Mohammad Reza Motamed MD 29, Seyed-Mohammad Fereshtehnejad 30, Nooshin Sadigh 2

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1 Dual antiplatelet therapy with clopidogrel and aspirin for stroke prevention following transient ischemic attack (TIA) or mild-to-moderate ischemic stroke Mohammad Reza Motamed MD 29, Seyed-Mohammad Fereshtehnejad 30, Nooshin Sadigh 2 Iranian Journal of Neurology, Vol.7, No.21 & 22, Spring & Summer 2008, Abstract Introduction: Patients who have transient ischemic attack (TIA) or ischemic stroke are at a high risk of having a first or recurrent stroke. Secondary prevention includes antithrombotic therapy, treatment of risk factors, and interventional treatment of carotid stenosis. The merits of antiplatelet therapy with different protocols in primary and secondary stroke prevention have been demonstrated across numerous trials which lead to somewhat contradictory findings. Our objective was to compare the effects of aspirin, clopidogrel, and clopidogrel plus aspirin in the prevention of recurrent stroke. Methods: Ninety-two patients with TIA or minor ischemic stroke were randomly assigned in three groups: Group A (aspirin, mg/day; 29 patients), group B (clopidogrel, 75 mg/day; 31 patients) and group C (clopidogrel 75 mg/day plus aspirin mg/day; 32 patients). All patients were followed for a period of 18 months. Rather than demographic data, the number of new attacks and the time it occurs were recorded for each patient. Kaplan-Meier analysis was performed to compare the median time to stroke outcome in each group. Results: The patients were 53 (57.6%) male and 39 (42.4%) female with the mean age of 65.47(SD=8.36) year which was not significantly different in three groups of study (P>0.05). After 18 months of follow-up, the mortality rate was 13.8%, none and 3.1% in groups A, B and C, respectively. The mean number of attacks was significantly lower in group C [0.63(standard deviation (SD)=0.49)] than groups A [1.59(SD=0.95)] and B [0.81(SD=0.65)] (P<0.001). Moreover, the mean time to stroke outcome was significantly longer in group C [16.12(Standard error (SE)=0.57) month] than groups A [6.76(SE=1.21) month] and B [13.71(SD=1.02) month] (Log rank P<0.001). Conclusion: Antiplatelet therapy is effective in secondary stroke prevention. Current recommendations are applied in clinical practice, but great variability between different centers remains. Our results showed that aspirin combined use with clopidogrel have better efficacy and decreased rate of recurrence in patients with TIA or minor ischemic stroke in this single-center study. Keywords: Transient ischemic attack (TIA), Stroke, Aspirin, Clopidogrel 29 Neurologist, Iran University of Medical Sciences 30 Medical Student, Iran University of Medical Sciences, Medical Student Research Committee

