Correspondence
Clopidogrel plus Aspirin in Atrial Fibrillation
N Engl J Med 2009; 361:1312-1315September 24, 2009
- Article
To the Editor:
The investigators of ACTIVE (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) (May 14 issue)1 address the pivotal clinical question, “Will the addition of clopidogrel to aspirin reduce the risk of vascular events in high-risk patients with atrial fibrillation for whom vitamin K antagonists are unsuitable?” The notion of the unsuitability of vitamin K antagonists warrants explanation, since the vast majority of patients in ACTIVE A (the part of the trial comparing clopidogrel plus aspirin with aspirin alone in patients with atrial fibrillation) did not have a risk factor for bleeding. Instead, “a physician's judgment that a vitamin K antagonist was inappropriate for the patient” (for 50% of the patients) and “the patient's preference not to take a vitamin K antagonist” (26%) dominated enrollment. Unfortunately, the authors do not provide a detailed explanation of the “physician's judgment” and “patient's preference” designations.2 It is noteworthy that 8.5% of the patients were receiving vitamin K antagonists at inclusion, but this treatment was discontinued due to the unsuitability of these agents. Also, 10% of the patients switched to vitamin K antagonists during follow-up after discontinuing the study drug. Was this switch due to unreported stroke that occurred while the patient was receiving placebo or clopidogrel? In summary, the meaning of the unsuitability of vitamin K antagonists in ACTIVE A is unclear, and the article may cause physicians to avoid vitamin K antagonists inappropriately.
2 ReferencesRon Pisters, M.D.
Trang Dinh, M.D.
Harry J. Crijns, M.D., Ph.D.
Maastricht University Medical Center, Maastricht, the Netherlands
r.pisters@mumc. nl 1
The ACTIVE Investigators
Full Text | Web of Science | Medline2
Nieuwlaat R ,Capucci A ,Lip GY , et al. Antithrombotic treatment in real-life atrial fibrillation patients: a report from the Euro Heart Survey on Atrial Fibrillation. Eur Heart J 2006;27:3018-3026
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To the Editor:
The ACTIVE investigators report that the addition of clopidogrel to aspirin reduced the incidence of stroke, myocardial infarction, systemic embolism, and vascular death, as compared with aspirin therapy alone, in patients with atrial fibrillation. All patients received aspirin at a dose of 75 to 100 mg per day; doses of 75 to 325 mg per day are recommended for low-risk patients with atrial fibrillation. However, this recommended dose of aspirin was derived from a generalization of the results of trials of aspirin for all antithrombotic indications, and the recommended dose balanced the efficacy versus the safety of aspirin therapy.1 Of all the randomized trials of aspirin in preventing thromboembolism in atrial fibrillation, only the Stroke Prevention in Atrial Fibrillation study, in which aspirin at a dose of 325 mg was given daily, showed a benefit.2 Other randomized trials of lower doses of aspirin showed no benefit in atrial fibrillation.3 Thus, the ACTIVE study used an aspirin dose that has not been shown to provide any benefit in atrial fibrillation. Patients in the placebo group of ACTIVE potentially received no effective background antithrombotic therapy; thus, the outcome was biased in favor of the group assigned to clopidogrel.
3 ReferencesDoson Chua, Pharm.D.
Michael Legal, Pharm.D.
Stephen J. Shalansky, Pharm.D.
St. Paul's Hospital, Vancouver, BC, Canada
dchua@providencehealth.bc. ca 1
Singer DE ,Albers GW ,Dalen JE , et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133:Suppl:546S-592S
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Stroke Prevention in Atrial Fibrillation study: final results. Circulation 1991;84:527-539
Web of Science | Medline3
The Atrial Fibrillation Investigators
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To the Editor:
In ACTIVE A, the investigators explored the association between clopidogrel plus aspirin and the occurrence of a combined vascular clinical end point in patients who were considered to be ineligible for vitamin K–antagonist therapy. They report an absolute reduction of 0.8 percentage points in the yearly incidence of the composite end point; this benefit is balanced by an increase in the risk of major bleeding of 0.7 percentage points per patient per year. However, in observational studies,1 the most frequent reason for not giving vitamin K antagonists was a specific risk of bleeding. In ACTIVE A, only 23% of the patients had such a risk. Among the 77% remaining patients, vitamin K antagonists were not administered because the patient declined treatment, the therapeutic international normalized ratio (INR) could not be maintained, or because of another unspecified reason based on the clinician's judgment. Thus, extending the results of ACTIVE A to a population with a high risk of hemorrhage would probably result in a much higher incidence of episodes of bleeding than the incidence reported in this trial.
