European Journal of Internal Medicine 25 (2014) e40–e41
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Letter to the Editor Switching from aspirin to clopidogrel in patients with aspirin resistance after an ischemic stroke. Is it a good solution? Keywords: Antiagregants Aspirin Aspirin resistance Clopidogrel Ischemic stroke Stroke prevention
Aspirin (ASA), the most commonly used antiplatelet agent, prevents stroke recurrence among patients with a recent stroke or transient ischemic attack (TIA). In a meta-regression analysis of placebo controlled trials of ASA therapy for secondary stroke prevention, the relative risk reduction for stroke was estimated at 15% (95% CI, 6% to 23%) [1]. However, clinical and laboratory evidence demonstrates diminished or no response to ASA in some patients that is called ASA resistance. This situation has been reported to be independently associated with an increased risk of adverse cardiovascular events: ASA resistance is associated with increased clinical severity and stroke infarct volume in acute stroke patients, increased the rate of recurrent stroke and other vascular events, and is also linked with short and long term mortality in these patients [2,3]. Nonetheless, there is a paucity of data from investigational studies regarding the most suitable therapeutic intervention in these cases. Current evidence-based guidelines provide little or no recommendations on the proper management strategy for stroke patients who have ASA resistance. Clopidogrel has also been used in monotherapy as an antiplatelet agent in stroke prevention. Currently, for patients with noncardioembolic ischemic stroke or TIA, monotherapy with clopidogrel of 75 mg is an acceptable option for initial therapy to reduce risk of recurrent stroke and other cardiovascular events (Class IIa; Level of Evidence B) [4]. However, it is not known whether patients with stroke and ASA resistance are better protected with clopidogrel. We aimed to evaluate the response to clopidogrel among ASAresistant stroke patients. Fifty patients aged 48–85 years (mean age: 68) who had ischemic stroke in the previous 6 months were assessed. ASA had been taken since the stroke episode. Resistance was analyzed using the PFA-100 aggregometer (Dade-Behring, Marburg, Germany). In those patients with ASA resistance ASA was switched to clopidogrel, and then clopidogrel resistance was assessed with the PFA-100 analyzer. We included 43 (86%) lacunar strokes and 7 (14%) non-lacunar strokes. Thirty-seven (74%) patients were male. Twenty-nine (58%) patients received ASA in a daily dose of 300 mg, 5 (10%) 150 mg/day, and 16 (32%) 100 mg/day. Hypertension was the commonest risk factor (36 patients, 72%). Other risk factors included
hypercholesterolemia (34 patients, 68%), diabetes mellitus (24 patients, 48%), smoking (20 patients, 40%), obesity (21 patients, 42%), and previous stroke (6 patients, 12%). ASA resistance was observed in 16 (32%) patients. We found no correlation between diminished response to ASA and vascular risk factors, ASA dosage, type of ischemic stroke, or sex. However, patients with resistance to ASA presented a higher frequency of previous stroke (p = 0.01). Clopidogrel resistance was tested in 12 of these ASA resistant patients. Two patients died and two patients didn't sign the informed consent form. Six of these ASA-resistant patients (50%) presented clopidogrel resistance. Though many studies have assessed the presence of ASA resistance in stroke patients, no previous studies have evaluated the prevalence of clopidogrel resistance in stroke patients with laboratory tested ASA resistance. In fact, current AHA/ASA stroke recommendations for antithrombotic therapy for non-cardioembolic stroke or TIA state that “there was no evidence that increasing the dose of aspirin provides additional benefit and no single agent or combination had been studied in patients who had an event while receiving aspirin” (Class IIb; Level of Evidence C) [4]. Despite the high frequency and clinical importance of this phenomenon, only one clinical trial, the Secondary Prevention of Small Subcortical Strokes (SPS3) [5] has recently directly addressed the issue of subsequent antiplatelet therapy for patients who experience recurrent episodes of brain ischemia while taking ASA. In a post-hoc analysis of the SPS3 trial, 838 patients with a recent lacunar stroke while taking aspirin were randomized to continued use of ASA versus the combination of clopidogrel plus ASA. Investigators found that among such clinical ASA failure patients, the risk of recurrent stroke was not reduced in the dual antiplatelet group, 3.1% per year compared to the ASA only group, 3.3% per year (HR, 0.91; 95% CI, 0.61–1.37). Moreover, this combination was associated with a higher risk of gastrointestinal bleeding (HR, 2.7; 95% CI, 1.1–6.9). In our study we evaluate the response to clopidogrel among ASA resistant stroke patients. Approximately, one in three patients was ASA resistant, and among them almost half were also resistant to clopidogrel. Therefore, it is likely that switching to clopidogrel in ASA resistant patients would not improve platelet aggregability and clinical outcome. Moreover, according to SP3S results, even adding clopidogrel in ASA resistant stroke patients would not reduce stroke recurrence [6]. Our results also confirm that ASA failure patients constitute a highrisk group with a higher residual platelet activity. Data from Warfarin Aspirin Recurrent Stroke Study (WARSS) [7] also demonstrated that patients who had their baseline event while taking ASA had higher recurrent-event rates than the overall study population. Accordingly, investigators from the SP3S found that the ASA failure group had a higher risk of recurrent ischemic stroke (2.9%/year vs. 1.9%/year; HR 1.36, 95% CI1.03–1.79; p = 0.03). Future studies are warranted regarding the most suitable therapeutic intervention in these patients and to support whether platelet function test-guided antiplatelet treatment is also needed in this population.
