Effects of clopidogrel added to aspirin in patients with recent lacunar stroke
Open accessAbstract
BACKGROUND: Lacunar infarcts are a frequent type of stroke caused mainly by cerebral small-vessel disease. The effectiveness of antiplatelet therapy for secondary prevention has not been defined. METHODS: We conducted a double-blind, multicenter trial involving 3020 patients with recent symptomatic lacunar infarcts identified by magnetic resonance imaging. Patients were randomly assigned to receive 75 mg of clopidogrel or placebo daily; patients in both groups received 325 mg of aspirin daily. The primary outcome was any recurrent stroke, including ischemic stroke and intracranial hemorrhage. RESULTS: The participants had a mean age of 63 years, and 63% were men. After a mean follow-up of 3.4 years, the risk of recurrent stroke was not significantly reduced with aspirin and clopidogrel (dual antiplatelet therapy) (125 strokes; rate, 2.5% per year) as compared with aspirin alone (138 strokes, 2.7% per year) (hazard ratio, 0.92; 95% confidence interval [CI], 0.72 to 1.16), nor was the risk of recurrent ischemic stroke (hazard ratio, 0.82; 95% CI, 0.63 to 1.09) or disabling or fatal stroke (hazard ratio, 1.06; 95% CI, 0.69 to 1.64). The risk of major hemorrhage was almost doubled with dual antiplatelet therapy (105 hemorrhages, 2.1% per year) as compared with aspirin alone (56, 1.1% per year) (hazard ratio, 1.97; 95% CI, 1.41 to 2.71; P<0.001). Among classifiable recurrent ischemic strokes, 71% (133 of 187) were lacunar strokes. All-cause mortality was increased among patients assigned to receive dual antiplatelet therapy (77 deaths in the group receiving aspirin alone vs. 113 in the group receiving dual antiplatelet therapy) (hazard ratio, 1.52; 95% CI, 1.14 to 2.04; P=0.004); this difference was not accounted for by fatal hemorrhages (9 in the group receiving dual antiplatelet therapy vs. 4 in the group receiving aspirin alone). CONCLUSIONS: Among patients with recent lacunar strokes, the addition of clopidogrel to aspirin did not significantly reduce the risk of recurrent stroke and did significantly increase the risk of bleeding and death. (Funded by the National Institute of Neurological Disorders and Stroke and others; SPS3 ClinicalTrials.gov number, NCT00059306.).
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Patients without atheroma may receive less long-term benefit from anti-atheromatous treatments.
“However it may be important to differentiate any due to focal atheroma from non-atheromatous lacunar ischaemic stroke as patients without atheroma may get less long term benefit from anti-atheromatous treatments.13,18,76”
From Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging (2013) · cites this paper as [13]
Clopidogrel plus aspirin versus aspirin alone caused an excess of haemorrhage and death in patients with lacunar stroke, possibly because lacunar patients lacked large artery atheromatous disease to prevent, which is further evidence that SVD is largely non-atheromatous.
“Clopidogrel plus aspirin versus aspirin alone caused an excess of haemorrhage (mostly systemic) and death in patients with lacunar stroke,13,76 possibly because patients with lacunar as opposed to other ischaemic stroke subtypes lacked any large artery atheromatous disease to prevent (eg myocardial infarction, large artery stroke, etc),18 further evidence of the largely non-atheromatous nature of”
From Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging (2013) · cites this paper as [13]
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Cites
(2001) · New England Journal of Medicine · doi:10.1056/nejmoa010746 · Cited by 6,470 · see citing works
Self-citationKernan, W. N., Ovbiagele, B., Black, H. R., Bravata, D. M., Chimowitz, M. I., Ezekowitz, M. D., Fang, M. C., Fisher, M., Furie, K. L., Heck, D. V., et al. (2014) · Stroke · doi:10.1161/str.0000000000000024 · Cited by 5,170 · see citing works
Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events
Bhatt, D. L., Fox, K. A. A., Hacke, W., Berger, P. B., Black, H. R., Boden, W. E., Cacoub, P., Cohen, E. A., Creager, M. A., Easton, J. D., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa060989 · Cited by 2,819 · see citing works
Diener, H.-C., Bogousslavsky, J., Brass, L. M., Cimminiello, C., Csiba, L., Kaste, M., Leys, D., Matias-Guiu, J., & Rupprecht, H.-J. (2004) · The Lancet · doi:10.1016/s0140-6736(04)16721-4 · Cited by 2,275 · see citing works
Effect of clopidogrel added to aspirin in patients with atrial fibrillation
The ACTIVE Investigators (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0901301 · Cited by 2,102 · see citing works
Guidelines for the Prevention of Stroke in Patients With Stroke or Transient Ischemic Attack
Furie, K. L., Kasner, S. E., Adams, R. J., Albers, G. W., Bush, R. L., Fagan, S. C., Halperin, J. L., Johnston, S. C., Katzan, I. L., Kernan, W. N., et al. (2010) · Stroke · doi:10.1161/str.0b013e3181f7d043 · Cited by 1,492 · see citing works
The Lausanne Stroke Registry: analysis of 1,000 consecutive patients with first stroke.
