conventional antiplatelet treatment ( cat ) with clopidogrel in addition to aspirin has been recommended for patients undergoing percutaneous coronary intervention ( pci ) since 2002 . however , patients have significantly varied responses to clopidogrel , and clopidogrel low response ( clr ) is an independent risk factor of adverse clinical outcomes in patients undergoing pci . a few randomized controlled trials ( rcts ) investigated the efficacy of intensified antiplatelet treatment ( iat ) guided by platelet function assays , but the results were controversial . the gauging responsiveness with a verifynow assay - impact on thrombosis and safety ( gravitas ) and testing platelet reactivity in patients undergoing elective stent placement on clopidogrel to guide alternative therapy with prasugrel ( trigger - pci ) trials showed that patients with clr did not benefit from iat guided by the verifynow assay . however , several other randomized trials reported that iat significantly reduced the incidence of stent thrombosis ( st ) or composite endpoints compared to cat for patients with clr undergoing stent implantation . accordingly , we conducted this meta - analysis to elucidate whether patients with clr can benefit from iat guided by platelet function assays . the literature was scanned using computerized searches of pubmed , the cochrane library , and the chinese medical journal network databases from their establishment to september 9 , 2014 . the search terms included three parts , clr , clinical events , and method of platelet function test . the search terms for clr included clopidogrel , low response or no response or high on - treatment platelet reactivity ( hopr ) or high residual platelet reactivity or high platelet reactivity or resistance . the search terms for clinical events included death or myocardial infarction ( mi ) or st or bleeding . the search terms for method of platelet function test included verifynow or light transmission aggregation ( lta ) or lta or aggregometer or aggregometry or multiple electrode aggregometry ( mea ) or multiplate analyzer or thrombelastography ( teg ) or vasodilator - stimulated phosphoprotein ( vasp ) or lta or teg or vasp or mea or platelet function analyser-100 . studies were selected according to the following criteria : ( 1 ) studies that recruited patients with coronary artery disease ( cad ) undergoing pci and initially treated with aspirin plus clopidogrel ; ( 2 ) studies that identified clr by platelet function assays ; ( 3 ) studies that randomly assigned the clr patients into cat or iat arms ; and ( 4 ) studies that reported clinical adverse events , including cardiovascular ( cv ) death , nonfatal mi , st , or bleeding . a total of 397 papers were initially screened , and 132 papers remained after limiting the article type to clinical trials . two experienced authors ( xu and zhang ) independently extracted the following data from the selected studies : author name and year of publication , study design , clinical diagnosis of participants , type of stent implanted , method of platelet function assay , cut - off line of hopr , number of patients randomized , the strategy of treatment adjustment , duration of follow - up , and clinical outcomes . the quality of the recruited studies was assessed using the modified jadad scale , which is based on methods of randomization , allocation concealment , blinding , and loss to follow - up . the total jadad score was 7 , which was based on a score of 2 for randomization , a score of 2 for allocation concealment , a score of 2 for blinding , and a score of 1 for the description of withdrawals and dropouts . we defined low - quality studies as those with a score of 13 and high - quality studies as those with a score of 47 . a conventional meta - analysis was performed using review manager 5.0.0 ( the cochrane collaboration , oxford , england ) , and a cumulative meta - analysis was performed using stata 12.0 ( lakeway drive , college station , texas , usa ) . the results are presented as the incidence of outcomes , relative risk ( rr ) , 95% confidence intervals ( cis ) , and p value . the cochran q - test and the i test ( with 95% cis ) were used to assess heterogeneity . a fixed - effects model was used if i < 50% , and a random - effects model was used if i  50% . publication bias was analyzed using funnel plots and was quantified by egger 's test . the literature was scanned using computerized searches of pubmed , the cochrane library , and the chinese medical journal network databases from their establishment to september 9 , 2014 . the search terms included three parts , clr , clinical events , and method of platelet function test . the search terms for clr included clopidogrel , low response or no response or high on - treatment platelet reactivity ( hopr ) or high residual platelet reactivity or high platelet reactivity or resistance . the search terms for clinical events included death or myocardial