Author + information
- Received October 2, 2013
- Revision received December 3, 2013
- Accepted December 9, 2013
- Published online March 25, 2014.
- Dániel Aradi, MD, PhD∗∗ (, )
- Adrienn Tornyos, MD†,
- Tünde Pintér, MD, PhD†,
- András Vorobcsuk, MD, PhD†,
- Attila Kónyi, MD, PhD†,
- József Faluközy, MD∗,
- Gábor Veress, MD, PhD∗,
- Balázs Magyari, MD†,
- Iván G. Horváth, MD, PhD† and
- András Komócsi, MD, DSc†
- ∗Department of Cardiology, Heart Center Balatonfüred, Balatonfüred, Hungary
- †Heart Institute, University of Pécs, Pécs, Hungary
- ↵∗Reprint requests and correspondence:
Dr. Dániel Aradi, Heart Center Balatonfüred, Department of Cardiology, 2 Gyógy Tér, Balatonfüred 8230, Hungary.
Objectives This study sought to evaluate the impact of treatment with prasugrel and high-dose clopidogrel on the basis of platelet function testing in patients with acute coronary syndrome (ACS) who are undergoing percutaneous coronary intervention (PCI).
Background The clinical impact of treatment with prasugrel in patients with ACS who have high platelet reactivity (HPR) is unknown.
Methods Patients with ACS who were pre-treated with clopidogrel and undergoing successful PCI were enrolled in a single-center, prospective registry. Platelet function was measured 12 to 36 h after PCI with the Multiplate device (Roche Diagnostics GmbH, Mannheim, Germany). Patients with HPR (>46 U) were switched to prasugrel or treated with high-dose clopidogrel, and those without HPR continued treatment with 75 mg of clopidogrel.
Results A total of 741 consecutive patients were enrolled in the study between September 2011 and August 2012, and 219 of these patients (29.5%) had HPR. Although platelet reactivity decreased after treatment adjustments in those with HPR, prasugrel provided significantly more potent platelet inhibition compared with high-dose clopidogrel (p < 0.0001). Compared with patients without HPR, the risk of all-cause death, myocardial infarction, stent thrombosis, or stroke at 1 year was significantly higher in the high-dose clopidogrel group (hazard ratio [HR]: 2.27; 95% confidence interval [CI]: 1.45 to 3.55; p < 0.0001), and patients who were switched to prasugrel had similar outcomes (HR: 0.90; 95% CI: 0.44 to 1.81; p = 0.76). Bleeding Academic Research Consortium (BARC) type 3/5 bleeding was also more frequent in patients treated with high-dose clopidogrel (HR: 2.09; 95% CI: 1.05 to 4.17; p = 0.04) than in patients switched to prasugrel (HR: 0.45; 95% CI: 0.11 to 1.91; p = 0.28). In a multivariate model, HPR with high-dose clopidogrel, but not with prasugrel, was an independent predictor of the composite ischemic endpoint (HR: 1.90; 95% CI: 1.17 to 3.08; p = 0.01).
Conclusions Switching patients with ACS who have HPR to treatment with prasugrel reduces thrombotic and bleeding events to a level similar to that of those without HPR; however, there is a higher risk of both thrombotic and bleeding complications with high-dose clopidogrel.
- high-dose clopidogrel
- high platelet reactivity
- platelet function testing
- stent thrombosis
Patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) should receive a P2Y12 inhibitor in addition to aspirin for 1 year (1–4). Recent European guidelines favor prasugrel and ticagrelor over clopidogrel (3,4), whereas American guidelines consider these options to be possible alternatives (1,2). Although both prasugrel and ticagrelor showed a significant reduction in death, myocardial infarction, or stroke compared with clopidogrel in patients with ACS (5,6), the higher risk of major bleeding together with the higher treatment costs limit their use in routine practice.
Theoretically, platelet function assays could be useful to measure the level of platelet inhibition and guide the choice of the optimal P2Y12 inhibitor to reduce costs and bleeding complications; however, all currently available large-scale, randomized studies failed to show clinical improvements when treatment modifications were implemented on the basis of platelet function testing (7–9). Notably, most of these studies used high-dose clopidogrel to overcome high platelet reactivity (HPR) or included patients at low risk for recurrent events, and there is a lack of evidence on the potential clinical benefits of switching patients with ACS who have HPR to treatment with prasugrel. Our aim was to evaluate the clinical and pharmacodynamic impact of using prasugrel or high-dose clopidogrel on the basis of platelet function testing in a consecutive, all-comer, single-center registry of nonelderly patients (younger than 80 years of age) with ACS after PCI.
