Methods

This observational prospective study initially included 491 patients who underwent coronary angiography with and without PCI at the Karolinska University Hospital from October 2006 to May 2011. The indications for coronary angiography were acute coronary syndromes, stable angina, or chest pain with high suspicion of coronary origin. Sixteen patients were excluded because of treatment with glycoprotein IIb/IIIa inhibitors before platelet function testing, and 1 patient was excluded because of treatment with prasugrel, leaving a study cohort of 474 patients. All patients not previously receiving clopidogrel and/or aspirin treatment received a loading dose of clopidogrel (150 to 800 mg) in addition to aspirin (300- to 500-mg loading dose, followed by 75 mg/day) before coronary angiography. If PCI was performed, a daily maintenance dose of clopidogrel 75 mg was postprocedurally recommended in addition to aspirin for 1 year in patients receiving drug-eluting stents, whereas 3 months of dual-antiplatelet treatment was recommended to patients receiving bare-metal stents. Patients already receiving clopidogrel treatment for >5 days before coronary angiography did not receive additional loading dose but continued with their daily maintenance dose (75 mg once daily).

Ten patients were receiving warfarin treatment, which was discontinued ≥7 days before coronary angiography. All interventions were performed according to international guidelines. The femoral approach was used in all but 32 interventions, in which the radial approach was used, and unfractionated heparin was given in weight-adjusted doses (50 to 100 IE/kg). The sheath size was 6Fr. A vascular closure device (Angio-Seal; St. Jude Medical, St. Paul, Minnesota) was used in 247 patients. A compression assist device (Femostop; St. Jude Medical) was used in the rest of the cohort and in patients with vascular closure devices when required for hemostasis. Use of periprocedural antiplatelet agents other than clopidogrel and aspirin, for example, glycoprotein IIb/IIIa inhibitors, was at the discretion of the interventionist.

At the start of each coronary angiographic procedure, a 4-ml blood sample was drawn from the arterial line. Assessment of adenosine diphosphate–induced platelet aggregation was performed by using single-platelet counting with the Plateletworks assay (Helena Laboratories, Beaumont, Texas). The test was always performed <10 minutes after blood sampling. The baseline platelet count was obtained by the addition of 1 ml whole blood to the first Plateletworks tube, primed with the synthetic anticoagulant ethylenediaminetetraacetic acid. One milliliter of whole blood was then added to the second Plateletworks tube, containing citrate and adenosine diphosphate (20 mmol), inducing platelet aggregation. For each tube, the platelet count was then measured with a cell counter (ABX Micros 60; Horiba ABX Diagnostics, Holliston, Massachusetts). Because platelet aggregates exceed normal platelet size, it is possible for the cell counter to discriminate between aggregated and nonaggregated platelets on the basis of size. The difference in platelet count between the 2 samples was used as a measurement of platelet aggregation. A research nurse, who was well familiar with the testing equipment and had received training from the manufacturer, conducted all blood sampling and subsequent platelet function testing. The physicians responsible for the patients during their hospital stays were not aware of the platelet function test results. Written informed consent was obtained from all patients. The regional human research ethics committee in Stockholm, Sweden, approved the study.

Data on in-hospital bleeding events were prospectively acquired, including location and extent, laboratory data, imaging data, medications, and treatment. The data on out-of-hospital bleeding events that did not require direct visits to health care professionals were registered at later routine follow-up visits. The study database and patients’ medical records were reexamined for every bleeding event by 2 researchers blinded to platelet aggregation to classify them according to the bleeding definitions. The primary outcome was the 30-day incidence of bleeding complications after coronary angiography in relation to quartile distribution of on-treatment platelet reactivity measured by Plateletworks. Bleeding was defined according the criteria of BARC and of the ARMYDA-BLEEDS study (>10-cm hematoma, pseudoaneurysm, arteriovenous fistula, or major Thrombolysis In Myocardial Infarction [TIMI] bleeding criteria). The National Cardiovascular Data Registry (NCDR) CathPCI Registry model was used for retrospective evaluation of preprocedural risk for bleeding. This predictive risk score is based on the variables ST-segment elevation myocardial infarction, age, body mass index, previous PCI, chronic kidney disease, shock, cardiac arrest <24 hours, gender, hemoglobin level, and PCI status. After returning to a referring hospital, 1 patient died from momentary iatrogenic lung bleeding during a chest drainage procedure, which aimed to evacuate a pleural effusion. This bleeding event was not regarded as an outcome for this study, because according to the autopsy protocol, it was a direct result of a surgical trauma.

