Reducing the Risks of Gastrointestinal Bleeding with Antiplatelet Therapies
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《新英格兰医药杂志》
In the treatment of cardiovascular disease, clinicians commonly are caught between the competing considerations of cardiovascular benefit and gastrointestinal risks. Low-dose aspirin (325 mg or less daily) lowers the risk of cardiovascular and cerebrovascular thrombotic events. Aspirin prevents thromboses and blocks platelet aggregation through inhibition of the cyclooxygenase enzyme, thereby reducing thromboxane synthesis. Owing to the inhibition of cyclooxygenase in the gastrointestinal tract, aspirin also causes gastrointestinal ulceration and major bleeding, which limit its usefulness as an antithrombotic agent.
The risk of gastrointestinal bleeding generally increases by a factor of two to three with the use of low-dose aspirin.1 Although the gastrointestinal risks associated with aspirin can be reduced by lowering the dose to the lowest effective amount,2 even the lowest doses have considerable risks — 75 mg daily doubles the risk of gastrointestinal bleeding,1 and the subtherapeutic dose of 10 mg daily substantially inhibits gastric cyclooxygenase and causes gastric ulceration.3 Thus, it is unlikely that there is a daily dose of aspirin that has antithrombotic efficacy without gastrointestinal risks.
A common clinical dilemma is how to manage patients who need antiplatelet therapy but are also at high risk for gastrointestinal bleeding, an example being patients with a recent history of upper gastrointestinal bleeding induced by aspirin or other nonsteroidal antiinflammatory (NSAID) drugs. Current cardiology guidelines recommend clopidogrel for patients unable to take aspirin because of previous gastrointestinal intolerance.4 Clopidogrel is an effective antithrombotic agent because it blocks the platelet activation of adenosine diphosphate (ADP) by irreversibly binding to the ADP receptors of platelets; this, in turn, prevents the ADP-dependent activation of the glycoprotein IIb/IIIa complex, the primary platelet receptor for fibrinogen. In a randomized, prospective study of the efficacy of 75 mg of clopidogrel given daily as compared with 325 mg of aspirin for the secondary prevention of thrombotic vascular events, clopidogrel was marginally more effective than aspirin and resulted in a moderately lower rate of gastrointestinal bleeding (0.5 percent vs. 0.7 percent).5 In endoscopic evaluations of healthy volunteers at one week, clopidogrel caused less gastroduodenal damage than did 325 mg of aspirin given daily.6
Several factors increase the risk of gastrointestinal complications with the use of NSAIDs such as aspirin. These include a history of ulcer or gastrointestinal complications, increased age, congestive heart failure, and concurrent anticoagulant or corticosteroid therapy.7,8 Among these factors, a history of gastrointestinal bleeding is associated with the highest risk of recurrent gastrointestinal bleeding in patients treated with NSAIDs.7,9 Conventional wisdom suggests that clopidogrel should be a safer, nonulcerogenic alternative for patients at high risk for aspirin-induced ulcers. For those at highest risk because of a history of gastrointestinal bleeding, however, the risk of subsequent bleeding with the use of clopidogrel had not been evaluated prospectively. Furthermore, a small, retrospective study suggested that a history of gastrointestinal bleeding was an important risk factor for gastrointestinal bleeding during treatment with clopidogrel.10
In this issue of the Journal, Chan and colleagues report the results of a study that evaluated antiplatelet therapies in 320 patients who had a history of aspirin-induced upper gastrointestinal bleeding.11 After healing and eradication of Helicobacter pylori, patients underwent randomization to receive 75 mg of clopidogrel daily or 80 mg of aspirin daily plus the proton-pump inhibitor esomeprazole at a dose of 20 mg twice daily. Over a one-year follow-up period, the patients in the group receiving clopidogrel had an astonishing increase in the rate of recurrent upper gastrointestinal bleeding from ulcers, as compared with those in the group taking aspirin plus esomeprazole (8.6 percent vs. 0.7 percent, P=0.001). Esomeprazole provided no discernible protection against aspirin-induced lower gastrointestinal bleeding, an observation consistent with expectations based on the pharmacologic gastrointestinal sites of action of proton-pump inhibitors. The observations in regard to upper gastrointestinal bleeding in this study challenge conventional wisdom and suggest that there are novel mechanisms underlying the pathogenesis of ulcers. The study results also confirm the capacity of proton-pump inhibitors to reduce recurrent upper gastrointestinal bleeding markedly in patients who take low-dose aspirin and are at high risk for gastrointestinal toxicity.9 In addition, this study reinforces the need to focus on baseline gastrointestinal risk factors in patients being considered for any type of antiplatelet therapy.