As of September 2011, Hungarian health insurers have approved and provided reimbursement for treatment with prasugrel in patients with ACS undergoing PCI who have either diabetes or acute myocardial infarction, but only when assessment of platelet function verifies that the patient did not respond to treatment with clopidogrel. This regulation practically acts as a prasugrel-prescribing policy for all interventional centers because of the high costs of unreimbursed prasugrel for patients. Acknowledging the lack of evidence behind this approach, we aimed to build a single-center registry in one of the large-volume academic centers in Hungary (Heart Institute, University of Pécs, Pécs, Hungary) to evaluate the clinical impact of optimizing P2Y12 inhibition on the basis of platelet function testing.
Starting on September 1, 2011, consecutive, high-risk patients with ACS admitted for urgent coronary angiography were enrolled in a prospective registry. All patients with ACS who were pre-treated with clopidogrel were eligible for enrollment if PCI was performed successfully with stent implantation and there was no contraindication to treatment with a P2Y12 inhibitor for 1 year. Pre-treatment with clopidogrel was defined as either a loading dose of 600 mg before admission or long-term treatment for more than 5 days with 75 mg/day. Exclusion criteria included an indication for chronic oral anticoagulation, age older than 80 years, lack of pre-treatment with clopidogrel, or administration of other P2Y12 inhibitors before or during PCI. Importantly, ticagrelor was not available in Hungary during enrollment in the registry. Because we aimed to recruit a real-life, high-risk, all-comer population of patients with ACS, patients with cardiogenic shock, in pulmonary edema, or who had successful resuscitation were not excluded. All patients received 60 to 80 IU/kg of unfractionated heparin for PCI, and tirofiban was given at the discretion of the operator as a 25-μg/kg bolus followed by an optional 6- to 12-h infusion. Patients gave informed consent to comply with the antiplatelet strategy offered and to be available for regular follow-ups and telephone checkups for 1 year after PCI.
Platelet function testing and choice of P2Y12 inhibitor treatment
Platelet function testing was performed with the Multiplate analyzer (Roche Diagnostics GmbH, Mannheim, Germany) 12 to 36 h after PCI. If tirofiban was administered, assessment of platelet function was postponed until 24 h after cessation of treatment. HPR was defined according to the consensus cutoff, which was an adenosine diphosphate (ADP)-test level >46 U (10).
In patients without HPR (ADP-test ≤46 U), standard-dose (75 mg/day), generic clopidogrel was continued after PCI (no HPR group). In contrast, patients with HPR were either switched to prasugrel (HPR + prasugrel group) with a loading dose of 60 mg followed by a maintenance dose of 10 mg/day or treated with adjusted, high-dose clopidogrel (HPR + clopidogrel group) as previously described and proposed by Bonello et al. (11). Briefly, patients were treated with additional loading doses of 600 mg of clopidogrel up to 4 times on the basis of controlled Multiplate testing each day to normalize platelet reactivity below the pre-defined cutoff of HPR. According to the achieved level of platelet reactivity after the second loading dose, a maintenance dose of 75 mg/day (no HPR) or 150 mg/day (HPR) was selected.
Patients were not randomly allocated to the prasugrel or high-dose clopidogrel groups; the choice of treatment was not influenced by strict local rules but was left to the discretion of the 7 expert operators. Some operators favored a switch to prasugrel, whereas others supported the use of high-dose clopidogrel.
The primary composite efficacy endpoint was all-cause mortality, stent thrombosis, nonfatal myocardial infarction, or stroke at 1 year. Secondary analyses were performed for each component of the primary endpoint, and rates of target vessel revascularization were also compared. The primary safety endpoint was the occurrence of major bleeding events during 1 year.
All-cause mortality was traced from hospital records, follow-up visits, and a national vital record database. The causes of fatal events were uncertain in many cases, so cardiovascular mortality was not calculated. Stent thrombosis was defined as definite or probable according to the Academic Research Consortium criteria. Nonfatal myocardial infarction was defined according to the universal definition, including type 1, 4a, and 4b. Major bleeding was defined according to the Bleeding Academic Research Consortium (BARC) criteria, including type 3 and 5 in the analysis.
