Antiplatelet agents are critical to prevent thrombotic events in patients with acute coronary syndromes, particularly those who undergo percutaneous coronary intervention. Prasugrel is a potent P2Y 12 –adenosine diphosphate receptor antagonist that is superior to clopidogrel in such patients. Previous studies have observed that nuisance and internal bleedings were relatively frequent in patients under clopidogrel therapy and were associated with noncompliance. Furthermore, premature drug discontinuation is associated with thrombotic recurrences. The aim of the present study was to investigate the rate of nuisance or internal bleedings in patients receiving prasugrel and its relation with compliance. This prospective multicenter study included 396 patients. Bleeding events were recorded and classified as alarming, nuisance, or internal according. Compliance with prasugrel therapy was assessed. Almost half of the patients (48.5%) were included for ST-segment elevation acute coronary syndromes. During the 1-month follow-up period, 54 patients (13.6%) had bleeding events. Most bleeding events were classified as internal or nuisance (96%). Internal and nuisance bleedings were associated with high rates of prasugrel discontinuation (16.6% and 14.7%, respectively). Nuisance and internal bleedings were significantly associated with prasugrel discontinuation in multivariate analysis (odds ratio 3.1, 95% confidence interval 1.01 to 9.2, p = 0.04). The rate of major adverse cardiovascular events was 2.3%. No relation was observed between minor bleeds, compliance, and major adverse cardiovascular events. In conclusion, in the present study, minor bleedings were common during the first month after percutaneous coronary intervention and were significantly associated with prasugrel withdrawal.
Most studies assessing the efficacy and safety of prolonged dual-antiplatelet therapy have reported bleeding events using the Thrombolysis In Myocardial Infarction (TIMI) or Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding criteria or specific classification. The TIMI and GUSTO definitions were established in the context of fibrinolytic therapy and may not be optimal to evaluate prolonged dual-antiplatelet therapy and are focused on major or severe bleedings. The rate of minor bleeding events is therefore mostly unknown. However, “nuisance” bleedings are commonly encountered in patients under dual-antiplatelet therapy and have been associated with drug cessation. Of importance, antiplatelet agent withdrawal after percutaneous coronary intervention (PCI), in particular after acute coronary syndromes, is detrimental to prognosis. Prasugrel is a new antiplatelet agent that induces a significantly higher level of platelet reactivity inhibition compared to clopidogrel. Prasugrel was associated in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel (TRITON)–TIMI 38, with a reduction of thrombotic events but an increase in TIMI bleedings compared to clopidogrel. In this study, we report the incidence of nuisance and internal bleedings during the first month after PCI using the previously validated bleeding classification and its relation with compliance to prasugrel.
Methods
This was a multicenter prospective study. The study cohort consisted of patients who underwent successful stent implantation for acute coronary syndromes and received prasugrel for ≥1 month. All patients gave written consent before entering the study. The protocol was approved by the local ethics committee and in accordance with the Declaration of Helsinki.
PCI was performed using a standard technique through a femoral or a radial approach. All patients were treated with aspirin 250 mg before PCI and loaded with prasugrel 60 mg. Dual-antiplatelet therapy was recommended for all patients for a minimum duration of 12 months with aspirin 75 mg/day and prasugrel 10 mg/day. During PCI, anticoagulation was performed using unfractionated heparin (a bolus of 40 U/kg and additional heparin to achieve an activated clotting time of 250 to 300 seconds). Use of adjunctive devices and platelet glycoprotein IIb/IIIa inhibitors was at the discretion of the operator.
Clinical follow-up was performed at 1 month after PCI by trained nurses who worked exclusively with the database to determine clinical events after PCI. Clinical follow-up was performed by telephone contact or office visit. Compliance with prasugrel therapy was recorded.
The study end point was Roy’s bleeding classification: alarming, internal, and nuisance bleeding. Alarming bleeding was defined as bleeding that was intracranial, life threatening, or required blood transfusion. Internal bleeding included hematoma, epistaxis, mouth bleeding, vaginal bleeding, melena, eye bleeding, hematuria, and hematemesis. Nuisance bleeding included easy bruising, bleeding from small cuts, petechiae, and ecchymosis. Alarming bleeding events were adjudicated by an independent committee. All other bleeding events were self-reported.
Major adverse cardiovascular events (MACEs) were a composite of cardiovascular death, nonfatal myocardial infarction, and stent thrombosis at 1 month. Cardiovascular death was considered as any death with a demonstrable cardiovascular cause or any death that was not clearly attributable to a noncardiovascular cause. Stent thrombosis was defined according to the Academic Research Consortium definition. Nonfatal myocardial infarction was defined as recurrent ischemic symptoms (>20 minutes) and/or electrocardiography changes after PCI with an increase ≥20% of troponin measured after the recurrent event, with ≥1 value greater than the 99th percentile of the reference range.
