Effect of Tailored Antiplatelet Therapy on Periprocedural Myonecrosis in Patients With Diabetes Mellitus (from the DM-Verify Now Trial)

Effect of Tailored Antiplatelet Therapy on Periprocedural Myonecrosis in Patients With Diabetes Mellitus (from the DM-Verify Now Trial) Jung-Won Suh, MD†, Chi-Hoon Kim, MD†, Il-Young Oh, MD, Chang-Hwan Yoon, MD, Kwang-Il Kim, MD, Young-Seok Cho, MD, Tae-Jin Youn, MD, In-Ho Chae, MD, and Dong-Ju Choi, MD* We investigated whether additional platelet inhibition with a glycoprotein IIb/IIIa inhibitor would be beneficial in reducing the risk of periprocedural myocardial infarction (PMI) in diabetic patients with high residual platelet reactivity (HPR). Patients with diabetes mellitus were administered aspirin and clopidogrel at a 300-mg loading dose 1 day before the procedure, and the VerifyNow P2Y12 assay was performed just before percutaneous coronary intervention. Patients with HPR, defined as a P2Y12 reaction unit of >270 were randomly assigned to group A or control group C1. Patients without HPR were assigned to control group C2. Conventional anticoagulation with heparin was given to groups C1 and C2, and group A received additional abciximab treatment. Clinically relevant PMI was defined as any elevation in the biomarkers creatine kinase-MB isoenzyme and cardiac troponin I >3 times the upper normal limit measured 8, 16, or 24 hours after percutaneous coronary intervention. Of the patients, 47 and 51 were assigned to group A and C1; the clinical and procedural characteristics in the 2 groups were balanced. Of the 47 patients in group A and 51 patients in group C1, 9 (19%) and 9 (18%), respectively, experienced a PMI event according to the creatine kinase-MB cutoff (p ⴝ 1.00), and 27 in group A (57%) and 29 in group C1 (57%) experienced a PMI event according to the troponin I cutoff (p ⴝ 1.00). Five minor bleeding events, including small and localized hematomas, were observed immediately after the procedure (4 in group A and 1 in group C1). Only 1 major bleeding event, retroperitoneal hemorrhage, was observed in group A. The patients in group C2 had a PMI event rate (50% of 32 patients, p ⴝ 1.00) similar to that of group C1. In conclusion, additional platelet inhibition using a tailored approach and a pointof-care assay did not improve the periprocedural outcome in diabetic patients with HPR. © 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:1749 –1755) High residual platelet reactivity (HPR) that persists despite antiplatelet therapy has been linked to impaired periprocedural outcomes in previous trials.1–3 These studies suggested that HPR might play a critical role in the development of periprocedural myocardial infarction (PMI). In patients with diabetes mellitus (DM), insufficient inhibition of platelet aggregation at the procedure can be more detrimental, even when applied with elective coronary stenting.4 The evidence from laboratory measurements has indicated that HPR reflects substantial interindividual variability in the platelet response to clopidogrel.5,6 These observations have provided the impetus for the use of point-of-care platelet function assays to identify

Department of Internal Medicine and Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea. Manuscript received June 24, 2012; revised manuscript received and accepted August 1, 2012. This study was supported by a grant from the Korean Society of Cardiology (Seoul, Korea) in 2008 and grant A100476 from the Korea Health Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea. *Corresponding author: Tel: (82) 31-787-7007; fax: (82) 31-787-4051. E-mail address: [email protected] (D.-J. Choi). †

Drs. Suh and Kim contributed equally to this article.

0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.08.009

at-risk patients and to predict their prognosis.2,7–9 We hypothesized that additional platelet inhibition with a glycoprotein IIb/IIIa inhibitor might be beneficial in reducing the risk of PMI in diabetic patients with HPR assessed using the VerifyNow P2Y12 assay. Methods We prospectively enrolled diabetic patients who were candidates for planned percutaneous coronary intervention (PCI) from June 2009 to July 2011 at Seoul National University Bundang Hospital (Seoul, Korea). All patients recruited in the present study were enrolled consecutively after verification by negative cardiac biomarker study findings. The levels of the creatinine kinase-MB isoenzyme (Dimension Vista 1500 System, Siemens Healthcare Diagnostics, Munich, Germany) and cardiac troponin I (TnI; VITROS 5600 System, Ortho Clinical Diagnostics, Raritan, New Jersey) were measured simultaneously at admission. Patients were excluded if they had a history of allergy to, or intolerance of, aspirin or clopidogrel, a history of cerebrovascular or other major bleeding, major surgery within the previous 6 months, a history of acute myocardial infarction or ischemic cerebral infarction, platelet count ⬍100,000/ mm3, or hematocrit ⬍30%. All patients provided written www.ajconline.org