Prior data were only available for the impact of treatment with high-dose clopidogrel in HPR, so the sample size was calculated to show a clinically relevant difference in all-cause death, myocardial infarction, stent thrombosis, or stroke between the HPR + clopidogrel and the no HPR groups. On the basis of the results of a prior registry (12), we estimated a 2-fold risk (relative risk [RR]: 2.00) in the primary endpoint between groups with an estimated 1-year absolute risk of 12% for the no HPR group (5,6). Assuming a 30% rate of HPR and an equal distribution of patients with HPR treated with high-dose clopidogrel or prasugrel, 605 patients were required to detect a difference between the HPR + clopidogrel and no HPR groups with 80% power at a 2-sided alpha level of 0.05. Together with the prasugrel group, 700 patients were needed. Allowing for dropouts, we planned to enroll 750 patients in the registry.
Continuous variables with normal distribution are presented as mean ± SD, whereas non-normally distributed variables are presented as median and interquartile range. Categorical variables are expressed as frequencies and percentages. Differences between the 2 groups were assessed with the Fisher exact test for categorical variables. Unpaired Student t tests were used for comparisons of normally distributed continuous variables between 2 groups, whereas non-normally distributed variables were compared using the Mann-Whitney U test.
Time-to-event data were visualized by Kaplan-Meier curves for each group. Event rates represent Kaplan-Meier estimates. Patients with HPR were compared with the no HPR group in Cox regression models. Unadjusted hazard ratios (HRs) together with 95% confidence intervals (CIs) were determined for clinical endpoints in univariate Cox proportional models, and then a multivariable Cox proportional hazards model was used to determine independent predictors of all-cause death, myocardial infarction, stent thrombosis, or stroke at 1 year. Of the 31 different baseline clinical, procedural, pharmacological, and laboratory values collected (Table 1) for all groups, variables with a p value < 0.05 in univariate analyses were entered into a forward stepwise Cox proportional model. To test for overfitting, sensitivity analyses were performed by building multivariate models with a predictor-event ratio of 1:10. These models contained either the clinically most relevant predictors or the strongest univariate predictors of the primary endpoint. Lack of violation of the proportional hazard assumption was checked by using log minus log survival plots.
Between September 1, 2011 and August 31, 2012, 1,519 patients with ACS were admitted to the Heart Institute at the University of Pécs for urgent coronary angiography. After coronary angiography, 976 patients underwent PCI with successful stenting. On the basis of the inclusion criteria, 741 patients were enrolled in the study (Fig. 1). Table 1 shows the baseline clinical, procedural, laboratory, and treatment characteristics of the recruited patients according to the treatment groups. In general, the cohort comprised a very high-risk, all-comer, consecutive cohort of patients with ACS; 85% had an acute myocardial infarction, 48% had an stent thrombosis-segment elevation myocardial infarction, and 4.5% had cardiogenic shock (Online Table 1). Patients with HPR were significantly younger and had a higher incidence of diabetes and stent thrombosis-segment elevation myocardial infarction as well as more complex coronary disease, reflected by a longer total stent length. In addition, platelet count, leukocyte count, and high-sensitivity C-reactive protein levels were significantly higher in patients with HPR compared with those without HPR (Online Table 1). In contrast, patients with HPR who were treated with prasugrel or high-dose clopidogrel had comparable baseline characteristics except for greater use of statins and beta-blockers in the prasugrel group (Table 1). No baseline clinical variables were found to predict allocation to the prasugrel group in patients with HPR; however, a trend was found for different use of prasugrel among the 7 operators (median prasugrel use: 44%; minimum: 18%; maximum: 56%; p = 0.09).
Platelet function results
On the basis of the Multiplate results after PCI, 219 patients (29.5%) had HPR (Figs. 1 and 2A). The 522 patients (70.5%) with normal platelet reactivity continued treatment with 75 mg/day of generic clopidogrel for 1 year. Of the 219 patients with HPR, 128 patients (58%) were treated with adjusted high-dose clopidogrel and 91 patients (42%) were switched to treatment with prasugrel (Fig. 1). In the high-dose clopidogrel group, 100%, 24%, and 7% of patients required a second, third, and fourth loading dose of 600 mg of clopidogrel, respectively. At discharge, 20% of the patients were being treated with 150 mg/day of clopidogrel and 76% were being treated with 75 mg/day. Four percent of the patients died before the maintenance dose could be established.
