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Original Paper

Free Access

Treatment with Clopidogrel Prior to Acute Non-Cardioembolic Ischemic Stroke Attenuates Stroke Severity

Tziomalos K. · Giampatzis V. · Bouziana S.D. · Spanou M. · Kostaki S. · Papadopoulou M. · Angelopoulou S.-M. · Tsopozidi M. · Savopoulos C. · Hatzitolios A.I.

Author affiliations

First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece

Corresponding Author

Konstantinos Tziomalos

First Propedeutic Department of Internal Medicine

AHEPA Hospital, 1 Stilponos Kyriakidi Street

GR-54636 Thessaloniki (Greece)

E-Mail ktziomalos@yahoo.com

Related Articles for ""

Cerebrovasc Dis 2016;41:226-232

Abstract

Background: Clopidogrel reduces the risk of non-cardioembolic ischemic stroke, but it is unclear whether it affects the severity and outcome of stroke. We aimed at evaluating the effect of prior treatment with clopidogrel on acute non-cardioembolic ischemic stroke severity and in-hospital outcome. Methods: We prospectively studied 608 consecutive patients (39.5% males, age 79.1 ± 6.6 years) who were admitted with acute ischemic stroke. The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). Severe stroke was defined as NIHSS ≥21. The outcome was assessed using the dependency rates that prevailed at the time of discharge (i.e. modified Rankin scale between 2 and 5) and with in-hospital mortality. Results: At admission, 397 patients did not have atrial fibrillation or heart valve disease. Among these 397 patients, 69 were receiving monotherapy with clopidogrel prior to stroke, 69 were receiving monotherapy with aspirin and 236 patients were not on any antiplatelet treatment. The prevalence of severe stroke was lower in patients who were receiving clopidogrel than in patients who were receiving aspirin and patients who were not on antiplatelets (1.4, 13.0 and 11.0%, respectively; p < 0.05). Independent predictors of severe stroke at admission were male gender (relative risk (RR) 0.31, 95% CI 0.12-0.78, p < 0.05) and treatment with clopidogrel prior to stroke compared with no antiplatelet treatment (RR 0.13, 95% CI 0.02-0.97, p < 0.05). Treatment with aspirin prior to stroke did not predict severe stroke compared with no antiplatelet treatment (RR 1.24, 95% CI 0.51-2.98, p = NS). The rate of dependency at discharge did not differ between patients who were receiving clopidogrel, patients who were receiving aspirin and those who were not on antiplatelets (57.9, 47.8 and 59.7%, respectively; p = NS). Independent predictors of dependency at discharge were age (RR 1.12, 95% CI 1.05-1.19, p < 0.001) and NIHSS at admission (RR 1.67, 95% CI 1.46-1.92, p < 0.001). In-hospital mortality rate also did not differ between patients who were receiving clopidogrel, patients who were receiving aspirin and those who were not on antiplatelets (4.3, 4.3 and 5.0%, respectively; p = NS). The only independent predictor of in-hospital mortality was NIHSS at admission (RR 1.22, 95% CI 1.14-1.30, p < 0.001). Conclusions: Treatment with clopidogrel prior to acute non-cardioembolic ischemic stroke attenuates the severity of stroke at admission but does not appear to affect the functional outcome at discharge or the in-hospital mortality of these patients.

© 2016 S. Karger AG, Basel


Introduction

Non-cardioembolic ischemic stroke represents approximately 58-80% of ischemic strokes [1,2,3,4]. Antiplatelet treatment is an essential component of the secondary prevention of non-cardioembolic ischemic stroke [5]. Options include aspirin, clopidogrel, and aspirin combined with dipyridamole [5]. In randomized controlled trials in patients with a history of ischemic stroke, clopidogrel was as effective as aspirin alone or in combination with dipyridamole in reducing cardiovascular events [6,7]. Moreover, treatment with clopidogrel was associated with a lower risk for bleeding than aspirin alone or in combination with dipyridamole [6,7]. On the other hand, the role of antiplatelet treatment in the primary prevention of ischemic stroke is more controversial. The current American Heart Association/American Stroke Association guidelines recommend the use of aspirin for primary prevention of ischemic stroke in high-risk patients [8]. In contrast, the European Society of Cardiology does not recommend the use of aspirin in patients without established cardiovascular disease (CVD) [9]. In this population, the reduction in the risk of cardiovascular events by aspirin is counterbalanced by an increased incidence of gastrointestinal and intracranial bleedings [10]. Neither clopidogrel monotherapy nor aspirin combined with dipyridamole has been evaluated for the primary prevention of CVD and are not recommended in this setting [8,9].