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135 diabetic patients for elective PCI loading dose of dual antiplatelets ((300mg g of aspirin p p g , D-1)) and clopidogrel, maintenance dose (100mg of aspirin/75mg of clopidogrel, D0)

VerifyNow™ assa assay (just before PCI procedure)

PRU ≥ 270

PRU < 270 34 patients

101 patients 3 patients excluded

2 patients excluded

Group A

Group C1

Group C2

heparin p 70 IU/kg g bolus + abciximab 0.25mg/kg bolus and 0.12μg/kg/min for 12 hour infusion 12-hour

heparin p 140 IU/kgg bolus

heparin p 140 IU/kgg bolus

47 patients / 70 lesions

51 patients / 78 lesions

32 patients / 51 lesions

Consecutive assessment of cardiac biomarkers ((CK-MB/TnI) K ) at the time of post-PCI 8, 16, 24hr post-PCI 1 month clinical follow-up Figure 1. Study flow.

informed consent, and the local ethics review board reviewed the study scheme. The full protocol of the present study has been registered at http://www.clinicaltrials.gov (clinical trial no. NCT01475552). All patients had DM and were treated routinely with both aspirin and clopidogrel at a 300-mg oral loading dose 1 day before the procedure. They were administered maintenance doses of 100 mg/day aspirin and 75 mg/day clopidogrel afterward. The VerifyNow P2Y12 assay was performed just before PCI in patients who were scheduled to receive a coronary stent implant after diagnostic angiography. The detailed characteristics of this assay and its reliability have been previously reported.10 The results were reported as P2Y12 reaction units and the percentage of inhibition. The cutoff value for HPR was P2Y12 reaction units of ⱖ270, a value associated with atherothrombotic complications within 6 months after coronary stenting in Korean patients.11,12 After 1:1 randomization of patients with HPR, these patients were randomized further to group A or group C1, and patients without HPR were allocated to group C2. All patients were followed up for 1 month (Figure 1). Groups C1 and C2 received conventional anticoagulation (140 U/kg intravenous bolus infusion) and group A was treated with a reduced dose of heparin (70 U/kg intravenous bolus infusion) and abciximab (0.25 mg/kg intravenous bolus followed by 0.125 mg/kg/hour continuous infusion for 12 hours). All procedures were performed in accordance with contemporary standards and at the physician’s discretion. The primary objective of the present trial was to compare the prevalence of PMI, as reflected by the TnI concentration, between groups C1 and A. To evaluate the extent of myocar-

Figure 2. Distribution of P2Y12 reaction units of patients with and without HPR.

dial damage during PCI, the TnI and creatine kinase-MB concentrations were both measured 8, 16, and 24 hours after PCI. In these successive assays, any increase in the level of these cardiac biomarkers greater than the 99th percentile upper limit of normal was defined as myonecrosis, and clinically relevant PMI was defined as a more than threefold elevation greater than the upper limit of normal for either of the 2

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Table 1 Baseline demographic characteristics, laboratory findings, and P2Y12 reaction units PRU ⱖ270

Variable

Demographic characteristics Men (%) Age (years) Body mass index (kg/m2) Clinical presentation Stable angina Unstable angina Involved vessel 1-Vessel disease 2-Vessel disease 3-Vessel disease Left main disease Diabetes duration (years) Median Interquartile range Hemoglobin A1c (%) Chronic renal failure* Hypertension Dyslipidemia Medications at admission Diabetes mellitus medications (n) Median Interquartile range Insulin therapy Antiplatelet agents Naive Single agents Dual agents Aspirin Clopidogrel Statin Major laboratory findings Hemoglobin (g/dl) Platelet (⫻103/␮l) Activated partial thromboplastin time (s) Prothrombin time and international normalized ratio Fasting blood glucose (mg/dl) Total cholesterol (mg/dl) Low-density lipoprotein cholesterol (mg/dl) High-sensitivity C-reactive protein (mg/L) Median Interquartile range Serum creatinine (mg/dl) Ejection fraction (%) P2Y12 reaction units Percentage of inhibition of P2Y12 reaction units