infarction ( mi ) or st or bleeding . the search terms for method of platelet function test included verifynow or light transmission aggregation ( lta ) or lta or aggregometer or aggregometry or multiple electrode aggregometry ( mea ) or multiplate analyzer or thrombelastography ( teg ) or vasodilator - stimulated phosphoprotein ( vasp ) or lta or teg or vasp or mea or platelet function analyser-100 . studies were selected according to the following criteria : ( 1 ) studies that recruited patients with coronary artery disease ( cad ) undergoing pci and initially treated with aspirin plus clopidogrel ; ( 2 ) studies that identified clr by platelet function assays ; ( 3 ) studies that randomly assigned the clr patients into cat or iat arms ; and ( 4 ) studies that reported clinical adverse events , including cardiovascular ( cv ) death , nonfatal mi , st , or bleeding . a total of 397 papers were initially screened , and 132 papers remained after limiting the article type to clinical trials . two experienced authors ( xu and zhang ) independently extracted the following data from the selected studies : author name and year of publication , study design , clinical diagnosis of participants , type of stent implanted , method of platelet function assay , cut - off line of hopr , number of patients randomized , the strategy of treatment adjustment , duration of follow - up , and clinical outcomes . the quality of the recruited studies was assessed using the modified jadad scale , which is based on methods of randomization , allocation concealment , blinding , and loss to follow - up . the total jadad score was 7 , which was based on a score of 2 for randomization , a score of 2 for allocation concealment , a score of 2 for blinding , and a score of 1 for the description of withdrawals and dropouts . we defined low - quality studies as those with a score of 13 and high - quality studies as those with a score of 47 . a conventional meta - analysis was performed using review manager 5.0.0 ( the cochrane collaboration , oxford , england ) , and a cumulative meta - analysis was performed using stata 12.0 ( lakeway drive , college station , texas , usa ) . the results are presented as the incidence of outcomes , relative risk ( rr ) , 95% confidence intervals ( cis ) , and p value . the cochran q - test and the i test ( with 95% cis ) were used to assess heterogeneity . a fixed - effects model was used if i < 50% , and a random - effects model was used if i  50% . publication bias was analyzed using funnel plots and was quantified by egger 's test . thirteen rcts with 5111 clr patients were finally recruited , and the characteristics of these studies are summarized in table 1 . assessment of the methodological quality using the modified jadad scale demonstrated that all 13 studies were ranked as high quality [ table 2 ] . the sample sizes of the studies ranged from 44 to 2214 , and the participants were aged from 45 to 80 years . platelet function assays , including the verifynow p2y12 , mea , lta , teg , and vasp were used in the recruited studies . in total , 2695 patients were randomly allocated to the iat arm and 2416 patients to the cat arm . the follow - up duration ranged from 1 to 12 months , with a mean follow - up period of 5.69  4.60 months . characteristics of included studies rct : randomized clinical trials ; hopr : high on_treatment platelet reactivity ; iat : intensified antiplatelet treatment ; cat : conventional antiplatelet treatment ; nstemi : non - st - segment elevation myocardial infarction ; stemi : st - segment elevation myocardial infarction ; cad : coronary artery disease ; acs : acute coronary syndrome ; pci : percutaneous coronary intervention ; ld : loading dose ; lta : light transmission aggregometry ; vasp : vasodilator - stimulated phosphoprotein ; mea : multiple electrode aggregometry ; pru : p2y12 reaction units ; pri : platelet reactivity index ; au : aggregation unit ; teg : thrombelastography ; adp : adenosine diphosphate . quality assessment of included studies for the numbers , 2 indicates that the method of randomization or concealed allocation or blinding was described in the paper , and it was appropriate ; 1 indicates that the method of randomization or concealed allocation or blinding or withdrawals and dropouts were described but were inappropriate ; 0 indicates that randomization , concealed allocation , blinding or withdrawals , and dropouts were not mentioned in the paper . heterogeneity assessment the studies were homogeneous when evaluated for the heterogeneity of both a single event and the combined events . similarly , the studies showed homogeneity when evaluated for the heterogeneity of different platelet function assays , such as lta , verifynow , and mea , except for the studies that showed heterogeneity in the vasp data ( i= 80% ) , in which the random - effects model was used for the vasp analysis . the funnel plots for cv death , nonfatal mi , st , and bleeding