(Stroke. 2000;31:983-a.)
© 2000 American Heart Association, Inc.
Letters to the Editor |
Supplement to the AHA Guidelines for the Management of Transient Ischemic Attacks
University of Colorado School of Medicine, Denver, Colorado
To the Editor:
I must respectfully disagree with the recent AHA Scientific Statement on the management of transient ischemic attacks.1
First, the inclusion of the combination antiplatelet agent extended release dipyridamole and aspirin (ERDP/ASA) as a "recommended therapy" is premature. The current data are insufficient to definitively establish that ERDP/ASA offers anything in addition to aspirin alone. Although the results of the ESPS-2 trial2 of ERDP/ASA are encouraging and generate great optimism for this and other combination strategies, serious questions remain. The ESPS-2 results are highly inconsistent with previous data on 5317 patients treated with the combination.3 Although a heterogeneous set of trials, these data were sufficient to all but abandon use of dipyridamole in the 1980s. Further, the high rate of subject dropout,2 the lack of any benefit in vascular death despite the stunning benefit in stroke,2 the 50-mg dose of ASA,2 4 and the scientific misconduct5 discovered in the trial collectively make ESPS-2 inadequate to certify ERDP/ASA as an established therapy by the AHA or any other body.6 Any new scientific finding that is a large departure from previous data or theory requires independent conformation. Such is true of ERDP/ASA.
Second, a variety of commonly used antithrombotic strategies deserve mention with ERDP/ASA as potentially useful, if unproven, alternatives. This includes the use of clopidogrel or ticlopidine with aspirin,7 8 9 a well-accepted standard for poststenting prophylaxis. For some warfarin patients, the addition of any antiplatelet agent can help also.10 11 Further, for those who are impressed with the dramatic ESPS-2 results of ERDP/ASA, comparable efficacy was observed in the ESPS-1 trial using the inexpensive (and currently available) combination of aspirin (325 mg) and regular dipyridamole (75 mg) 3 times a day.12 Time and more data will tell if any of these combinations, ERDP/ASA included, can be recommended for general use.
References
1. Albers G, Hart R, Helmi L, Newell D, Sacco R. Supplement to the Guidelines for the Management of Transient Ischemic Attacks: a statement from the Ad Hoc Committee on Guidelines for the Management of Transient Ischemic Attacks, Stroke Council, American Heart Association. Stroke. 1999;(30):2502–2511.
2. Diener H, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurosci.. 1996;143:1–13.
3. Antiplatelet Trialists Collaboration. Collaborative overview of randomized trials of antiplatelet therapy, 1: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ.. 1994;308:87–106.
4.
Barnett H, Kaste M, Meldrum H, Eliasziw M. Aspirin
Dose in stroke prevention: beautiful hypotheses slain by ugly facts.
Stroke.. 1996;27:588–592.
5.
Enserink M. Fraud and ethics charges hit stroke drug
trial. Science.. 1996;274:2004.
6.
Wilterdink J, Easton J. Dipyridamole
plus aspirin in cerebrovascular disease. Arch Neurol.. 1999;56:1087–1092.
7.
Popma J, Weitz J, Bittl J, Ohman M, Kuntz R, Lansky A,
King S. Antithrombotic therapy in patients undergoing coronary
angioplasty. Chest.. 1998;114:728S–741S.
8.
Hall P, Nakamura S, Maiello L, Blengino S, Martini G,
Ferraro M, Colombo A. A randomized comparison of combined ticlopidine
and aspirin therapy versus aspirin therapy alone after successful
intravascular ultrasound-guided stent implantation.
Circulation.. 1996;93:215–222.
9. Die CLASSICS-Studie. Clopidigrel+ASS Versu Ticlopidin+ASS bie Stent-Patienten [in German]. Internist. 1999;40(5 suppl Clopidogre):1–4.
10.
Stein P, Alpert J, Dalen J, Horstkotte D, Turpie A.
Antithrombotic therapy in patients with mechanical and biological
prosthetic heart valves. Chest.. 1998;114:602S–610S.
11. Tiede D, Nishimura R, Gastineau D, Mullany C, Orszulak T, Schaff H. Modern management of prosthetic valve anticoagulation. Mayo Clin Proc.. 1998;73:665–680.[Abstract]
12.
ESPS Group. European Stroke Prevention Study.
Stroke.. 1990;21:1122–1130.
Response to Dr Hughes:
Stanford Stroke Center, Stanford University School of Medicine, Palo Alto, California
Department of Medicine/Neurology, The University of Texas Health Science Center at San Antonio
Oregon Stroke Center, Oregon Health Sciences University, Portland, Oregon
Department of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington
Neurological Institute, Columbia–Presbyterian Medical Center, New York, NY
We appreciate the opportunity to respond to Dr Hughes. After carefully considering his concerns, we do not believe any modifications of the American Heart Association recommendationsR1 are justified. A balanced review of all available data regarding the efficacy of the combination of aspirin/dipyridamole was recently published.R2 When all studies performed in cerebrovascular patients are considered, a substantial and statistically significant benefit of aspirin/dipyridamole over aspirin therapy alone for stroke prevention was detected. The most compelling data supporting the benefits of this combination come from the second European Stroke Prevention Study (ESPS-2) trial that evaluated an extended-release form of dipyridamole (400 mg/d) in combination with aspirin (50 mg/d).R3 As discussed in detail in our report,R1 there is no evidence that the 50-mg dose of aspirin is any less effective for stroke prevention than higher doses, and the aspirin dose recommended by the Food and Drug Administration for stroke prevention is 50 to 325 mg/d. The "scientific misconduct" referred to by Dr Hughes in the ESPS-2 trial reflects a single fraudulent investigator who was identified prior to study completion. The data supplied by this investigator were removed prior to unblinding and analyzing the ESPS-2 data and did not influence the results of study. The dropout rate in the ESPS-2 study did not differ from many similar stroke prevention trials. In addition, a high dropout rate typically dilutes, rather than accentuates, the benefits of an effective agent. The failure of ESPS-2 to demonstrate a reduction in vascular death is also not unique to the aspirin/extended-release dipyridamole combination; neither ticlopidine, clopidogrel, nor any single trial of aspirin therapy has demonstrated a significant reduction in vascular death in patients with cerebrovascular disease.
The American Heart Association is not the first group to recognize the aspirin/extended-release dipyridamole combination as a safe and effective therapy for stroke prevention—this combination was recently approved by the Food and Drug Administration. Other combinations of antiplatelet agents or anticoagulants have not been adequately tested in stroke or transient ischemic attack patients. Therefore, their safety and efficacy are not established.
References
1.
Albers GW, Hart RG, Lutsep HL, Newell DW,
Sacco RL. Supplement to the guidelines for the management of transient
ischemic attacks: a statement from the Ad Hoc Committee on
Guidelines for the Management of Transient Ischemic Attacks,
Stroke Council, American Heart Association. Stroke. 1999;30:2502–2511.
2. Wilterdink JL, Easton D. Dipyridamole plus aspirin in cerebrovascular disease. Arch Neurol. 1999;56:1087–1092.
3. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143:1–13.[Medline] [Order article via Infotrieve]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||