Bogousslavsky, J., van Melle, G., & Regli, F. (1988) · Stroke · doi:10.1161/01.str.19.9.1083 · Cited by 1,352 · see citing works
Kolominsky-Rabas, P. L., Weber, M., Gefeller, O., Neundoerfer, B., & Heuschmann, P. U. (2001) · Stroke · doi:10.1161/hs1201.100209 · Cited by 1,281 · see citing works
Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke
Sacco, R. L., Diener, H.-C., Yusuf, S., Cotton, D., Ôunpuu, S., Lawton, W. A., Palesch, Y., Martin, R. H., Albers, G. W., Bath, P., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0805002 · Cited by 961 · see citing works
Dose Comparisons of Clopidogrel and Aspirin in Acute Coronary Syndromes
The CURRENT–OASIS 7 Investigators (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0909475 · Cited by 767 · see citing works
Self-citationPeters, R. J. G., Mehta, S. R., Fox, K. A. A., Zhao, F., Lewis, B. S., Kopecky, S. L., Díaz, R., Commerford, P., Valentín, V., & Yusuf, S. (2003) · Circulation · doi:10.1161/01.cir.0000091201.39590.cb · Cited by 704 · see citing works
Avoiding Central Nervous System Bleeding During Antithrombotic Therapy
Hart, R. G., Tonarelli, S. B., & Pearce, L. A. (2005) · Stroke · doi:10.1161/01.str.0000170642.39876.f2 · Cited by 354 · see citing works
Clinical determinants of dememtia related to stroke
Tatemichi, T. K., Desmond, D. W., Paik, M. C., Figueroa, M., Gropen, T., Stern, Y., Sano, M. C., Remien, R. H., Williams, J. B. W., Mohr, J. P., et al. (1993) · Annals of Neurology · doi:10.1002/ana.410330603 · Cited by 293 · see citing works
Lavados, P., Sacks, C., Prina, L., Escobar, A., Tossi, C., Araya, F., Feuerhake, W., Gálvez, M., Salinas, R., & Álvarez, G. (2005) · The Lancet · doi:10.1016/s0140-6736(05)66779-7 · Cited by 264 · see citing works
Drug drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding
Delaney, J. A., Opatrny, L., Brophy, J. M., & Suissa, S. (2007) · Canadian Medical Association Journal · doi:10.1503/cmaj.070186 · Cited by 245 · see citing works
Wardlaw, J. M. (2005) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2004.039982 · Cited by 233 · see citing works
Wolfe, C. D. A. (2002) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.72.2.211 · Cited by 231 · see citing works
Berger, P. B., Bhatt, D. L., Fuster, V., Steg, P. G., Fox, K. A. A., Shao, M., Brennan, D. M., Hacke, W., Montalescot, G., Steinhubl, S. R., et al. (2010) · Circulation · doi:10.1161/circulationaha.109.895342 · Cited by 231 · see citing works
Bousser, M., Amarenco, P., Chamorro, Á., Fisher, M., Ford, I., Fox, K. M., Hennerici, M. G., Mattle, H. P., Rothwell, P. M., de Cordoüe, A., et al. (2011) · The Lancet · doi:10.1016/s0140-6736(11)60600-4 · Cited by 214 · see citing works
Race-ethnic differences in stroke risk factors among hospitalized patients with cerebral infarction
