Methods

This prospective observational study enrolled consecutive patients undergoing PCI for stable CAD or non–ST elevation acute coronary syndrome at the Department of Cardiovascular Sciences, Campus Bio-Medico University, Rome, Italy, and at Cardiovascular Center Aalst, Aalst, Belgium. Exclusion criteria were ST elevation myocardial infarction (MI), radial approach, upstream use of glycoprotein IIb/IIIa inhibitors, platelet count <70 × 10 ⁹ /L, active bleeding or bleeding diathesis, dialysis, and any malignancy. The study was performed in accordance with the Declaration of Helsinki and the protocol was approved by the institutional ethics committees, with all patients giving written informed consent. All interventions were performed with standard technique by way of the femoral approach. Before the procedure, patients were given unfractionated heparin (70 to 100 IU/kg body weight). All patients received aspirin before PCI. Patients received a 600-mg clopidogrel loading dose ≥6 hours before intervention or were pretreated with clopidogrel 75 mg/day for ≥5 days. Technicalities of the procedure, including use of drug-eluting stents and glycoprotein IIb/IIIa inhibitors, were left to the operator’s discretion. Procedural success was defined as a reduction in percent diameter stenosis to below 30% and presence of Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 in the main vessel and all side branches ≥2 mm in diameter.

Baseline serum creatinine levels were assessed at hospital admission in all patients. The estimated glomerular filtration rate (GFR) was calculated using the abbreviated Modification of Diet in Renal Disease formula. CKD was defined according to the National Kidney Foundation’s classification as follows: normal renal function to mild renal impairment with a GFR of ≥60 ml/min/1.73 m ² and moderate-to-severe CKD with a GFR of <60 ml/min/1.73 m ² .

PR was measured in the catheterization laboratory using the VerifyNow P2Y12 assay (Accumetrics, Inc., San Diego, California) immediately before PCI. Blood was drawn from the femoral artery immediately after sheath insertion. After discarding the first 5 ml of blood to avoid unwanted platelet activation, samples were collected into a 2-ml tube containing 3.2% sodium citrate. The VerifyNow P2Y12 assay is a turbidimetry-based optical detection system that measures platelet-induced aggregation by P2Y12 antagonist as an increase in light transmittance. The assay contains 20-mol adenosine diphosphate and 22-nmol prostaglandin E1 to reduce the activation contribution from adenosine diphosphate binding to P2Y12 receptors. Values are expressed as P2Y12 reaction units (PRUs). The lower the PRU value, the greater the degree of P2Y12 receptor inhibition by clopidogrel and vice versa. According to previous studies, high platelet reactivity (HPR) was defined as a PRU value of ≥240 and low platelet reactivity (LPR) as a PRU value of ≤178.

The primary end point was the 30-day incidence of net adverse clinical events (NACEs), defined as the occurrence of both ischemic and bleeding events. Secondary end point was the occurrence of any of the components of the primary end point. Ischemic events included death, MI, and target vessel revascularization. MI accounted for both periprocedural and spontaneous events. Periprocedural MI was defined as a postprocedural increase in creatine kinase-MB >3 times the ninety-ninth percentile of the upper reference limit for patients with baseline negative myocardial necrosis markers. In patients with increased baseline levels of creatine kinase-MB, a subsequent increase >50% of the baseline value fulfilled the criteria for periprocedural MI. Occurrence of spontaneous MI was defined as the presence of symptoms compatible with recurrent ischemia associated with electrocardiographic changes indicative of new ischemia (new ST-T changes or new left bundle branch block). Definite stent thrombosis was defined according to the Academic Research Consortium definition. Target vessel revascularization included bypass surgery or clinically driven repeat PCI of the target vessel(s). Bleeding events were defined as major bleeding according to the TIMI criteria or large entry-site hematoma (>10 cm in diameter). Entry-site hematomas were repeatedly monitored throughout the hospitalization and the largest size detected was used for the analysis.