1 ReferencesThibault Richard, M.D.
Fabrizio Butaffuoco, M.D.
Michel Vanhaeverbeek, M.D.
Hôpital André Vésale, Montigny-le-Tilleul, Belgium
thibault.richard@chu-charleroi. be 1
Sudlow M ,Thomson R ,Thwaites B ,Rodgers H ,Kenny RA . Prevalence of atrial fibrillation and eligibility for anticoagulants in the community. Lancet 1998;352:1167-1171
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To the Editor:
The ACTIVE investigators report that the addition of clopidogrel to aspirin in patients with atrial fibrillation for whom vitamin K–antagonist therapy was unsuitable reduced the risk of major vascular events but increased the risk of major hemorrhage. The overall effect of the combination of clopidogrel and aspirin, as compared with aspirin alone, was neutral. The rate of major vascular events decreased 0.8% per year, whereas the rate of major hemorrhage increased 0.7% per year (relative risk, 0.97; 95% confidence interval, 0.89 to 1.06; P=0.54). Moreover, the rate of intracranial hemorrhage, which increased 87% with the combination therapy, was not considered a major vascular event. ACTIVE W,1 the ACTIVE study that compared clopidogrel plus aspirin with a vitamin K agonist, previously showed that oral anticoagulation was superior to clopidogrel plus aspirin in patients with atrial fibrillation and was associated with similar risks of major bleeding (2.2% vs. 2.4% per year, P=0.53); these rates were similar to the 2.0% risk per year reported in ACTIVE A. ACTIVE A suggests that clopidogrel plus aspirin is not more or less effective than aspirin alone, and there is no evidence that the combination therapy carries a lower risk of bleeding than oral anticoagulants.
1 ReferencesLarry B. Goldstein, M.D.
Duke University, Durham, NC
golds004@mc.duke. edu 1
The ACTIVE Writing Group
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To the Editor:
The ACTIVE investigators found an absolute reduction of 0.9 percentage points in the risk of stroke per year among patients with atrial fibrillation with the addition of clopidogrel to aspirin, as compared with aspirin alone (2.4% vs. 3.3%). The number needed to treat with clopidogrel to avoid stroke in 1 patient was 111. Given the recent interest in health care costs, we were surprised to see no discussion of the potential costs of this treatment. Clopidogrel costs approximately $152 (U.S. dollars) for a 30-day supply, according to one source.1 Using a back-of-the-envelope decision analysis, we estimate it would cost $202,464 to prevent a single stroke per year in this population (i.e., to treat 111 patients with clopidogrel for 1 year at a cost of $1,824 per patient). Traditionally, $50,000 per quality-adjusted life-year (QALY) is the cutoff point of cost-effectiveness. Admittedly, we do not factor in the cost of caring for patients with strokes, QALY reductions in patients with strokes, and other costs (e.g., the treatment of major bleeding), but this still seems too expensive a strategy to advocate.
Young E. Lee, M.D., M.B.A.
Kent J. DeZee, M.D., M.P.H.
William Beaumont Army Medical Center, El Paso, TXThe opinions expressed in this letter are solely those of the authors and do not reflect the official policies of William Beaumont Army Medical Center, the Department of Defense, the U.S. Army, or any federal agency.
1 References1
Drugstore.com home page. (Accessed September 3, 2009, at http://www.drugstore.com/.)
To the Editor:
The ACTIVE investigators report that there was no significant difference in the rate of myocardial infarction between the clopidogrel group and the placebo group, although the clopidogrel group had a significantly increased rate of gastrointestinal bleeding. There is growing interest in a possible interaction between clopidogrel and proton-pump inhibitors, since clopidogrel is converted to an active metabolite by the isoenzyme CYP2C19, which can be inhibited by proton-pump inhibitors.1 Some reports on the concomitant use of clopidogrel with a proton-pump inhibitor showed an adverse cardiovascular outcome,2 whereas others did not show any such effect.3 The concern regarding this interaction has also been raised by the Food and Drug Administration, which has issued an early communication and stressed the need for further studies.4
It would therefore be of interest to know how many patients in ACTIVE A received both clopidogrel and a proton-pump inhibitor, and the rate of cardiovascular events among these patients.