Group A

Group C1

28 (60%) 67.5 ⫾ 6.6 24.9 ⫾ 2.5

27 (53%) 66.5 ⫾ 7.2 25.6 ⫾ 3.5

35 (75%) 12 (26%)

45 (88%) 6 (12%)

14 (30%) 17 (36%) 16 (34%) 5 (11%)

13 (26%) 25 (49%) 13 (26%) 7 (14%)

10 7–20 7.8 ⫾ 1.6 11 (23%) 42 (89%) 26 (55%)

10 5–16 7.7 ⫾ 1.2 10 (20%) 46 (90%) 29 (57%)

2 1–2 13 (28%)

2 1–2 9 (18%)

7 (15%) 28 (60%) 12 (26%) 37 (79%) 12 (26%) 25 (53%)

10 (20%) 29 (57%) 12 (24%) 37 (73%) 14 (28%) 28 (55%)

12.7 ⫾ 1.4 222 ⫾ 54 35 ⫾ 4 1.00 ⫾ 0.07 138 ⫾ 60 163 ⫾ 40 87 ⫾ 29

13.2 ⫾ 1.3 224 ⫾ 61 37 ⫾ 7 1.00 ⫾ 0.24 119 ⫾ 36 161 ⫾ 35 90 ⫾ 29

3.0 3.0–3.0 1.06 ⫾ 0.61 61.1 ⫾ 6.7 330 ⫾ 40 11.5 ⫾ 9.3

3.0 3.0–3.2 1.11 ⫾ 1.39 59.4 ⫾ 7.9 336 ⫾ 47 8.4 ⫾ 8.9

p Value (A vs C1)

PRU ⬍270 Group C2

0.509 0.555 0.403 0.079

24 (75%) 64.4 ⫾ 9.6 25.7 ⫾ 2.6

p Value (C1 vs C2)

0.064 0.423 0.603 0.001

18 (56%) 14 (44%) 0.425

0.641 0.114

0.889 0.647 1.000 0.878

0.922 9 (28%) 16 (50%) 7 (22%) 6 (19%) 9 3–20 7.4 ⫾ 1.3 4 (13%) 30 (94%) 23 (72%)

0.171

0.235 0.852

0.478 0.830 0.865 0.061 0.887 0.105 0.896 0.074 0.802 0.613 0.479

0.819 0.267 0.370 0.091

0.540 0.675

0.308 0.440 0.701 0.169 0.091

1 1–2 6 (19%) 4 (13%) 16 (50%) 12 (38%) 26 (81%) 13 (41%) 18 (56%) 14.2 ⫾ 1.8 232 ⫾ 65 35 ⫾ 4 0.98 ⫾ 0.08 118 ⫾ 40 166 ⫾ 41 92 ⫾ 34 3.0 3.0–3.0 0.94 ⫾ 0.25 57.3 ⫾ 9.2 206 ⫾ 58 34.6 ⫾ 19.6

0.899 0.395

0.367 0.212 0.904 0.007 0.575 0.410 0.632 0.868 0.565 0.806 0.340

0.496 0.307 ⬍0.001 ⬍0.001

* Estimated glomerular filtration rate ⬍60 ml/min/1.73 m2.

biomarkers. The laboratory upper limit of normal in our institution was 0.045 ng/ml for TnI and 0.28 ng/ml for creatine kinase-MB. The primary end point was the prevalence of PMI, as assessed by the TnI concentration. The secondary end point was the prevalence of PMI, as assessed by the creatine kinase-MB concentration. A greater than fivefold increase over the upper limit of normal for these biomarkers and the maximal extent of the change from the baseline value were also evaluated as secondary end points. Clinical events such as bleeding or major adverse cardiac events, defined as the composite of cardiac death, nonfatal spontaneous myocardial in-

farction, and urgent target vessel revascularization, were also noted at the 1-month follow-up visit. Bleeding events of safety concern were reported according to the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding classification.13 Quantitative coronary angiography was performed for all target lesions, and immediate post-PCI angiographic complications were analyzed for all cases. All biochemical, clinical, and angiographic findings were assessed in a blinded manner. Assuming PMI event rates by the TnI criterion of 57% in group C1 and 29% in group A and a withdrawal rate of 5%, we