It is curious that an agent such as clopidogrel, which does not inhibit cyclooxygenase but targets the ADP receptors of platelets, has gastrointestinal ulcerogenic properties. Among patients taking no medications, asymptomatic gastroduodenal ulcers spontaneously form at a rate of up to 2 percent per month.12 These ulcers are not related to drugs or to H. pylori and are of uncertain cause. Because of the increased tendency to cause bleeding, all antiplatelet agents can convert asymptomatic ulcers into clinically apparent, bleeding ulcers. In addition, all of the antiplatelet agents currently available impair the healing of spontaneous, asymptomatic ulcers — through the inhibition of cyclooxygenase in the case of aspirin and, with clopidogrel, through mechanisms that do not inhibit cyclooxygenase. The study by Chan et al. suggests that impairment of healing may be the primary mechanism through which antiplatelet agents cause bleeding ulcers.
The impairment of ulcer healing by clopidogrel has not been widely appreciated. Platelet aggregation plays a critical role in healing, through the release of various platelet-derived growth factors that promote angiogenesis, which is essential for ulcer healing. For example, animals with thrombocytopenia have reduced ulcer angiogenesis and impaired healing of gastric ulcers.13 ADP-receptor antagonists impair the healing of gastric ulcers by inhibiting the release by platelets of proangiogenic growth factors such as vascular endothelial growth factor,13 which promotes endothelial proliferation and accelerates the healing of ulcers. Gastrointestinal bleeding is a major toxic effect of new chemotherapeutic agents composed of monoclonal antibodies, which are directed at circulating vascular endothelial growth factor.14 Although clopidogrel and other agents that impair angiogenesis might not be the primary cause of gastrointestinal ulcers, their antiangiogenic effects may impair the healing of background ulcers; when combined with the propensity to increase bleeding, these agents may convert small, silent ulcers into large ulcers that bleed profoundly.
There are several potential limitations of the study by Chan et al. First, the medications that were used were repackaged in color-coded capsules to maintain blinding. It is unclear how this repackaging affected outcomes. Aspirin-induced ulcers are a consequence of systemic effects and of local mucosal aspirin concentrations. It is possible that the capsules protected the stomach and moved the gastrointestinal site of injury by aspirin distally. Alternatively, and more likely, the decrease in aspirin-induced gastric ulceration was the result of protective effects of proton-pump inhibitors. Furthermore, all the patients in the study were negative for H. pylori infection or had been cured of such infection, and none were taking anticoagulants or corticosteroids. Thus, it is uncertain how the findings reported by Chan and colleagues apply to other patients at high risk for gastrointestinal complications of aspirin therapy.
It is reasonable to conclude that the lowest effective dose of aspirin should be used for patients at high risk for gastrointestinal complications who need antiplatelet therapy to prevent thrombotic complications. The more challenging question is what therapy to provide for patients who already have had gastrointestinal complications while taking aspirin or other NSAIDs. The current recommendation for these patients is to replace aspirin with clopidogrel.4 The study by Chan et al. clearly indicates that this recommendation is harmful and that such patients should be given aspirin plus a proton-pump inhibitor.11
Dr. Cryer reports having been a paid consultant for McNeil Consumer, Specialty Pharmaceuticals, and TAP Pharmaceutical Products and a paid speaker for AstraZeneca and TAP Pharmaceutical Products.
Source Information
From the Gastroenterology Section, Department of Medicine, University of Texas Southwestern Medical School and Dallas Veterans Affairs Medical Center, Dallas.
References
Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000;321:1183-1187.
Peters RJG, Mehta SR, Fox KAA, et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 2003;108:1682-1687.
Cryer B, Feldman M. Effects of very low doses of daily, long-term aspirin therapy on gastric, duodenal and rectal prostaglandin levels and on mucosal injury in healthy humans. Gastroenterology 1999;117:17-25.
Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction -- 2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). Circulation 2002;106:1893-1900.
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339.
Fort FT, Lafolie P, Tóth E, Lindg?rde F. Gastroduodenal tolerance of 75 mg clopidogrel versus 325 mg aspirin in healthy volunteers: a gastroscopic study. Scand J Gastroenterol 2000;35:464-469.
Laine L. Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology 2001;120:594-606.
Weideman RA, Kelly KC, Kazi S, et al. Risks of clinically significant upper gastrointestinal events with etodolac and naproxen: a historical cohort analysis. Gastroenterology 2004;127:1322-1328.
Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med 2002;346:2033-2038.
Ng FH, Wong SY, Chang CM, et al. High incidence of clopidogrel-associated gastrointestinal bleeding in patients with previous peptic ulcer disease. Aliment Pharmacol Ther 2003;18:443-449.
Chan FKL, Ching JYL, Hung LCT, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med 2005;352:238-244.
Laine L, Maller ES, Yu C, Quan H, Simon T. Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double-blind trial. Gastroenterology 2004;127:395-402.