A power calculation was done on the basis of the ARMYDA-BLEEDS study, which showed 10.1% and 1.3% incidence rates of bleeding in the first and fourth platelet aggregation quartiles, respectively. For the present study, assuming that the bleeding event rate would be similar, it would require 85 patients in each platelet aggregation quartile (a total of 340 patients) to show a statistical difference between the first and the fourth quartiles (p <0.05, 80% power).

Patients were divided into quartiles according to adenosine diphosphate–induced platelet aggregation. Normal distribution for continuous variables was tested with the Shapiro-Wilk test. Continuous variables are described as mean ± SD or medians with interquartile ranges (IQRs) and were compared with Student’s t test when normally distributed and with the Mann-Whitney U test when not normally distributed. Categorical variables are described as percentages and were compared with either the chi-square test or Fisher’s exact test. The optimal cutoff for each bleeding definition was assessed with receiver-operating characteristic (ROC) curve. To identify possible variables associated with bleeding, an initial univariate Cox regression analysis was performed. Variables with p values <0.10 in the univariate analysis were considered for the stepwise forward and backward manual multivariate Cox regression analysis. The bleeding events in the different quartiles over time were visualized with Kaplan-Meier curves. Two-sided p values <0.05 were considered significant. All statistical analyses were performed with SPSS version 21.0 (SPSS, Inc., Chicago, Illinois).

Results

Detailed clinical and procedural patient data are listed in Table 1 and Table 2 , including comparisons between the lowest and the highest platelet aggregation quartiles. As listed in Table 1 , the different clopidogrel loading doses were evenly distributed among quartiles. Median time from clopidogrel loading dose to coronary angiography was higher in quartile 1 compared with quartile 4. At 30-day follow-up, data on bleeding were available for all patients, except for 1 patient who had moved abroad (0.2%). Three patients had gastrointestinal bleedings, 2 had bladder or urethral bleedings, 1 had an intracranial bleeding, 1 had an eye bleeding, and the remaining bleeding complications were entry-site bleedings. If a patient had >1 bleeding event within 30 days, the most extensive bleeding was included in the analysis.

The incidence of any BARC bleeding (type ≥1) was 26.8% (127 of 474 patients; Table 3 ). Patients who experienced any BARC bleeding within 30 days had a higher median NCDR CathPCI risk score compared with patients without bleeding (70 [IQR 55 to 80] vs 60 [IQR 50 to 75], p = 0.019). Median platelet aggregation was lower in patients with any BARC bleeding compared with patients without bleeding (51.0% [IQR 32.8% to 84.0%] vs 79.1% [IQR 52.5% to 92.0%], p = 0.001). Patients in the first quartile had a higher incidence of any BARC bleeding compared with the fourth quartile and the third quartile, as listed in Table 3 .

Table 3

Quartile distribution of bleeding events

	Total (n = 474)	1 st Quartile (n = 118)	2 nd Quartile (n = 119)	3 rd Quartile (n = 117)	4 th Quartile (n = 120)	p-Value ∗
Median [range] of platelet aggregation	75% [0–100%]	29% [0–46%]	63% [47–75%]	84% [75–91%]	96% [91–100%]
BARC bleeding
Type 1	76 (16%)	28 (24%)	20 (17%)	16 (14%)	12 (10%)	<0.01
Type 2	39 (8%)	14 (12%)	12 (10%)	5 (4%)	8 (7%)	0.17
Type 3a	5 (1%)	3 (3%)	1 (1%)	1 (1%)	—	0.12
3b	5 (1%)	2 (2%)	1 (1%)	2 (2%)	—	0.25
3c	1 (1%)	—	—	1 (1%)	—	N/A
Type 4	1 (1%)	1 (1%)	—	—	—	0.50
Type 5a	—	—	—	—	—	N/A
5b	—	—	—	—	—	N/A
≥Type 1	127 (27%)	48 (41%)	34 (29%)	25 (21%)	20 (17%)	<0.001
≥Type 2	51 (11%)	20 (17%)	14 (12%)	9 (8%) †	8 (7%)	0.014
ARMYDA-BLEEDS defined bleeding
Major TIMI bleeding	6 (1%)	4 (3%)	1 (1%)	1 (1%)	—	0.06
Entry site complications
>10 cm hematoma	14 (3%)	5 (4%)	4 (3%)	3 (3%)	2 (2%)	0.28
Pseudoaneurysm	6 (1%)	1 (1%)	3 (3%)	—	2 (2%)	1.0
AV-fistula	—	—	—	—	—	N/A
Combined end point ‡	22 (5%)	10 (8%)	7 (6%)	3 (3%) §	2 (2%)	0.016

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