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Table 2 Percutaneous coronary intervention procedure and angiographic findings PRU ⱖ270

Variable

Lesion characteristics Target lesion Left anterior descending artery Left circumflex artery Right coronary artery Type B2/C lesion De novo lesion Chronic total occlusion Ostial lesion Bifurcation Procedural characteristics Stents per target lesion (n) Median Interquartile range Stent type Plain balloon angioplasty Bare metal stent Drug-eluting stent Intravascular ultrasound guidance Direct stenting Adjuvant ballooning Maximal ballooning pressure (atm) Median Interquartile range Femoral access Anticoagulation after percutaneous coronary intervention Quantitative coronary angiography Stent diameter (mm) Median Interquartile range Total stent length (mm) Median Interquartile range Before percutaneous coronary intervention Lesion length (mm) Median Interquartile range Lesion reference diameter (mm) Median Interquartile range Minimum lesion diameter (mm) Median Interquartile range Lesion diameter stenosis (%) Median Interquartile range After percutaneous coronary intervention Minimum lesion diameter (mm) Median Interquartile range Lesion diameter stenosis (%) Median Interquartile range

Group A

Group C1

31 (44%) 16 (23%) 23 (33%) 62 (89%) 69 (99%) 5 (7%) 3 (4%) 10 (14%)

42 (5%) 16 (21%) 20 (26%) 60 (71%) 75 (96%) 3 (4%) 1 (1%) 21 (27%)

1 1–2

1 1–1

4 (4%) 2 (2%) 86 (94%) 14 (20%) 1 (1%) 55 (79%)

4 (4%) 2 (2%) 87 (94%) 21 (27%) 2 (3%) 63 (81%)

18 12–20 42 (89%) 1 (2%)

14 12–18 44 (86%) 3 (6%)

3.0 2.5–3.0

3.0 2.8–3.3

26 18–48

27 22–34

21.8 15.7–35.6

23.5 17.0–30.2

2.8 2.4–3.1

2.8 2.5–3.0

0.8 0.5–1.1

0.9 0.7–1.2

72.5 61.3–82.9

67.1 59.1–74.2

2.4 2.1–2.7

2.5 2.2–2.8

12.6 8.3–16.6

10.7 6.8–15.5

p Value (A vs C1)

PRU ⬍270 (Group C2)

0.50

0.19 0.62 0.48 0.34 0.07

0.63 23 (45%) 13 (26%) 15 (29%) 44 (86%) 49 (96%) 7 (14%) 6 (12%) 14 (28%)

0.14

0.17 1.00 0.05 0.02 1.00 0.53

1 1–1 1.00

0.32 1.00 0.84 0.11

0.76 0.62

0.87 2 (3%) 2 (3%) 59 (94%) 11 (22%) 3 (6%) 41 (80%) 16 14–20 27 (84%) 0 (0%)

0.19

0.49 0.38 1.00 0.22

1.00 0.28 0.09

3.0 2.8–3.5 0.80

0.91 25 18–38

0.90

0.24 21.7 15.4–28.8

0.98

0.02 3.0 2.5–3.2

0.06

0.87 0.9 0.60–1.1

0.06

0.13 71.2 62.7–76.9

0.11

0.06 2.6 2.3–3.0

0.10

estimated that a sample of 100 patients with P2Y12 reaction units of ⱖ270 would provide 80% power to detect a 50% reduction in the PMI rate at the 2-sided ␣ of 0.05. Categorical variables are presented as percentages, and the values were compared between groups using the chi-square or Fisher’s exact test. Continuous variables are presented as the mean ⫾

p Value (C1 vs C2)

0.92 11.8 6.4–14.7

SD and were compared between groups using an unpaired t test or Mann-Whitney U test. Nonparametric tests were used after confirming a non-normal distribution with the KolmogorovSmirnov test. p Values ⬍0.05 were considered significant. The statistical analyses were performed using the SPSS, version 17.0, statistical package (IBM, New York, New York).

