Clinical trial NCT00413309: Gastrointestinal Ulceration in Patients on Dual Antiplatelet Therapy After Percutaneous Coronary Intervention
Official title: Gastrointestinal Ulceration in Patients on Dual Antiplatelet Therapy After Percutaneous Coronary Intervention
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Acute Coronary Syndrome
Keywords: Acute Coronary Syndrome
Percutaneous Coronary Intervention
Antiplatelet Therapy
PillCam
Endoscopy
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2006-12-19
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 1,200,000 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 8.9% 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 1.3% 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 2.3 for 75 mg ⁄day; 3.2 for 150 mg ⁄day; 3.9 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 (3.7 %) than the risk of GI bleeding with the combination of clopidogrel and aspirin in the lowest dose group (3.0 %).

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 2.6, 2.7, and 3.1, 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 (e.g., 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 3.6% and 6.8% 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 4.0 for a mean of 14.0 h with esomeprazole, 12.1 h with rabeprazole, 11.8 h with omeprazole, 11.5 h with lansoprazole, and 10.1 h with pantoprazole.

Esomeprazole also provided a significantly higher percentage of patients with an intragastric pH greater than 4.0 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 8.6% in patients who received clopidogrel and 0.7% 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 receiving/recording unit is worn on patient's 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.

Eligibility criteria: Inclusion Criteria:

1. Patients who have undergone PCI within the preceding 72 hrs
2. Patients on aspirin and clopidogrel
3. Age greater than 18 years and less than 80 years
4. Written informed consent

Exclusion Criteria:

1. Active bleeding
2. Pregnancy
3. Patients already on H2 antagonists
4. Patients already on PPI
5. Patients with implanted cardiac defibrillator (ICD)
6. Patients with GI strictures, swallowing disorders, or bowel obstruction and fistulas.
7. Patients with significant gastrointestinal diverticular disease
8. Patients likely to require MRI imaging during the time the PillCam is still in the digestive tract (8 to 72 hours after the PillCam procedure)

Primary outcomes:
measure: A composite of overt and occult GI bleeding, gastritis, and esophageal, gastric, or duodenal ulcerations.
timeFrame: 90 Days
measure: Overt GI symptoms include GI bleeding requiring hospitalization, blood transfusion, and/or interventions like endoscopy or surgery or gastroesophageal acid reflux (GERD) requiring acid-suppressive therapy.
timeFrame: 90 Days
measure: Occult GI ulcerations and erosions include those detected by capsule endoscopy (PillCamÒ ESO) within 80 to 90 days after initiation of dual antiplatelet therapy.
timeFrame: 90 Days
Secondary outcomes:
Other outcomes:
Locations:
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
Study officials:
affiliation: Brigham and Women's Hospital
name: Samuel Z. Goldhaber, MD
role: PRINCIPAL_INVESTIGATOR
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