Author + information
- Received December 16, 2011
- Revision received February 8, 2012
- Accepted February 23, 2012
- Published online July 31, 2012.
- Dirk Sibbing, MD⁎ (, )
- Isabell Bernlochner, MD,
- Stefanie Schulz, MD,
- Steffen Massberg, MD,
- Albert Schömig, MD,
- Julinda Mehilli, MD and
- Adnan Kastrati, MD
- ↵⁎Reprint requests and correspondence:
Dr. Dirk Sibbing, Deutsches Herzzentrum München and 1. Medizinische Klinik rechts der Isar, Technische Universität München, Lazarettstrasse 36, 80636 München, Germany
Objectives The ISAR-REACT 4 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment-4) platelet substudy aimed to determine the relevance of high on-clopidogrel treatment platelet reactivity (HPR) in non–ST-segment elevation myocardial infarction patients that received abciximab with unfractionated heparin (UFH) or bivalirudin during percutaneous coronary intervention (PCI).
Background In patients undergoing PCI, HPR has been linked to a higher risk for ischemic events. The influence of HPR on clinical outcomes may differ with regard to the adjunctive antithrombotic treatment administered. In ISAR-REACT 4, bivalirudin treatment showed similar efficacy profiles as compared to abciximab with UFH. The impact of HPR on clinical outcomes in abciximab with UFH versus bivalirudin treated non–ST-segment elevation myocardial infarction patients has never been investigated specifically.
Methods A total of 564 patients (274 in abciximab/UFH group vs. 290 in bivalirudin group) were enrolled in this study. Presence or absence of HPR following clopidogrel loading was determined by platelet function testing on a Multiplate analyzer (Verum Diagnostica, Munich, Germany). Per study group and stratified in HPR and no-HPR patients, the 30-day incidence of a combined efficacy endpoint (death, myocardial infarction, urgent target vessel revascularization) was determined.
Results For abciximab with UFH, the incidence of the efficacy endpoint was similar in HPR versus no-HPR patients (9.4% vs. 6.7%; odds ratio: 1.4; 95% confidence interval: 0.6 to 3.5; p = 0.43). For bivalirudin, the incidence of the efficacy endpoint was significantly higher in HPR versus no-HPR patients (22.0% vs. 5.0%; odds ratio: 5.4; 95% confidence interval: 2.4 to 12.1; p < 0.0001).
Conclusions For patients with a risk profile similar to the subjects enrolled in this platelet substudy, the impact of HPR on clinical outcomes may depend on the type of adjunctive antithrombotic therapy used during PCI. Further investigations are warranted to clarify whether assessment of platelet function may help tailoring antithrombotic therapy during PCI. (Randomized Comparison of Abciximab Plus Heparin With Bivalirudin in Acute Coronary Syndrome [ISAR-REACT 4]; NCT00373451)
Responsiveness to clopidogrel treatment is not uniform (1) and a high on-clopidogrel treatment platelet reactivity (HPR) has been linked to an increased risk for ischemic events in numerous studies (2–5) as well as their meta-analyses (6). Results from recently reported randomized trials such as the GRAVITAS (Gauging Responsiveness With A VerifyNow Assay: Impact On Thrombosis And Safety) trial (7) and the TRIGGER-PCI (Testing platelet Reactivity In patients underGoing elective stent placement on clopidogrel to Guide alternative thErapy with pRasugrel) trial (8) as well as data from the ADAPT-DES (Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents) registry (9) suggested that the existence of HPR and switching patients to intensified treatment regimens may play a more prominent role in acute coronary syndrome (ACS) patients undergoing urgent percutaneous coronary intervention (PCI) procedures and may only play a minor role in stable patients undergoing elective PCI.