After PCI, there was no difference between the HPR + clopidogrel group and the prasugrel group in the level of platelet reactivity (Fig. 2B). Although both prasugrel and repeated loading doses of 600 mg of clopidogrel reduced platelet reactivity from baseline (p < 0.0001 for both), a single loading dose of 60 mg of prasugrel followed by a maintenance dose of 10 mg/day provided significantly more potent platelet inhibition than the repeated boluses of 600 mg of clopidogrel at discharge (p < 0.0001) (Fig. 2B). Although platelet reactivity significantly increased with the 10-mg/day dose of prasugrel during the maintenance phase (p < 0.0001), 86% of the prasugrel-treated patients still remained below the cut point for HPR. In contrast, the standard dose and the doubled maintenance dose of clopidogrel were ineffective to maintain the level of platelet reactivity achieved with repeated loading doses of clopidogrel, resulting in rebound platelet reactivity during the chronic phase (p < 0.0001), with 51% of patients returning to HPR (Fig. 2). Notably, there was no difference between the effect of 75 mg/day and 150 mg/day of clopidogrel in patients with HPR (p = 0.42).
During 1-year follow-up, all-cause mortality was 8.1%. The rate of definite/probable stent thrombosis was 2.8%, and 5.3% of patients had major bleeding. When all patients in the HPR groups were pooled and compared with the no HPR group, a significant increase in all-cause mortality or stent thrombosis was observed (Fig. 3A, Online Table 2). Despite treatment adjustments, the risk of the primary composite endpoint increased 1.7-fold in the HPR group compared with the no HPR group (HR: 1.67; 95% CI: 1.11 to 2.51; p = 0.015), whereas there was no difference in major bleeding complications between the groups (Fig. 3B).
When the high-dose clopidogrel group was compared with patients without HPR, a significantly higher risk of thrombotic events was observed (Figs. 4A to 4C, Table 2). The risk of all-cause death, nonfatal myocardial infarction, stent thrombosis, or stroke was more than 2-fold higher in the high-dose clopidogrel group than in the no HPR group (HR: 2.27; 95% CI: 1.45 to 3.55; p < 0.0001). Notably, BARC type 3 or 5 major bleeding was also significantly increased (Fig. 4D, Table 2). In contrast, patients with HPR who were switched to treatment with prasugrel had rates of thrombotic complications that were similar to those in the no HPR group without any difference in all-cause death, myocardial infarction, stent thrombosis, or stroke (HR: 0.90; 95% CI: 0.44 to 1.81; p = 0.76) (Figs. 4A to 4C, Table 2). There was no excess of major bleeding after switching patients to treatment with prasugrel compared with others without HPR (Fig. 4D).
Patients in the high-dose clopidogrel group and the prasugrel group were not randomized, so all baseline characteristics were compared extensively (Table 1). After adjusting for age, diabetes, cardiogenic shock, drug-eluting stent(s), angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, beta-blocker use, statin use, and creatinine level, there was still a 2.5-fold increased risk of the primary composite endpoint in the high-dose clopidogrel group versus the prasugrel group (HR: 2.53; 95% CI: 1.08 to 5.93; p < 0.03) (Online Table 3).
Because of the clinical differences between patients with and without HPR, univariate and multivariate models were generated to identify independent predictors of the composite primary endpoint. Using univariate models, 20 baseline variables were identified that were significantly associated with all-cause death, myocardial infarction, stent thrombosis, or stroke (Table 3). According to the multivariate model, HPR with high-dose clopidogrel remained a significant, independent predictor of the primary endpoint (HR: 1.90; 95% CI: 1.17 to 3.08; p = 0.01), whereas patients with HPR who were switched to treatment with prasugrel had no increase in thrombotic events (Table 3).
When the impact of outcome events was tested on subsequent mortality, both stent thrombosis and major bleeding proved to be a strong and independent predictor of 1-year mortality (Online Table 4). Interestingly, patients with stent thrombosis had a 6-fold higher risk of major bleeding (RR: 6.23; 95% CI: 2.93 to 13.25; p < 0.00001), and patients with a major bleeding event had a 7-fold risk of stent thrombosis (RR: 7.20; 95% CI: 2.96 to 17.54; p < 0.00001).