Sacco, R. L., Kargman, D. E., & Zamanillo, M. C. (1995) · Neurology · doi:10.1212/wnl.45.4.659 · Cited by 194 · see citing works
Saposnik, G., & Brutto, Ó. H. D. (2003) · Stroke · doi:10.1161/01.str.0000088063.74250.db · Cited by 194 · see citing works
A COMPARISON OF THREE INDICATORS FOR IDENTIFYING MEXICAN AMERICANS IN EPIDEMIOLOGIC RESEARCH
Hazuda, H. P., Comeaux, P. J., D, M. P. S. M., Haffner, S. M., Eifler, C. W., & Rosenthal, M. (1986) · American Journal of Epidemiology · doi:10.1093/oxfordjournals.aje.a114228 · Cited by 182 · see citing works
Steinhubl, S. R., Bhatt, D. L., Brennan, D. M., Montalescot, G., Hankey, G. J., Eikelboom, J. W., Berger, P. B., Topol, E. J., & on behalf of the CHARISMA Investigators (2009) · Annals of Internal Medicine · doi:10.7326/0003-4819-150-6-200903170-00006 · Cited by 179 · see citing works
Characterization of risk factors for vascular dementia
Ross, G. W., Petrovitch, H., White, L. R., Masaki, K., Li, C. Y., Curb, J. D., Yano, K., Rodríguez, B. L., Foley, D. J., Blanchette, P. L., et al. (1999) · Neurology · doi:10.1212/wnl.53.2.337 · Cited by 151 · see citing works
The Secondary Prevention of Small Subcortical Strokes (SPS3) Study
Benavente, O., White, C. L., Pearce, L. A., Pérgola, P. E., Roldan, A., Benavente, M.-F., Coffey, C. S., McClure, L. A., Szychowski, J. M., CONWIT, R. A., et al. (2011) · International Journal of Stroke · doi:10.1111/j.1747-4949.2010.00573.x · Cited by 151 · see citing works
Brutto, Ó. H. D., Mosquera, A., Sánchez, X., et al. (1993) · Stroke · doi:10.1161/01.str.24.12.1833 · Cited by 56 · see citing works
Impact of Race and Ethnicity on Ischemic Stroke
Zweifler, R. M., Lyden, P. D., Taft, B. J., et al. (1995) · Stroke · doi:10.1161/01.str.26.2.245 · Cited by 56 · see citing works
Effect of Addition of Clopidogrel to Aspirin on Mortality: Systematic Review of Randomized Trials
Palacio, S., Hart, R. G., Pearce, L. A., & Benavente, O. R. (2012) · Stroke · doi:10.1161/strokeaha.112.656173 · Cited by 47 · see citing works
Usman, M., Notaro, L. A., Nagarakanti, R., Brahin, E., Dessain, S. K., Gracely, E. J., & Ezekowitz, M. D. (2009) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2009.01.003 · Cited by 46 · see citing works
Prognosis for Survival, Handicap and Recurrence of Stroke in Lacunar and Superficial Infarction
Boiten, J., & Lodder, J. (1993) · Cerebrovascular Diseases · doi:10.1159/000108704 · Cited by 35 · see citing works
White, C. L., Szychowski, J. M., Roldan, A., Benavente, M.-F., Pretell, E. J., Brutto, Ó. H. D., Kase, C. S., Araúz, A., Meyer, B. C., Meissner, I., et al. (2012) · Journal of Stroke and Cerebrovascular Diseases · doi:10.1016/j.jstrokecerebrovasdis.2012.03.002 · Cited by 32 · see citing works
Survey of the causes of stroke among Mexican Americans in South Texas.
