Abstract & Commentary
Synopsis: In patients with healed upper GI lesions that had caused bleeding and who needed antiplatelet therapy for cardiovascular reasons, aspirin plus esomeprazole was superior to clopidogrel for preventing recurrent upper GI bleeding.
Source: Chan FKL, et al. N Engl J Med. 2005;352:238-244.
In patients with cardiovascular indications for chronic antiplatelet therapy, but a history of upper gastrointestinal (GI) bleeding, there are 2 recommended alternatives: clopidogrel or aspirin plus a proton-pump inhibitor. Although the ACC/AHA guidelines recommend the former, there has been no comparative data.
Thus, Chan and colleagues randomized patients using aspirin (325 mg or less/day) who presented with upper GI bleeding, but were now healed by endoscopy to clopidogrel 75 mg/day plus esomeprazole placebo or 80 mg of aspirin plus 20 mg of esomeprazole (the purple pill) twice a day for 1 year. Patients were excluded who needed other anti-inflammatory drugs or anticoagulants, severe GI disease, renal failure, or other chronic conditions that might truncate continuation in the study. The primary end point was recurrent upper GI bleeding, and the secondary end point was lower GI bleeding. Of the 320 patients enrolled, 161 were assigned to clopidogrel and 159 to aspirin plus esomeprazole. Recurrent upper GI bleeding occurred in 13 clopidogrel-treated patients (8.6%) and 1 aspirin plus esomeprazole patient (0.7%) for an absolute difference of 7.9%, P = .001. Compliance was good in that 94% of the patients in both groups took at least 80% of the study drugs. Clopidogrel was stopped in 4.3% and aspirin plus esomeprazole in 8.8% for adverse events. None of the 14 patients with recurrent upper GI bleeding had H. pylori infection. The incidence of lower GI bleeding was the same on both treatments, 4.6%. Chan et al concluded that in patients with healed upper GI lesions that had caused bleeding and who needed antiplatelet therapy for cardiovascular reasons, aspirin plus esomeprazole was superior to clopidogrel for preventing recurrent upper GI bleeding.
Comment by Michael H. Crawford, MD
When no randomized data exist, guidelines often rely on observational studies and expert opinion. All too frequently this approach is flawed, as this study illustrates. Because normal control subjects taking clopidogrel showed no GI damage, it has been assumed that it would be superior to aspirin in patients needing antiplatelet therapy who had a history of upper GI intolerance to aspirin. However, the patient with cardiovascular disease, or at risk for it, may be different from normal controls, as might patients recovering from an upper GI bleed. This study suggests that clopidogrel may have some detrimental effect on healing upper GI lesions, since bleeding recurred in the same location in 70% of the bleeding episodes.
The risk of recurrent bleeding with clopidogrel was about 9%, which is less than that reported for aspirin alone in other studies of up to 15%. Aspirin plus esomeprazole resulted in a rate of < 1%, which has been seen in other studies. Thus, proton-pump inhibitors seem to protect against bleeding with aspirin therapy in susceptible patients. In this study, esomeprazole was taken twice a day. Whether once a day therapy would work as well is not known.
Interestingly, lower GI bleeding and extra GI bleeding was no different between the 2 therapies. Also, the incidence of cardiovascular events was low and not different between the 2 groups. Therefore, the recommendation that clopidogrel should be used in aspirin-intolerant patients who need antiplatelet therapy, may not always be correct; at least in patients with previous upper GI bleeding, it would appear that low-dose aspirin plus a proton-pump inhibitor is superior with equal cardiovascular protection. The major limitation of this study was that there was no control group on aspirin alone. Given the up to 15% reported incidence of recurrent GI bleeding on aspirin in other studies, this approach was considered unethical.
Dr. Crawford, Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco, is Editor of Clinical Cardiology Alert.