Summary
Background
Antiplatelet therapies, including prasugrel, are a cornerstone in the treatment of ST-segment elevation myocardial infarction (STEMI), but are associated with a bleeding risk. This risk has been evaluated in randomized trials, but few data on real-world patients are available.
Aim
To evaluate prasugrel safety in real-world patients with STEMI.
Methods
Consecutive patients with STEMI were recruited over 1 year. Follow-up was done at 3 months and 1 year to evaluate prasugrel safety from hospital discharge to the STEMI anniversary date. The primary outcome was occurrence of any major bleeding according to the Bleeding Academic Research Consortium (BARC) 3 or 5 definitions, or minor bleeding according to the BARC 2 definition.
Results
Overall, 1083 patients were recruited. Compared to patients treated with aspirin + clopidogrel, patients treated with aspirin + prasugrel had fewer BARC 3 or 5 bleedings (two [0.4%] patients vs. nine [1.8%] patients; P = 0.04), but more BARC 2 bleedings (45 [9.3%] patients vs. 20 [4.0%] patients; P < 0.001). The baseline characteristics of prasugrel- and clopidogrel-treated patients differed because the former were carefully selected (younger, higher body mass index, less frequent history of stroke). In the overall population, rates of in-hospital and out-of-hospital major bleeding were 2.6% ( n = 28) and 1.3% ( n = 13), respectively.
Conclusion
The rate of major bleeding, particularly out-of-hospital bleeding, in patients treated with prasugrel is low within 1 year after a STEMI. Accurate selection of patient candidates for prasugrel is likely to have reduced the risk of bleeding.
Résumé
Contexte
Les traitements antiplaquettaires, dont le prasugrel, sont un élément majeur dans le traitement du syndrome coronarien aigu avec sus-décalage du segment ST (SCA ST+) mais entraînent un sur-risque hémorragique. Ce risque a été évalué dans des essais cliniques randomisés mais il existe peu de données dans la « vraie vie ».
Objectif
Évaluer la sécurité du prasugrel chez des patients adressés pour un syndrome coronarien aigu avec sus-décalage du segment ST dans la « vraie vie ».
Méthodes
Les patients avec SCA ST+ ont été recrutés pendant un an et le suivi a été effectué, par téléphone, 3 mois et 1 an après le SCA ST+ afin d’évaluer la sécurité du prasugrel, en particulier pendant la période post-hospitalière. Le critère d’évènement principal était la survenue d’un évènement hémorragique majeur défini selon la classification Bleeding Academic Research Consortium (BARC) 3 ou 5 ou d’un évènement hémorragique mineur défini selon la classification BARC 2.
Résultats
Mille quatre-vingt-trois patients ont été recrutés. Les patients traités par aspirine + clopidogrel avaient moins de saignements BARC 3 ou 5 que les patients traités par aspirine + prasugrel (9 patients, 1,8 % vs 2 patients, 0,4 % ; p = 0,04) mais ils avaient plus de saignements BARC 2 (20 patients, 4,0 % vs 45 patients, 9,3 % ; p < 0,001). Les caractéristiques des patients traités par prasugrel étaient différentes des patients traités par clopidogrel car la sélection était attentive : patients plus jeunes, indice de masse corporelle plus élevé, moins d’antécédent d’accident vasculaire cérébral. Les pourcentages de saignement intra-hospitalier majeur et de saignement extra-hospitalier majeur étaient respectivement de 2,6 % ( n = 28) et 1,3 % ( n = 13).
Conclusion
Les saignements majeurs, en particulier extra-hospitaliers, sont peu fréquents chez les patients traités par prasugrel dans l’année qui suit un SCA ST+. Une sélection attentive des patients pouvant bénéficier du prasugrel peut expliquer une diminution de ce risque.