In addition to the reduced risk of non-cardioembolic stroke with antiplatelet treatment, some studies suggested that patients who are receiving aspirin prior to stroke experience less severe stroke and have better outcomes [11,12,13,14]. However, other reports did not confirm these beneficial effects of aspirin [15,16,17,18,19]. On the other hand, very few studies assessed the effects of prior treatment with clopidogrel on acute non-cardioembolic ischemic stroke severity and outcome and yielded conflicting results [13,17,20]. If treatment with clopidogrel before stroke attenuates stroke severity and improves outcome, this would further support its use as a first-line agent in patients with non-cardioembolic ischemic stroke, who are at high risk for recurrent stroke.

The aim of this study was to evaluate the effect of prior treatment with clopidogrel on acute non-cardioembolic (i.e. not associated with atrial fibrillation (AF) or heart valve disease) ischemic stroke severity, functional outcome at discharge and in-hospital mortality.

Patients and Methods

We prospectively studied all patients who were admitted in our department with acute ischemic stroke between September 2010 and February 2014 (n = 608; 39.5% males, age 79.1 ± 6.6 years).

At admission, demographic data (age, sex), history of cardiovascular risk factors (hypertension, type 2 diabetes mellitus (T2DM), AF, smoking, excessive alcohol consumption, family history of premature CVD), history of concomitant CVD (coronary heart disease (CHD), previous ischemic stroke, heart failure, heart valve disease) and pharmacological treatment were recorded. Anthropometric parameters (weight, height, waist and hip circumference) and systolic and diastolic blood pressure were also measured. The severity of stroke was assessed at admission using the National Institutes of Health Stroke Scale (NIHSS). Severe stroke was defined as NIHSS at admission ≥21.

Routine laboratory investigations were performed after overnight fasting at the first day after admission and included serum levels of glucose, total cholesterol, high-density lipoprotein cholesterol, triglycerides, creatinine and uric acid. Low-density lipoprotein cholesterol levels were calculated using Friedewald's formula [21]. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease equation [22]. Chronic kidney disease was defined as estimated GFR <60 ml/min/1.73 m2. All patients underwent brain computed tomography at admission and a second brain computed tomography was performed if clinically indicated.

The outcome was assessed with dependency rates at discharge and with in-hospital mortality. Dependency was defined as a modified Rankin scale (mRS) at discharge between 2 and 5.

Statistical Analysis

All data were analyzed with the statistical package SPSS (version 17.0; SPSS, Chicago, Ill., USA). Data are presented as percentages for categorical variables and as mean and SD for continuous variables. Differences in categorical variables between groups were assessed with the chi-square test. Differences in continuous variables between groups were assessed with one-way analysis of variance and post hoc tests were performed with the Holm-Sidak test. Binary logistic regression analysis was used to identify independent predictors of severe stroke, dependency at discharge and in-hospital mortality. In all cases, a 2-tailed p < 0.05 was considered significant.

Results

At admission, 397 patients (65.3% of the total study population) did not have AF, a history of AF, prosthetic heart valve or a history of hemodynamically relevant valve disease. Among these 397 patients, 69 patients were receiving monotherapy with clopidogrel prior to stroke, 69 patients were receiving monotherapy with aspirin, 236 patients were not on any antiplatelet treatment and 23 patients were on other antiplatelet agents (aspirin plus clopidogrel (n = 15), aspirin plus dipyridamole (n = 2) or triflusal alone (n = 6)). Characteristics of patients without AF or heart valve disease who were on monotherapy with clopidogrel prior to stroke, of patients without AF or heart valve disease who were on monotherapy with aspirin and of patients without AF or heart valve disease who were on no antiplatelet treatment are shown in the table 1.

