Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke

Ralph L Sacco; Hans-Christoph Diener; Salim Yusuf; Daniel Cotton; Stephanie Ounpuu; William A Lawton; Yuko Palesch; Reneé H Martin; Gregory W Albers; Philip Bath; Natan Bornstein; Bernard P L Chan; Sien-Tsong Chen; Luis Cunha; Björn Dahlöf; Jacques De Keyser; Geoffrey A Donnan; Conrado Estol; Philip Gorelick; Vivian Gu; Karin Hermansson; Lutz Hilbrich; Markku Kaste; Chuanzhen Lu; Thomas Machnig; Prem Pais; Robin Roberts; Veronika Skvortsova; Philip Teal; Danilo Toni; Cam Vandermaelen; Thor Voigt; Michael Weber; Byung-Woo Yoon; PRoFESS Study Group; Helle Klingenberg Iversen

doi:10.1056/NEJMoa0805002

Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke

Ralph L Sacco, Hans-Christoph Diener, Salim Yusuf, Daniel Cotton, Stephanie Ounpuu, William A Lawton, Yuko Palesch, Reneé H Martin, Gregory W Albers, Philip Bath, Natan Bornstein, Bernard P L Chan, Sien-Tsong Chen, Luis Cunha, Björn Dahlöf, Jacques De Keyser, Geoffrey A Donnan, Conrado Estol, Philip Gorelick, Vivian GuKarin Hermansson, Lutz Hilbrich, Markku Kaste, Chuanzhen Lu, Thomas Machnig, Prem Pais, Robin Roberts, Veronika Skvortsova, Philip Teal, Danilo Toni, Cam Vandermaelen, Thor Voigt, Michael Weber, Byung-Woo Yoon, PRoFESS Study Group, Helle Klingenberg Iversen

Department of Clinical Medicine

734 Citations (Scopus)

Abstract

BACKGROUND: Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel.

METHODS: In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned.

RESULTS: A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA-ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA-ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11).

CONCLUSIONS: The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.)

Original language	English
Journal	New England Journal of Medicine
Volume	359
Issue number	12
Pages (from-to)	1238-51
Number of pages	14
ISSN	0028-4793
DOIs	https://doi.org/10.1056/NEJMoa0805002
Publication status	Published - 18 Sept 2008

Keywords

Aged
Angiotensin-Converting Enzyme Inhibitors
Aspirin
Benzimidazoles
Benzoates
Brain Ischemia
Delayed-Action Preparations
Dipyridamole
Double-Blind Method
Drug Therapy, Combination
Factor Analysis, Statistical
Female
Hemorrhage
Humans
Kaplan-Meier Estimate
Male
Middle Aged
Myocardial Infarction
Platelet Aggregation Inhibitors
Proportional Hazards Models
Risk
Secondary Prevention
Stroke
Ticlopidine
Vascular Diseases

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10.1056/NEJMoa0805002

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Sacco, R. L., Diener, H-C., Yusuf, S., Cotton, D., Ounpuu, S., Lawton, W. A., Palesch, Y., Martin, R. H., Albers, G. W., Bath, P., Bornstein, N., Chan, B. P. L., Chen, S-T., Cunha, L., Dahlöf, B., De Keyser, J., Donnan, G. A., Estol, C., Gorelick, P., ... Iversen, H. K. (2008). Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. New England Journal of Medicine, 359(12), 1238-51. https://doi.org/10.1056/NEJMoa0805002

Sacco, RL, Diener, H-C, Yusuf, S, Cotton, D, Ounpuu, S, Lawton, WA, Palesch, Y, Martin, RH, Albers, GW, Bath, P, Bornstein, N, Chan, BPL, Chen, S-T, Cunha, L, Dahlöf, B, De Keyser, J, Donnan, GA, Estol, C, Gorelick, P, Gu, V, Hermansson, K, Hilbrich, L, Kaste, M, Lu, C, Machnig, T, Pais, P, Roberts, R, Skvortsova, V, Teal, P, Toni, D, Vandermaelen, C, Voigt, T, Weber, M, Yoon, B-W, PRoFESS Study Group & Iversen, HK 2008, 'Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke', New England Journal of Medicine, vol. 359, no. 12, pp. 1238-51. https://doi.org/10.1056/NEJMoa0805002

