  thromboxane and adp , which are among the mediators of platelet activation and aggregation , play 
 a key role in initiating and propagating coronary thrombosis and are raised 
 during myocardial infarction .
simultaneous inhibition of both of these pathways 
 with the combination of clopidogrel and aspirin produces 
 greater antiplatelet effects than either agent alone [ 1 , 2 ] . in recent reports , 

dual antiplatelet therapy with aspirin and clopidogrel showed significant 
 improvements on prognosis in st - elevating myocardial infarction ( stemi ) [ 35 ] . 

moreover , this beneficial effect is not only limited to the acute phase , but 
 also extended to a 1-year follow - up period . but
substantial uncertainty 
 remained regarding the net effects of adding clopidogrel to aspirin upon the 
 reperfusion , acute inflammatory response , and ischemic events in this setting . 
 in this study
, we evaluated the effect of the addition of clopidogrel to 
 standard reperfusion protocol on reperfusion and acute inflammatory response .
  from december 2006 to january 2008 , consecutive patients were enrolled who presented 
 with ischemic discomfort lasting > 20 minutes at rest within 12 hours , before 
 randomization pain lasting > 20 minutes , st - segment elevation of at least 0.2 mv in at least two contiguous 
 precordial leads .
the study was limited to only anteriorly located myocardial 
 infarction to homogenize the investigated population .
the exclusion criteria 
 were conduction or rhythm abnormalities ( bundle branch block , idioventricular 
 rhythm , etc . ) ; any contraindication to thrombolytics ; early coronary 
 angiography ( within first 48 hours ) due to recurrent ischemia or failed 
 thrombolysis ; those patients under the treatment of aspirin or thienopyridines ; any contraindication to aspirin or 
 clopidogrel ; past history of mi or coronary revascularization ; presence of clinically 
 assessed heart failure ( killip ii / iii ) or cardiogenic shock ; hepatic failure ; 
 renal failure ( serum creatinine > 2.5 mg / dl ) ; thrombocytopenia ( < 100.000/mm ) and patients older than 70 years old were excluded .
the study protocol was approved by 
 institutional review board , and written informed consent was taken from all 
 patients .
a total of 175 patients were included in the present 
 study and were allocated in 2 groups .
one was the standard pharmacological 
 reperfusion therapy group ( group 1 , n : 90 ) , consisting of patients who received 
 300 mg aspirin at first then 150 mg / d thereafter , 70 u / kg ( maximum 5000 u ) 
 bolus , and 12 u / kg / hr continuous infusion of unfractioned heparin and accelerated t - pa therapy ( 15 mg intravenous 
 bolus followed by an infusion of 0.75 mg / kg ( maximum 50 mg ) over 30 minutes , 
 followed by an infusion of 0.5 mg / kg ( maximum 35 mg ) over 60 minutes ) . 

clopidogrel 450 mg loading and 75 mg / d thereafter was added to standard 
 reperfusion therapy in the other group ( group 2 , n : 85 ) .
the st - segment 
 resolution within 120 minutes , ck - mb parameters within first 24 hours , and high - sensitive 
 c - reactive protein ( hs - crp ) parameters within 48 hours were measured .
standard 12-lead electrocardiograms were 
 obtained at baseline and at 30-minute periods during the first120 minutes after 
 initiation of fibrinolytic therapy .
st - segment elevation was analyzed manually 
 with lens - intensified calipers to the nearest of 0.025 mv 20 milliseconds after the end of qrs complex with the pr segment as the reference 
 baseline from leads i , avl , and v1 through v6 for 
 anterior infarction .
the sum of st deviation was measured at baseline and at 
 30 , 60 , 90 , 120 minutes using previously described methods .
the percent 
 resolution of st deviation from baseline to 30 , 60 , 90 , 120 minutes was 
 calculated and categorized as complete ( 70% ) , partial ( 30% to 70% ) , or no 
 resolution ( 30% ) .
blood samples were obtained for ck - mb and 
 hs - crp analysis at 0 , 4 , 8 , 12 , 24 and 0 , 24 , 48 hours of admission , respectively . 

biochemical and haematological parameters were measured by an olympus au 600 
 autoanalyzer ( olympus optical co. , ltd .