are presented in supplementary figure 1 . funnel plots for evaluating publication bias of clinical events . ( a - d ) represent cv death , nonfatal mi , st , and bleeding , respectively . y axis shows the standard error ( se ) of log ( rr ) of effect size from each study . cv : cardiovascular ; mi : myocardial infarction ; st : stent thrombosis rr : risk ratio . risk ratio for ischemic events and bleeding the incidence of combined ischemic endpoints was significantly lower in the iat arm compared to the cat arm ( rr = 0.45 , 95% ci : 0.360.57 , p < 0.000,01 ) [ figure 2 ] . separately , the incidence of cv death was significantly lower in the iat arm compared to the cat arm ( rr = 0.46 , 95% ci : 0.280.75 , p = 0.002 ) . the incidence of mi was significantly lower in the iat arm compared to the cat arm ( rr = 0.49 , 95% ci : 0.350.69 , p < 0.0001 ) , and the incidence of st was also significantly lower in the iat arm compared to the cat arm ( rr = 0.44 , 95% ci : 0.270.73 , p = 0.001 ) . the incidence of bleeding was comparable between the two arms ( rr = 1.05 , 95% ci : 0.861.27 , p = 0.65 ) [ figure 3 ] . ( a - d ) represent for cv death , nonfatal mi , st , and the combined endpoints , respectively . iat : intensified antiplatelet treatment ; cat : conventional antiplatelet treatment ; cv : cardiovascular ; mi : myocardial infarction ; st : stent thrombosis ; ci : confidence interval . forest plot for the effect of iat versus cat on bleeding . iat : intensified antiplatelet treatment ; cat : conventional antiplatelet treatment ; ci : confidence interval . cumulative meta - analyses were performed to evaluate the effectiveness of iat sorted by year . the results showed that the cumulative effect of iat on the incidence of combined endpoints was superior to that of cat from the initial trial in 2008 ( rr = 0.40 , 95% ci : 0.230.70 ) . if the trials were sorted by the population size , the overall effect of iat remained relatively stable with similar point estimates , whereas the later studies had an increased population size and narrowed the cis [ figure 4b ] . cumulative meta - analysis sorted by year ( a ) and sample size ( b ) to show the effect of iat versus cat on the combined endpoints . subgroup analysis showed that the combined endpoints were significantly decreased in the iat arm compared to the cat arm as guided by the lta and mea ( p = 0.004 and p < 0.000,01 , respectively ) [ figure 5a5d ] . one trial adopted teg to determine the iat , which resulted in decreased combined endpoints in the iat arm compared to the cat arm [ p = 0.04 ; figure 5e ] . however , there were no significant differences in the combined endpoints between the two arms guided by either vasp or verifynow [ p = 0.09 and p = 0.18 , respectively ; figure 5b and 5c ] . lta : light transmission aggregometry subgroup ( a ) ; vasp : vasodilator - stimulated phosphoprotein subgroup ( b ) ; verifynow and mea : multiplate analyzer subgroup ( c ) and subgroup ( d ) ; teg : thrombelastography hemostasis analyzer subgroup ( e ) . iat : intensified antiplatelet treatment ; cat : conventional antiplatelet treatment ; ci : confidence interval . thirteen rcts with 5111 clr patients were finally recruited , and the characteristics of these studies are summarized in table 1 . assessment of the methodological quality using the modified jadad scale demonstrated that all 13 studies were ranked as high quality [ table 2 ] . the sample sizes of the studies ranged from 44 to 2214 , and the participants were aged from 45 to 80 years . platelet function assays , including the verifynow p2y12 , mea , lta , teg , and vasp were used in the recruited studies . in total , 2695 patients were randomly allocated to the iat arm and 2416 patients to the cat arm . the follow - up duration ranged from 1 to 12 months , with a mean follow - up period of 5.69  4.60 months . characteristics of included studies rct : randomized clinical trials ; hopr : high on_treatment platelet reactivity ; iat : intensified antiplatelet treatment ; cat : conventional antiplatelet treatment ; nstemi : non - st - segment elevation myocardial infarction ; stemi : st - segment elevation myocardial infarction ; cad : coronary artery disease ; acs : acute coronary syndrome ; pci : percutaneous coronary intervention ; ld : loading dose ; lta : light transmission aggregometry ; vasp : vasodilator - stimulated phosphoprotein ; mea : multiple electrode aggregometry ; pru : p2y12 reaction units ; pri : platelet reactivity index ; au : aggregation unit ; teg : thrombelastography ; adp : adenosine diphosphate . quality assessment of included studies for the numbers , 2 indicates that the method of randomization or concealed allocation or blinding was described in the paper , and it was appropriate ; 1 indicates that the method of randomization or concealed allocation or blinding or withdrawals and dropouts were described but were inappropriate ; 0 indicates that randomization , concealed allocation , blinding or withdrawals , and dropouts were not mentioned in the paper . heterogeneity assessment the studies were homogeneous when evaluated for the heterogeneity of both a single event and the combined events . similarly , the studies showed homogeneity when evaluated for the heterogeneity of different platelet function assays , such as lta , verifynow , and mea , except for the studies that showed heterogeneity in the vasp data ( i= 80% ) , in which the random - effects model was used for the vasp analysis . the funnel plots for cv death , nonfatal mi , st , and bleeding are presented in supplementary figure 1 . funnel plots for evaluating publication bias of clinical events . ( a - d ) represent cv death , nonfatal mi , st , and bleeding , respectively . y axis shows the standard error ( se ) of log ( rr ) of effect size from each study . cv : cardiovascular ; mi : myocardial infarction ; st : stent thrombosis rr : risk ratio . risk ratio for ischemic events and bleeding the incidence of combined ischemic endpoints was significantly lower in the iat arm compared to the cat arm ( rr = 0.45 , 95% ci : 0.360.57 , p < 0.000,01 ) [ figure 2 ] . separately , the incidence of cv death was significantly lower in the iat arm compared to the cat arm ( rr = 0.46 , 95% ci : 0.280.75 , p = 0.002 ) . the incidence of mi was significantly lower in the iat arm compared to the cat arm ( rr = 0.49 , 95% ci : 0.350.69 , p < 0.0001 ) , and the incidence of st was also significantly lower in the iat arm compared to the cat arm ( rr = 0.44 , 95% ci : 0.270.73 , p = 0.001 ) . the incidence of bleeding was comparable between the two arms ( rr = 1.05 , 95% ci : 0.861.27 , p = 0.65 ) [ figure 3 ] . ( a - d ) represent for cv death , nonfatal mi , st , and the combined endpoints , respectively . iat : intensified antiplatelet treatment ; cat : conventional antiplatelet treatment ; cv : cardiovascular ; mi : myocardial infarction ; st : stent thrombosis ; ci : confidence interval . forest plot for the effect of iat versus cat on bleeding . iat : intensified antiplatelet treatment ; cat : conventional antiplatelet treatment ; ci : confidence interval . cumulative meta - analyses were performed to evaluate the effectiveness of iat sorted by year . the results showed that the cumulative effect of iat on the incidence of combined endpoints was superior to that of cat from the initial trial in 2008 ( rr = 0.40 , 95% ci : 0.230.70 ) . if the trials were sorted by the population size , the overall effect of iat remained relatively stable with similar point estimates , whereas the later studies had an increased population size and narrowed the cis [ figure 4b ] . cumulative meta - analysis sorted by year ( a ) and sample size ( b ) to show the effect of iat versus cat on the combined endpoints . subgroup analysis showed that the combined endpoints were significantly decreased in the iat arm compared to the cat arm as guided by the lta and mea ( p = 0.004 and p < 0.000,01 , respectively ) [ figure 5a5d ] . one trial adopted teg to determine the iat , which resulted in decreased combined endpoints in the iat arm compared to the cat arm [ p = 0.04 ; figure 5e ] . however , there were no significant differences in the combined endpoints between the two arms guided by either vasp or verifynow [ p = 0.09 and p = 0.18 , respectively ; figure 5b and 5c ] . lta : light transmission aggregometry subgroup ( a ) ; vasp : vasodilator - stimulated phosphoprotein subgroup ( b ) ; verifynow and mea : multiplate analyzer subgroup ( c ) and subgroup ( d ) ; teg : thrombelastography hemostasis analyzer subgroup ( e ) . iat : intensified antiplatelet treatment ; cat : conventional antiplatelet treatment ; ci : confidence interval . this study revealed that platelet function assay - guided iat significantly decreased the incidences of cv death , mi , and st without an increased risk of bleeding compared to cat in cad patients undergoing pci . the result of this meta - analysis might provide evidence - based science for clinical guideline development . theoretically , any intensified antiplatelet therapy that improves the platelet response should improve the patient 's clinical outcome . however , most studies investigating the benefits of iat yielded negative results , and several critical issues regarding the design of these trials have been noted . first , the participants recruited in these studies were in stable condition . in the gravitas , non - st - segment elevation myocardial infarction and st - segment elevation myocardial infarction , patients accounted for only 10% and 0.4% of the study population , respectively . in the trigger - pci , 100% of the participants were stable cad patients , and the low incidence of the primary endpoint ( 2.3% vs. the expected 7% rate ) resulted in the early discontinuation of the trial . therefore , the low - risk population with a low incidence of primary endpoints might contribute to the negative results of these