Ma L, Elliott SN, Cirino G, Buret A, Ignarro LJ, Wallace JL. Platelets modulate gastric ulcer healing: role of endostatin and vascular endothelial growth factor release. Proc Natl Acad Sci U S A 2001;98:6470-6475.
Kabbinovar F, Hurwitz HI, Fehrenbaacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil(FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003;21:60-65.(Byron Cryer, M.D.)
The risk of gastrointestinal bleeding generally increases by a factor of two to three with the use of low-dose aspirin.1 Although the gastrointestinal risks associated with aspirin can be reduced by lowering the dose to the lowest effective amount,2 even the lowest doses have considerable risks — 75 mg daily doubles the risk of gastrointestinal bleeding,1 and the subtherapeutic dose of 10 mg daily substantially inhibits gastric cyclooxygenase and causes gastric ulceration.3 Thus, it is unlikely that there is a daily dose of aspirin that has antithrombotic efficacy without gastrointestinal risks.
A common clinical dilemma is how to manage patients who need antiplatelet therapy but are also at high risk for gastrointestinal bleeding, an example being patients with a recent history of upper gastrointestinal bleeding induced by aspirin or other nonsteroidal antiinflammatory (NSAID) drugs. Current cardiology guidelines recommend clopidogrel for patients unable to take aspirin because of previous gastrointestinal intolerance.4 Clopidogrel is an effective antithrombotic agent because it blocks the platelet activation of adenosine diphosphate (ADP) by irreversibly binding to the ADP receptors of platelets; this, in turn, prevents the ADP-dependent activation of the glycoprotein IIb/IIIa complex, the primary platelet receptor for fibrinogen. In a randomized, prospective study of the efficacy of 75 mg of clopidogrel given daily as compared with 325 mg of aspirin for the secondary prevention of thrombotic vascular events, clopidogrel was marginally more effective than aspirin and resulted in a moderately lower rate of gastrointestinal bleeding (0.5 percent vs. 0.7 percent).5 In endoscopic evaluations of healthy volunteers at one week, clopidogrel caused less gastroduodenal damage than did 325 mg of aspirin given daily.6
Several factors increase the risk of gastrointestinal complications with the use of NSAIDs such as aspirin. These include a history of ulcer or gastrointestinal complications, increased age, congestive heart failure, and concurrent anticoagulant or corticosteroid therapy.7,8 Among these factors, a history of gastrointestinal bleeding is associated with the highest risk of recurrent gastrointestinal bleeding in patients treated with NSAIDs.7,9 Conventional wisdom suggests that clopidogrel should be a safer, nonulcerogenic alternative for patients at high risk for aspirin-induced ulcers. For those at highest risk because of a history of gastrointestinal bleeding, however, the risk of subsequent bleeding with the use of clopidogrel had not been evaluated prospectively. Furthermore, a small, retrospective study suggested that a history of gastrointestinal bleeding was an important risk factor for gastrointestinal bleeding during treatment with clopidogrel.10
In this issue of the Journal, Chan and colleagues report the results of a study that evaluated antiplatelet therapies in 320 patients who had a history of aspirin-induced upper gastrointestinal bleeding.11 After healing and eradication of Helicobacter pylori, patients underwent randomization to receive 75 mg of clopidogrel daily or 80 mg of aspirin daily plus the proton-pump inhibitor esomeprazole at a dose of 20 mg twice daily. Over a one-year follow-up period, the patients in the group receiving clopidogrel had an astonishing increase in the rate of recurrent upper gastrointestinal bleeding from ulcers, as compared with those in the group taking aspirin plus esomeprazole (8.6 percent vs. 0.7 percent, P=0.001). Esomeprazole provided no discernible protection against aspirin-induced lower gastrointestinal bleeding, an observation consistent with expectations based on the pharmacologic gastrointestinal sites of action of proton-pump inhibitors. The observations in regard to upper gastrointestinal bleeding in this study challenge conventional wisdom and suggest that there are novel mechanisms underlying the pathogenesis of ulcers. The study results also confirm the capacity of proton-pump inhibitors to reduce recurrent upper gastrointestinal bleeding markedly in patients who take low-dose aspirin and are at high risk for gastrointestinal toxicity.9 In addition, this study reinforces the need to focus on baseline gastrointestinal risk factors in patients being considered for any type of antiplatelet therapy.
It is curious that an agent such as clopidogrel, which does not inhibit cyclooxygenase but targets the ADP receptors of platelets, has gastrointestinal ulcerogenic properties. Among patients taking no medications, asymptomatic gastroduodenal ulcers spontaneously form at a rate of up to 2 percent per month.12 These ulcers are not related to drugs or to H. pylori and are of uncertain cause. Because of the increased tendency to cause bleeding, all antiplatelet agents can convert asymptomatic ulcers into clinically apparent, bleeding ulcers. In addition, all of the antiplatelet agents currently available impair the healing of spontaneous, asymptomatic ulcers — through the inhibition of cyclooxygenase in the case of aspirin and, with clopidogrel, through mechanisms that do not inhibit cyclooxygenase. The study by Chan et al. suggests that impairment of healing may be the primary mechanism through which antiplatelet agents cause bleeding ulcers.