, schimatsu - mishima , japan ) and bayer advia 120 cell cbc counter hematologia 
 autoanalyzer ( bayer advia 120 cbc counter , nj , usa ) .
hs - c - reactive protein was measured by 
 the high - sensitivity nephelometric method ( dade behring , marburg , germany ) .
the spss for windows program ( version 15.0 ) was 
 used for all data analysis .
numerical variables were compared by mann - whiney u - test , 
 whereas nonnumerical ones were compared by chi - squere test .
a total of 175 patients were included in the study 
 ( group 1 , n : 90 ; group 2 , n : 85 ) .
three 
 patients due to ischemic events in group 1 ( 2 failed thrombolysis , 1 heart 
 failure ) and patients in group 2 
 were excluded from the study due to ischemic and hemorrhagic events ( 1 heart 
 failure , 1 gluteal hemorrhage ) .
however , there were no important differences in 
 baseline clinical characteristics and initial therapy between the two treatment 
 groups .
complete st resolution was achieved in 32 of 
 patients ( 36.8% ) in group 1 and 53 of patients ( 63.8% ) in group 2 ( p < .001 ) 
 at the end of 120 minutes ( table 2 and figure 1 ) .
the difference between groups 
 started after 60th minute 
 of the therapy , and it became more significant at 120th minute ( figure 2 ) .
peak ck - mb values were reached at 1012th hours in group 1 , whereas 
 in group 2 they were 
 at 810th hours .
 145 u / l in group 1 and 
 132.5  122 u / l in group 2 ( p = .01 ) , and at the end of 24 hours ck - mb value 
 was 138  88
u / l in group 1 , and 56  35 u / l in group 2 ( p = .001 ) ( table 3 ) .
although baseline hs - crp values were similar at 
 baseline ( group 1 : 1.6  0.9 mg / l , group 2 : 1.9  1.3 mg / l ; p = .67 ) , they were greater in 
 group 1 than group 2 at 48th hour ( group 1 : 9.4  0.1 mg / l , group 2 : 3.7  1.4 mg / l ; p = .000 ) ( figure 3 ) .
no death was observed in both groups . failed 
 thrombolysis in two patients and heart failure in one patient were seen in 
 group 1 ; one patient with heart failure and one patient with major hemorrhage 
 ( 2 unit blood transfusion ) were seen in group 2 .
however , there is no 
 significant difference between the groups with respect to these unfavorable 
 events ( p > .05 ) .
platelet activation and aggregation play a key 
 role initiating and propagating coronary artery thrombosis , and antiplatelet 
 therapy improves outcomes across the spectrum of acute coronary syndromes . beside 
 this , it was thought that simultaneous inhibition of platelet activation and 
 aggregation pathways with specific antiplatelet combinations might be more 
 efficient in acute coronary syndromes [ 1 , 2 ] .
we observed improvements in both 
 reperfusion and inflammatory response with the early addition of clopidogrel to 
 standard reperfusion therapy in stemi patients in this study .
moreover , these 
 findings supported the hypothesis of dual antiplatelet inhibition with aspirin 
 and clopidogrel might be more beneficial in acute coronary syndrome . currently , there are promising developments in 
 the prevention of ischemic complications in sympthomatic atherothrombotic 
 cases .
the clarity - timi 28 study demonstrated that the addition of clopidogrel 
 to aspirin in patients with stemi receiving fibrinolytic therapy improved the 
 patency rate of the infarct - related artery after 48 hours and reduced ischemic 
 complications . among the patients in this trial
who underwent percutaneous 
 coronary intervention ( pci ) , described in the pci - clarty substudy , clopidogrel 
 pretreatment significantly reduced the incidence of cardiac death or ischemic 
 complications both before and after pci . in the commit trial ,
the routine 
 addition of clopidogrel 75 mg / d to aspirin therapy for 4 weeks in patients with 
 acute myocardial infarction resulted in a 9% proportional reduction in death , 
 reinfarction , or stroke ( p = .002 ) and a 7% proportional reduction in 
 death ( p = .03 ) . even though no loading dose was used ,
the benefit of 
 clopidogrel therapy was seen almost immediately by an 11% proportional 
 reduction in mortality in the first 2 days after the initiation of therapy ( p = .019 ) 
 .
the results of both clarity - timi 28 and commit showed that adding 
 clopidogrel to aspirin and other standard treatments safely reduced mortality 
 and major vascular events in patients with acute myocardial infarction .
( i ) clopidogrel may facilitate initial fibrinolysis and thereby 
 improve early reperfusion with a glycoprotein iib - iiia inhibitor -like 
 effect .