Along with a dual antiplatelet treatment consisting of aspirin and a P2Y12 receptor inhibitor such as clopidogrel, different adjunctive antithrombotic treatment regimens are being used in the setting of PCI (10). Identifying the best adjunctive treatment approach for PCI treated patients in different clinical settings ranging from stable coronary artery disease (CAD) patients to CAD patients presenting with ST-segment elevation myocardial infarction (STEMI) has been the focus of extensive research during the last decades (11–15). Just recently, we reported the results of the ISAR-REACT 4 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 4) trial that aimed to compare the safety and efficacy of combined abciximab with unfractionated heparin (UFH) treatment versus bivalirudin treatment alone in clopidogrel treated non–ST-segment elevation myocardial infarction (NSTEMI) patients undergoing urgent PCI (16). When comparing both treatment groups, the cumulative incidence of the combined efficacy endpoint (death, any recurrent myocardial infarction [MI], urgent target-vessel revascularization [TVR]) was similar during a 30-day follow-up period. However, bivalirudin was associated with a markedly reduced risk of major bleeding.
Keeping in mind the different pharmacological properties of these 2 treatment approaches with bivalirudin as a direct and rapidly acting thrombin inhibitor that also shows antiplatelet action (17) and with UFH inhibiting free thrombin indirectly and the glycoprotein IIb/IIIa inhibitor abciximab being a potent antiplatelet agent, presence or absence of HPR in clopidogrel treated NSTEMI patients may have a differential impact on the risk for post-PCI ischemic events. With regard to this, the prognostic value of HPR in relation to different adjunctive antithrombotic treatment regimens has never been investigated specifically.
Thus, the objective of the ISAR-REACT 4 platelet substudy was to determine the relevance of HPR in NSTEMI patients that received either combined abciximab with UFH or bivalirudin treatment during the PCI procedure.
Study population and design
All patients recruited for this platelet substudy were part of the ISAR-REACT 4 trial (16) that aimed to compare the clinical outcome of NSTEMI patients receiving either abciximab with UFH or bivalirudin treatment during PCI. The present platelet substudy included a cohort of 564 patients with platelet function measurements available for the index PCI procedure. The inclusion and exclusion criteria for this study were identical to those of the ISAR-REACT 4 trial (16). In brief, the primary trial enrolled patients with the following inclusion criteria: an accelerating pattern of angina pectoris or angina lasting >20 min or recurrent episodes of angina (either at rest or during minimal exertion) within the preceding 48 h; levels of cardiac biomarkers (troponin T or creatine kinase-myocardial band isoenzymes) that were above the upper limit of normal range; and coronary stenoses requiring urgent PCI. A detailed description of exclusion criteria is listed elsewhere (16).
All patients included here were recruited at 2 participating centers of the multicenter ISAR-REACT 4 trial. These centers were the Deutsches Herzzentrum München and the Klinikum rechts der Isar (Technische Universität München, Munich, Germany). A flow chart of the study population showing all patients enrolled in these 2 centers (with and without platelet function results available) is illustrated in Figure 1. Within both study groups all patients received a single high loading dose of 600 mg of clopidogrel and 500 mg aspirin i.v. in preparation for the PCI procedure. Post-interventional antiplatelet treatment consisted of clopidogrel 75 mg twice daily for the remainder of the hospitalization up to 3 days, followed by 75 mg/day. The recommended duration of clopidogrel treatment was 12 months. Aspirin 100 mg twice daily was recommended for an indefinite period. Platelet function testing was performed instantaneously before PCI, after clopidogrel loading, and prior to the administration of any study drug.
Patients in the abciximab plus UFH group received a bolus of 0.25 mg abciximab as well as a bolus dose of 70 units UFH per kilogram body weight, followed by a continuous infusion of 0.125 μg abciximab per kilogram body weight per minute for 12 h. Patients in the bivalirudin group were assigned to a bolus dose of 0.75 mg per kilogram bivalirudin, followed by a continuous infusion of 1.75 mg per kilogram per hour during PCI. The study protocol was approved by the institutional ethics committee and all patients gave written informed consent before entering the study.