0953-6205/$ – see front matter © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2014.01.007
Letter to the Editor
Conflict of interests The authors state that they have no conflicts of interest. References [1] Sandercock PAG, Counsell C, Gubitz GJ, Tseng MC. Antiplatelet therapy for acute ischemic stroke. Cochrane Database Syst Rev 2008;3 [CD000029]. [2] Zheng AS, Churilov L, Colley RE, Goh C, Davis SM, Yan B. Association of aspirin resistance with increased stroke severity and infarct size. JAMA Neurol 2013;70:208–13. [3] Yi X, Zhou Q, Lin J, Chi L. Aspirin resistance in Chinese stroke patients increased the rate of recurrent stroke and other vascular events. Int J Stroke 2013;8:535–9. [4] Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:227–76. [5] Côté R, Zhang Y, Hart RG, McClure LA, Anderson DC, Talbert RL, et al. ASA failure: does the combination ASA/clopidogrel confer better long-term vascular protection? Neurology 2014 Jan 2 [Epub ahead of print]. [6] Castilla-Guerra L, Sacco RL. Treating lacunar strokes occurring on Aspirin. Adding clopidogrel is not the simple solution. Neurology 2014;82:1–2. [7] Mohr JP, Sciacca RR, Thompson JLP, Levin B, Sacco RL. The WARSS Group. Aspirin failure in the warfarin aspirin recurrent stroke study. Stroke 2003;34:238 [Abstract].
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Luis Castilla-Guerra Department of Internal Medicine, Hospital de la Merced, Osuna, Seville, Spain Corresponding author at: Servicio de Medicina Interna, Hospital de la Merced, Osuna, 41640 Seville, Spain. Tel.: +34 955077261; fax: +34 955077260. E-mail address: [email protected]. Maria del Carmen Fernandez-Moreno Department of Neurology, Hospital de Valme, University of Seville, Seville, Spain María Sierra Navas-Alcantara Department of Internal Medicine, Hospital de la Merced, Osuna, Seville, Spain Francisco Jimenez-Gonzalo Department of Hematology, Hospital de la Merced, Osuna, Seville, Spain 9 January 2014
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Letter to the Editor Switching from aspirin to clopidogrel in patients with aspirin resistance after an ischemic stroke. Is it a good solution? Keywords: Antiagregants Aspirin Aspirin resistance Clopidogrel Ischemic stroke Stroke prevention
Aspirin (ASA), the most commonly used antiplatelet agent, prevents stroke recurrence among patients with a recent stroke or transient ischemic attack (TIA). In a meta-regression analysis of placebo controlled trials of ASA therapy for secondary stroke prevention, the relative risk reduction for stroke was estimated at 15% (95% CI, 6% to 23%) [1]. However, clinical and laboratory evidence demonstrates diminished or no response to ASA in some patients that is called ASA resistance. This situation has been reported to be independently associated with an increased risk of adverse cardiovascular events: ASA resistance is associated with increased clinical severity and stroke infarct volume in acute stroke patients, increased the rate of recurrent stroke and other vascular events, and is also linked with short and long term mortality in these patients [2,3]. Nonetheless, there is a paucity of data from investigational studies regarding the most suitable therapeutic intervention in these cases. Current evidence-based guidelines provide little or no recommendations on the proper management strategy for stroke patients who have ASA resistance. Clopidogrel has also been used in monotherapy as an antiplatelet agent in stroke prevention. Currently, for patients with noncardioembolic ischemic stroke or TIA, monotherapy with clopidogrel of 75 mg is an acceptable option for initial therapy to reduce risk of recurrent stroke and other cardiovascular events (Class IIa; Level of Evidence B) [4]. However, it is not known whether patients with stroke and ASA resistance are better protected with clopidogrel. We aimed to evaluate the response to clopidogrel among ASAresistant stroke patients. Fifty patients aged 48–85 years (mean age: 68) who had ischemic stroke in the previous 6 months were assessed. ASA had been taken since the stroke episode. Resistance was analyzed using the PFA-100 aggregometer (Dade-Behring, Marburg, Germany). In those patients with ASA resistance ASA was switched to clopidogrel, and then clopidogrel resistance was assessed with the PFA-100 analyzer. We included 43 (86%) lacunar strokes and 7 (14%) non-lacunar strokes. Thirty-seven (74%) patients were male. Twenty-nine (58%) patients received ASA in a daily dose of 300 mg, 5 (10%) 150 mg/day, and 16 (32%) 100 mg/day. Hypertension was the commonest risk factor (36 patients, 72%). Other risk factors included