Background
Cardiovascular diseases, including acute myocardial infarction, are currently one of the leading causes of death in Western countries. Medical therapies focus on anticoagulation and platelet inhibition to reduce the risk of thrombotic events and improve ischaemic outcomes in patients with ST-segment elevation myocardial infarction (STEMI). These therapies, coupled with early use of cardiac catheterization and revascularization, reduce the rate of death and reinfarction, but carry a bleeding risk. Indeed, bleeding is the most common non-cardiac complication of antithrombotic therapy in acute coronary syndromes (ACS), and has been associated with adverse outcomes, including myocardial infarction, stroke and death . Thus, clinicians must balance antithrombotic treatment efficacy in preventing ischaemic events with the need to minimize the risk of serious bleeding complications. Bleeding is even more frequent when percutaneous coronary intervention (PCI) is performed in the context of acute STEMI, compared with bleeding complicating an elective procedure .
Several new antiplatelet therapies, including prasugrel, have been evaluated in randomized trials; they reduce the ischaemic risk but are associated with an increased risk of major bleeding. In patients with STEMI undergoing PCI, prasugrel is more effective than clopidogrel in the prevention of ischaemic events, without excess bleeding . However, there are few data on the safety of new antiplatelet agents and bleeding risk within 1 year after STEMI in real-world patients . The Bleeding and Myocardial Infarction (Bleed-MI) Study sought to evaluate the safety of prasugrel in real-world patients with STEMI, from hospital discharge to the anniversary date of the STEMI. Safety was assessed by analysing out-of-hospital bleeding.
Methods
Study patients
From 1st April 2011 to 31st March 2012, patients were included if they had a STEMI and were hospitalized in any of the nine primary percutaneous intervention centres in Brittany, France, within 24 hours after the onset of symptoms. There were no exclusion criteria. Data were recorded in the ORBI-registry, which was approved by the Commission nationale informatique et liberté. All patients were informed of the aims of the study and could request to be excluded. The follow-up interviews were conducted by telephone by research nurses at 3 months and 1 year. The follow-up questionnaire elicited key information about antiplatelet and anticoagulation therapies, medical treatment and occurrence of bleeding or ischaemic events. In case of bleeding or ischaemic events, the hospitalization reports and all medical examination results (e.g. blood tests, medical imaging, etc.) were recovered, so that all data were centralized. Patients for whom follow-up data were lacking were considered lost to follow-up.
Definitions
The Bleeding Academic Research Consortium (BARC) was used to define bleeding events occurring within 1 year after a STEMI. BARC 3 or 5 bleedings were considered major bleedings; BARC 2 bleedings were considered minor bleedings. BARC 1 bleedings were not collected because they do not require treatment by a healthcare professional; thus, their collection would not have been exhaustive. Coronary artery bypass graft (CABG)-related bleedings (BARC 4 bleedings) were not analysed. Bleeding rates were also defined according to thrombolysis in myocardial infarction (TIMI) definitions . Cardiovascular death was any death resulting from a new ACS, severe cardiac arrhythmia, refractory congestive heart failure, cardiogenic shock, stroke, sudden death or unwitnessed death. Acute myocardial infarction was defined in accordance with the universal definition of myocardial infarction proposed in 2012 . Evaluation for stent thrombosis was performed according to the Academic Research Consortium criteria .
Study outcomes
The primary outcome was the occurrence of any minor or major bleeding between discharge and the end of follow-up at 1 year. A “bleeding events” committee validated, classified and located the site of each bleeding event, using telephone interviews, the hospitalization reports and the medical examination results. Prespecified secondary outcomes included in-hospital major bleeding and rates of premature discontinuation (transitory or not) of any antithrombotic treatment after a bleeding complication. The rates of major adverse cardiac events, including cardiovascular death, non-fatal STEMI, non-fatal stroke and stent thrombosis, were calculated.
