Clopidogrel versus Aspirin and Esomeprazole to Prevent Recurrent Bleeding
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Chan et al. (Jan. 20 issue)1 conclude that aspirin plus a proton-pump inhibitor is superior to clopidogrel in the prevention of recurrent ulcer bleeding. The authors of the study and Cryer, in an accompanying editorial,2 state that the current American College of Cardiology–American Heart Association (ACC–AHA) guidelines, which recommend that aspirin be replaced with clopidogrel in patients who have a history of gastrointestinal complications, are harmful and that such patients should be given aspirin plus a proton-pump inhibitor.
The ACC–AHA guidelines state, "Clopidogrel should be administered to hospitalized patients who are unable to take ASA [acetylsalicylic acid] because of hypersensitivity and major gastrointestinal intolerance."3 This recommendation is based on the 8.7 percent reduction in the relative risk of cardiovascular events with clopidogrel as compared with acetylsalicylic acid in the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial.4 The CAPRIE trial excluded patients with a history of gastrointestinal bleeding and reported lower rates of gastrointestinal bleeding or ulcers in the clopidogrel group than in the aspirin group. Of note, the guidelines do not imply that patients with a history of major gastrointestinal intolerance of aspirin should receive clopidogrel without appropriate treatment for their gastrointestinal condition. Such general medical decisions are beyond the scope of the guidelines. The use of proton-pump inhibitors in patients with a history of bleeding ulcers is known to reduce ulcer complications.5,6
Therefore, we are disturbed by the scientific rationale and questionable design of the current trial, in which the clopidogrel group did not receive a proton-pump inhibitor. We do not find the results in conflict with the current guidelines, but we will review the results as part of the regular process of updating all of our guidelines.
Michael J. Wolk, M.D.
American College of Cardiology Foundation
Bethesda, MD 20814-1699
Alice K. Jacobs, M.D.
American Heart Association
Dallas, TX 75231-4596
References
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.
Cryer B. Reducing the risks of gastrointestinal bleeding with antiplatelet therapies. N Engl J Med 2005;352:287-289.
Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction -- 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). J Am Coll Cardiol 2002;40:1366-1374.
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339.
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.
Leontiadis GI, Sharma VK, Howden CW. Systematic review and meta-analysis of proton pump inhibitor therapy in peptic ulcer bleeding. BMJ 2005;330:568-568.
To the Editor: Chan et al. state that their findings do not support the current ACC–AHA guidelines, which recommend the use of clopidogrel in patients with gastrointestinal intolerance to aspirin. Their findings are based on a study of only 320 patients who initially presented with gastrointestinal ulcerations. Because patients in the clopidogrel group were not given a proton-pump inhibitor, there is little question as to which group was going to have higher rates of bleeding. The question that begs to be answered, however, is how such a study could receive approval by an institutional review board. Denying prophylactic therapy to patients at high risk for the development of bleeding is completely unethical. Furthermore, on the basis of the results of two trials, the manufacturers of clopidogrel warn against its use in patients with a recent history of ulcers.1,2,3 To suggest, indirectly, that the ACC–AHA guidelines be revised is unfounded and is counterproductive to the care each year of hundreds of thousands of patients with acute coronary syndromes. A larger, properly designed trial needs to be conducted before such a conclusion is made.
Kurt A. Wargo, Pharm.D.
Auburn University Harrison School of Pharmacy
Auburn, AL 36830
wargoka@auburn.edu
Sharon R. Baty, Pharm.D.
Gregg Knowles, Pharm.D.
Huntsville Hospital
Huntsville, AL 35801
References
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339.
The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.
Plavix (clopidogrel bisulfate). New York: Bristol-Myers Squibb/Sanofi Pharmaceuticals, 2003 (package insert).
To the Editor: As a pharmacist working in a large grocery-store chain, I see on a daily basis patients who have to choose between buying groceries and paying for their prescriptions. I must admit that I was rather encouraged to read the findings reported by Chan et al. The use of a proton-pump inhibitor and aspirin, rather than clopidogrel, would in effect save each patient more than $100 per month in prescription costs alone. The average cost of 30 tablets of clopidogrel is about $137; in comparison, a bottle of over-the-counter aspirin and a box of over-the-counter omeprazole together cost less than $30.
Peter R. Barski, Jr., Pharm.D.
