The incremental predictive value of high inflammatory status and high on-treatment platelet reactivity (HPR) on the occurrence of periprocedural myocardial infarction (PMI) after percutaneous coronary intervention (PCI) has not been characterized. The aim of this study was to evaluate the correlation of elevated C-reactive protein (CRP) level and/or HPR with the incidence of PMI in patients who undergo PCI. Five hundred consecutive patients treated with clopidogrel who underwent PCI had preprocedural measurement of CRP levels and platelet reactivity using the point-of-care VerifyNow P2Y 12 assay. Elevated inflammatory status was defined as CRP >3 mg/L and HPR as P2Y 12 reactivity units ≥240. The primary end point was the incidence of PMI in relation to platelet reactivity and/or inflammatory status. Rates of PMI were increased in patients with CRP levels >3 mg/L (10.9% vs 4.6% in those with normal levels, odds ratio 2.4, 95% confidence interval 1.2 to 4.5, p = 0.015) and in patients with HPR (11% vs 5.5% in those without HPR, odds ratio 2.2, 95% confidence interval 1.2-4.4, p = 0.018). The occurrence of PMI was highest in the subgroup with HPR and high inflammatory status (16.6% vs 3.6% in patients with CRP ≤3 mg/L and P2Y 12 reactivity units <240, odds ratio 4.3, 95% confidence interval 1.5 to 12.6, p = 0.008). HPR in association with elevated CRP levels resulted in a significant increase in the discriminatory power of a model including clinical and procedural variables in predicting PMI (area under the curve 0.811, p = 0.041). In conclusion, in patients who undergo PCI, baseline stratification according to platelet reactivity and inflammatory status may identify those at higher risk for PMI.
The degree of platelet inhibition at the time of the procedure influences clinical outcome in patients who undergo percutaneous coronary intervention (PCI). Given the wide intersubject variability in response to clopidogrel, various studies have explored the issue of whether high on-treatment platelet reactivity (HPR) is associated with a poorer prognosis after coronary stent implantation ; in particular, impaired response to clopidogrel at platelet function testing was demonstrated to have an independent predictive role for the incidence of periprocedural ischemic events and major adverse cardiac events during follow-up. Previous data have demonstrated that inflammatory status at the time of PCI may also influence subsequent clinical outcomes, with higher occurrence of clinical events in patients with increased C-reactive protein (CRP) levels ; however, no study has specifically assessed the correlation between inflammatory status and the incidence of periprocedural myocardial infarction (PMI) in the setting of PCI. Thus, the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty (ARMYDA) study group designed a prospective study to investigate whether (1) elevated baseline CRP level is independently associated with increased risk for PMI after coronary stenting and (2) the combination of pre-PCI high CRP level and HPR may have an incremental predictive value for the occurrence of PMI.
Methods
ARMYDA-CRP is a prospective investigation of patients who underwent PCI for a variety of coronary ischemic syndromes at Campus Bio-Medico University of Rome from June 2010 to November 2011. All patients were receiving clopidogrel therapy at the time of intervention (75 mg/day for ≥7 days or a 600-mg loading dose given ≥6 hours before PCI). A total of 589 patients were initially screened, and 89 were excluded for the presence of ≥1 of the following criteria: primary PCI for ST-segment elevation myocardial infarction, upstream use of glycoprotein IIb/IIIa inhibitors (to avoid interference with pre-PCI platelet reactivity measurement), platelet count <70 × 10 9 /L, use of prasugrel or ticagrelor, need for oral anticoagulant therapy, chronic renal failure with serum creatinine >2 mg/dl, cardiogenic shock, and concomitant systemic inflammatory conditions. Thus, a total of 500 patients were included in this study.
All interventions were performed using standard techniques. All patients received aspirin before PCI. A blood sample was drawn from the arterial sheath, and platelet reactivity was immediately measured in the catheterization laboratory before PCI using the VerifyNow P2Y 12 assay (Accumetrics Inc., San Diego, California), which is a rapid cartridge-based assay specifically measuring effects of clopidogrel on the platelet P2Y 12 receptor. Technical details of the assay have been previously described. Results are expressed as P2Y 12 reactivity units (PRU); the lower the PRU value, the greater the degree of P2Y 12 receptor inhibition by clopidogrel, and vice versa. Creatine kinase-MB (mass) and troponin I (mass) levels were evaluated before PCI and at 8 and 24 hours in all patients; further measurements were done if clinically indicated. Measurements were obtained using the Access 2 immunochemiluminometric assay (Beckman Coulter, Brea, California), with normal limits of ≤4 ng/ml for creatine kinase-MB and ≤0.08 ng/ml for troponin I. High-sensitivity CRP levels were also measured before the procedure using the Kryptor ultrasensitive immunofluorescent assay (B·R·A·H·M·S GmbH, Hennigsdorf, Germany), with a detection limit of 0.06 mg/L. The interventional cardiologist performing the procedure was blinded to the PRU and CRP results. Each patient gave informed consent to participate in the study.
