Intensifying Platelet Inhibition With Tirofiban in Poor Responders to Aspirin, Clopidogrel, or Both Agents Undergoing Elective Coronary Intervention
Results From the Double-Blind, Prospective, Randomized Tailoring Treatment With Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel Study
Background— Inhibition of platelet aggregation after aspirin or clopidogrel intake varies greatly among patients, and previous studies have suggested that poor response to oral antiplatelet agents may increase the risk of thrombotic events, especially after coronary angioplasty. Whether this reflects suboptimal platelet inhibition per se, which might benefit from more potent antiplatelet agents such as tirofiban, is unknown.
Methods and Results— We screened 1277 patients to enroll 93 aspirin, 147 clopidogrel, and 23 dual poor responders, based on a point-of-care assay, who underwent elective coronary angioplasty at 10 European sites for stable or low-risk unstable coronary artery disease. Patients were randomly assigned in a double-blind manner to receive either tirofiban (n=132) or placebo (n=131) on top of standard aspirin and clopidogrel therapy. The primary end point, consisting of troponin I/T elevation at least 3 times the upper limit of normal, was attained in 20.4% (n=27) in the tirofiban group compared with 35.1% (n=46) in the placebo group (relative risk, 0.58; 95% confidence interval, 0.39 to 0.88; P=0.009). The rate of major adverse cardiovascular events within 30 days in the tirofiban group also was reduced (3.8% versus 10.7%; P=0.031). The overall incidence of bleeding was low, likely explained by a substantial use of the transradial approach, and did not differ between the 2 groups.
Conclusions— In low-risk patients according to clinical presentation who had poor responsiveness to standard oral platelet inhibitors via a point-of-care assay, intensified platelet inhibition with tirofiban lowers the incidence of myocardial infarction after elective coronary intervention.
Received November 2, 2008; accepted April 30, 2009.
Current treatment strategies for patients with coronary artery disease ignore the individual response to antiplatelet agent(s) and likewise fail to identify therapeutic targets for platelet reactivity necessary to titrate the intensity of treatment. This largely contrasts with the existing practice for many other cardiovascular medications, including antihypertensive1 and lipid-lowering agents2 or even various antithrombotic drugs,3,4 in which the response or lack thereof drives subsequent treatment decisions.
Clinical Perspective on p 3222
Inhibition of platelet aggregation after aspirin or clopidogrel intake varies greatly among patients.5–11 Poor response to oral antiplatelet agents has been shown to increase the risk of thrombotic events, including myocardial infarction (MI), 1.8- to 10-fold, particularly after coronary angioplasty.12–20 Whether this reflects suboptimal platelet inhibition per se, which might benefit from alternative/more potent antiplatelet agents, is unknown.5,6,9 Studies aimed at improving outcomes while intensifying platelet inhibition in these patients are critical to establishing a causal relationship between poor response to a standard antiplatelet regimen and worse outcome.21 We hypothesized that intensifying platelet inhibition with tailored infusion of tirofiban, a platelet glycoprotein IIb/IIIa inhibitor, in patients who are identified as poor responders to aspirin, clopidogrel, or both of these agents on the basis of a point-of-care assay may reduce the incidence of MI after elective coronary angioplasty compared with standard care.
We prospectively enrolled patients at 10 sites in Italy, Belgium, France, and Spain to participate in the Tailoring Treatment With Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel (3T/2R) study. The study protocol was approved by the ethics committee at each institution and was conducted according to the principles of the Declaration of Helsinki. All patients provided written informed consent before enrollment.
The design of the study has previously been detailed.22 Briefly, all patients >18 years of age scheduled for coronary angiography, percutaneous coronary intervention (PCI), or both who presented with stable or troponin-negative non–ST-segment elevation acute coronary syndrome were eligible for screening. The exclusion criteria included any evidence of myocardial damage as witnessed by a rise of cardiac specific injury markers and ongoing MI, defined as the presence of ST-segment elevation at ECG or new or presumably new left bundle-branch block.