18967 SE Bryant Dr.
Jupiter, FL 33469
jordanbarski@bellsouth.net
Dr. Chan replies: Our institutional review board approved this study on the basis of the ACC–AHA guidelines, which indicate that clopidogrel should be administered to hospitalized patients who cannot take aspirin because of major gastrointestinal intolerance (a class IA recommendation). In Australia, one approved indication for clopidogrel is the secondary prevention of atherosclerotic events in patients in whom aspirin poses an unacceptable risk of gastrointestinal bleeding.1 The manufacturers warn against the use of clopidogrel in patients with an active peptic ulcer only, not a recent history of ulcer.2 All our patients were confirmed to have healed ulcers before they were enrolled. If clopidogrel does not damage the stomach, what is the rationale for using prophylactic therapy? In the absence of an active peptic ulcer or concomitant use of aspirin or nonsteroidal antiinflammatory drugs, we cannot agree with Wargo and colleagues' criticism — that denying prophylactic therapy to our patients receiving clopidogrel was unethical. The high rate of recurrent bleeding in the clopidogrel group was unexpected.
The ACC–AHA use the results of the CAPRIE trial3 to justify their guidelines. The real question that begs to be answered is whether the evidence is good enough to justify a class IA recommendation. The CAPRIE trial was not designed to compare the gastrointestinal safety of clopidogrel with that of aspirin. Gastrointestinal bleeding was not a predefined end point. We cannot accept a class IA recommendation solely on the basis of a post hoc subgroup analysis. Can we infer from this subgroup analysis that clopidogrel carries a lower risk of gastrointestinal bleeding than aspirin? In the CAPRIE trial, the incidence of gastrointestinal bleeding in the aspirin group (dose of aspirin, 325 mg per day) was 1.3 times that in the clopidogrel group. This comparison, however, was unfair because the risk of gastrointestinal bleeding with 325 mg of aspirin per day is almost double that with 81 mg of aspirin per day.4
The ACC–AHA argued that the decision regarding use of prophylactic therapy was beyond the scope of their guideline. If prophylactic therapy is still required in patients receiving clopidogrel because of intolerance to aspirin, what is the advantage of using clopidogrel and a proton-pump inhibitor rather than aspirin and a proton-pump inhibitor? We do not deny the benefits of the combination of clopidogrel and aspirin for patients with acute coronary syndromes. Clopidogrel alone, however, is only marginally superior to aspirin for cardiovascular protection.5
Our message is simple. For patients who can benefit from aspirin alone, switching to clopidogrel because of aspirin intolerance is expensive, unfounded, and counterproductive. They should continue to take aspirin and receive a proton-pump inhibitor.
Francis K.L. Chan, M.D.
Chinese University of Hong Kong
Hong Kong, China
fklchan@cuhk.edu.hk
for the Gastrointestinal Research Group
References
Kubler PA, Pillans PI, Marrinan MC, Frogley M. Concordance between clopidogrel use and prescribing guidelines. Intern Med J 2004;34:663-667.
Plavix (clopidogrel bisulfate). New York: Bristol-Myers Squibb/Sanofi Pharmaceuticals, 2003 (package insert).
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339.
Weil J, Colin-Jones D, Langman M, et al. Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ 1995;310:827-830.
Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.
The ACC–AHA guidelines state, "Clopidogrel should be administered to hospitalized patients who are unable to take ASA [acetylsalicylic acid] because of hypersensitivity and major gastrointestinal intolerance."3 This recommendation is based on the 8.7 percent reduction in the relative risk of cardiovascular events with clopidogrel as compared with acetylsalicylic acid in the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial.4 The CAPRIE trial excluded patients with a history of gastrointestinal bleeding and reported lower rates of gastrointestinal bleeding or ulcers in the clopidogrel group than in the aspirin group. Of note, the guidelines do not imply that patients with a history of major gastrointestinal intolerance of aspirin should receive clopidogrel without appropriate treatment for their gastrointestinal condition. Such general medical decisions are beyond the scope of the guidelines. The use of proton-pump inhibitors in patients with a history of bleeding ulcers is known to reduce ulcer complications.5,6
Therefore, we are disturbed by the scientific rationale and questionable design of the current trial, in which the clopidogrel group did not receive a proton-pump inhibitor. We do not find the results in conflict with the current guidelines, but we will review the results as part of the regular process of updating all of our guidelines.
Michael J. Wolk, M.D.
American College of Cardiology Foundation
Bethesda, MD 20814-1699
Alice K. Jacobs, M.D.
American Heart Association
Dallas, TX 75231-4596
References
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.
Cryer B. Reducing the risks of gastrointestinal bleeding with antiplatelet therapies. N Engl J Med 2005;352:287-289.
Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction -- 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). J Am Coll Cardiol 2002;40:1366-1374.
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339.
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.
Leontiadis GI, Sharma VK, Howden CW. Systematic review and meta-analysis of proton pump inhibitor therapy in peptic ulcer bleeding. BMJ 2005;330:568-568.