hypercholesterolemia (34 patients, 68%), diabetes mellitus (24 patients, 48%), smoking (20 patients, 40%), obesity (21 patients, 42%), and previous stroke (6 patients, 12%). ASA resistance was observed in 16 (32%) patients. We found no correlation between diminished response to ASA and vascular risk factors, ASA dosage, type of ischemic stroke, or sex. However, patients with resistance to ASA presented a higher frequency of previous stroke (p = 0.01). Clopidogrel resistance was tested in 12 of these ASA resistant patients. Two patients died and two patients didn't sign the informed consent form. Six of these ASA-resistant patients (50%) presented clopidogrel resistance. Though many studies have assessed the presence of ASA resistance in stroke patients, no previous studies have evaluated the prevalence of clopidogrel resistance in stroke patients with laboratory tested ASA resistance. In fact, current AHA/ASA stroke recommendations for antithrombotic therapy for non-cardioembolic stroke or TIA state that “there was no evidence that increasing the dose of aspirin provides additional benefit and no single agent or combination had been studied in patients who had an event while receiving aspirin” (Class IIb; Level of Evidence C) [4]. Despite the high frequency and clinical importance of this phenomenon, only one clinical trial, the Secondary Prevention of Small Subcortical Strokes (SPS3) [5] has recently directly addressed the issue of subsequent antiplatelet therapy for patients who experience recurrent episodes of brain ischemia while taking ASA. In a post-hoc analysis of the SPS3 trial, 838 patients with a recent lacunar stroke while taking aspirin were randomized to continued use of ASA versus the combination of clopidogrel plus ASA. Investigators found that among such clinical ASA failure patients, the risk of recurrent stroke was not reduced in the dual antiplatelet group, 3.1% per year compared to the ASA only group, 3.3% per year (HR, 0.91; 95% CI, 0.61–1.37). Moreover, this combination was associated with a higher risk of gastrointestinal bleeding (HR, 2.7; 95% CI, 1.1–6.9). In our study we evaluate the response to clopidogrel among ASA resistant stroke patients. Approximately, one in three patients was ASA resistant, and among them almost half were also resistant to clopidogrel. Therefore, it is likely that switching to clopidogrel in ASA resistant patients would not improve platelet aggregability and clinical outcome. Moreover, according to SP3S results, even adding clopidogrel in ASA resistant stroke patients would not reduce stroke recurrence [6]. Our results also confirm that ASA failure patients constitute a highrisk group with a higher residual platelet activity. Data from Warfarin Aspirin Recurrent Stroke Study (WARSS) [7] also demonstrated that patients who had their baseline event while taking ASA had higher recurrent-event rates than the overall study population. Accordingly, investigators from the SP3S found that the ASA failure group had a higher risk of recurrent ischemic stroke (2.9%/year vs. 1.9%/year; HR 1.36, 95% CI1.03–1.79; p = 0.03). Future studies are warranted regarding the most suitable therapeutic intervention in these patients and to support whether platelet function test-guided antiplatelet treatment is also needed in this population.
0953-6205/$ – see front matter © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2014.01.007
Letter to the Editor
Conflict of interests The authors state that they have no conflicts of interest. References [1] Sandercock PAG, Counsell C, Gubitz GJ, Tseng MC. Antiplatelet therapy for acute ischemic stroke. Cochrane Database Syst Rev 2008;3 [CD000029]. [2] Zheng AS, Churilov L, Colley RE, Goh C, Davis SM, Yan B. Association of aspirin resistance with increased stroke severity and infarct size. JAMA Neurol 2013;70:208–13. [3] Yi X, Zhou Q, Lin J, Chi L. Aspirin resistance in Chinese stroke patients increased the rate of recurrent stroke and other vascular events. Int J Stroke 2013;8:535–9. [4] Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:227–76. [5] Côté R, Zhang Y, Hart RG, McClure LA, Anderson DC, Talbert RL, et al. ASA failure: does the combination ASA/clopidogrel confer better long-term vascular protection? Neurology 2014 Jan 2 [Epub ahead of print]. [6] Castilla-Guerra L, Sacco RL. Treating lacunar strokes occurring on Aspirin. Adding clopidogrel is not the simple solution. Neurology 2014;82:1–2. [7] Mohr JP, Sciacca RR, Thompson JLP, Levin B, Sacco RL. The WARSS Group. Aspirin failure in the warfarin aspirin recurrent stroke study. Stroke 2003;34:238 [Abstract].
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Luis Castilla-Guerra Department of Internal Medicine, Hospital de la Merced, Osuna, Seville, Spain Corresponding author at: Servicio de Medicina Interna, Hospital de la Merced, Osuna, 41640 Seville, Spain. Tel.: +34 955077261; fax: +34 955077260. E-mail address: [email protected]. Maria del Carmen Fernandez-Moreno Department of Neurology, Hospital de Valme, University of Seville, Seville, Spain María Sierra Navas-Alcantara Department of Internal Medicine, Hospital de la Merced, Osuna, Seville, Spain Francisco Jimenez-Gonzalo Department of Hematology, Hospital de la Merced, Osuna, Seville, Spain 9 January 2014
