 for 150 mg day 39 for 300 mg day In the Clopidogrel for Unstable angina to prevent Recurrent Events CURE study Peters et al showed that the risk of bleeding at the highest dose of aspirin 200mg given with placebo was higher 37 than the risk of GI bleeding with the combination of clopidogrel and aspirin in the lowest dose group 30
Kelly et al showed that the relative risks of upper GI bleeding for plain enteric-coated and buffered aspirin at average daily doses of 325 mg or less were 26 27 and 31 respectively Conventional thinking is that compared with the stomach the relatively alkaline duodenum is less susceptible to aspirin-induced damage However Kelly et al found in contrast to conventional thinking that the relative risk point estimates for all three forms of aspirin were approximately the same for gastric and duodenal bleeding A possible explanation is that systemic effects eg on platelets and prostaglandin synthesis are unlikely to differ according to the aspirin preparation used and may overwhelm any differences in local effects on the gastric or duodenal mucosa
In addition to local irritation of the gastric mucosa aspirin and other antiplatelet agents cause gastric damage through inhibition of prostaglandin synthesis and by producing microcirculatory injury Antiplatelet drugs might interfere with gastric ulcer healing by suppressing the release of growth factors such as vascular endothelial growth factor VEGF from platelets
Patients who are at highest risk for GI bleeding while on antiplatelet therapy are the elderly patients with history of gastric ulcers gastroesophageal reflux disease GERD esophagitis untreated Helicobacter pylori infection intestinal polyps cancer and those with concomitant use of anticoagulants steroids or nonsteroidal anti-inflammatory drugs NSAIDS Patients on dual antiplatelet therapy can develop both upper and lower GI bleeding GI hemorrhage is associated with an increased mortality rate a greater need for surgery blood transfusions a prolonged length of hospital stay and increased overall health care costs While upper GI bleeding can be prevented with appropriate prophylaxis there is no prophylaxis for lower GI bleeding
Acid-suppressive therapy is beneficial in the prevention of upper GI bleeding Two major classes of agents for the prevention of upper GI bleeding due to ulcer complications from antiplatelet therapy are 1 acid-suppressive therapy with H2-antagonists and 2 proton pump inhibitors PPIs H2-antagonists exert their therapeutic effects by reversibly blocking H2-receptors on the basolateral membrane of gastric parietal cells Until the early 1990s H2-antagonists were the mainstay of pharmacotherapy for the prevention and management of upper GI bleeding Between 1984 and 2000 32 randomized controlled trials were conducted comparing H2-antagonists with placebo Agents evaluated in these studies included cimetidine ranitidine and famotidine Many were limited by small sample size and wide variations in study design In a meta analysis of 11 randomized controlled trials with H2-antagonists Koch et al showed that H2-antagonists did not prevent gastric ulcers either in the short-term 2weeks or long-term 4weeks of NSAID treatment The average baseline risks for gastric ulcers were found to be 36 and 68 with short- and long-term NSAID treatment respectively The average baseline risks for gastric lesions were 53 and 27 with short- and long-term NSAID treatment respectively The H2 blockers did not lead to a significant risk reduction in gastric lesions during either short-term or long-term therapy A statistical advantage of H2 blockers was shown only in 1 of 9 studies
The average baseline risks for a duodenal ulcer were found to be 3 and 4 with short- and long-term NSAID treatment respectively The H2 blockers did not lead to a significant reduction in risk for duodenal ulcer during short-term treatment A statistical advantage of H2 blockers was shown in 3 of 5 long-term studies but in none of the 4 short-term trials The average baseline risks for duodenal lesions were found to be 11 and 12 with short- and long-term NSAID treatment respectively The H2 blockers did not lead to a significant reduction in the risk for duodenal lesions either during short-term or long-term treatment
Factors limiting the utility of H2-antagonists include the development of tachyphylaxis the need for dosage adjustment in renal insufficiency thrombocytopenia and mental status changes seen with higher doses of these medications With the introduction of safer and more effective agents like PPIs the role of H2-antagonists in the prevention and management of upper GI bleeding has diminished
PPIs work by irreversibly inhibiting H pumps in gastric parietal cells PPIs have a number of theoretical advantages over H2-antagonists First PPIs block the final step of acid production negating stimulation of gastric secretion by gastrin histamine and acetylcholine leading to prolonged acid suppression Second unlike H2-antagonists tachyphylaxis has not been noted with PPIs