2 204/ Iran. J. Neurol. Vol.7; No. 21 & 22, Spring & Summer 2008 Introduction Transient ischemic attack (TIA) as an early warning sign of atherosclerotic disease, including stroke is defined clinically by the temporary nature of the associated neurologic symptoms, which last less than 24 hours by the classic definition. However, the arbitrary nature of the 24-hour time limit and lack of specific pathophysiologic meaning have hampered the clinical and research utility of the term "TIA." Nowadays, cerebrovascular disease is the third leading cause of death in developed countries after heart disease and cancer; the overall prevalence is 794 per 100,000. It is estimated that more than 700,000 patients have a stroke each year in the United States. (1) A populationbased study reported that the incidence rate of TIA was 68 per 100,000. (2) The loss of these patients from the work force and the extended hospitalization they require during recovery make the economic impact of the disease one of the most devastating in medicine. Patients with transient ischemic attack (TIA) or minor stroke are at increased risk of recurrent stroke. Clinical TIAs associated with neuroimaging evidence of infarction (ie, transient symptoms with infarction or TSI) may be at particularly high risk of ischemic stroke. Epidemiologic studies revealed that about 200,000 of the 700,000 instances of stroke each year in the United States represent recurrent attacks. (1) A metaanalysis of four studies involving 1709 strokes showed that patients with stroke caused by large-artery atherosclerosis had a threefold risk of recurrence up to 3 months after the first event. (3) Another analysis of > 17,000 stroke patients demonstrated that these patients are at highest risk for another stroke and/or myocardial infarction (MI). (4) Antiplatelet therapy is a proven component of secondary prevention in patients with transient ischaemic attack or ischaemic stroke. (5) Aspirin has been the mainstay of therapy for patients who have experienced TIAs. This approach is based upon the results of several large clinical trials, which found that aspirin reduced the incidence of stroke by 15 to 25 percent in these individuals. (6-12) However, in the CAPRIE trial clopidogrel was superior to aspirin in the overall population of patients with recent ischaemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease, reducing the relative risk for the primary endpoint (ischaemic stroke, myocardial infarction, or vascular death) by 8.7% versus aspirin. (13) It seems that the merits of antiplatelet therapy with different protocols in primary and secondary stroke prevention demonstrated across numerous trials lead to somewhat contradictory findings. Therefore, our objective was to compare the effects of aspirin, clopidogrel, and clopidogrel plus aspirin in the prevention of recurrent stroke.

3 205/ Dual antiplatelet therapy with clopidogrel and aspirin. Methods & Patients Patients This was a randomized controlled clinical trial (RCT) study. Between May 2006, and January 2008, we enrolled individuals at a single center (Firoozgar Hospital) in Tehran, Iran. Patients were eligible for inclusion in the study if they had had an ischaemic stroke or transient ischaemic attack in the previous 3 months and had one or more of five additional risk factors including previous ischaemic stroke, previous myocardial infarction, angina pectoris, diabetes mellitus, or symptomatic peripheral arterial disease within the previous 3 years. Ischaemic stroke was categorized with the TOAST classification. (14) Major exclusion criteria were: age younger than 40 years; severe comorbid conditions; increased risk of bleeding (clinical evidence of severe hepatic insufficiency, current peptic ulceration, history of systemic bleeding, or other history of bleeding diathesis or coagulopathy); scheduled for major surgery or vascular surgery; and contraindications for aspirin or clopidogrel. An independent ethics review was completed and patients gave written informed consent. Finally, ninety-two patients with TIA or minor ischemic stroke were randomly assigned in three groups: Group A (aspirin, mg/day; 29 patients), group B (clopidogrel, 75 mg/day; 31 patients) and group C (clopidogrel 75 mg/day plus aspirin mg/day; 32 patients). All patients were followed for a period of 18 months. Procedures Patients were randomly allocated either aspirin mg once daily (Group A); or clopidogrel 75 mg once daily (Group B) or both aspirin mg once daily and clopidogrel 75 mg once daily (Group C). Treatment allocation was done centrally and was based on a computer-generated list of treatment numbers. Study treatment was started on the day of randomization and continued for 18 months. After the randomization visit, follow-up visits were scheduled at 1, 3, 6, 12, and 18 months. These visits were supplemented by monthly followup telephone calls to the patient. The primary endpoint was the first occurrence of an event in the composite of ischaemic stroke, myocardial infarction, vascular death (including haemorrhagic death of any origin), or rehospitalisation for an acute ischaemic event (including unstable angina pectoris, worsening of peripheral arterial disease requiring therapeutic intervention or urgent revascularization, or transient ischaemic attack). The secondary endpoint was defined as the death due to stroke. Therefore, rather than demographic data, the number of new attacks and the time it occurs were recorded for each patient.