Continuous variables following a normal distribution are expressed as mean ± SD and were compared with Student t test. Variables not following a normal distribution are expressed as median and were compared with Mann-Whitney U test. Normal distribution of PRU levels in the study population was confirmed by Kolmogorov-Smirnov test. Comparisons between categorical variables were evaluated using Fisher’s exact test or the Pearson chi-square test, as appropriate. The association between clinical and procedural features, including the presence of moderate-to-severe CKD and pre-PCI PR groups, with 30-day NACE was assessed using logistic regression. Only variables with a p value <0.15 were then entered into the final multivariate logistic regression model providing odds ratios and 95% confidence intervals. A p value <0.05 was considered statistically significant. Statistical analysis was performed using SPSS 15.0 (SPSS, Inc., Chicago, Illinois).

Results

A total of 800 patients were included in the study. Baseline clinical characteristics, laboratory data, and angiographic features are described in Table 1 . Procedural success was achieved in all patients. A total of 173 patients (22%) had moderate-to-severe CKD. Patients with moderate-to-severe CKD were more likely to be older than those without (68 ± 10 vs 66 ± 10, p = 0.008), although the 2 groups did not differ in terms of cardiovascular risk factors and clinical presentation ( Table 1 ). A total of 256 (32%) had HPR and 272 (34%) LPR. Patients with moderate-to-severe CKD had similar PRU values compared with those without (208 ± 67 vs 207 ± 75, p = 0.819); similarly, the proportion of HPR and LPR did not differ significantly in the 2 groups (32.9% vs 31.2%, p = 0.763 and 32.9% vs 34.3%, p = 0.741, respectively). No differences were found between patients with and without non–ST elevation acute coronary syndrome.

Clinical follow-up at 30 days was obtained in all patients. NACE occurred in 91 patients (11.4%), with 66 ischemic events (8.3%) and 28 bleeding events (3.5%). Ischemic events included 3 deaths, 56 MI (49 periprocedural and 7 spontaneous, of which 5 were due to stent thrombosis), and 7 target vessel revascularization. The sources of major bleeding were genitourinary in 5 patients and gastrointestinal in 3 patients. Twenty patients had entry-site hematoma >10 cm. The incidence of 30-day NACEs was 19.7% (34 of 173) in patients with moderate-to-severe CKD and 9.1% (57 of 627) in those without (p <0.001). NACEs were significantly higher in patients with moderate-to-severe CKD and HPR or LPR (25.4%) and lowest in those without moderate-to-severe CKD and without HPR or LPR (6.6%, p for trend <0.001; Figure 1 ). At multivariate analysis, the combination of moderate-to-severe CKD with LPR or HPR was the strongest predictor of NACE (odds ratio 3.4, 95% confidence interval 2.0 to 5.6, p <0.001; Figure 2 ).

Incidence of NACE according to renal function and PR.

Multivariate analysis. Odds ratios (presented on log axis) for NACE. GPI = glycoprotein IIb/IIIa inhibitors.

The incidence of 30-day ischemic events was significantly greater in patients with moderate-to-severe CKD (12.1% vs 7.2%, p = 0.036), as well as the incidence of bleeding events (8.7% vs 2.1%, p <0.001). Patients with HPR presented a greater incidence of ischemic events compared with those without (14.5% vs 5.3%, p = 0.001), while patients with LPR had a greater incidence of bleeding events compared with patients without (8.1% vs 2.3%, p <0.001). The presence of HPR was associated with higher rates of ischemic events in both patients with moderate-to-severe CKD (21.1% vs 7.6%, p = 0.012) and in those without (12.6% vs 4.7%, p <0.001; Figure 3 ). Likewise, LPR was associated with higher rates of bleeding in both patients with (19.3% vs 3.4%, p <0.001) and without moderate-to-severe CKD (5.1% vs 0.5%, p<0.001; Figure 3 ). The incidence of the single end points in the different patients groups is reported in Table 2 .

Incidence of ischemic (A) and bleeding (B) events according to renal function and PR.

Table 2

Incidence of the single end points according to renal function and PR

Variable	GFR (ml/min/1.73 m 2 )				p Value
	≥60/No HPR (n = 428)	<60/No HPR (n = 116)	≥60/HPR (n = 199)	<60/HPR (n = 57)
Death	0 (0)	2 (1.7)	1 (0.5)	0 (0)	0.081
MI	18 (4.2)	6 (5.2)	22 (11.1)	10 (17.5)	<0.001
Stent thrombosis (definite)	0 (0)	1 (0.9)	3 (1.5)	1 (1.8)	0.026
Target vessel revascularization	0 (0)	2 (1.8)	4 (2)	1 (1.8)	0.007

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