Blood sampling and platelet function testing
Whole blood for platelet function testing on the Multiplate analyzer (Verum Diagnostica, Munich, Germany) was obtained in the cath lab from the arterial sheath of all patients directly before PCI and prior to the administration of study drug treatment. Blood was placed in 4.5-ml plastic tubes containing the anticoagulant lepirudin (25 μg/ml; Refludan, Dynabyte, Munich, Germany). The adenosine diphosphate–induced platelet aggregation was assessed. Details of this method have been reported previously (3,18). Aggregation measured on the Multiplate device is quantified as area under the curve of aggregation units (AU) (area under the curve = AU × min). All material used for platelet function testing was obtained from the manufacturer. During the course of the ISAR-REACT 4 trial, patients for this platelet substudy were enrolled at the core times of the central laboratory and not at night or outside the core times, which was due to logistic reasons.
Study endpoints and definitions
The primary outcome measure of this platelet substudy was the pre-specified combined efficacy endpoint of the ISAR-REACT 4 trial (16), which was defined as a composite of death, MI, or urgent TVR at 30 days after PCI. To allow an overview, results for this combined endpoint are reported for all patients (with and without platelet function results available) recruited in the 2 participating centers of this platelet substudy.
For the patients within the platelet substudy cohort, presence or absence of HPR was determined per study group. The definition of HPR (≥468 AU × min) was based on prior studies (3,19) and the consensus document (4) of the Working Group on High On-Treatment Platelet Reactivity. We also assessed the incidence of death, MI, TVR, large MI, and definite stent thrombosis in the 2 study groups for HPR and no-HPR patients. Definitions of the ischemic endpoints are identical to the definitions used in the ISAR-REACT 4 trial and have been summarized elsewhere (16). In addition, we report on the incidence of Thrombolysis In Myocardial Infarction (TIMI) major bleeding per study group in patients with versus without an enhanced response (= low platelet reactivity [LPR]) to clopidogrel. LPR (AU × min ≤188) was defined as previously described (19).
Variables are presented as mean ± SD, numbers (percentages), or median with interquartile range. Categorical variables were compared using chi-square test. Kolmogorov-Smirnov test was used to check for normal distribution of continuous data. Platelet function data were non-normally distributed and were compared across groups with 2-sided unpaired Wilcoxon test. Normally distributed continuous data were compared across 2 groups with 2-sided unpaired t test. We also tested for interactions regarding the combined efficacy endpoint: 1) between study treatment arm and availability of platelet function testing; and 2) between study treatment arm and platelet aggregation. Interaction was tested in a Cox proportional hazards model. Kaplan-Meier curves were plotted to illustrate the cumulative incidence of the combined efficacy endpoint per study group and with regard to presence or absence of HPR. All analyses were performed using the software package S-PLUS (TIBCO Software Inc., Palo Alto, California). For all statistical analyses a p value <0.05 was considered statistically significant.
Study flow and study population
From the entire multicenter study population (1,721 patients) of the ISAR-REACT 4 trial, 1,195 patients were enrolled in the 2 participating centers of platelet substudy. As outlined in the study flow chart (Fig. 1), whole blood for platelet function testing was available in 564 patients (47.2%), who constitute the platelet substudy cohort. No blood for platelet function testing was available in the remaining 631 patients (52.8%). This is due to the fact that the device for platelet function testing was not available during the early course of the trial (91 patients were enrolled in the 2 centers before the device was installed) and also because patients for the platelet substudy were enrolled at the core times of the central laboratory and not at night or outside the core times. Some baseline and procedural characteristics differed between patients with (n = 564) and without (n = 631) platelet function results available (Online Tables 1 and 2). Of note, patients outside the platelet substudy cohort had a lower ejection fraction and more often a history of prior MI.