Yeomans et al showed that omeprazole PPIs is more effective than H2 receptor antagonists in gastric acid suppression preventing ulcers and healing ulcers related to chronic use of NSAIDS
In a randomized open-label five-way crossover study the 24-h intragastric pH profile of oral esomeprazole 40 mg lansoprazole 30 mg omeprazole 20 mg pantoprazole 40 mg and rabeprazole 20 mg once daily in 34 patients with symptoms of gastroesophageal reflux disease was evaluated Intragastric pH was maintained above 40 for a mean of 140 h with esomeprazole 121 h with rabeprazole 118 h with omeprazole 115 h with lansoprazole and 101 h with pantoprazole
Esomeprazole also provided a significantly higher percentage of patients with an intragastric pH greater than 40 for more than 12 h relative to the other proton pump inhibitors The frequency of adverse events was similar among treatment groups Esomeprazole at the standard dose of 40 mg once daily provided more effective control of gastric acid at steady state than standard doses of other PPIs
Chan et al randomized 320 patients with previous bleeding on aspirin to clopidogrel and placebo versus aspirin and esomeprazole The cumulative incidence of ulcer bleeding in this study was 86 in patients who received clopidogrel and 07 in patients who received aspirin and esomeprazole
Esomeprazole 40 mg once a day was found to be more efficacious than esomeprazole 20 mg once a day and 10 mg once a day in healing of erosive esophagitis and gastritis without significant difference in long-term safety or tolerability
Esomeprazole is extensively metabolized in the liver by CYP3A4 but no clinically relevant interactions with drugs metabolized by the CYP system have been reported
Assessment of GI Ulceration
To detect GI ulcerations endoscopy is the gold standard However the invasiveness of traditional endoscopy in PCI patients with coronary artery disease makes this approach inappropriate
An alternative imaging test that is noninvasive and does not require sedation is the PillCamÒ ESO capsule endoscope The disposable ingestible PillCamÒESO endoscope is an 11 X 26 mm capsule and acquires video images from both ends of the device during passage through the esophagus The capsule transmits the acquired images via digital radiofrequency communication channel to the data recorder unit located outside the body
The data recorder an external receivingrecording unit is worn on patients belt It receives the data transmitted by the capsule Upon completion of the examination the physician transfers accumulated data in the data recorder is transferred to computer software for processing and interpretation
The sensitivity of the PillCamÒ ESO in diagnosing any esophageal abnormalities is 92 and the negative predictive value NPV is 88 Specificity and positive predictive value in diagnosing any esophageal abnormalities PPV are 95 and 97 respectively
The PillCamÒ ESO capsule is intended for visualization of the esophagus and not the stomach in adult patients but detection of gastritis is feasible
The PillCamÒ ESO capsule is contraindicated for use under the following conditions
Known or suspected GI obstruction strictures or fistulas based on the clinical picture or pre-procedure testing and profile
Cardiac pacemakers or other implanted electromedical devices
Swallowing disorders
In this investigator-initiated trial we will enroll 30 patients requiring dual antiplatelet therapy after PCI to determine the rate of occult and overt GI ulceration in patients on antiplatelet therapy after PCI All patients will receive PillCamÒ ESO endoscopy after 80-90 days of aspirin and clopidogrel therapy to detect gastric erosions and ulcers This will provide us with an event rate of GI ulceration in patients on dual antiplatelet therapy without acid suppressive medication prophylaxis
Percutaneous coronary intervention PCI is the standard of care for patients with acute coronary syndrome ACS Approximately 1200000 PCIs were performed in 2002 in the United States Drug-eluting coronary stents have nearly abolished the clinical problem of in-stent restenosis at a cost of increased susceptibility to in-stent thrombosis a catastrophic event associated with a 6-month mortality rate of 89 and a myocardial infarction rate that exceeds 50
To prevent in-stent thrombosis PCI patients receive aspirin 325 mg and a minimum loading dose of clopidogrel 300 mg prior to stent deployment In actual practice many patients are now receiving a clopidogrel loading dose of 600 mg to ensure adequate platelet inhibition Muller et al showed that administration of a higher loading dose 600mg of clopidogrel to patients undergoing PCI accelerates suppression of platelet aggregation when evaluated by aggregometry When patients were given a higher loading dose 600mg of clopidogrel as opposed to the conventional loading dose 300mg there was a 50 reduction in myocardial infarction after PCI in patients who received the higher dose If a 600 mg loading dose of clopidogrel is adopted as routine practice there may be a further increase in the risk of major gastrointestinal GI ulceration