Statistical methods
Data description started with displaying the number of patients with haemorrhage or who were censored with no event 12 months after myocardial infarction. Descriptive statistics included mean and standard deviation for normally distributed continuous variables, median and interquartile range otherwise, and number and percentage for categorical variables. Comparisons according to dual antiplatelet regimen on discharge used the Chi-square test or Fisher’s exact test for categorical variables and Student’s t test or the Wilcoxon test for continuous variables. For the main outcome, a survival analysis was used. Only one event per subject could occur in the analysis.
First, univariate (marginal) Wald test statistics using the Cox model were performed for each covariate. Then, multivariable modelling was completed with a Cox proportional hazards model that contained all covariates significantly associated in the univariate analyses at the P = 0.15 level. We used a hand-made stepwise backward elimination process: following the fit of the multivariable model, we used the P -values from the Wald tests of the individual coefficients to identify covariates that might be deleted from the model. The linearity of the relationship between continuous covariates was not rejected except for haematocrit value when considering death; a cut-off at 37.4% was identified from martingale residuals analysis. In addition, the graphical and numerical methods derived from cumulative sums of martingale residuals over follow-up times or the covariate values of Lin et al. were used for checking the proportional hazard assumption. For all statistical analyses, SAS software, version 9.3 (SAS Institute, Cary, NC, USA) was used.
Results
Study patients and in-hospital events
Overall, 1083 consecutive patients with STEMI from nine centres in Brittany were recruited from 1st April 2011 to 31st March 2012. No patient asked to be excluded. Follow-up occurred from 1st July 2011 to 31st March 2013. The baseline characteristics of the patients are summarized in Table 1 . Coronary angiography was performed in 1060 (97.9%) patients, with radial access in 564 (53.2%) patients, and angioplasty was performed in 974 (89.9%) patients; 91.6% ( n = 892) of stented patients received at least one stent, and 22.5% ( n = 219) of stented patients had at least one drug-eluting stent. Glycoprotein IIb/IIIa inhibitors were used in 489 (45.2%) patients.
| Population ( n = 1083) | Aspirin + clopidogrel ( n = 505) | Aspirin + prasugrel ( n = 483) | P | |
|---|---|---|---|---|
| Age (years) | 62.7 ± 14.0 | 67.3 ± 14.2 | 55.9 ± 10.2 | <0.0001 |
| Women | 282 (26.0) | 171 (33.9) | 67 (13.9) | <0.0001 |
| Body weight (kg) | 75.5 ± 15.0 | 71.2 ± 14.7 | 80.7 ± 13.4 | <0.0001 |
| BMI (kg/m 2 ) | 26.3 ± 4.3 | 25.4 ± 4.3 | 27.2 ± 4.0 | <0.0001 |
| Cardiovascular risk factors | ||||
| Habitual smoker | 439 (40.5) | 159 (31.7) | 254 (52.6) | <0.0001 |
| Arterial hypertension | 460 (42.5) | 252 (49.9) | 150 (31.1) | <0.0001 |
| Diabetes mellitus | 147 (13.6) | 72 (14.3) | 59 (12.2) | 0.34 |
| Other medical history | ||||
| Stroke/TIA | 34 (3.1) | 20 (4.0) | 5 (1.0) | 0.0034 |
| Chronic renal disease | 23 (2.1) | 15 (3.0) | 5 (1.0) | 0.0309 |
| Gastroduodenal ulcer | 34 (3.1) | 11 (2.2) | 7 (1.4) | 0.39 |
| Initial use of glycoprotein IIb/IIIa inhibitors | 489 (45.2) | 233 (46.1) | 233 (48.2) | 0.51 |
| Occurrence of bleeding events during follow-up | ||||
| Total | 23 (4.6) | 43 (8.9) | 0.0110 | |
| BARC 2 | 15 (3.0) | 42 (8.7) | 0.0003 | |
| BARC 3 | 6 (1.2) | 1 (0.2) | 0.13 | |
| BARC 5 | 2 (0.4) | 0 (0) | 0.50 | |
| BARC 3 + 5 | 8 (1.6) | 1 (0.2) | 0.0389 | |
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