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Table 3 Measurements of cardiac biomarkers and major outcome of the study PRU ⱖ270

Consecutive measurements of cardiac biomarkers Creatine kinase-MB (ng/ml) Baseline After intervention 8 hours 16 hours 24 hours Peak Maximum change Troponin I (ng/m) Baseline After intervention 8 hours 16 hours 24 hours Peak Maximum change Myonecrosis and PMI according to creatine kinaseMB and troponin I Myonecrosis by creatine kinase-MB (ⱖ⫻1 upper limit of normal) PMI by creatine kinase-MB (ⱖ⫻3 upper limit of normal) PMI by creatine kinase-MB (ⱖ⫻5 upper limit of normal) Myonecrosis by troponin I (ⱖ⫻1 upper limit of normal) PMI by troponin I (ⱖ⫻3 upper limit of normal) PMI by troponin I (ⱖ⫻5 upper limit of normal) Immediate postintervention complications Dissection No reflow Side branch “jailing” In-hospital bleeding events

p Value (A vs C1)

PRU ⬍270 Group C2

p Value (C1 vs C2)

Group A

Group C1

0.5 (0.5–0.6)

0.7 (0.5–1.5)

0.23

0.8 (0.5–1.1)

0.84

0.7 (0.5–2.1) 1.4 (0.5–6.6) 1.5 (0.6–8.2) 1.4 (0.6–6.7) 0.8 (0.1–3.8)

1.1 (0.5–2.5) 1.5 (0.7–5.4) 2.7 (0.9–5.8) 1.4 (0.8–4.7) 0.6 (0.1–2.5)

0.47 0.83 0.87 0.78 0.60

0.9 (0.5–1.6) 1.2 (0.5–5.1) 2.1 (0.5–4.5) 1.4 (0.5–5.5) 0.8 (0–3.1)

0.25 0.32 0.41 0.49 0.87

0.035 (0.025–0.035)

0.035 (0.014–0.039)

0.81

0.035 (0.031–0.035)

0.53

0.052 (0.035–0.210) 0.157 (0.040–1.210) 0.317 (0.035–1.460) 0.200 (0.041–1.150) 0.145 (0.010–0.707)

0.060 (0.035–0.311) 0.189 (0.035–1.091) 0.554 (0.099–1.540) 0.153 (0.035–0.988) 0.118 (0–0.973)

0.83 0.88 0.75 0.68 0.58

0.074 (0.035–0.322) 0.117 (0.046–0.692) 0.140 (0.039–0.868) 0.081 (0.008–0.630) 0.081 (0.008–0.630)

0.95 0.64 0.27 0.98 0.88

15 (32%)

18 (35%)

0.83

11 (34%)

1.00

9 (19%)

9 (18%)

1.00

4 (13%)

0.56

6 (13%)

5 (10%)

0.75

3 (9%)

1.00

35 (75%)

35 (69%)

0.66

24 (75%)

0.62

27 (57%) 20 (43%)

29 (57%) 24 (47%)

1.00 0.69

16 (50.0%) 13 (41%)

0.65 0.65

6 (13%) 1 (2%) 1 (2%) 5 (11%)

6 (12%) 0 (0%) 0 (0%) 1 (2%)

1.00 0.48 0.48 0.10

Results Figure 1 shows the study flow throughout the study period. Three patients in group A and 2 patients in group C2 withdrew because of failed PCI or withdrawal of consent. No differences were found in the P2Y12 reaction units between groups A and C1 (Figure 2). No bailout abciximab treatment was performed in group C1 or C2. The baseline clinical and angiographic characteristics did not differ between groups A and C1 (Tables 1 and 2). No differences between groups A and C1 were observed for PCI-related immediate angiographic complications such as flow-limiting vessel dissection, no-reflow phenomenon, or large side branch occlusion. No patient in group A or C1 exhibited acute coronary thrombosis or vasospasm at the procedure. The PMI rates did not differ between groups A and C1 when assessed by TnI and creatine kinase-MB level (Table 3 and Figure 3). Bleeding events were followed up for 1 month after PCI. Bleeding events were more frequent in group A than in group C1 or C2, although the difference was statistically insignificant. One patient in group C1 and four in group A had mild bleeding events, according to the GUSTO scale, including