Table 1

Characteristics at admission of patients without AF or heart valve disease who were on clopidogrel prior to stroke, of patients without AF or heart valve disease who were on aspirin prior to stroke and of patients without AF or heart valve disease who were on no antiplatelet treatment prior to stroke

http://www.karger.com/WebMaterial/ShowPic/491626

At admission, 36 of the 374 patients (9.6%) who were receiving monotherapy with clopidogrel or aspirin prior to stroke or were not on any antiplatelet treatment had a severe stroke. The prevalence of severe stroke was lower in patients who were receiving clopidogrel prior to stroke than in patients who were receiving aspirin prior to stroke and patients who were not on any antiplatelet agent (1.4, 13.0 and 11.0%, respectively; p < 0.05; fig. 1). Patients with severe stroke were more frequently females than patients with non-severe stroke (80.0 and 56.7%, respectively; p < 0.05) and had higher prevalence of obesity (40.1 and 23.3%, respectively; p < 0.05). In binary logistic regression analysis, independent predictors of severe stroke at admission were male gender (relative risk (RR) 0.31, 95% CI 0.12-0.78, p < 0.05) and treatment with clopidogrel prior to stroke compared with no antiplatelet treatment (RR 0.13, 95% CI 0.02-0.97, p < 0.05). Treatment with aspirin prior to stroke did not predict severe stroke compared with no antiplatelet treatment (RR 1.24, 95% CI 0.51-2.98, p = NS).

Fig. 1

Outcomes in patients who were receiving clopidogrel prior to stroke, in patients who were receiving aspirin prior to stroke and in patients who were not on any antiplatelet agent prior to stroke. Severe stroke: NIHSS at admission ≥21. Dependency: mRS at discharge between 2 and 5.

http://www.karger.com/WebMaterial/ShowPic/491625

The mRS at discharge did not differ between patients who were receiving clopidogrel prior to stroke, patients who were receiving aspirin prior to stroke and patients who were not on any antiplatelet agent (2.6 ± 2.0, 2.3 ± 2.1 and 2.7 ± 2.1, respectively; p = NS). The rates of dependency at discharge did not differ between patients who were receiving clopidogrel prior to stroke, patients who were receiving aspirin prior to stroke and those who were not on any antiplatelet agent (57.9, 47.8 and 59.7%, respectively; p = NS; fig. 1). Patients who were dependent at discharge were older than those who were independent (79.7 ± 6.7 and 77.1 ± 6.5 years, respectively; p < 0.001) and had higher NIHSS at admission (9.9 ± 7.4 and 2.0 ± 2.4, respectively; p < 0.001). In binary logistic regression analysis, independent predictors of dependency at discharge were age (RR 1.12, 95% CI 1.05-1.19, p < 0.001) and NIHSS at admission (RR 1.67, 95% CI 1.46-1.92, p < 0.001).

In-hospital mortality rates did not differ between patients who were receiving clopidogrel prior to stroke, patients who were receiving aspirin prior to stroke and those who were not on any antiplatelet agent (4.3, 4.3 and 5.0%, respectively; p = NS; fig. 1). Patients who died during hospitalization had higher prevalence of obesity than patients who were discharged (36.4 and 23.5%, respectively; p < 0.05) and also had higher heart rate at admission (85 ± 17 and 77 ± 14, respectively; p < 0.05) and higher NIHSS at admission (26.8 ± 7.1 and 6.7 ± 7.1, respectively; p < 0.001). In binary logistic regression analysis, the only independent predictor of in-hospital mortality was NIHSS at admission (RR 1.22, 95% CI 1.14-1.30, p < 0.001).

Discussion

This is one of the few studies that evaluated the effects of treatment of clopidogrel prior to stroke on stroke severity and outcome and the first study to exclusively evaluate patients with non-cardioembolic stroke, who are expected to benefit more from antiplatelet treatment. The main finding of our study is that treatment with clopidogrel prior to non-cardioembolic ischemic stroke is independently associated with less severe stroke at admission. In contrast, treatment with clopidogrel prior to non-cardioembolic ischemic stroke does not appear to affect the functional outcome at discharge and the in-hospital mortality risk of these patients.

Our study suggests that patients who are on clopidogrel prior to non-cardioembolic ischemic stroke have less severe stroke than those who are on no antiplatelet treatment. Very few studies evaluated the association between prior treatment with clopidogrel and acute ischemic stroke severity [13,17]. An early study did not identify any effect of clopidogrel or ticlopidine on ischemic stroke severity at admission [17]. However, the former study included only 51 patients who were treated with clopidogrel or ticlopidine prior to stroke and the number of patients treated with clopidogrel was not reported [17]. In a more recent and larger study performed in Canada, patients who were on clopidogrel prior to ischemic stroke (n = 447) had less severe stroke at admission compared with patients who were not on antiplatelets [13]. However, both studies included cardioembolic strokes in the analysis of the association between clopidogrel treatment and stroke severity [13,17]. It is well established that single antiplatelet treatment has limited efficacy in reducing cardiovascular events in patients with AF compared with placebo [23,24] and therefore, it is recommended only in patients with AF who have contraindications to oral anticoagulants or who refuse treatment with the latter agents [25]. Moreover, several studies showed that antiplatelet treatment prior to stroke in patients with AF does not affect the severity of stroke or the short-term outcome [26,27,28,29,30]. Therefore, we included in our analyses only patients without AF, prosthetic valve or hemodynamically relevant heart valve disease and we showed that clopidogrel attenuates the severity of non-cardioembolic stroke. This beneficial effect is most probably due to the antiplatelet actions of clopidogrel, which might lead to smaller thrombus size or to faster thrombus degradation and therefore to smaller infarct size [31,32,33]. However, clopidogrel also appears to exert antiinflammatory and antioxidant actions and to improve endothelial function, which might confer a neuroprotective effect during acute stroke [34,35,36,37].