The 30-day combined efficacy endpoint (death, MI, urgent TVR) occurred in 151 (13%) patients of the entire cohort (n = 1,195) of patients enrolled in the 2 participating centers. For patients included in the platelet substudy (n = 564), the combined efficacy endpoint occurred in 54 (9.6%) patients. The cumulative incidence of this endpoint did not differ between patients (n = 274) treated with abciximab plus UFH as compared with patients (n = 290) treated with bivalirudin (21 [7.7%] vs. 33 [11.4%] patients, respectively; p = 0.13). For patients not included in the platelet substudy (n = 631), the combined efficacy endpoint occurred in 97 (15.0%) patients. The cumulative incidence of this endpoint did not differ between patients (n = 324) treated with abciximab plus UFH as compared with patients (n = 307) treated with bivalirudin (52 [16.0%] vs. 45 [14.7%] patients, respectively; p = 0.63). No significant interaction was observed between study treatment arm and availability of platelet function testing regarding the combined efficacy endpoint (p for interaction = 0.12).
Platelet substudy cohort
The mean age of patients (n = 564) included in this cohort was 67.7 years and the proportion of women was 22% (n = 126). Baseline characteristics of the study population including age, gender, and cardiovascular risk factors were similar between the 2 study treatment arms (Table 1). Angiographic and procedural characteristics (Table 2) of the study population were similar between both treatment arms as well except for the stenosis after the procedure, which was slightly higher in the bivalirudin group. Clinical follow-up at 30 days was completed (100%) for all 564 patients.
The adenosine diphosphate–induced platelet aggregation values (median [interquartile range]) at the time point of the PCI procedure and following loading with 600 mg of clopidogrel were similar between the 2 treatment groups (305 [169 to 597] AU × min in the abciximab with UFH group vs. 329 [197 to 582] AU × min in the bivalirudin group; p = 0.31). In the entire platelet substudy cohort a total of 205 patients (36%) showed an HPR at the time point of the PCI procedure. The proportion of patients with HPR was comparable between the 2 study groups (96 [35.0%] in the abciximab with UFH group vs. 109 [37.6%] patients in the bivalirudin group; p = 0.53).
Clinical outcome data per group and HPR
In the abciximab with UFH group the incidence of the combined efficacy endpoint was similar in HPR versus no-HPR patients (9.4% vs. 6.7%; odds ratio [OR]: 1.4; 95% confidence interval [CI]: 0.6 to 3.5; p = 0.43) (Fig. 2A). For bivalirudin treated patients, the incidence of the combined efficacy endpoint was significantly higher in HPR versus no-HPR patients (22.0% vs. 5.0%; OR: 5.4; 95% CI: 2.4 to 12.1; p < 0.0001) (Fig. 2B). A significant interaction was observed between study treatment arm and platelet aggregation regarding the combined efficacy endpoint (p for interaction = 0.037). Table 3 shows the entire clinical outcome data in the 2 study groups according to the presence or absence of HPR. For abciximab treated patients, none of the ischemic events investigated showed significant differences between HPR and no-HPR patients (Table 3). For bivalirudin treated patients, a significantly higher risk for any recurrent MI, death, or any recurrent MI, as well as large MI, was observed in HPR versus no-HPR patients (Table 3).
In the entire study cohort (n = 564) and regardless of whether bivalirudin or abciximab plus UFH was administered during the PCI procedure, the incidence of the combined efficacy endpoint was significantly higher in HPR (n = 205) versus no-HPR (n = 359) patients (16.1% vs. 5.8%; OR: 3.1; 95% CI: 1.7 to 5.5; p < 0.0001). Major bleeding (according to TIMI criteria) occurred in 5 patients (5 of 274 = 1.8%) in the abciximab with UFH group and events were numerically higher in patients exhibiting a status of LPR (AU × min ≤188) as compared with patients without LPR (4 events [4.9%] in 82 patients vs. 1 event [0.5%] in 192 patients, respectively; p [Fisher exact] = 0.06). In the bivalirudin group, only 1 (1 of 290 = 0.3%) major bleeding event occurred in a patient without LPR.