2 (6%) 1 (3%) 2 (6%) 0 (0%)

0.48 0.39 0.15 1.00

puncture site oozing or a small hematoma (all ⬍5 cm) in the inguinal area, soon after the end of the procedure. Another patient in group A experienced a major bleeding event requiring transfusion with 2 U of packed red blood cells. Computed tomography of this patient revealed a large retroperitoneal hematoma adjacent to the right external iliac vein. Except for these hemorrhagic complications, no other adverse events, such as death, nonfatal myocardial infarction, or stent thrombosis, were reported during the entire study period. Groups C1 and C2 had similar PMI event rates, and the P2Y12 assay result that was less than the cutoff value had no influence on the periprocedural outcome (Table 3). No documented adverse events such as death, nonfatal myocardial infarction, stent thrombosis, or bleeding complications occurred during the entire study period. Discussion Patients with DM undergoing PCI were reported to have greater platelet reactivity at PCI despite clopidogrel pretreatment and to have worse periprocedural outcomes than those without DM.4 Our study has confirmed that 101 of 135 (75%) diabetic patients had HPR, defined as P2Y12 reaction units of

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CK-MB

TnI 90%

pp=0.66

Group A

p=0.62

Group C1

80%

Group C2

p=1.00

70%

pp=00.65 65 p=0.69

60%

p=0.65

50%

p=0.83 p=1.00 p=1.00

40%

p=0.56

30%

p=0.75 p=1.00

20% 10% 0%

Myonecrosis (≥x1 ULN)

PMI (≥x3 ULN)

PMI (≥x5 ULN)

Myonecrosis (≥x1 ULN)

PMI (≥x3 ULN)

PMI (≥x5 ULN)

Figure 3. Incidence of PMI and myonecrosis by cutoff values of TnI and creatine kinase-MB.

ⱖ270, as determined from clinical trials from Korea. Adopting the cutoff value of 230 P2Y12 reaction units used in Western countries increased the prevalence of HPR to 87% (118 of 135).9,14 The European Society of Cardiology guidelines have recommended that a 300-mg loading dose of clopidogrel should be administered ⱖ6 hours before PCI.15 However, our results have suggested that a 300-mg loading dose of clopidogrel is insufficient in patients with DM, even when administered 1 day before the procedure. HPR is associated with the extent of coronary artery atherosclerosis and the incidence of PMI in patients undergoing PCI.7,16 Patients with both DM and HPR had the greatest incidence of PMI in a recent study.4 In this context, we aimed to determine whether the use of abciximab to overcome HPR would improve the periprocedural outcomes in patients with DM and HPR. Various mechanisms have been suggested as responsible for the pathogenesis of PMI, including the burden of plaque microembolization, release of vasoactive factors from the atherosclerotic plaque, platelet activation, or preexisting vulnerability of the myocardium.17 Considering the negative results of the present study, we have concluded that platelet activation does not play a main role in the pathogenesis of PMI. In contrast to previous trials, the present study showed that the PMI incidence did not differ between patients with DM without HPR (group C2) and those with DM and HPR (group C1). The unfavorable angiographic characteristics in group C2 might have diminished the influence of platelet reactivity on PMI. It is not clear whether tailoring the doses or choosing antiplatelet agents according to the results of a platelet function test can improve the prognosis of patients with HPR. The Gauging Responsiveness with a VerifyNow Assay— Impact on Thrombosis and Safety (GRAVITAS) trial did not show a benefit for high-dose clopidogrel therapy in patients