To the Editor: Chan et al. state that their findings do not support the current ACC–AHA guidelines, which recommend the use of clopidogrel in patients with gastrointestinal intolerance to aspirin. Their findings are based on a study of only 320 patients who initially presented with gastrointestinal ulcerations. Because patients in the clopidogrel group were not given a proton-pump inhibitor, there is little question as to which group was going to have higher rates of bleeding. The question that begs to be answered, however, is how such a study could receive approval by an institutional review board. Denying prophylactic therapy to patients at high risk for the development of bleeding is completely unethical. Furthermore, on the basis of the results of two trials, the manufacturers of clopidogrel warn against its use in patients with a recent history of ulcers.1,2,3 To suggest, indirectly, that the ACC–AHA guidelines be revised is unfounded and is counterproductive to the care each year of hundreds of thousands of patients with acute coronary syndromes. A larger, properly designed trial needs to be conducted before such a conclusion is made.
Kurt A. Wargo, Pharm.D.
Auburn University Harrison School of Pharmacy
Auburn, AL 36830
wargoka@auburn.edu
Sharon R. Baty, Pharm.D.
Gregg Knowles, Pharm.D.
Huntsville Hospital
Huntsville, AL 35801
References
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339.
The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.
Plavix (clopidogrel bisulfate). New York: Bristol-Myers Squibb/Sanofi Pharmaceuticals, 2003 (package insert).
To the Editor: As a pharmacist working in a large grocery-store chain, I see on a daily basis patients who have to choose between buying groceries and paying for their prescriptions. I must admit that I was rather encouraged to read the findings reported by Chan et al. The use of a proton-pump inhibitor and aspirin, rather than clopidogrel, would in effect save each patient more than $100 per month in prescription costs alone. The average cost of 30 tablets of clopidogrel is about $137; in comparison, a bottle of over-the-counter aspirin and a box of over-the-counter omeprazole together cost less than $30.
Peter R. Barski, Jr., Pharm.D.
18967 SE Bryant Dr.
Jupiter, FL 33469
jordanbarski@bellsouth.net
Dr. Chan replies: Our institutional review board approved this study on the basis of the ACC–AHA guidelines, which indicate that clopidogrel should be administered to hospitalized patients who cannot take aspirin because of major gastrointestinal intolerance (a class IA recommendation). In Australia, one approved indication for clopidogrel is the secondary prevention of atherosclerotic events in patients in whom aspirin poses an unacceptable risk of gastrointestinal bleeding.1 The manufacturers warn against the use of clopidogrel in patients with an active peptic ulcer only, not a recent history of ulcer.2 All our patients were confirmed to have healed ulcers before they were enrolled. If clopidogrel does not damage the stomach, what is the rationale for using prophylactic therapy? In the absence of an active peptic ulcer or concomitant use of aspirin or nonsteroidal antiinflammatory drugs, we cannot agree with Wargo and colleagues' criticism — that denying prophylactic therapy to our patients receiving clopidogrel was unethical. The high rate of recurrent bleeding in the clopidogrel group was unexpected.
The ACC–AHA use the results of the CAPRIE trial3 to justify their guidelines. The real question that begs to be answered is whether the evidence is good enough to justify a class IA recommendation. The CAPRIE trial was not designed to compare the gastrointestinal safety of clopidogrel with that of aspirin. Gastrointestinal bleeding was not a predefined end point. We cannot accept a class IA recommendation solely on the basis of a post hoc subgroup analysis. Can we infer from this subgroup analysis that clopidogrel carries a lower risk of gastrointestinal bleeding than aspirin? In the CAPRIE trial, the incidence of gastrointestinal bleeding in the aspirin group (dose of aspirin, 325 mg per day) was 1.3 times that in the clopidogrel group. This comparison, however, was unfair because the risk of gastrointestinal bleeding with 325 mg of aspirin per day is almost double that with 81 mg of aspirin per day.4
The ACC–AHA argued that the decision regarding use of prophylactic therapy was beyond the scope of their guideline. If prophylactic therapy is still required in patients receiving clopidogrel because of intolerance to aspirin, what is the advantage of using clopidogrel and a proton-pump inhibitor rather than aspirin and a proton-pump inhibitor? We do not deny the benefits of the combination of clopidogrel and aspirin for patients with acute coronary syndromes. Clopidogrel alone, however, is only marginally superior to aspirin for cardiovascular protection.5
Our message is simple. For patients who can benefit from aspirin alone, switching to clopidogrel because of aspirin intolerance is expensive, unfounded, and counterproductive. They should continue to take aspirin and receive a proton-pump inhibitor.
Francis K.L. Chan, M.D.
Chinese University of Hong Kong
Hong Kong, China
fklchan@cuhk.edu.hk
for the Gastrointestinal Research Group
References
Kubler PA, Pillans PI, Marrinan MC, Frogley M. Concordance between clopidogrel use and prescribing guidelines. Intern Med J 2004;34:663-667.
Plavix (clopidogrel bisulfate). New York: Bristol-Myers Squibb/Sanofi Pharmaceuticals, 2003 (package insert).
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339.
Weil J, Colin-Jones D, Langman M, et al. Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ 1995;310:827-830.
Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.