Worley, K. L., Lalonde, D. R., Kerr, D. R., et al. (1998) · PubMed · Cited by 15 · see citing works
McClure, L. A., Szychowski, J. M., Benavente, O., & Coffey, C. S. (2012) · Contemporary Clinical Trials · doi:10.1016/j.cct.2012.06.007 · Cited by 10 · see citing works
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2021 ESC Guidelines on cardiovascular disease prevention in clinical practice
Visseren, F. L. J., Mach, F., Smulders, Y. M., Carballo, D., Koskinas, K. C., Bäck, M., Benetos, A., Biffi, A., Boavida, J.-M., Capodanno, D., et al. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehab484 · Cited by 6,485 · see citing works
Kernan, W. N., Ovbiagele, B., Black, H. R., Bravata, D. M., Chimowitz, M. I., Ezekowitz, M. D., Fang, M. C., Fisher, M., Furie, K. L., Heck, D. V., et al. (2014) · Stroke · doi:10.1161/str.0000000000000024 · Cited by 5,170 · see citing works
Kleindorfer, D. O., Towfighi, A., Chaturvedi, S., Cockroft, K. M., Gutierrez, J., Lombardi-Hill, D., Kamel, H., Kernan, W. N., Kittner, S. J., Leira, E. C., et al. (2021) · Stroke · doi:10.1161/str.0000000000000375 · Cited by 3,237 · see citing works
Twelve or 30 Months of Dual Antiplatelet Therapy after Drug-Eluting Stents
Mauri, L., Kereiakes, D. J., Yeh, R. W., Driscoll-Shempp, P., Cutlip, D. E., Steg, P. G., Normand, S.-L. T., Braunwald, E., Wiviott, S. D., Cohen, D. J., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1409312 · Cited by 1,928 · see citing works
Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging
Wardlaw, J. M., Smith, C., & Dichgans, M. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70060-7 · Cited by 1,657 · see citing works
Bushnell, C., McCullough, L. D., Awad, I. A., Chireau, M. V., Fedder, W. N., Furie, K. L., Howard, V. J., Lichtman, J. H., Lisabeth, L. D., Piña, I. L., et al. (2014) · Stroke · doi:10.1161/01.str.0000442009.06663.48 · Cited by 941 · see citing works
Lackland, D. T., Roccella, E. J., Deutsch, A. F., Fornage, M., George, M. G., Howard, G., Kissela, B. M., Kittner, S. J., Lichtman, J. H., Lisabeth, L. D., et al. (2014) · Stroke · doi:10.1161/01.str.0000437068.30550.cf · Cited by 815 · see citing works
Iadecola, C., Yaffe, K., Biller, J., Bratzke, L. C., Faraci, F. M., Gorelick, P. B., Gulati, M., Kamel, H., Knopman, D. S., Launer, L. J., et al. (2016) · Hypertension · doi:10.1161/hyp.0000000000000053 · Cited by 746 · see citing works
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DeFronzo, R. A., Inzucchi, S., Abdul-Ghani, M., & Nissen, S. E. (2019) · Diabetes and Vascular Disease Research · doi:10.1177/1479164118825376 · Cited by 223 · see citing works
Young, L. H., Viscoli, C. M., Curtis, J. P., Inzucchi, S. E., Schwartz, G. G., Lovejoy, A. M., Furie, K. L., Gorman, M. J., Conwit, R., Abbott, J. D., et al. (2017) · Circulation · doi:10.1161/circulationaha.116.024863 · Cited by 66 · see citing works
Pearce, L. A., McClure, L. A., Anderson, D. C., Jacova, C., Sharma, M., Hart, R. G., & Benavente, O. R. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70224-8 · Cited by 135 · see citing works
- Authors
- The SPS3 Investigators
- Corresponding author
- The SPS3 Investigators
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2012-08-30
- Volume
- 367
- Issue
- 9
- Pages
- 817-825
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4067036
- OpenAlex
- W191849520
- Cited by
- 679
- References
- 33
- Citations by year
- 2026: 13 · 2025: 28 · 2024: 40 · 2023: 51 · 2022: 52 · 2021: 51 · 2020: 44 · 2019: 66 · 2018: 42 · 2017: 42 · 2016: 49 · 2015: 65 · 2014: 70 · 2013: 57 · 2012: 6
- FWCI
- 40.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (U01NS038529, U01NS38529-04A1)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Antiplatelet Therapy and Cardiovascular Diseases
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cerebrovascular and Carotid Artery Diseases
- Keywords
- clopidogrel, aspirin, dual antiplatelet therapy, lacunar infarction, stroke recurrence, secondary stroke prevention, cerebral small vessel disease, intracranial hemorrhage, all-cause mortality, ischemic stroke, antiplatelet therapy
- MeSH terms
- Clopidogrel, Aspirin, Double-Blind Method, Drug Therapy, Combination, Female, Follow-Up Studies, Hemorrhage, Humans, Male, Middle Aged, Platelet Aggregation Inhibitors, Recurrence, Ticlopidine, Stroke, Stroke, Lacunar
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