In this study, treatment with clopidogrel prior to non-cardioembolic ischemic stroke had no effect on the functional outcome at discharge. However, patients who were on clopidogrel had higher prevalence of T2DM and prior stroke, which are associated with worse functional outcome [38,39,40,41,42,43,44]. Therefore, it is possible that clopidogrel might have a beneficial effect on the functional outcome of ischemic stroke. On the other hand, the aforementioned Canadian study also did not identify any difference in the functional outcome between patients who were on clopidogrel prior to ischemic stroke and those who were not on antiplatelets [13]. Moreover, in a substudy of the clopidogrel for high atherothrombotic risk and ischemic stabilization, management and avoidance trial, the functional outcome at 3 months after a first or recurrent stroke did not differ between patients treated with clopidogrel and those treated with placebo [45]. However, all patients were treated with aspirin in the former trial and both hemorrhagic and all types of ischemic stroke were analyzed [45]. Given the paucity of studies that assessed the effects of prior treatment with clopidogrel on the functional outcome of patients with acute non-cardioembolic stroke, more data are needed to evaluate this association.

In-hospital mortality rates did not differ in our study between patients treated with clopidogrel prior to stroke and those who were not on any antiplatelet agent. Nevertheless, patients who were on clopidogrel had a more adverse cardiovascular risk profile, that is, they had higher prevalence of T2DM, CHD, heart failure and prior stroke. Therefore, it is possible that these patients might have had experienced higher mortality rates if they were not on clopidogrel prior to stroke. In the aforementioned Canadian study, in-hospital mortality rates also did not differ between patients who were on clopidogrel prior to ischemic stroke and those who were not on antiplatelet agents [13]. In a more recent small study, mortality at 7 and 30 days after stroke did not differ between patients who were receiving clopidogrel prior to ischemic stroke (n = 63) and those who were not [20]. However, all types of ischemic stroke were included in the former report and stroke severity at admission was not evaluated and not adjusted for in the analysis of mortality risk [20]. Clearly, more studies are needed to clarify whether clopidogrel can reduce in-hospital mortality risk in patients who suffer a non-cardioembolic ischemic stroke.

Even though clopidogrel appears to attenuate stroke severity, it should be emphasized that patients who were receiving clopidogrel prior to stroke in our study are by definition non-responders to clopidogrel, since they suffered an ischemic stroke despite treatment with clopidogrel. In our study, these patients were elderly and had a high rate of T2DM and obesity, that is, they had several clinical parameters that are associated with reduced response to clopidogrel [46,47]. Patients who were treated with aspirin prior to stroke were also elderly and had a high prevalence of T2DM and obesity, which are also related to aspirin resistance [47]. Given the ageing of the population and the rising prevalence of T2DM and obesity [48,49], it is clear that there is a pressing need for novel, effective and safe antiplatelet agents for the primary and secondary prevention of stroke.

Our study has a number of limitations. Our patient population is skewed in clinical parameters and therefore, a lot of confounders may be present. This suggests that our study does not have adequate power to provide firm conclusions regarding the effects of clopidogrel on stroke severity and outcome.

In conclusion, our study suggests that treatment with clopidogrel prior to acute non-cardioembolic ischemic stroke attenuates the severity of stroke at admission. On the other hand, clopidogrel does not appear to affect the functional outcome at discharge or the in-hospital mortality of these patients. Larger studies are needed to confirm these findings. Moreover, there is a need for newer antiplatelet agents that will improve the outcome of patients with non-cardioembolic ischemic stroke.

Disclosure Statement

We have no conflict of interest to declare.