In multivariable analysis the strongest predictor of stent thrombosis is premature discontinuation of dual antiplatelet therapy exceeding other independent predictors such as renal failure bifurcation lesions diabetes and low ejection fraction Hence following PCI with drug-eluting stents dual antiplatelet therapy with aspirin 75 to 162 mg lifelong in combination with clopidogrel 75 mg for at least 3 months is prescribed
The risk of overt GI bleeding with dual antiplatelet therapy can be as high as 13 within the first 30 days of therapy Weil et al found that all doses of aspirin were associated with an increased risk of GI bleeding and that the risk of GI bleeding due to low-dose aspirin was dose-related odds ratio 23 for 75 mg day 32 for 150 mg day 39 for 300 mg day In the Clopidogrel for Unstable angina to prevent Recurrent Events CURE study Peters et al showed that the risk of bleeding at the highest dose of aspirin 200mg given with placebo was higher 37 than the risk of GI bleeding with the combination of clopidogrel and aspirin in the lowest dose group 30
Kelly et al showed that the relative risks of upper GI bleeding for plain enteric-coated and buffered aspirin at average daily doses of 325 mg or less were 26 27 and 31 respectively Conventional thinking is that compared with the stomach the relatively alkaline duodenum is less susceptible to aspirin-induced damage However Kelly et al found in contrast to conventional thinking that the relative risk point estimates for all three forms of aspirin were approximately the same for gastric and duodenal bleeding A possible explanation is that systemic effects eg on platelets and prostaglandin synthesis are unlikely to differ according to the aspirin preparation used and may overwhelm any differences in local effects on the gastric or duodenal mucosa
In addition to local irritation of the gastric mucosa aspirin and other antiplatelet agents cause gastric damage through inhibition of prostaglandin synthesis and by producing microcirculatory injury Antiplatelet drugs might interfere with gastric ulcer healing by suppressing the release of growth factors such as vascular endothelial growth factor VEGF from platelets
Patients who are at highest risk for GI bleeding while on antiplatelet therapy are the elderly patients with history of gastric ulcers gastroesophageal reflux disease GERD esophagitis untreated Helicobacter pylori infection intestinal polyps cancer and those with concomitant use of anticoagulants steroids or nonsteroidal anti-inflammatory drugs NSAIDS Patients on dual antiplatelet therapy can develop both upper and lower GI bleeding GI hemorrhage is associated with an increased mortality rate a greater need for surgery blood transfusions a prolonged length of hospital stay and increased overall health care costs While upper GI bleeding can be prevented with appropriate prophylaxis there is no prophylaxis for lower GI bleeding
Acid-suppressive therapy is beneficial in the prevention of upper GI bleeding Two major classes of agents for the prevention of upper GI bleeding due to ulcer complications from antiplatelet therapy are 1 acid-suppressive therapy with H2-antagonists and 2 proton pump inhibitors PPIs H2-antagonists exert their therapeutic effects by reversibly blocking H2-receptors on the basolateral membrane of gastric parietal cells Until the early 1990s H2-antagonists were the mainstay of pharmacotherapy for the prevention and management of upper GI bleeding Between 1984 and 2000 32 randomized controlled trials were conducted comparing H2-antagonists with placebo Agents evaluated in these studies included cimetidine ranitidine and famotidine Many were limited by small sample size and wide variations in study design In a meta analysis of 11 randomized controlled trials with H2-antagonists Koch et al showed that H2-antagonists did not prevent gastric ulcers either in the short-term 2weeks or long-term 4weeks of NSAID treatment The average baseline risks for gastric ulcers were found to be 36 and 68 with short- and long-term NSAID treatment respectively The average baseline risks for gastric lesions were 53 and 27 with short- and long-term NSAID treatment respectively The H2 blockers did not lead to a significant risk reduction in gastric lesions during either short-term or long-term therapy A statistical advantage of H2 blockers was shown only in 1 of 9 studies
The average baseline risks for a duodenal ulcer were found to be 3 and 4 with short- and long-term NSAID treatment respectively The H2 blockers did not lead to a significant reduction in risk for duodenal ulcer during short-term treatment A statistical advantage of H2 blockers was shown in 3 of 5 long-term studies but in none of the 4 short-term trials The average baseline risks for duodenal lesions were found to be 11 and 12 with short- and long-term NSAID treatment respectively The H2 blockers did not lead to a significant reduction in the risk for duodenal lesions either during short-term or long-term treatment