4 206/ Iran. J. Neurol. Vol.7; No21 & 22, Spring & Summer 2008 Prior to entering this trial, patients were fully informed of the conduct and consequences of the study and signed a consent form. This study was conducted following approval by institutional review board and ethics committee and was in accordance with the ethical principles described in the Declaration of Helsinki. Statistical analysis The SPSS software package (13.0) was used for all analyses. Values are expressed as mean (SD) or mean (SEM). In order to examine differences between patients of all three groups of study, the Chi-square test and One Way ANOVA or Kruskal Wallis tests for categorical and parametric or non-parametric quantitative data were employed, respectively. Kaplan Meier survival analysis was used to calculate the mean times to event in each group of study and the Log-rank test was employed to compare survival between groups and strata. Cox regression model was also performed to determine the factors which could significantly predict the survival time of the occurrence of recurrent stroke within follow-up period. All P values were two-tailed and a P value <0.05 was considered significant. Results The patients were 53 (57.6%) male and 39 (42.4%) female with the mean age of 65.47(SD=8.36) year which was not significantly different in three groups of study (P>0.05). All baseline and demographic variables are shown in Table 1. Table 1. Demographic variables of each group of the study VARIABLE A ASA (N=29) B CLOPIDOGREL (N=31) C ASA+CLOPIDOGREL (N=32) P- VALUE Age (year) 63.69± ± ± mean±sd Gender % female 11(37.9%) 13(41.9%) 15(46.9%) Diabetes Mellitus % 12(41.4%) 13(41.9%) 14(43.8%) Hypertension % 25(86.2%) 28(90.3%) 31(96.9%) Hyperlipidemia % 24(82.8%) 21(67.7%) 28(87.5%) Positive Family history of 9(31%) 0 4(12.5%) * early stroke % Smoking % 11(37.9%) 8(25.8%) 8(25%) * Statistical significant difference

5 207/ Dual antiplatelet therapy with clopidogrel and aspirin. After 18 months of follow-up, the mortality rate was 13.8%, none and 3.1% in groups A, B and C, respectively. The results of Chi 2 test demonstrated that this difference was statistically significant (P=0.048). Follow-up variables of each group of the study are shown in Table 2. Table 2. Follow-up variables of each group of the study VARIABLE A ASA B CLOPIDOGREL C ASA+CLOPIDOG P-VALUE (N=29) (N=31) REL(N=32) Recurrent stroke % 24(82.8%) 21(67.7%) 20(62.5%) Death due to stroke % 4(13.8%) 0 1(3.1%) * Time to first new attack (month) mean±sd No. of attacks mean±sd * Statistical significant difference 4.42± ± ±3.64 <0.001 * 1.59± ± ±0.49 <0.001 * As listed, the rate of the occurrence of recurrent stroke in groups A, B and C was 82.8%, 67.7% and 62.5%, respectively. Although the rate of recurrent stroke was higher in group A, this failed to show a meaningful difference (P=0.202). However, the time to first new attack during follow-up period was significantly lower in group A than groups B and C. As illustrated in Figures 1 and 2, the results of Kaplan Meier survival analysis showed that the mean time to stroke outcome was significantly longer in group C [16.12(Standard error (SE)=0.57) month] than groups A [6.76(SE=1.21) month] and B [13.71(SD=1.02) month] (Log rank P<0.001). Figure 1. Hazard function graph of three groups of study to encounter the first recurrent stroke during follow-up period (Log Rank p-value<0.001)

6 208/ Iran. J. Neurol. Vol.7; No. 21 & 22, Spring & Summer 2008 Figure 2. Survival function graph of three groups of study to encounter the first recurrent stroke during follow-up period (Log Rank p-value<0.001) Moreover, the mean number of attacks was significantly lower in group C [0.63(standard deviation (SD)=0.49)] than groups A [1.59(SD=0.95)] and B [0.81(SD=0.65)] (P<0.001). More analysis with Cox regression model was performed and showed that lacunar [B=1.697(SE=0.388), P<0.001] and massive infarctions [B=1.138(SE=0.344), P=0.001] in MRI, small vessel disease [B=0.989(SE=0.287), P=0.001] and receiving clopidogrel [B= (SE=0.277), P=0.001] were the significant variables to predict the survival time of the occurrence of recurrent stroke within follow-up period (P<0.001) Discussion Antiplatelet therapy is effective in secondary stroke prevention. Current recommendations are applied in clinical practice, but great variability between different centers remains. Our results showed that aspirin combined use with clopidogrel have better efficacy and decreased rate of recurrence in patients with TIA or minor ischemic stroke in this single-center study. Evaluating the effects of each drug separately, aspirin has demonstrated a 15 25% reduction in risk of recurrent stroke vs. placebo and remains the foundation in secondary stroke prevention. (7-15)