with HPR.18 The Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel (TRIGGER-PCI) study was stopped early after an interim analysis revealed a primary event rate too low to allow for any meaningful comparison between clopidogrel and prasugrel.19 Our findings are consistent with previous reports, which could not show a clinical benefit of platelet function tests to guide antiplatelet therapy. The use of glycoprotein IIb/IIIa inhibitors is generally accepted as an effective measure to lessen the risk of periprocedural adverse events.20,21 However, this benefit was more evident in patients with acute coronary syndrome and elevated biomarker levels before the procedure.22 A recent studies questioned the usefulness of abciximab for attenuating the periprocedural risk, especially in patients with diabetes.23,24 Our findings are consistent with these previous results, showing that abciximab fails to lower the risk of PMI even in selected diabetic patients with HPR. In terms of bleeding, in the present study, those receiving abciximab experienced more hemorrhagic complications than did patients given conventional treatment, although the difference was not statistically significant. Considering the doubtful benefit of abciximab therapy for diabetic patients with HPR, routine administration of abciximab according to platelet function assay results is not recommended. The study limitations were that we did not monitor the extent of additional platelet inhibition after selective administration of standard-dose abciximab. Although abciximab was reported to have consistent antiplatelet effects, substantial variability was also present in the level of platelet inhibition during infusion of standard-dose abciximab.25,26 Second, we could not extrapolate our results to high-risk acute coronary syndrome patients with elevated cardiac biomarkers at baseline. Finally, we only tested the efficacy of abciximab and could not

Coronary Artery Disease/Selective Antiplatelet Therapy in DM/CAD

exclude that other antiplatelet agents might have a beneficial effect on reducing PMI in diabetic patients with HPR. In conclusion, about 75% of the patients with DM had HPR at PCI, but abciximab treatment did not reduce the incidence of PMI in these patients. 1. Kereiakes DJ, Gurbel PA. Peri-procedural platelet function and platelet inhibition in percutaneous coronary intervention. JACC Cardiovasc Interv 2008;1:111–121. 2. Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study. Circulation 2005;111:1153–1159. 3. Cuisset T, Hamilos M, Sarma J, Sarno G, Wyffels E, Vanderheyden M, Barbato E, Bartunek J, De Bruyne B, Wijns W. Relation of low response to clopidogrel assessed with point-of-care assay to periprocedural myonecrosis in patients undergoing elective coronary stenting for stable angina pectoris. Am J Cardiol 2008;101:1700 –1703. 4. Mangiacapra F, Patti G, Peace A, Gatto L, Vizzi V, Ricottini E, D’Ambrosio A, Muller O, Barbato E, Di Sciascio G. Comparison of platelet reactivity and periprocedural outcomes in patients with versus without diabetes mellitus and treated with clopidogrel and percutaneous coronary intervention. Am J Cardiol 2010;106:619 – 623. 5. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107:2908 –2913. 6. Michelson AD, Linden MD, Furman MI, Li Y, Barnard MR, Fox ML, Lau WC, McLaughlin TJ, Frelinger AL. Evidence that pre-existent variability in platelet response to ADP accounts for clopidogrel resistance. J Thromb Haemost 2007;5:75– 81. 7. Mangiacapra F, Barbato E, Patti G, Gatto L, Vizzi V, Ricottini E, D’Ambrosio A, Wijns W, Di Sciascio G. Point-of-care assessment of platelet reactivity after clopidogrel to predict myonecrosis in patients undergoing percutaneous coronary intervention. JACC Cardiovasc Interv 2010;3:318 –323. 8. Patti G, Nusca A, Mangiacapra F, Gatto L, D’Ambrosio A, Di Sciascio G. Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity Predicts Outcome) study. J Am Coll Cardiol 2008;52:1128 –1133. 9. Price MJ, Endemann S, Gollapudi RR, Valencia R, Stinis CT, Levisay JP, Ernst A, Sawhney NS, Schatz RA, Teirstein PS. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-ofcare assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008;29:992–1000. 10. Angiolillo DJ, Capranzano P, Goto S, Aslam M, Desai B, Charlton RK, Suzuki Y, Box LC, Shoemaker SB, Zenni MM, Guzman LA, Bass TA. A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: results of the OPTIMUS-2 study. Eur Heart J 2008;29:2202–2211. 11. Park KW, Jeon KH, Kang SH, Oh IY, Cho HJ, Lee HY, Kang HJ, Park SK, Koo BK, Oh BH, Park YB, Kim HS. Clinical outcomes of high on-treatment platelet reactivity in Koreans receiving elective percutaneous coronary intervention (from results of the CROSS VERIFY study). Am J Cardiol 2011;108:1556 –1163. 12. Ahn SG, Lee SH, Yoon JH, Kim WT, Lee JW, Youn YJ, Ahn MS, Kim JY, Yoo BS, Yoon J, Choe KH. Different prognostic significance of high on-treatment platelet reactivity as assessed by the VerifyNow P2Y12 assay after coronary stenting in patients with and without acute myocardial infarction. JACC Cardiovasc Interv 2011;5:259 –267. 13. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO Investigators. N Engl J Med 1993;329:673– 682.