Response to aspirin and clopidogrel was assessed by means of the VerifyNow Aspirin and P2Y12 assays, respectively (Accumetrics Inc, San Diego, Calif), according to the manufacturer’s instructions.22 Patients were eligible for aspirin response evaluation if they were taking aspirin orally at doses of at least 80 mg/d for ≥5 days or received intravenous 500 mg aspirin ≥15 minutes before and did not receive clopidogrel or ticlopidine in the previous 7 days. Aspirin nonresponsiveness was defined as aspirin reaction units >550.23 Patients meeting aspirin poor responsiveness criteria qualified for randomization before PCI only when clopidogrel screening requirements (as detailed below) were met. Screening for clopidogrel response was undertaken in patients at steady state for aspirin provided at least 1 of the following 2 requirements was fulfilled: the patient received a 600- or 300-mg loading dose ≥2 or 6 hours before, respectively, or the patient received a 75-mg maintenance clopidogrel dose for ≥7 consecutive days. Poor clopidogrel responsiveness was defined as <40% platelet inhibition.24 Intravenous aspirin at the time of coronary angioplasty in patients at steady state for the treatment was allowed by the protocol and left to the discretion of the treating physician.
An independent study nurse at each site performed assignments of study treatments via a procedure using sealed envelopes. In preselected blocks of 6, patients were stratified according to the presence of stable or unstable coronary artery disease and poor responsiveness to aspirin, clopidogrel, or both. Patients showing poor response to both antiplatelet agents followed the aspirin poor responders randomization scheme. In patients randomly allocated to receive tirofiban, 50 mL of drug was diluted in 200 mL of 0.9% NaCl (1:5) solution, whereas in patients allocated to receive placebo, 50 mL of 0.9% NaCl was injected in 200 mL of 0.9% NaCl solution by an unblinded research study nurse. This procedure allowed the investigators and medical and nursing staff to remain blinded to assignment of study treatment. Bailout use of tirofiban was allowed by the protocol, which did not result in unblinding of treatment assignments. Tirofiban or 0.9% NaCl solution was started by the unblinded study nurse in patients allocated to placebo or tirofiban, respectively, if the treating physician called for bailout use of study treatment.
Study Medications and Interventions
Tirofiban was given as a bolus of 25 μg · kg−1 · 3 min−1, followed by an infusion of 0.15 μg · kg−1 · min−1 for 14 to 24 hours based on previous experience.22,25 Periprocedural administration of either unfractionated heparin or bivalirudin was allowed in all patients regardless of their receiving tirofiban or placebo. However, each site was required to prespecify 1 agent and then use it exclusively in both arms. Heparin was titrated as follows: Patients assigned to tirofiban received 50 to 70 U/kg heparin (≈7000 IU), whereas patients assigned to placebo received an initial bolus of 100 U/kg (maximum, 10 000 IU). Bivalirudin was administered as an intravenous bolus of 0.75 mg/kg, followed by an infusion of 1.75 mg · kg−1 · h−1. Arterial sheath removal with an arteriotomy closure device was allowed immediately after intervention or with external compression when activated clotting time was <180 seconds. In cases when a radial access site was obtained, the sheath had to be removed immediately after angioplasty.
Study End Points and Definitions
The primary end point was the rate of periprocedural MI defined as an elevation of troponin I/T ratio ≥3 times the upper limit of normal (ULN) within 48 hours after completion of the PCI according to the recent universal definition of MI.26
Key secondary end points included assessment of any myocardial injury according to an elevation within 30 days of serum creatine kinase-MB (CK-MB) mass >1, 3, or 5 times the ULN; the rate of any elevation of troponin I or T above the ULN; the rate of major adverse cardiovascular events defined as the composite of death, MI, or urgent target vessel revascularization within 30 days; and the incidence of stent thrombosis. CK-MB and troponin I or T were measured before and 6, 12, and 18 or 24 hours after intervention. Bleedings were collected according to the criteria of the Thrombolysis in Myocardial Infarction trials. An independent clinical events committee adjudicated all serious adverse events based on the review of the original source documents.
The sample size of at least 240 patients was based on an anticipated reduction in event rate from 45% in the standard care/placebo group to 25% in the tirofiban group with an estimated power of 90% at a 2-sided α level of 0.05. Categorical variables are expressed as frequency (percentage); continuous variables are expressed as median (interquartile range). Continuous variables were compared between randomized groups by use of the Wilcoxon rank-sum test; for binary variables, Fisher exact test was used. Risk ratios and 95% confidence intervals (CIs) were calculated for the primary end-point outcomes and for several prespecified subgroups as an exploratory analysis.
The Breslow-Day statistic test was used to assess the homogeneous association of risk ratios between treatment and study primary end point across prespecified subgroups, including age; sex; presence of diabetes mellitus; poor responsiveness to aspirin, clopidogrel, or both; indication to PCI; and number and complexity of treated lesions.