The primary end point was the incidence of PMI in relation to baseline platelet reactivity (by PRU) and/or inflammatory status (by CRP level); this end point was prospectively determined. PMI was defined in patients with normal baseline levels of these markers as a postintervention increase in creatine kinase-MB or troponin I increase >3 times the 99th percentile of the upper reference limit ; in patients with acute coronary syndromes and increased baseline cardiac marker levels, the definition of a subsequent elevation ≥50% of the baseline value was applied. The cutoff for defining an elevated inflammatory status was a CRP level >3 mg/L. According to the ARMYDA–Platelet Reactivity Predicts Outcome (ARMYDA-PRO) study, which identified a clinically driven threshold of platelet reactivity to identify patients at higher risk for PMI, HPR was defined as PRU ≥240. The secondary end point was the correlation of platelet reactivity and CRP level with post-PCI peak levels of cardiac markers.
We assumed a 6% overall incidence of PMI in patients without HPR and as an effect size for the power analysis a 2.5-fold increased risk for PMI in those with HPR ; we hypothesized a similar increased risk in patients with high CRP. Thus, a study population of ≥495 patients would be needed to verify this hypothesis with an α level of 0.05 (2 tailed, after Sidak correction for multiple comparisons) and a β value of 0.8. Categorical variables are expressed as percentages and continuous variables as mean ± SD, unless otherwise specified. Proportions were compared using Fisher’s exact test when the expected frequency was <5; otherwise, the chi-square test (with Yates’ correction) was applied, with Bonferroni’s correction in case of multiple comparisons. Continuous variables were compared using Student’s t tests for normally distributed values (as assessed using the Kolmogorov-Smirnov test); otherwise, the Mann-Whitney U test was used. Correlations were determined using Spearman’s rank test. Odds ratios (OR) and 95% confidence intervals (CIs) investigating the independent predictive role of HPR and/or high CRP level on the occurrence of the primary end point were assessed using logistic regression. The following parameters were first evaluated in a univariate model: platelet reactivity, CRP values, and each of the clinical and procedural variables listed in Tables 1 and 2 . Variables with p values <0.15 were then entered into the final model of multivariate logistic regression analysis. We also assessed the incremental value of incorporating HPR and/or high CRP levels into a model of clinical and procedural variables in predicting the primary end point. The area under the curve and its 95% CI were calculated for each logistic regression model, and differences between areas under the curve for different models were assessed using the jackknife method, as previously described. All calculations were performed using SPSS version 15.0 (SPSS, Inc., Chicago, Illinois), and 2-sided p values <0.05 were considered significant.
| Variable | CRP ≤3 mg/L (n = 262) | CRP >3 mg/L (n = 238) | p Value |
|---|---|---|---|
| Age (yrs) | 66 ± 9 | 68 ± 10 | 0.019 |
| Men | 210 (80%) | 184 (77%) | 0.50 |
| Systemic hypertension | 207 (79%) | 200 (84%) | 0.18 |
| Diabetes mellitus | 107 (41%) | 96 (40%) | 0.98 |
| Hypercholesterolemia ∗ | 190 (71%) | 165 (75%) | 0.49 |
| Cigarette smoking | 48 (18%) | 53 (22%) | 0.32 |
| Body mass index (kg/m 2 ) | 28 ± 4 | 28 ± 4 | 1 |