The ISAR-REACT 4 platelet substudy is the first study that specifically aimed to investigate and to compare the prognostic value of HPR in NSTEMI patients that either received adjunctive antithrombotic treatment with combined abciximab plus UFH or bivalirudin during the PCI procedure. To the best of our knowledge, this study is also the first to evaluate the prognostic value of clopidogrel response testing in a cohort of NSTEMI patients that was primarily recruited and treated in a randomized and well-controlled fashion within a large-scale clinical trial investigating the value of different adjunctive antithrombotic treatment options for patients undergoing urgent PCI. Key results of this platelet substudy can be summarized as the following: The prognostic value of HPR determined by periprocedural platelet function testing for predicting ischemic events in NSTEMI patients may depend on the adjunctive antithrombotic agent administered. Whereas the presence of HPR in bivalirudin treated patients was relevant and predictive for the occurrence of early ischemic events, presence of HPR in abciximab with UFH treated patients had little relevance in this regard. Present data suggest that stronger platelet inhibition, such as provided by abciximab, is beneficial in NSTEMI patients who still have HPR after 600 mg clopidogrel loading. This finding is in line with prior studies that reported on a beneficial effect of glycoprotein IIb/IIIa inhibitors in PCI treated patients showing HPR on clopidogrel treatment (20,21).
Of note, not all patients of the ISAR-REACT 4 trial were included in this platelet substudy and the overall event rates of patients with and without platelet function testing results available differed with event rates being numerically higher in patients without platelet function testing. This could be explained by the circumstance that blood for testing was only obtained during the core time of the 2 participating centers of this platelet substudy. As a consequence, the platelet substudy cohort must be considered as a lower-risk cohort when compared with the entire study population, as patients enrolled outside core time or even at night generally constitute a high-risk group of patients with higher event rates (22). This is also reflected in differences of baseline characteristics when comparing patients with and without platelet function testing available.
In the entire ISAR-REACT 4 study cohort (16), the pre-specified efficacy endpoint did not differ between abciximab with UFH versus bivalirudin treated patients and for all ischemic endpoint studied both treatment options showed similar efficacy profiles. Importantly, the overall event rates for the same combined efficacy endpoint did not differ between the 2 study groups within this platelet substudy cohort as well. Further on, strengths of the present study cohort include the circumstance that both study groups were comparable in terms of their baseline, their procedural, and their platelet function characteristics. These observations are important and set the basis for further stratifying patients according to the presence or absence of HPR with the aim of investigating the ischemic risk within the distinct subgroups.
Whereas the proportion of HPR patients (about 35% per group) was similar between both study groups, the ischemic event rates, however, showed a completely different pattern. Finding only little differences for HPR and no-HPR patients within the abciximab/UFH group, the observed differences in the bivalirudin arm are remarkable and warrant further discussion. On the one hand, no-HPR patients (about two-thirds of patients) in the bivalirudin arm showed the lowest event rate from all subgroups investigated here and their event rate (5.0%) was found to be far below the overall event rate (9.6%) of this substudy cohort and also below the event rate reported for the entire trial cohort (16). In concert with the overall ISAR-REACT 4 trial results (16), this is a strong argument for the use of bivalirudin in NSTEMI patients who show an adequate level of P2Y12 receptor inhibition. The level of platelet inhibition achieved in that subgroup may be an optimal level and further inhibition, temporarily delivered with abciximab, may not confer to further risk reduction for ischemic events. On the other hand, the high event rate of 22% in HPR patients (about one-third of patients) receiving adjunctive bivalirudin might argue for more potent P2Y12 receptor inhibitors or additional abciximab treatment in this group of patients. Both the third-generation thienopyridine prasugrel and the nonthienopyridine P2Y12 receptor inhibitor ticagrelor should be considered as a better treatment option here. Reflecting the results of the TRITON–TIMI 38 (TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel–Thrombolysis In Myocardial Infarction 38) (23) and the PLATO (PLATelet inhibition and patient Outcomes) (24) trials, both drugs (prasugrel and ticagrelor) have shown superior efficacy profiles over clopidogrel in ACS patients in general. This is why both agents have just recently received a class IB indication for treatment of ACS patients, while clopidogrel is recommended for patients who cannot receive ticagrelor or prasugrel (10). However, the potent P2Y12 receptor blockers are associated with a higher risk of non–coronary artery bypass graft major bleeding (23,24). Unfortunately, in both the TRITON–TIMI 38 and PLATO trials it was not reported on the differential outcome of HPR and no-HPR patients with regard to the P2Y12 receptor inhibitor used. It may well be that specifically in ACS patients receiving first-line clopidogrel therapy and showing HPR, the more rapid and more potent platelet inhibition of prasugrel or ticagrelor shows greatest benefit by reducing thrombotic risk burden without increasing bleeding risk.