Estimation of the cumulative major adverse cardiovascular event rate was done with the Kaplan-Meier method, and events over time were compared by use of the log-rank test. A 2-sided value of P<0.05 was considered significant. All analyses, carried out on the intention-to-treat principle, were performed with STATA, version 9.2 (Stata Corp, College Station, Tex).
The corresponding author had full access to the data in the study and had final responsibility for the decision to submit for publication. All authors have read and agree to the manuscript as written.
Between February 2006 and June 2008, 1277 patients were screened; of these, 136 (14.8%) showed poor response to aspirin, 174 (27%) were clopidogrel poor responders, and 26 (9.2%) met the criteria for poor responsiveness to both drugs (Figure 1). Of these, 54 patients did not undergo PCI after coronary angiogram, 14 failed to meet inclusion criteria, and 5 refused to participate; thus, 263 patients were finally enrolled in the study. Baseline characteristics and the type of intervention performed for the study population are shown in Tables 1 and 2⇓. The median age was 69 years; 67% had either silent or stable angina; 73% had multivessel disease; slightly >40% and <40% had a history of MI and PCI, respectively; 25% had diabetes mellitus; and almost 60% of the target lesions were type B2 or C. Anticoagulation was established with infusion of bivalirudin in 4 patients only who received concomitant transradial intervention. Intervention was performed in multiple lesions in 40% of the tirofiban group and 34% of the placebo group (P=0.55). Thirty-day follow-up was complete in all patients.
Periprocedural MI, according to the primary end-point definition, occurred in 27 (20.4%) and 46 (35.1%) patients in the tirofiban and placebo groups, respectively (relative risk, 0.58; 95% CI, 0.39 to 0.88; P=0.0089; Figure 2). Figure 3 shows the incidence of periprocedural MI according to multiples of the upper limit of reference value for either troponin I or T and CK-MB. One Q-wave MI (0.8%) occurred in the placebo arm compared with none in the tirofiban arm (P=0.99). The efficacy of tirofiban was consistent among multiple prespecified subgroups, including both aspirin and clopidogrel poor responders (Figure 4). Bailout tirofiban was called for in 3 patients in the tirofiban group and 11 in the placebo arm (P=0.053).
At 30 days, there was 1 fatal event (0.8%) in the placebo arm resulting from massive pulmonary embolism and 2 cases of nonfatal MI: 1 after a staged percutaneous intervention and 1 episode of definite stent thrombosis that required urgent reintervention. In the tirofiban group, no patient died and 1 patient developed a periprocedural MI after a staged percutaneous intervention performed under standard care consisting of treatment with aspirin and clopidogrel. The cumulative incidence of major adverse cardiovascular events, based on CK-MB elevation >3 times the ULN in at least 2 consecutive samples per the definition of periprocedural MI, also was reduced in the tirofiban group (10.7% versus 3.8%; P=0.031).
No major bleeding occurred. Two patients in the tirofiban group (1.5%) and 1 in the placebo group (0.8%; P=0.99) experienced minor bleeding that did not require transfusion. One patient in each group developed mild thrombocytopenia.
The main findings of this study can be summarized as follows: Triple antiplatelet therapy, including a tailored infusion of tirofiban in patients who responded poorly to aspirin, clopidogrel, or both, resulted in a >40% reduction in the incidence of periprocedural MI compared with standard care. This treatment effect was consistent across all exploratory definitions of periprocedural MI, with proportional reductions in ischemic events ranging from 37% to ≥70% based on an elevation of CK-MB ratio >5 times the ULN in at least 1 or 2 consecutive blood sample, respectively. These results suggest that the incremental risk for worse outcomes conveyed by poor response to aspirin, clopidogrel, or both7,9 may be significantly mitigated in the PCI setting by tailored intensification of platelet inhibition.
Notably, the rate of bleeding, which has recently emerged as an independent mortality predictor, was low and did not differ in the 2 study groups, nor did the incidence of thrombocytopenia, and no patient required transfusion of blood products during hospitalization. Whether patients who respond poorly to aspirin, clopidogrel, or both, who likely present with higher residual platelet reactivity after treatment, are intrinsically at lower risk for bleeding complications is currently unknown and worth further investigation.27 Alternatively, the extensive use of transradial intervention and the implementation of the well-validated Thrombolysis in Myocardial Infarction classification explain the overall low bleeding rate observed in our study.