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14. Marcucci R, Gori AM, Paniccia R, Giusti B, Valente S, Giglioli C, Buonamici P, Antoniucci D, Abbate R, Gensini GF. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up. Circulation 2009;119:237–242. 15. Wijns W, Kolh P, Danchin N, Di Mario C, Falk V, Folliguet T, Garg S, Huber K, James S, Knuuti J, Lopez-Sendon J, Marco J, Menicanti L, Ostojic M, Piepoli MF, Pirlet C, Pomar JL, Reifart N, Ribichini FL, Schalij MJ, Sergeant P, Serruys PW, Silber S, Sousa Uva M, Taggart D, Sousa Uva M, Taggart D. Guidelines on myocardial revascularization. Eur Heart J 2010;31:2501–2555. 16. Mangiacapra F, De Bruyne B, Muller O, Trana C, Ntalianis A, Bartunek J, Heyndrickx G, Di Sciascio G, Wijns W, Barbato E. High residual platelet reactivity after clopidogrel: extent of coronary atherosclerosis and periprocedural myocardial infarction in patients with stable angina undergoing percutaneous coronary intervention. JACC Cardiovasc Interv 2010;3:35– 40. 17. Prasad A, Herrmann J. Myocardial infarction due to percutaneous coronary intervention. N Engl J Med 2011;364:453– 464. 18. Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D, Puri S, Robbins M, Garratt KN, Bertrand OF, Stillabower ME, Aragon JR, Kandzari DE, Stinis CT, Lee MS, Manoukian SV, Cannon CP, Schork NJ, Topol EJ, Topol EJ; GRAVITAS Investigators. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 2011;305:1097–1105. 19. Trenk D, Stone GW, Gawaz M, Kastrati A, Angiolillo DJ, Müller U, Richardt G, Jakubowski JA, Neumann FJ. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 2012;59:2159 –2164. 20. Cai Q, Skelding KA, Armstrong AT Jr, Desai D, Wood GC, Blankenship JC. Predictors of periprocedural creatine kinase-myocardial band elevation complicating elective percutaneous coronary intervention. Am J Cardiol 2007;99:616 – 620. 21. Babu GG, Walker JM, Yellon DM, Hausenloy DJ. Peri-procedural myocardial injury during percutaneous coronary intervention: an important target for cardioprotection. Eur Heart J. 2011;32:23–31. 22. Desai NR, Bhatt DL. The state of periprocedural antiplatelet therapy after recent trials. JACC Cardiovasc Interv 2010;3:571–583. 23. Wu Y, Shi Y, Wu H, Bian C, Tang Q, Xu G, Yang J. Efficacy and safety of abciximab in diabetic patients who underwent percutaneous coronary intervention with thienopyridines loading: a meta-analysis. PLoS ONE 2011;6:e20759. 24. Mehilli J, Kastrati A, Schühlen H, Dibra A, Dotzer F, von Beckerath N, Bollwein H, Pache J, Dirschinger J, Berger PP, Schömig A; Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics (ISAR-SWEET) Study Investigators. Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel. Circulation 2004;110:3627–3635. 25. Steinhubl SR, Kottke-Marchant K, Moliterno DJ, Rosenthal ML, Godfrey NK, Coller BS, Topol EJ, Lincoff AM. Attainment and maintenance of platelet inhibition through standard dosing of abciximab in diabetic and nondiabetic patients undergoing percutaneous coronary intervention. Circulation 1999;100:1977–1982. 26. Steinhubl SR, Talley JD, Braden GA, Tcheng JE, Casterella PJ, Moliterno DJ, Navetta FI, Berger PB, Popma JJ, Dangas G, Gallo R, Sane DC, Saucedo JF, Jia G, Lincoff AM, Theroux P, Holmes DR, Teirstein PS, Kereiakes DJ. Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the gold (AU-Assessing Ultegra) multicenter study. Circulation 2001;103:2572–2578.