In general, an insufficient level of P2Y12 receptor inhibition may warrant attention and may require its assessment especially in situations when a coronary stenting procedure is performed in a prothrombotic milieu, as it is the case in ACS patients (25). Moreover, patients with an ACS/NSTEMI are commonly treated with an early invasive strategy, as it was also the case in ISAR-REACT 4 trial. The often delayed (26) and commonly insufficient (27) antiplatelet action of clopidogrel in ACS patients explains the high rate of HPR patients (>35%) observed in our study here and may also explain the high event rate for HPR patients within the bivalirudin study group. The contention that bivalirudin treated ACS patients are in need of an adequate P2Y12 receptor blocker pretreatment was also highlighted in a post hoc analysis (28) of the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial (14). Investigating the role of 2 different clopidogrel loading doses (300 mg vs. 600 mg) in STEMI patients, it was shown that the higher loading dose reduced the risk for ischemic events in the early course after the PCI procedure (28). Thus, there is room for further improving the outcome of bivalirudin treated ACS patients when an optimal level of P2Y12 receptor inhibition is achieved at the time point of the procedure. Contrariwise, administration of abciximab in a similar setting may abate the importance of adequate clopidogrel pre-treatment at the time point of the intervention and thus diminish the relevance of HPR during the stenting procedure. In general, the full antiplatelet action of clopidogrel is not immediate in all patients and may be reached in some patients as recently as on the day after the PCI procedure (26). Abciximab, a potent and rapidly acting antiaggregative agent, is able to bridge the time span of insufficient platelet inhibition and may also dampen the prothrombotic milieu (25) that is most pronounced around the PCI procedure. This leaves time for patients to reach a sufficient level of active clopidogrel metabolite generation and when the antiplatelet action of abciximab sets off, these patients are sufficiently inhibited via the P2Y12 receptor pathway and the prothrombotic milieu is likely to settle step by step in the early days after PCI. This may explain the observation that the event rates within the abciximab plus UFH group show a similar pattern over the entire 30-day course and not a later separation toward higher events in the HPR group, when the antiplatelet action of abciximab sets off. Thus, our results do also argue for a vulnerable phase in NSTEMI patients, directly surrounding the invasive procedure, where sufficient platelet inhibition is of utmost importance. Platelet function testing during this phase may help to monitor and to guide a tailored antiplatelet treatment to the needs of the individual patient.
The usefulness and possible need for routine platelet function testing has been a topic of heated debate in recent years (4). Studies like GRAVITAS (7) and TRIGGER-PCI (8) aimed to assess a possible benefit of a tailored and intensified antiplatelet treatment in HPR patients undergoing coronary stenting. Both studies failed to show a benefit of tailoring treatment on the basis of platelet function testing. Properties of the study design, an overall low event rate within the studies, and also the circumstance that only low-to-intermediate risk patients were enrolled in these studies have been put forward as possible explanations for the negative study results. Of note, the proportion of NSTEMI and STEMI patients was low in both TRIGGER-PCI and GRAVITAS (7,8). Exactly NSTEMI/STEMI patients, however, may constitute a cohort of patients that could benefit most from platelet function monitoring for guiding pharmacological therapy during and after the PCI procedure. Moreover, testing may be beneficial in the setting of different P2Y12 receptor blockers as treatment with both clopidogrel (1) and prasugrel (29) is associated with a relevant proportion of patients that continue to exhibit a status of HPR.