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  42. Park KY, Chung PW, Kim YB, Moon HS, Suh BC, Won YS, Kim JM, Youn YC, Kwon OS: Serum vitamin D status as a predictor of prognosis in patients with acute ischemic stroke. Cerebrovasc Dis 2015;40:73-80.
  43. Yao X, Dong Q, Song Y, Wang Y, Deng Y, Li Y: Thrombelastography maximal clot strength could predict one-year functional outcome in patients with ischemic stroke. Cerebrovasc Dis 2014;38:182-190.
  44. Fonville S, Zandbergen AA, Koudstaal PJ, den Hertog HM: Prediabetes in patients with stroke or transient ischemic attack: prevalence, risk and clinical management. Cerebrovasc Dis 2014;37:393-400.
  45. Hankey GJ, Hacke W, Easton JD, Johnston SC, Mas JL, Brennan DM, Bhatt DL, Fox KA, Topol EJ; CHARISMA Trial Investigators: Effect of clopidogrel on the rate and functional severity of stroke among high vascular risk patients: a prespecified substudy of the clopidogrel for high atherothrombotic risk and ischemic stabilization, management and avoidance (CHARISMA) trial. Stroke 2010;41:1679-1683.
  46. Siller-Matula JM, Trenk D, Schrör K, Gawaz M, Kristensen SD, Storey RF, Huber K; EPA (European Platelet Academy): Response variability to P2Y12 receptor inhibitors: expectations and reality. JACC Cardiovasc Interv 2013;6:1111-1128.
  47. Mijajlovic MD, Shulga O, Bloch S, Covickovic-Sternic N, Aleksic V, Bornstein NM: Clinical consequences of aspirin and clopidogrel resistance: an overview. Acta Neurol Scand 2013;128:213-219.
  48. Yang L, Colditz GA: Prevalence of overweight and obesity in the United States, 2007-2012. JAMA Intern Med 2015;175:1412-1413.
  49. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE: Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014;103:137-149.

Author Contacts

Konstantinos Tziomalos

First Propedeutic Department of Internal Medicine

AHEPA Hospital, 1 Stilponos Kyriakidi Street

GR-54636 Thessaloniki (Greece)

E-Mail ktziomalos@yahoo.com


Article / Publication Details

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Abstract of Original Paper

Received: August 13, 2015
Accepted: December 30, 2015
Published online: January 22, 2016
Issue release date: April 2016

Number of Print Pages: 7
Number of Figures: 1
Number of Tables: 1

ISSN: 1015-9770 (Print)
eISSN: 1421-9786 (Online)

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  42. Park KY, Chung PW, Kim YB, Moon HS, Suh BC, Won YS, Kim JM, Youn YC, Kwon OS: Serum vitamin D status as a predictor of prognosis in patients with acute ischemic stroke. Cerebrovasc Dis 2015;40:73-80.
  43. Yao X, Dong Q, Song Y, Wang Y, Deng Y, Li Y: Thrombelastography maximal clot strength could predict one-year functional outcome in patients with ischemic stroke. Cerebrovasc Dis 2014;38:182-190.
  44. Fonville S, Zandbergen AA, Koudstaal PJ, den Hertog HM: Prediabetes in patients with stroke or transient ischemic attack: prevalence, risk and clinical management. Cerebrovasc Dis 2014;37:393-400.
  45. Hankey GJ, Hacke W, Easton JD, Johnston SC, Mas JL, Brennan DM, Bhatt DL, Fox KA, Topol EJ; CHARISMA Trial Investigators: Effect of clopidogrel on the rate and functional severity of stroke among high vascular risk patients: a prespecified substudy of the clopidogrel for high atherothrombotic risk and ischemic stabilization, management and avoidance (CHARISMA) trial. Stroke 2010;41:1679-1683.
  46. Siller-Matula JM, Trenk D, Schrör K, Gawaz M, Kristensen SD, Storey RF, Huber K; EPA (European Platelet Academy): Response variability to P2Y12 receptor inhibitors: expectations and reality. JACC Cardiovasc Interv 2013;6:1111-1128.
  47. Mijajlovic MD, Shulga O, Bloch S, Covickovic-Sternic N, Aleksic V, Bornstein NM: Clinical consequences of aspirin and clopidogrel resistance: an overview. Acta Neurol Scand 2013;128:213-219.
  48. Yang L, Colditz GA: Prevalence of overweight and obesity in the United States, 2007-2012. JAMA Intern Med 2015;175:1412-1413.
  49. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE: Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014;103:137-149.
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