trials . second , randomization was performed late during the gravitas and trigger - pci trials ( 1224 h after pci and 27 h after the patients were first administered clopidogrel , respectively ) ; therefore , some periprocedural events might have not been included in these trials . third , inappropriate cutoff values for clr with less iat might also contribute to the negative results . in the gravitas trial , clr was defined as 230 platelet reaction units ( pru ) using the verifynow p2y12 test . however , price et al . performed a post hoc analysis and found that using pru < 208 as a cutoff level , the iat was associated with a lower risk of adverse clinical events . currently available potent antiplatelet agents , such as ticagrelor and prasugrel , were not available or used in most of the recruited trials . in fact , most studies used an increased dose of clopidogrel as iat [ table 1 ] ; however , 40% of the clr patients remained low response to clopidogrel although the dose of clopidogrel was doubled . our study results were verified by cumulative meta - analysis , which indicated that iat significantly diminished the major cv events , whereas the study sample size was increased to a statistically reasonable level . however , future studies should also consider recruiting higher risk patients and using more intensified antiplatelet agents . hopefully , current ongoing studies , such as antarctic and tropical - acs , will increase our knowledge of the value of iat guided by platelet function assays . we performed a subgroup analysis on different platelet function assays and found that lta and mea - guided iats improved the combined endpoints of the clr patients , whereas vasp- and verifynow - guided iat did not . these results are consistent with reports that lta and mea are highly correlated to ischemic events although tang et al . found that teg - guided iat also decreased the incidence of ischemic cv events compared to cat . it should be noted that some important trials were not recruited in our meta - analysis because they did not meet our inclusion criteria . the mea in patients receiving dual antiplatelet therapy to guide treatment with novel platelet antagonists ( madonna ) study found that personalized antiplatelet treatment according to platelet function testing with mea resulted in an improved efficacy with equal safety compared to the standard treatment . however , it was excluded because it was a cohort study rather than an rct . although the assessment by a double randomization of a conventional antiplatelet strategy versus a monitoring - guided strategy for drug - eluting stent implantation and of treatment interruption versus continuation 1 year after stenting ( arctic ) study was an rct , it randomized all recruited patients , not only the clr patients , into the iat and cat arms , which did not meet our inclusion criteria . to the best of our knowledge , . however , several differences existed between the study of aradi et al . and ours . first , to ensure the quality of the studies and to diminish the heterogeneity , all rcts included in our study must randomize the clr patients into the iat and cat arms . was recruited in the study of aradi et al . , but was excluded in our study for the same reason as the arctic study . we proposed that because both arms involve patients who normally responded to clopidogrel such as in these studies , this would dilute the efficacy of the iat causing the results to be less reliable . second , we recruited the latest rcts that were not included in the study of aradi et al . third , in addition to the conventional meta - analysis , we also performed a cumulative meta - analysis , which further confirmed our study results . however , the studies were homogeneous for the evaluation of heterogeneity of different platelet function assays , such as lta and verifynow . although the studies showed heterogeneity in the vasp analysis , the random - effects model was used for the vasp analysis . second , the cutoff values for clr varied between studies [ table 1 ] , which might result in different strengths of the iats . third , the follow - up period of some recruited studies was relatively short ( one month ) , and late adverse events might have not occurred during the study period . in conclusion , this meta - analysis demonstrates that iat guided by platelet function assays reduces the risk of cv death , nonfatal mi , and st without an increased risk of bleeding . supplementary information is linked to the online version of the paper on the chinese medical journal website . this work was supported by grants from the national natural science funding of china ( no . 81170181 ) , and the priority academic program development of jiangsu higher education institutes ( no . this work was supported by grants from the national natural science funding of china ( no . 81170181 ) , and the priority academic program development of jiangsu higher education institutes ( no .