7 209/ Dual antiplatelet therapy with clopidogrel and aspirin. Table 3. Cox regression model to predict the occurrence of recurrent stroke within follow-up period (p-value<0.001) VARIABLE A ASA B CLOPIDOGREL C ASA+CLOPIDOG P-VALUE (N=29) (N=31) REL(N=32) Recurrent stroke % 24(82.8%) 21(67.7%) 20(62.5%) Death due to stroke % 4(13.8%) 0 1(3.1%) * Time to first new attack (month) mean±sd No. of attacks mean±sd * Statistical significant difference 4.42± ± ±3.64 <0.001 * 1.59± ± ±0.49 <0.001 * High doses ( mg/day) and low doses (30 mg/day) had similar efficacy in preventing vascular events. (7-15) The Antithrombotic Trialists Collaboration meta-analysis of 287 studies involving > 200,000 patients indicated that high-dose aspirin ( mg/day) was no more effective, and was more gastrotoxic, than medium doses ( mg/day) or lower doses. (5) The findings from these studies support use of aspirin mg/day for long-term prevention of serious vascular events among highrisk patients. By the way, regarding the mechanisms of it s action, aspirin Inhibits cyclooxygenase, preventing prostaglandin and thromboxane production from anachidonic acid. (16) On the other hand, clopidogrel Decreases platelet aggregation by inhibiting binding of ADP receptor antagonists that inhibits ADP-induced fibrinogen binding to platelets. (16) The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, a randomized, blinded trial, assessed the efficacy of clopidogrel (75 mg/day) vs. aspirin (325 mg/day) in reducing risk of ischaemic stroke, MI or death because of vascular causes among 19,185 patients with symptomatic vascular disease, including recent ischaemic stroke (1 week to 6 months previously). (13) Among all patients, clopidogrel was associated with an 8.7% relative risk reduction (RRR) for ischaemic stroke, MI or death because of vascular causes compared with aspirin (annual event rate, 5.32% vs. 5.83%; P=0.043). For patients with peripheral arterial disease, the advantage of clopidogrel over aspirin was most pronounced (annual event rate, 3.71% vs. 4.86%; P=0.0028). For the 6431 patients with stroke, the benefit of clopidogrel over aspirin was not statistically significant (annual event rate, 7.15% vs. 7.71%). A higher rate of severe gastrointestinal haemorrhage was observed in the aspirin group than in the clopidogrel group (0.71% vs. 0.49%; P<0.05). The bleeding risk of aspirin likely relates to the relatively high dose (325 mg) used in the trial. In a post hoc