Factors limiting the utility of H2-antagonists include the development of tachyphylaxis the need for dosage adjustment in renal insufficiency thrombocytopenia and mental status changes seen with higher doses of these medications With the introduction of safer and more effective agents like PPIs the role of H2-antagonists in the prevention and management of upper GI bleeding has diminished
PPIs work by irreversibly inhibiting H pumps in gastric parietal cells PPIs have a number of theoretical advantages over H2-antagonists First PPIs block the final step of acid production negating stimulation of gastric secretion by gastrin histamine and acetylcholine leading to prolonged acid suppression Second unlike H2-antagonists tachyphylaxis has not been noted with PPIs
Yeomans et al showed that omeprazole PPIs is more effective than H2 receptor antagonists in gastric acid suppression preventing ulcers and healing ulcers related to chronic use of NSAIDS
In a randomized open-label five-way crossover study the 24-h intragastric pH profile of oral esomeprazole 40 mg lansoprazole 30 mg omeprazole 20 mg pantoprazole 40 mg and rabeprazole 20 mg once daily in 34 patients with symptoms of gastroesophageal reflux disease was evaluated Intragastric pH was maintained above 40 for a mean of 140 h with esomeprazole 121 h with rabeprazole 118 h with omeprazole 115 h with lansoprazole and 101 h with pantoprazole
Esomeprazole also provided a significantly higher percentage of patients with an intragastric pH greater than 40 for more than 12 h relative to the other proton pump inhibitors The frequency of adverse events was similar among treatment groups Esomeprazole at the standard dose of 40 mg once daily provided more effective control of gastric acid at steady state than standard doses of other PPIs
Chan et al randomized 320 patients with previous bleeding on aspirin to clopidogrel and placebo versus aspirin and esomeprazole The cumulative incidence of ulcer bleeding in this study was 86 in patients who received clopidogrel and 07 in patients who received aspirin and esomeprazole
Esomeprazole 40 mg once a day was found to be more efficacious than esomeprazole 20 mg once a day and 10 mg once a day in healing of erosive esophagitis and gastritis without significant difference in long-term safety or tolerability
Esomeprazole is extensively metabolized in the liver by CYP3A4 but no clinically relevant interactions with drugs metabolized by the CYP system have been reported
Assessment of GI Ulceration
To detect GI ulcerations endoscopy is the gold standard However the invasiveness of traditional endoscopy in PCI patients with coronary artery disease makes this approach inappropriate
An alternative imaging test that is noninvasive and does not require sedation is the PillCamÒ ESO capsule endoscope The disposable ingestible PillCamÒESO endoscope is an 11 X 26 mm capsule and acquires video images from both ends of the device during passage through the esophagus The capsule transmits the acquired images via digital radiofrequency communication channel to the data recorder unit located outside the body
The data recorder an external receivingrecording unit is worn on patients belt It receives the data transmitted by the capsule Upon completion of the examination the physician transfers accumulated data in the data recorder is transferred to computer software for processing and interpretation
The sensitivity of the PillCamÒ ESO in diagnosing any esophageal abnormalities is 92 and the negative predictive value NPV is 88 Specificity and positive predictive value in diagnosing any esophageal abnormalities PPV are 95 and 97 respectively
The PillCamÒ ESO capsule is intended for visualization of the esophagus and not the stomach in adult patients but detection of gastritis is feasible
The PillCamÒ ESO capsule is contraindicated for use under the following conditions
Known or suspected GI obstruction strictures or fistulas based on the clinical picture or pre-procedure testing and profile
Cardiac pacemakers or other implanted electromedical devices
Swallowing disorders
In this investigator-initiated trial we will enroll 30 patients requiring dual antiplatelet therapy after PCI to determine the rate of occult and overt GI ulceration in patients on antiplatelet therapy after PCI All patients will receive PillCamÒ ESO endoscopy after 80-90 days of aspirin and clopidogrel therapy to detect gastric erosions and ulcers This will provide us with an event rate of GI ulceration in patients on dual antiplatelet therapy without acid suppressive medication prophylaxis
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None