( ii ) clopidogrel may exert its effects in myocardial infarction mainly 
 by preventing reocclusion or by limiting microvascular effects of platelet 
 activation rather than enhancing fibrinolysis .
while most of the benefit of 
 clopidogrel has been attributed to inhibition of platelet activation , blockage 
 of the p2y12 receptor may also have pleotropic effects with respect to 
 endothelial cell function , leukocyte activation , and inflammation .
a reduction in the number of 
 platelet - leukocyte interactions has been described [ 12 , 13 ] , and one study 
 reported a special benefit of the drug in reducing the augmented risk of 
 percutaneous interventions in patients with elevated levels of c - reactive 
 protein . in another study
, it was stated that clopidogrel pretreatment 
 attenuated the periprocedural increase in crp by 65% .
said that clopidogrel pretreatment reduces platelet inflammatory marker expression in patients undergoing 
 pci , and they also concluded that it might be very important for clinical 
 events .
all these findings constituted an important clue for us to investigate 
 the limiting effect of clopidogrel in increment of high - sensitive c - reactive protein in stemi and to verify 
 this .
activated 
 platelets have been clearly implicated in the tendency for microembolization 
 during acute coronary syndrome [ 17 , 18 ] and play an important role in the 
 inflammatory response .
studies have shown that activated platelets express the 
 cd40 ligand , a potent stimulus of vascular inflammation [ 19 , 20 ] . the cd40 
 ligand promotes platelet - leukocyte interactions   and induces tissue factor 
 expression , thus providing a link among inflammation , platelet activation , 
 embolization , and coagulation .
the inhibition of subcellular platelet cd40 
 ligand by clopidogrel treatment may explain the mechanism of reduction in 
 inflammation as expressed by an attenuation in c - reactive protein increase 
 after acute stemi . by the way
, we think that large extensive clinical trials 
 are needed to exactly clarify the mechanisms of beneficial effects of 
 clopidogrel on clinical results in previous ones and that is what we have 
 determined in our study because the impressive improvement in clinical results 
 with added clopidogrel on aspirin requires   some other mechanisms except for a 
 potent antiplatelet effect .
the first and most important limitation is the small 
 study population and the lack of a placebo control group .
only the anteriorly 
 located stemi patients were included to homogenize the study population , and a 
 fibrinolytic agent only rt - pa was used and this condition was an important 
 limiting factor for our study . clopidogrel loading dose ( 450 mg ) may be a 
 limitation .
we think that different 
 dosages ( 300600 mg ) should be 
 applied for both evaluations 
 of safety and efficacy because there is a correlation between loading dose and 
 time to reach maximal antiplatelet effect .
another limiting factor of our 
 study was the restriction of the study with 48 hours .
a long follow - up period 
 would be more useful to exactly realize all the efficiency and safety of 
 clopidogrel ( major and minor hemorrhages 
 included ) treatment .
so that with long follow - up period , difference among the 
 groups of medical treatment , pci and coronary artery bypass grefting in the direction of angiographic findings could 
 be clearly understood .
in conclusion , we found that addition of 
 clopidogrel to medical reperfusion therapy in stemi had favorable effects on 
 reperfusion and suppression of hs - crp .
we think that these favorable clinical 
 and laboratory effects of dual antiplatelet therapy with clopidogrel are not only limited to 
 its antiplatelet effect , but also there may be some pleiotropic effects of 
 clopidogrel ; those were not explained clearly .
large extensive studies are 
 needed to explain the complete effect of clopidogrel in acute stemi .
 we investigated the effects of clopidogrel on reperfusion and inflammatory process in stemi . 
 a total of 175 stemi patients with similar clinical characteristics were included to this study . 
 one was the standard pharmacological reperfusion therapy group ( group 1 , n : 90 ) , who received 300 mg aspirin , 70 u / kg bolus , and 12 u / kg / hr continuous infusion of   unfractioned heparin and accelerated t - pa . 
 clopidogrel 450 mg loading and 75 mg / d thereafter was added to standard reperfusion therapy in the other group ( group 2 , n : 85 ) . 
 the st - segment resolution , ck - mb , and high - sensitive crp ( hs - crp ) parameters were measured . 
 complete st resolution was observed in 32 patients ( 36.8% ) in group 1 and 53 patients ( 63.8% ) in group 2 ( p < .001 ) . 
 also in the first 24 hours , the ck - mb levels of patients in group 1 were significantly higher than those of group 2 ( p = .001 ) . 
 the hs - crp values were   greater in group 1 than group 2 at 48th hour ( gruop 1 : 9.4  0.1 mg / l , group 2 : 3.7  1.4 mg / l ; p = .000 ) . we concluded that adding clopidogrel to standard treatment in stemi patients provided early reperfusion and suppression of inflammatory response . 
1. Introduction
2. Material
and Methods
3. Results
4. Discussion
5. Limitations
6. Conclusions