Statistical analysis was performed using PASW Statistics version 17.0 (SPSS, Inc., Chicago, Illinois). Descriptive data are expressed as mean ± SD for quantitative variables and as counts and percentages for qualitative variables. Pearson’s chi-square test and Fisher’s exact test were used for comparison of categorical variables, and Student’s t test was used for comparison of continuous variables. Multivariate analysis using logistic regression was performed to determine variables independently associated with nuisance and internal bleedings. Factors with p values <0.20 on univariate analysis (gender, nuisance or internal bleedings, hemoglobin, and fibrinogen) were entered into the multivariate model. Adjusted odds ratios with their corresponding 95% confidence intervals were calculated. The threshold for statistical significance was p <0.05.
Results
Baseline characteristics of patients are summarized in Table 1 . The study population was composed of 396 patients who received prasugrel therapy for acute coronary syndromes. No patient underwent coronary artery bypass surgery. During the 1-month follow-up period, 54 patients (13.6%), had bleeding events, including alarming bleeding in 2 (3.7%), internal bleeding in 18 (33.3%), and nuisance bleeding in 34 (63%).
| Variable | Value |
|---|---|
| Age (years) | 58 ± 10 |
| Men | 347 (87%) |
| Body mass index (kg/m 2 ) | 28 ± 5 |
| Previous myocardial infarction | 65 (16%) |
| Smokers | 216 (54%) |
| Hypercholesterolemia ⁎ | 125 (32%) |
| Diabetes mellitus | 96 (24%) |
| Hypertension † | 158 (40%) |
| ST-segment elevation acute coronary syndromes | 188 (47%) |
| Non–ST-segment elevation acute coronary syndromes | 208 (53%) |
| Radial access | 321 (81%) |
| Glycoprotein IIb/IIIa inhibitor use | 26 (7%) |
| Hemoglobin (g/dl) | 14 ± 1.6 |
| Fibrinogen (g/L) | 3.7 ± 1 |
⁎ Includes patients with previously documented diagnoses of hypercholesterolemia. Patients may be treated with diet or medication. A new diagnosis can be made during this hospitalization, with a total cholesterol level >250 mg/dl. Does not include patients with elevated triglycerides.
† Includes patients with previously documented diagnoses of hypertension. A new diagnoses can be made during hospitalization, with an elevated blood pressure >140/90 mm Hg at rest.
Among patients with bleeding, 52 (96%) had minor bleedings, either nuisance or internal. We compared patients with nuisance or internal bleedings and those without. We observed that those with minor bleedings tended to be more often women (p = 0.10; Table 2 ). On multivariate analysis, nuisance or internal bleedings were significantly more frequent in women (odds ratio 2.6, 95% confidence interval 1.1 to 6.1, p = 0.03).
| Variable | Minor (Nuisance and Internal) Bleeding | p Value | |
|---|---|---|---|
| Yes (n = 52) | No (n = 344) | ||
| Age (years) | 58 ± 10 | 58 ± 11 | 1.00 |
| Men | 42 (81%) | 305 (89%) | 0.10 |
| Body mass index (kg/m 2 ) | 28 ± 4 | 28 ± 5 | 0.70 |
| Previous myocardial infarction | 12 (23%) | 53 (15%) | 0.20 |
| Smokers | 24 (46%) | 192 (56%) | 0.20 |
| Hypercholesterolemia ⁎ | 12 (23%) | 103 (30%) | 0.30 |
| Diabetes mellitus | 13 (25%) | 83 (24%) | 1.00 |
| Hypertension † | 23 (44%) | 135 (39%) | 0.50 |
| Family history of coronary artery disease | 9 (17%) | 66 (19%) | 0.90 |
| ST-segment elevation acute coronary syndromes | 26 (50%) | 162 (47%) | 0.80 |
| Non–ST-segment elevation acute coronary syndromes | 26 (50%) | 182 (53%) | |
| Radial access | 43 (82%) | 278 (81%) | 0.80 |
| Glycoprotein IIb/IIIa inhibitor use | 3 (6%) | 23 (7%) | |
| Hemoglobin (g/dl) | 13.7 ± 2.0 | 14.1 ± 1.5 | 0.20 |
| Fibrinogen (g/L) | 3.5 ± 0.8 | 3.8 ± 1.1 | 0.20 |
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