| Previous myocardial infarction | 91 (35%) | 96 (40%) | 0.11 |
| Previous coronary angioplasty | 125 (48%) | 85 (35%) | 0.009 |
| Previous coronary bypass surgery | 20 (8%) | 9 (4%) | 0.10 |
| Clinical presentation | |||
| Stable angina pectoris | 188 (72%) | 139 (58%) | 0.002 |
| Unstable angina/non–ST-segment elevation myocardial infarction | 74 (28%) | 99 (42%) | 0.002 |
| Left ventricular ejection fraction (%) | 56 ± 5 | 55 ± 9 | 0.12 |
| Serum creatinine (mg/dl) | 0.96 ± 0.26 | 1.01 ± 0.28 | 0.039 |
| Treated coronary artery | |||
| Left main | 5 (2%) | 5 (2%) | 0.84 |
| Left anterior descending | 132 (43%) | 111 (39%) | 0.37 |
| Left circumflex | 85 (27%) | 81 (28%) | 0.90 |
| Right | 85 (27%) | 87 (30%) | 0.49 |
| Saphenous vein graft | 3 (1%) | 3 (1%) | 0.75 |
| Type B2/C lesions | 133 (51%) | 121 (51%) | 0.94 |
| Bifurcating lesions | 27 (10%) | 18 (8%) | 0.36 |
| Restenotic lesions | 23 (9%) | 29 (12%) | 0.27 |
| Multivessel intervention | 48 (18%) | 49 (21%) | 0.60 |
| Use of stents | 237 (90%) | 222 (93%) | 0.32 |
| Number of stents/patient | 1.42 ± 0.94 | 1.38 ± 0.88 | 0.62 |
| Use of drug-eluting stents | 82 (31%) | 77 (32%) | 0.87 |
| Direct stenting | 116 (44%) | 105 (44%) | 0.95 |
| Medical therapy | |||
| β blockers | 99 (38%) | 95 (40%) | 0.69 |
| Statins | 209 (80%) | 200 (84%) | 0.26 |
| Glycoprotein IIb/IIIa inhibitors | 21 (8%) | 11 (5%) | 0.17 |
| Unfractionated heparin | 238 (91%) | 210 (88%) | 0.42 |
| Bivalirudin | 24 (9%) | 28 (12%) | 0.42 |
| Variable | PRU <240 (n = 312) | PRU ≥240 (n = 188) | p Value |
|---|---|---|---|
| Age (yrs) | 66 ± 10 | 69 ± 10 | 0.001 |
| Men | 260 (83%) | 134 (71%) | 0.002 |
| Systemic hypertension | 257 (82%) | 150 (80%) | 0.55 |
| Diabetes mellitus | 129 (41%) | 74 (39%) | 0.73 |
| Hypercholesterolemia ∗ | 225 (72%) | 130 (69%) | 0.54 |
| Cigarette smoking | 75 (24%) | 26 (14%) | 0.008 |
| Body mass index (kg/m 2 ) | 27 ± 4 | 28 ± 4 | 0.007 |
| Previous myocardial infarction | 119 (38%) | 68 (36%) | 0.73 |
| Previous coronary angioplasty | 129 (41%) | 81 (43%) | 0.77 |
| Previous coronary bypass surgery | 19 (6%) | 10 (5%) | 0.87 |
| Clinical presentation | |||
| Stable angina pectoris | 205 (66%) | 122 (65%) | 0.93 |
| Unstable angina/non–ST-segment elevation myocardial infarction | 107 (34%) | 66 (35%) | 0.93 |
| Left ventricular ejection fraction (%) | 55 ± 8 | 56 ± 8 | 0.18 |
| Serum creatinine (mg/dl) | 0.99 ± 0.26 | 0.98 ± 0.29 | 0.69 |
| Treated coronary artery | |||
| Left main | 6 (2%) | 4 (2%) | 0.86 |
| Left anterior descending | 141 (38%) | 102 (45%) | 0.09 |
| Left circumflex | 112 (30%) | 54 (24%) | 0.13 |
| Right | 110 (29%) | 62 (28%) | 0.66 |
| Saphenous vein graft | 3 (1%) | 3 (1%) | 0.84 |
| Type B2/C lesions | 154 (49%) | 100 (53%) | 0.46 |
| Bifurcating lesions | 30 (10%) | 15 (8%) | 0.64 |
| Restenotic lesions | 30 (10%) | 22 (12%) | 0.56 |
| Multivessel intervention | 60 (19%) | 37 (20%) | 0.99 |
| Use of stents | 288 (92%) | 171 (91%) | 0.71 |
| Number of stents/patient | 1.37 ± 0.88 | 1.46 ± 0.96 | 0.28 |
| Use of drug-eluting stents | 99 (32%) | 60 (32%) | 0.95 |
| Direct stenting | 134 (43%) | 87 (46%) | 0.53 |
| Medical therapy | |||
| β blockers | 121 (39%) | 73 (39%) | 0.87 |
| Statins | 259 (83%) | 150 (80%) | 0.43 |
| Glycoprotein IIb/IIIa inhibitors | 21 (7%) | 11 (6%) | 0.84 |
| Unfractionated heparin | 285 (91%) | 163 (87%) | 0.13 |
| Bivalirudin | 27 (9%) | 25 (13%) | 0.13 |
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