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title = "Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke",

abstract = "BACKGROUND: Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel.METHODS: In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned.RESULTS: A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA-ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA-ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11).CONCLUSIONS: The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.)",

keywords = "Aged, Angiotensin-Converting Enzyme Inhibitors, Aspirin, Benzimidazoles, Benzoates, Brain Ischemia, Delayed-Action Preparations, Dipyridamole, Double-Blind Method, Drug Therapy, Combination, Factor Analysis, Statistical, Female, Hemorrhage, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Myocardial Infarction, Platelet Aggregation Inhibitors, Proportional Hazards Models, Risk, Secondary Prevention, Stroke, Ticlopidine, Vascular Diseases",

author = "Sacco, {Ralph L} and Hans-Christoph Diener and Salim Yusuf and Daniel Cotton and Stephanie Ounpuu and Lawton, {William A} and Yuko Palesch and Martin, {Rene{\'e} H} and Albers, {Gregory W} and Philip Bath and Natan Bornstein and Chan, {Bernard P L} and Sien-Tsong Chen and Luis Cunha and Bj{\"o}rn Dahl{\"o}f and {De Keyser}, Jacques and Donnan, {Geoffrey A} and Conrado Estol and Philip Gorelick and Vivian Gu and Karin Hermansson and Lutz Hilbrich and Markku Kaste and Chuanzhen Lu and Thomas Machnig and Prem Pais and Robin Roberts and Veronika Skvortsova and Philip Teal and Danilo Toni and Cam Vandermaelen and Thor Voigt and Michael Weber and Byung-Woo Yoon and {PRoFESS Study Group} and Iversen, {Helle Klingenberg}",

note = "2008 Massachusetts Medical Society",

year = "2008",

month = sep,

day = "18",

doi = "10.1056/NEJMoa0805002",

language = "English",

volume = "359",

pages = "1238--51",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "12",

}

TY - JOUR

T1 - Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke

AU - Sacco, Ralph L

AU - Diener, Hans-Christoph

AU - Yusuf, Salim

AU - Cotton, Daniel

AU - Ounpuu, Stephanie

AU - Lawton, William A

AU - Palesch, Yuko

AU - Martin, Reneé H

AU - Albers, Gregory W

AU - Bath, Philip

AU - Bornstein, Natan

AU - Chan, Bernard P L

AU - Chen, Sien-Tsong

AU - Cunha, Luis

AU - Dahlöf, Björn

AU - De Keyser, Jacques

AU - Donnan, Geoffrey A

AU - Estol, Conrado

AU - Gorelick, Philip

AU - Gu, Vivian

AU - Hermansson, Karin

AU - Hilbrich, Lutz

AU - Kaste, Markku

AU - Lu, Chuanzhen

AU - Machnig, Thomas

AU - Pais, Prem

AU - Roberts, Robin

AU - Skvortsova, Veronika

AU - Teal, Philip

AU - Toni, Danilo

AU - Vandermaelen, Cam

AU - Voigt, Thor

AU - Weber, Michael

AU - Yoon, Byung-Woo

AU - PRoFESS Study Group

AU - Iversen, Helle Klingenberg

N1 - 2008 Massachusetts Medical Society

PY - 2008/9/18

Y1 - 2008/9/18

N2 - BACKGROUND: Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel.METHODS: In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned.RESULTS: A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA-ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA-ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11).CONCLUSIONS: The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.)

AB - BACKGROUND: Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel.METHODS: In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned.RESULTS: A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA-ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA-ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11).CONCLUSIONS: The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.)

KW - Aged

KW - Angiotensin-Converting Enzyme Inhibitors

KW - Aspirin

KW - Benzimidazoles

KW - Benzoates

KW - Brain Ischemia

KW - Delayed-Action Preparations

KW - Dipyridamole

KW - Double-Blind Method

KW - Drug Therapy, Combination

KW - Factor Analysis, Statistical

KW - Female

KW - Hemorrhage

KW - Humans

KW - Kaplan-Meier Estimate

KW - Male

KW - Middle Aged

KW - Myocardial Infarction

KW - Platelet Aggregation Inhibitors

KW - Proportional Hazards Models

KW - Risk

KW - Secondary Prevention

KW - Stroke

KW - Ticlopidine

KW - Vascular Diseases

U2 - 10.1056/NEJMoa0805002

DO - 10.1056/NEJMoa0805002

M3 - Journal article

C2 - 18753638

SN - 0028-4793

VL - 359

SP - 1238

EP - 1251

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 12

ER -

Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke

Abstract

Keywords

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