The main findings of this single-center registry can be summarized as follows. First, switching patients with HPR to treatment with prasugrel resulted in quicker and more potent P2Y12 inhibition than repeating high-dose boluses of clopidogrel on the basis of platelet function testing. A lack of HPR can be maintained with 10 mg/day of prasugrel during long-term treatment, but a clear rebound in platelet reactivity occurred with maintenance doses of clopidogrel. Second, patients with ACS who had HPR and were treated with high-dose clopidogrel had an elevated risk of thrombotic events after PCI, whereas those who were switched to treatment with prasugrel had event rates that were comparable to those of patients without HPR. In addition, patients treated with high-dose clopidogrel had a higher risk of major bleeding complications. Third, in a multivariate model, use of high-dose clopidogrel in patients with HPR was an independent predictor of all-cause mortality, myocardial infarction, stent thrombosis, or stroke at 1 year, whereas switching to treatment with prasugrel was not associated with thrombotic events.
Prasugrel and ticagrelor provide more potent and more predictable P2Y12 receptor inhibition than clopidogrel (1–4). Two large-scale randomized studies confirmed a reduction in cardiovascular death, myocardial infarction, or stroke among patients with ACS who were treated with novel P2Y12 inhibitors as compared with clopidogrel (5,6). However, there were significant increases in major bleeding complications with both prasugrel and ticagrelor (5,6). In an era in which clopidogrel has become generic, the high treatment costs of novel P2Y12 inhibitors together with the higher risk of bleeding limit their use in current practice.
A possible solution to these limitations might be to use prasugrel or ticagrelor selectively, that is, to restrict their use in patients with HPR on clopidogrel who are being treated with clopidogrel while continuing to treat good responders with generic clopidogrel. However, this strategy has never been tested in a randomized setting in patients with ACS. The only evidence we currently have from 2 randomized studies is that the use of platelet function testing to treat patients with high-dose clopidogrel who are at low-to-moderate risk for mortality and have HPR does not improve outcomes (7,9). However, frequent criticisms of these 2 studies are that they completely (7) or predominantly (9) used high-dose clopidogrel in patients with HPR and included patients at low risk for thrombotic events. A lack of clinical effectiveness of high-dose clopidogrel in patients with HPR was further supported by the RECLOSE-2 ACS (REsponsiveness to CLOpidogrel and Stent-related Events in Acute Coronary Syndromes) registry (12), establishing the concept that HPR may be a marker of higher risk but not a modifiable risk factor (13). However, no data are available on the clinical impact of prasugrel or ticagrelor in patients with ACS who have HPR.
In this respect, the results of our single-center, nonrandomized ACS registry might be of interest for several reasons. First, we recruited a real-life patient population of all-comer, consecutive, high-risk patients with ACS, similar to the populations enrolled in TRITON (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel) (5), PLATO (Study of PLATelet Inhibition and Patient Outcomes) (6), and/or the RECLOSE-2 ACS registry but not like the cohorts of prior platelet function studies (7–9). Compared with an all-cause mortality of 2% in ARCTIC (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 One Year after Stenting) (9), <1% in GRAVITAS (Gauging Responsiveness with A VerifyNow assay–Impact on Thrombosis And Safety) (7), and 0% in TRIGGER PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) (8), we found an 8.1% all-cause mortality rate in our high-risk cohort. These differences can help explain how almost twice as many primary endpoint events occurred in a study that was one-third the size of the entire GRAVITAS study (95 vs. 50). Our results are also in line with the RECLOSE-2 ACS registry (12), which showed a more than 2-fold higher risk of all-cause death, myocardial infarction, stent thrombosis, or stroke in patients with HPR despite up-titration of the dose of clopidogrel. The only large-scale randomized study to show a benefit for high-dose clopidogrel is the CURRENT (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events) trial, which suggested a slight advantage in the subgroup of patients with ACS undergoing PCI (14). However, because the trial compared a loading dose of 300 and 600 mg of clopidogrel with and without use of a double maintenance dose for 1 week, the results are not comparable to our registry and to prior platelet function studies and prevent any meaningful conclusion on dose escalations of clopidogrel in patients receiving a loading dose of 600 mg (14).
On the basis of the discussed evidence, high-dose clopidogrel seems to have an insufficient clinical effect to overcome the higher risk of events in patients with ACS who have HPR (7,9,12). Therefore, our registry suggests that switching patients to treatment with prasugrel might decrease the risk of thrombotic events to a level similar to that of patients without HPR (Fig. 4). Platelet function results supported these findings at the pharmacodynamic level, confirming superior platelet inhibition by prasugrel (Fig. 2).