The early benefit, in terms of periprocedural MI, was largely maintained at 30 days, with the cumulative incidence of major adverse cardiovascular events reduced from 21.2% in the tailored tirofiban group to 36.6% in the placebo group based on the primary end-point definition of periprocedural MI and from 10.7% to 3.8%, respectively, when the periprocedural MI rate was defined according ≥3 times the ULN for CK-MB elevation in ≥2 consecutive samples. In exploratory analysis, the effect of tailored tirofiban infusion was consistent across all subgroups, including both aspirin and clopidogrel poor responders. Thus, data are provided for the first time showing that implementing alterative treatment strategies in this patient population may result in an improved outcome compared with standard care.
Our focus on stable and low-risk unstable coronary artery disease patients undergoing PCI with evidence of poor response to aspirin, clopidogrel, or both is based on the following: First, in this setting, the untailored use of a glycoprotein IIb/IIIa inhibitor failed to reduce the incidence of ischemic events when administered on top of dual antiplatelet therapy with aspirin and clopidogrel.28,29 Second, poor response to aspirin and clopidogrel may frequently be associated,30,31 and both carry an independent risk for periprocedural MI after elective PCI performed under standard care.20,32 Consistently, the periprocedural event rate observed in the placebo arm of our study was substantially higher than that previously reported in unselected patients undergoing elective PCI.28,29 This observation is in keeping with previous findings12–14,17,20 and confirms the notion that poor response to standard oral antiplatelet agents identifies a high-risk patient population whose outcomes remains suboptimal when treated under standard care.
Adjusting clopidogrel loading doses according to a vasodilator-stimulated phosphoprotein phosphorylation index has been suggested to reduce the rate of major adverse cardiovascular events in poor responders to standard clopidogrel loading dose regimen.33 However, despite repeated loading doses (up to 2400 mg) over days, clopidogrel did not yield adequate platelet inhibition in all patients. In addition, vasodilator-stimulated phosphoprotein phosphorylation assessment requires the use of flow cytometric assay, which introduces logistic and economic concerns and, like light transmittance aggregometry, cannot be considered a bedside tool. This highlights the need for more user-friendly platelet function assays and alternative antithrombotic agents such as glycoprotein IIb/IIIa inhibitors as used in our study, which more promptly achieve enhanced platelet inhibition.34 We used the VerifyNow system in our study because of evidence that it correlates to measurements with standard light transmittance aggregometry.35 Further driving this decision were previous studies in which poor response to either aspirin20 or clopidogrel,32,36 as detected by this point-of-care assay, independently predicted worse outcomes after coronary intervention.
Our protocol defined clopidogrel poor responder patients with <40% platelet inhibition. Notably, in clopidogrel poor responders presenting with platelet inhibition above a median value (21%), the incidence of the primary end point was low, and the proportional event rate reduction by treatment with tirofiban was in the range of 30%, which did not reach statistical significance. Conversely, both the absolute event rate in the placebo arm and the relative risk reduction driven by treatment were almost doubled in those with platelet inhibition below the median value. This may suggest, in keeping with recent studies,6,12,36,37 that those patients showing minimal platelet inhibition after clopidogrel intake, who are at even greater risk for worse cardiovascular outcomes, may derive the greatest benefit from a tailored intensification of platelet inhibition. CIs remain wide in our exploratory analyses of subgroups, as reflected by a lack of statistical interaction between response to clopidogrel and treatment effect. Thus, confirmation from larger data sets as to which threshold for response to clopidogrel should trigger a tailored intensified antiplatelet strategy remains warranted. It is currently debated whether the relative change in platelet inhibition after treatment or absolute posttreatment platelet reactivity is better for use in identifying patients who may benefit from a tailored intensification of platelet inhibition. We arbitrary decided to use the former in our study. Interestingly, the percentage of platelet inhibition by clopidogrel and absolute platelet reactivity units by the VerifyNow system were highly inversely correlated in our patient population undergoing screening for response to clopidogrel (r=−0.86; P<0.001), with 20% inhibition corresponding to platelet reactivity units in the range of 210 in regression analysis (data not shown).
Several limitations of our study deserve attention. To minimize the potential for bias, the protocol mandated double-blind administration of study drug, which was obtained through the assistance of an unblinded independent study nurse at each site. Ideally, no care providers should be aware of the randomization scheme, but this would require dedicated manufacturing of drug and placebo.