The impairment of ulcer healing by clopidogrel has not been widely appreciated. Platelet aggregation plays a critical role in healing, through the release of various platelet-derived growth factors that promote angiogenesis, which is essential for ulcer healing. For example, animals with thrombocytopenia have reduced ulcer angiogenesis and impaired healing of gastric ulcers.13 ADP-receptor antagonists impair the healing of gastric ulcers by inhibiting the release by platelets of proangiogenic growth factors such as vascular endothelial growth factor,13 which promotes endothelial proliferation and accelerates the healing of ulcers. Gastrointestinal bleeding is a major toxic effect of new chemotherapeutic agents composed of monoclonal antibodies, which are directed at circulating vascular endothelial growth factor.14 Although clopidogrel and other agents that impair angiogenesis might not be the primary cause of gastrointestinal ulcers, their antiangiogenic effects may impair the healing of background ulcers; when combined with the propensity to increase bleeding, these agents may convert small, silent ulcers into large ulcers that bleed profoundly.
There are several potential limitations of the study by Chan et al. First, the medications that were used were repackaged in color-coded capsules to maintain blinding. It is unclear how this repackaging affected outcomes. Aspirin-induced ulcers are a consequence of systemic effects and of local mucosal aspirin concentrations. It is possible that the capsules protected the stomach and moved the gastrointestinal site of injury by aspirin distally. Alternatively, and more likely, the decrease in aspirin-induced gastric ulceration was the result of protective effects of proton-pump inhibitors. Furthermore, all the patients in the study were negative for H. pylori infection or had been cured of such infection, and none were taking anticoagulants or corticosteroids. Thus, it is uncertain how the findings reported by Chan and colleagues apply to other patients at high risk for gastrointestinal complications of aspirin therapy.
It is reasonable to conclude that the lowest effective dose of aspirin should be used for patients at high risk for gastrointestinal complications who need antiplatelet therapy to prevent thrombotic complications. The more challenging question is what therapy to provide for patients who already have had gastrointestinal complications while taking aspirin or other NSAIDs. The current recommendation for these patients is to replace aspirin with clopidogrel.4 The study by Chan et al. clearly indicates that this recommendation is harmful and that such patients should be given aspirin plus a proton-pump inhibitor.11
Dr. Cryer reports having been a paid consultant for McNeil Consumer, Specialty Pharmaceuticals, and TAP Pharmaceutical Products and a paid speaker for AstraZeneca and TAP Pharmaceutical Products.
Source Information
From the Gastroenterology Section, Department of Medicine, University of Texas Southwestern Medical School and Dallas Veterans Affairs Medical Center, Dallas.
References
Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000;321:1183-1187.
Peters RJG, Mehta SR, Fox KAA, et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 2003;108:1682-1687.
Cryer B, Feldman M. Effects of very low doses of daily, long-term aspirin therapy on gastric, duodenal and rectal prostaglandin levels and on mucosal injury in healthy humans. Gastroenterology 1999;117:17-25.
Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction -- 2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). Circulation 2002;106:1893-1900.
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339.
Fort FT, Lafolie P, Tóth E, Lindg?rde F. Gastroduodenal tolerance of 75 mg clopidogrel versus 325 mg aspirin in healthy volunteers: a gastroscopic study. Scand J Gastroenterol 2000;35:464-469.
Laine L. Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology 2001;120:594-606.
Weideman RA, Kelly KC, Kazi S, et al. Risks of clinically significant upper gastrointestinal events with etodolac and naproxen: a historical cohort analysis. Gastroenterology 2004;127:1322-1328.
Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med 2002;346:2033-2038.
Ng FH, Wong SY, Chang CM, et al. High incidence of clopidogrel-associated gastrointestinal bleeding in patients with previous peptic ulcer disease. Aliment Pharmacol Ther 2003;18:443-449.
Chan FKL, Ching JYL, Hung LCT, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med 2005;352:238-244.
Laine L, Maller ES, Yu C, Quan H, Simon T. Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double-blind trial. Gastroenterology 2004;127:395-402.
Ma L, Elliott SN, Cirino G, Buret A, Ignarro LJ, Wallace JL. Platelets modulate gastric ulcer healing: role of endostatin and vascular endothelial growth factor release. Proc Natl Acad Sci U S A 2001;98:6470-6475.
Kabbinovar F, Hurwitz HI, Fehrenbaacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil(FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003;21:60-65.(Byron Cryer, M.D.)