8 210/ Iran. J. Neurol. Vol.7; No. 21 & 22, Spring & Summer 2008 study of the CAPRIE population, patients with high-risk symptomatic atherosclerotic disease had higher rates of ischaemic stroke, MI or death because of vascular causes. Event rates at 3 years were 20.4% with clopidogrel and 23.8% with aspirin (RRR, 14.9%; P=0.045). (17) Combination therapy with clopidogrel plus aspirin for patients with stroke was first tested in the Management of Atherothrombosis With Clopidogrel in High-risk Patients (MATCH) trial, in which clopidogrel (75 mg/day) plus aspirin (75 mg/day) was compared with clopidogrel monotherapy. (18) For the primary end-point of ischaemic stroke, MI or death because of vascular causes, no significant benefit was observed with the combination over clopidogrel monotherapy (15.7% vs. 16.7% respectively). Combination therapy was associated with twofold risk of major bleeding (2% vs. 1%; p<0.001) and threefold risk of life-threatening bleeding (3% vs. 1%; p<0.001). This study did not include an aspirin monotherapy group and therefore, provided no additional information over CAPRIE as to the advantage of clopidogrel over aspirin. Whereas, we have a group of monotherapy with aspirin in our study which has the worst results. Briefly in MATCH study (18) the authors declared that in most patients, a consistent reduction of primary and secondary vascular events was recorded with aspirin added to clopidogrel, although the differences were not significant. Addition of aspirin to clopidogrel in the MATCH trial resulted in a significantly higher bleeding rate that offset any beneficial effect. No significant increase in fatal bleeding was recorded and mortality was the same in both groups. Besides intracranial haemorrhage, the principal type of major or life-threatening bleeding that was increased by adding aspirin to clopidogrel was gastrointestinal bleeding. Another recent study known as CARESS (19) has demonstrated that dual antiplatelet therapy with clopidogrel and aspirin results in a rapid reduction in asymptomatic embolization compared with aspirin alone. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial included high-risk asymptomatic patients (multiple risk factors but no established cardiovascular disease, n=3284) and symptomatic (documented cardiovascular disease, n=12,153, including 4320 secondary stroke prevention patients). CHARISMA assessed clopidogrel (75 mg/day) plus low-dose aspirin ( mg/day) vs. low-dose aspirin alone. (20) The combination regimen did not reduce stroke risk in the group as a whole after median follow-up of 28 months compared with aspirin alone. However, the rate of severe bleeding episodes was higher with the combination (1.7% vs.

9 211/ Dual antiplatelet therapy with clopidogrel and aspirin. 1.3%; P=0.09), as was the rate of moderate bleeding episodes (2.1% vs. 1.3; P<0.001) that required transfusions. The rate of death from cardiovascular causes was also higher with combination therapy than with aspirin alone (3.9% vs. 2.2%; P=0.01). The rate of MI, stroke or cardiovascularrelated death among asymptomatic patients was 6.6% with clopidogrel plus aspirin and 5.5% with aspirin alone. However, this primary end-point occurred in 6.9% and 7.9% of symptomatic patients, respectively, for an RRR of 12% (P=0.046) with combination therapy. Thus, treatment with clopidogrel plus aspirin may benefit patients with documented cardiovascular disease but may harm patients who have multiple risk factors with no established cardiovascular disease. In general, clopidogrel plus aspirin did not show clear superiority over low-dose aspirin monotherapy in reducing the rate of MI, stroke or death from cardiovascular causes. Most review articles revealed that the most important determinant for the choice between aspirin and clopidogrel was the use of aspirin before the index event. This indicates that clopidogrel is commonly used as a drug of second choice once a patient has suffered a cerebrovascular event under therapy with aspirin therapy. Although it may seem plausible to switch to an alternative drug once a patient has suffered a cerebrovascular event under aspirin therapy, this strategy is not based on existing evidence because this question was not addressed in the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial. (13) Clopidogrel was also preferably used in patients with a known cause of the event (large- or small-artery disease compared with events of undetermined origin). In those patients who suffered the index event under therapy with aspirin, a history of CAD was also associated with the use of clopidogrel. Again, this finding is not directly supported by the results of the CAPRIE trial, in which no significant benefit of clopidogrel in patients with CAD was found. Interestingly, clopidogrel was almost as frequently prescribed in patients who suffered a TIA, although clopidogrel has not been formally tested in this group of patients and is currently not registered in Austria for patients with TIA. (21) Conclusively, antiplatelet therapy is effective in secondary stroke prevention. Although great variability between different centers still remains, our results showed that aspirin combined use with clopidogrel have better efficacy and decreased rate of recurrence in patients with TIA or minor ischemic stroke in this single-center study. By the way, some limitations of our study include not considering blinding and low sample size in some aspects including the rate of patients with recurrent stroke. Finally, more studies with enough sample size and longer follow-up period to evaluate the rate of death more accurately is needed

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