We would like to acknowledge that, unlike for clopidogrel, molecular mechanisms subtending hyporesponsiveness to aspirin are only poorly understood and are likely far more complex than failure of the drug to “hit the target.”9 Moreover, it remains unclear whether aspirin poor responsiveness and clopidogrel poor responsiveness are equally associated with higher atherothrombotic risks.
Our study was designed as a proof-of-concept study and as such was powered to assess the effect of treatment on PCI-related myocardial necrosis. Although the rate of major adverse cardiovascular events was significantly reduced at 30 days in the tirofiban arm, this reduction almost exclusively reflected the different rate of periprocedural MI because the event rate, which was not related to the intervention itself, was extremely low up to 30 days. Moreover, by implementing random allocation of tirofiban versus placebo in the study, we focused on short-term outcome after intervention. Studies investigating alternative maintenance treatment strategies in poor responders to standard regimen of clopidogrel are underway and will complement our findings. Although there is no consensus on the most appropriate definition of aspirin and clopidogrel poor responsiveness,6,21 in the present study, we used cutoff values previously reported in the scientific literature.24 Data from other studies36 and this study suggest, however, that a higher threshold to define clopidogrel poor responsiveness may be desirable in future investigations. In clopidogrel-naïve patients, longer duration of clopidogrel pretreatment after a 300- or 600-mg loading dose may decrease the rate of drug poor responsiveness and consequently diminish the need for an additional intravenous antiplatelet agent at the time of PCI.
Ideally, the effect of intensified platelet inhibition versus placebo in patients who failed to meet the poor responsiveness criteria for aspirin, clopidogrel, or both may have complemented our findings by showing no or marginal benefit on ischemic end points. This may have further corroborated the importance of on-treatment high residual platelet activity as a key player in ischemic events. The inclusion of patients at steady state for the treatment or who received clopidogrel at different loading regimens also may be perceived as a study limitation. Importantly, subgroup analysis did not disclose any heterogeneity of results based on different pretreatment modalities.
We showed that the intensification of platelet inhibition through the infusion of tirofiban in poor responders to aspirin, clopidogrel, or both who undergo elective PCI decreased the rate of periprocedural MI and resulted in a lower rate of major adverse cardiovascular events at 30 days. Our study provides proof of concept for a new treatment strategy in patients with coronary artery disease that, by assessing response to standard antiplatelet agents by a point-of-care assay, modulates the intensity of treatment accordingly.
Sources of Funding
This study was partially supported by a research grant from Merck, USA, and Iroko, USA, which had no role in the study design; collection, analysis, and interpretation of data; writing of the report; and the decision to submit the paper for publication.
Dr Valgimigli has received honoraria for lectures from or served on advisory boards for Merck/Iroko, The Medicines Co, Eli Lilly Co, and Daiichi Sankyo Inc and has received research grants from Merck/Iroko and Eli Lilly. Dr Angiolillo has received honoraria for lectures from or served on advisory boards for Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly Co, The Medicines Co, Portola, Novartis, and Daiichi Sankyo Inc. Dr Hamon has received honoraria for lectures from The Medicines Co, GSK, Nycomed, and Merck.
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Previous studies have shown that individual response to aspirin or clopidogrel intake may vary significantly among patients, and those who respond less have been reported to be at higher risk for worse cardiovascular outcomes, especially if treated with percutaneous coronary intervention. It is unknown whether this worse cardiovascular outcome directly reflects suboptimal platelet inhibition per se, which might benefit from more potent antiplatelet agents. Alternatively, this may simply represent a “marker” of worse prognosis without clear therapeutic implications. In this study, we have shown that intensifying platelet inhibition through the use of tirofiban, a potent intravenous antiplatelet agent, in patients undergoing percutaneous coronary intervention who have previously been selected to be poor responders to aspirin, clopidogrel, or both agents leads to lower incidence of periprocedural myocardial infarction compared with standard care consisting of aspirin and clopidogrel. Thus, data are provided for the first time showing that implementing alterative treatment strategies in this patient population may result in an improved outcome compared with standard care. Our results may suggest a causal relationship between suboptimal platelet inhibition and worse outcomes in this selected patient population.
Clinical trial registration information—URL: http://clinicaltrials.gov. Unique identifier: NCT00398463.