4 ReferencesS. Shalimar, M.D.
All India Institute of Medical Sciences, New Delhi, India
drshalimar@yahoo.com Ghan Shyam Pangtey, M.D.
Lady Hardinge Medical College, New Delhi, IndiaKumar Kirti Singh, M.D.
All India Institute of Medical Sciences, New Delhi, India1
Furuta T ,Sugimoto M ,Shirai N ,Ishizaki T . CYP2C19 pharmacogenomics associated with therapy of Helicobacter pylori infection and gastro-esophageal reflux diseases with a proton pump inhibitor. Pharmacogenomics 2007;8:1199-1210
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Ho PM ,Maddox TM ,Wang L , et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301:937-944
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Sibbing D ,Morath T ,Stegherr J , et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009;101:714-719
Web of Science | Medline4
Food and Drug Administration. Early communication about an ongoing safety review of clopidogrel bisulfate (marketed as Plavix). (Accessed September 3, 2009, at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm079520.htm.)
Author/Editor Response
Pisters et al. raise the issue of how physicians decide whether warfarin is unsuitable for patients with atrial fibrillation. As we pointed out in our article, only about 50% of high-risk patients with atrial fibrillation receive warfarin. Many patients are unable or unwilling to make the considerable commitment required for safe warfarin therapy. Many patients cannot take adjusted-dose warfarin because of a lack of access to good anticoagulation monitoring, because of widely fluctuating or poorly controlled INRs, or because of other contraindications. International guidelines provide little specific guidance on how to assess the benefits and risks of warfarin treatment, and physicians must use their clinical judgment, weighing many factors.
Chua et al. suggest that the dosage of aspirin used in ACTIVE A was low. International guidelines1,2 recommend a wide range of aspirin dosages for use in atrial fibrillation because of the lack of convincing evidence that any one dosage is superior in atrial fibrillation.
Richard et al. discuss whether patients with a high risk of bleeding would benefit from the addition of clopidogrel to aspirin. The 23% of patients who were enrolled in ACTIVE A because of an increased relative risk of bleeding if given warfarin had a relative risk of major bleeding with clopidogrel that was similar to that of other patients in ACTIVE A.
Goldstein discusses the risk–benefit ratio of clopidogrel. Intracerebral bleeding in ACTIVE A was reported as part of the stroke outcome and also as intracranial hemorrhage. Subdural hematomas were not included as strokes but counted as intracranial bleeding. Considering all intracranial events (i.e., all strokes and subdural hematomas), the rate was 2.6% per year among 320 patients who received clopidogrel plus aspirin and 3.4% per year among 415 patients who received aspirin alone. Goldstein's statement that there is no evidence that the combination therapy carries a lower risk of bleeding than oral anticoagulants is not accurate. Among participants in ACTIVE W who were not receiving warfarin at entry, the risk of major bleeding was substantially lower with clopidogrel plus aspirin than with warfarin3; this finding is in line with a recent systematic review.4 Available data indicate that clopidogrel plus aspirin carries a lower risk of major bleeding than warfarin unless the patient is safely taking warfarin already.
Lee and DeZee comment on the possible lack of cost-effectiveness of clopidogrel in atrial fibrillation, but they acknowledge that the long-term costs of caring for patients with stroke are very high, especially for the larger strokes seen in atrial fibrillation. Detailed economic analysis is required to understand the cost-effectiveness of clopidogrel in atrial fibrillation. With regard to the comments of Shalimar et al.: we did not collect data related to the use of proton-pump inhibitors in ACTIVE.
4 ReferencesStuart J. Connolly, M.D.
Salim Yusuf, M.D.
Population Health Research Institute, Hamilton, ON, Canada
stuart.connolly@phri. ca Robert G. Hart, M.D.
University of Texas, San Antonio, TXfor the ACTIVE Steering Committee
1
Singer DE ,Albers GW ,Dalen JE , et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133:Suppl:546S-592S
CrossRef | Web of Science | Medline2
Fuster V ,Ryden LE ,Cannom DS , et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation -- executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation). J Am Coll Cardiol 2006;48:854-906[Erratum, J Am Coll Cardiol 2007;50:562.]
CrossRef | Web of Science | Medline3
The ACTIVE Writing Group
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Usman U ,Notaro LA ,Nagarakanti R , et al. Combination antiplatelet therapy for secondary stroke prevention: enhanced efficacy or double trouble? Am J Cardiol 2009;103:1107-1112
CrossRef | Web of Science | Medline