In a prior large-scale platelet function registry, Stone et al. (15) found that HPR after PCI was an independent predictor of both stent thrombosis and major bleeding. In addition, both stent thombosis and major bleeding were independent predictors of mortality that associations were also replicated in our cohort. On the basis of this bidirectional association, they speculated that it will be impossible to reduce mortality in patients with HPR using more potent P2Y12 inhibitor strategies, because for every stent thrombosis prevented, 4 extra major bleeds will be caused (15). Our results suggest that the impact of more potent P2Y12 inhibitor strategies on major bleeding and stent thrombosis is more complex; the less potent clopidogrel reloading approach caused not only more stent thrombosis but also more major bleedings (Fig. 4). The lower rate of bleeding with prasugrel might be somewhat surprising in light of the results of TRITON (5); however, we administered prasugrel selectively to patients with HPR instead of a general population as analyzed in the cited trial. Although the observed differences in bleeding might be due to chance because of the low number of events or might be attributed to a less sensitive bleeding scale used during follow-up (BARC 3/5 instead of BARC ≥2), a recent Scandinavian registry also found a lower rate of visible bleeding with prasugrel (16). These results should not confute the higher risk of bleeding with prasugrel in a general ACS population but suggest that selected patients (such as those with HPR on clopidogrel) might tolerate more potent P2Y12 inhibition without an excess risk of bleeding.
First and most importantly, the prasugrel and clopidogrel groups were not randomized. Although this might decrease the validity of our comparisons, registries are important for collecting real-life data on unselected patients. Although it was left to the discretion of the operator whether to choose prasugrel or high-dose clopidogrel, the 2 groups ended up with a very balanced distribution (42% vs. 58%) and most baseline variables were well matched between the 2 groups (Table 1). In addition, we observed similar results when adjusting for possible confounders between the HPR groups (Online Table 3). Furthermore, high-dose clopidogrel in patients with HPR prevailed as an independent predictor of the primary endpoint, corroborating the clinical relevance of our observations (Table 3). Second, it is unknown how these findings are transferable to ticagrelor because the drug was not available during the enrollment period in Hungary. Third, we only collected data on BARC type 3/5 major bleeding events, and the difference in major and minor bleeding complications remains unknown. Although BARC type 3/5 major bleeding was significantly associated with all-cause mortality (Online Table 4) and was a reliable marker of safety in TRITON (5), it might also have been a reason for a lower risk of bleeding among the prasugrel-treated patients. Finally, our results cannot be extrapolated to elderly patients (older than 80 years of age) who might require dose reduction with prasugrel but were generally excluded from our registry.
Treatment with prasugrel in patients with ACS who have HPR is significantly more effective than adjusted high-dose clopidogrel both after loading doses and during the maintenance phase. In parallel to the pharmacodynamic findings, treatment with prasugrel reduced thrombotic and bleeding events to a level similar to that of patients without HPR, whereas treatment with high-dose clopidogrel resulted in a higher risk of both thrombotic and bleeding complications. Further randomized studies are warranted to confirm the relevance of a platelet function-based selection of P2Y12 inhibitors in patients with ACS after PCI, but such studies should avoid dose escalations of clopidogrel.
The research was supported by the Hungarian Scientific Research Funds [83464 to Dr. Komócsi]. Dr. Aradi has received research grants and consulting fees from Verum Diagnostica and lecture fees from Eli Lilly/Daiichi Sankyo, AstraZeneca, Verum Diagnostica, Roche, Krka, Abbott Vascular, Pfizer Inc., and Bayer. Dr. Horváth has received lecture fees from Eli Lilly/Daiichi Sankyo and Abbott. Dr. Komócsi has received research grants and consulting fees from Eli Lilly/Daiichi Sankyo and Krka and lecture fees from Eli Lilly/Daiichi Sankyo and Krka. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute coronary syndrome(s)
- Bleeding Academic Research Consortium
- confidence interval
- high platelet reactivity
- hazard ratio
- percutaneous coronary intervention
- relative risk
- Received October 2, 2013.
- Revision received December 3, 2013.
- Accepted December 9, 2013.
- American College of Cardiology Foundation
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