Generally, results of this platelet substudy do not argue against the routine use of bivalirudin in NSTEMI patients undergoing urgent PCI. Instead, our data indicate that there may be a differential impact of HPR during PCI, which may depend on the choice of adjunctive antithrombotic treatment used. Further on, it is crucial to note that present data are observational, stem from a post hoc analysis of a randomized trial, and must be considered as hypothesis generating. Therefore, further studies are warranted here and it seems obvious to investigate this issue in the setting of prasugrel or ticagrelor treatment, both of which now have a Class IB recommendation for ACS patients (10). Of note, high on-treatment platelet reactivity is also an issue with prasugrel (29), whereas data are lacking so far for ticagrelor, and assessing its relevance for these 2 agents in the setting of different adjunctive antithrombotic treatment regimens seems mandatory. Moreover, it remains unknown in how far our findings here can be extrapolated to stable CAD patients undergoing elective PCI. Further studies are necessary to close these gaps of knowledge.
First, we only measured platelet function in a part of the entire study cohort of the ISAR-REACT 4 trial. Second, we only assessed platelet function with 1 single device (Multiplate analyzer) and at 1 pre-specified time point during the study (directly before PCI). Multiple measurements at different time points with different devices would have been helpful to study the prognostic value of clopidogrel response testing in NSTEMI patients in more detail. Third, present results cannot be extrapolated to prasugrel or ticagrelor treated patients and further studies are needed here. Finally, a further limitation of the present study is that this analysis was a post hoc analysis of a study population that stems from a randomized trial and, therefore, it is subject to limitations inherent to all such analysis.
The impact of HPR on clinical outcomes may depend on the type of adjunct antithrombotic therapy used during PCI. It is more pronounced in patients treated with bivalirudin than in those treated with UFH plus abciximab. Further investigations are warranted to clarify whether assessment of platelet function may help tailoring antithrombotic therapy during PCI.
For an expanded Results section, please see the online version of this article.
Prognostic Value of a High On-Clopidogrel Treatment Platelet Reactivity in Bivalirudin Versus Abciximab Treated Non– ST-Segment Elevation Myocardial Infarction Patients: The ISAR-REACT 4 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 4) Platelet Substudy
This work was supported in part by Nycomed Pharma, Unterschleissheim, Germany (former distributor of bivalirudin in Europe), and a grant (KKF 04-06 ) from Deutsches Herzzentrum, Munich, Germany. Material for platelet function testing was in part provided free of charge from Verum Diagnostica. The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. Dr. Sibbing has received fees for advisory board activities from Verum Diagnostica and Eli Lilly; and speaker fees from AstraZeneca. Dr. Kastrati has received consulting fees from AstraZeneca, Bristol-Myers Squibb, and Daiichi Sankyo/Eli Lilly and lecture fees from Abbott, Biotronik, Cordis, and Medtronic. Dr. Mehilli has received lecture fees from Abbott, Daiichi Sankyo/Eli Lilly, and Terumo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Sibbing and Bernlochner both contributed equally to this work.
- Abbreviations and Acronyms
- acute coronary syndrome
- aggregation unit
- coronary artery disease
- confidence interval
- high on-clopidogrel treatment platelet reactivity
- low platelet reactivity
- myocardial infarction
- non–ST-segment elevation myocardial infarction
- odds ratio
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- target vessel revascularization
- unfractionated heparin
- Received December 16, 2011.
- Revision received February 8, 2012.
- Accepted February 23, 2012.
- American College of Cardiology Foundation
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