Author + information
- Received November 7, 2013
- Revision received January 14, 2014
- Accepted January 17, 2014
- Published online May 13, 2014.
- Wouter J. Kikkert, MD∗,
- Nan van Geloven, PhD†,
- Mariet H. van der Laan∗,
- Marije M. Vis, MD, PhD∗,
- Jan Baan Jr., MD, PhD∗,
- Karel T. Koch, MD, PhD∗,
- Ron J. Peters, MD, PhD∗,
- Robbert J. de Winter, MD, PhD∗,
- Jan J. Piek, MD, PhD∗,
- Jan G.P. Tijssen, PhD∗ and
- José P.S. Henriques, MD, PhD∗∗ ()
- ∗Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- †Clinical Research Unit, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- ↵∗Reprint requests and correspondence to:
Dr. J. P. S. Henriques, Department of Cardiology, B2-115, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
Objectives The aim of the present analysis was to compare 1-year mortality prediction of Bleeding Academic Research Consortium (BARC)-defined bleeding complications with existing bleeding definitions in patients with ST-segment elevation myocardial infarction (STEMI) and to investigate the prognostic value of the individual data elements of the bleeding classifications for 1-year mortality.
Background BARC recently proposed a novel standardized bleeding definition.
Methods The in-hospital occurrence of bleeding defined according to the BARC, TIMI (Thrombolysis In Myocardial Infarction), GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries), and ISTH (International Society on Thrombosis and Haemostasis) bleeding classifications was assessed in 2,002 STEMI patients undergoing primary percutaneous coronary intervention between January 1, 2003, and July 31, 2008.
Results BARC types 2, 3, 4, and 5 bleeding occurred in 4.4%, 14.2%, 1.4%, and 0.3% of patients, respectively. By multivariable analysis, GUSTO- and ISTH-defined bleeding was not significantly associated with 1-year mortality, whereas TIMI major and BARC type 3b or 3c bleeding conferred a 2-fold higher risk of 1-year mortality (hazard ratios [HRs]: 2.00 [95% confidence interval (CI): 1.32 to 3.01] and 1.84 [95% CI: 1.23 to 2.77], respectively). Data elements most strongly associated with mortality were a hemoglobin decrease ≥5 g/dl (HR: 1.94 [95% CI: 1.26 to 2.98]), the use of vasoactive agents for bleeding (HR: 2.01 [95% CI: 0.91 to 4.44]), cardiac tamponade (HR: 2.38 [95% CI: 0.56 to 10.1]), and intracranial hemorrhage (HRs for 1-year mortality were not computable because there was only 1 patient with intracranial bleeding).
Conclusions Both the BARC and TIMI bleeding classification identified STEMI patients at risk of 1-year mortality.
Antithrombotic therapy in conjunction with primary percutaneous coronary intervention (PPCI) reduces the risk of recurrent ischemic events and death in patients with ST-segment elevation myocardial infarction (STEMI), at the expense of an increase in iatrogenic bleeding complications (1,2). Major bleeding complications in patients undergoing percutaneous coronary intervention (PCI) and in patients with acute coronary syndromes are associated with short-term mortality and morbidity, prolonged length of stay, and greater resource consumption (3–5). Consequently, inclusion of bleeding as a safety endpoint in randomized controlled trials has become pivotal for the assessment of new antithrombotic agents and interventional techniques. In previous studies, a broad variety of bleeding classifications have been used to report hemorrhagic complications. This variety has hampered direct comparison of the incidence of bleeding complications across different trials or even within studies, because reported bleeding events may vary widely according to the bleeding definition applied (6).
BARC (Bleeding Academic Research Consortium) has recently developed a standardized hierarchical bleeding classification system (7). The prognostic value of BARC-defined bleeding complications was recently established in patients with non–ST-segment elevation acute coronary syndrome and in patients undergoing elective PCI but has not been investigated in high-risk patients, such as in those with STEMI (8). Furthermore, it is of particular interest to investigate the prognostic impact of the individual data elements that comprise the BARC and other bleeding classifications because this might contribute to further optimizing bleeding definitions (9,10). Therefore, the aim of the present study was: 1) to investigate the relationship of BARC bleeding with 30-day and 1-year mortality; 2) to investigate how the BARC bleeding definition compares with existing bleeding definitions with regard to mortality prediction; and 3) to investigate the incidence and prognostic value of the separate bleeding data elements that comprise the bleeding definitions.
Source population and procedures
The data analyzed in this study were obtained from STEMI patients accepted for PPCI at the Academic Medical Center, University of Amsterdam, between January 1, 2003, and July 31, 2008. The study complied with the principles of the Declaration of Helsinki, and the local ethics committee approved the study protocol. In general, patients qualified for PPCI if they had typical ischemic chest pain and at least a 1-mm ST-segment elevation in 2 or more contiguous leads, a new left bundle branch block, or a true posterior myocardial infarction. Patients received a standard 300- to 600-mg loading dose of clopidogrel. If a coronary stent was implanted, clopidogrel was prescribed for at least 1 month to patients with a bare metal stent and for 6 to 12 months to patients with a drug-eluting stent. Patients were routinely pretreated with 300 mg of aspirin and 5,000 IU of unfractionated heparin. An additional heparin bolus was administered at the catheterization laboratory if necessary to achieve a targeted activated clotting time of 300 s followed by an infusion of 12 U/kg/h with titration to achieve a target activated partial thromboplastin time (aPTT) of 1.5 to 2.0 times the control. Glycoprotein IIb/IIIa inhibitors were used at the discretion of the operator.
Procedural and angiographic data were prospectively collected and entered into a dedicated database by interventional cardiologists and specialized nurses. Chart review for consecutive STEMI patients with available aPTT measurements was performed in the context of a study designed to investigate the relationship between aPTT and clinical outcome in STEMI patients treated with PPCI. A detailed description of the study protocol has been published previously (11). Source documentation (laboratory results, discharge letters, case history, and nurse reports) was collected for every hospital admission for each patient in both the PCI center and in referring hospitals and was assessed for the occurrence of clinical events, including hemorrhage. Follow-up information regarding vital status was obtained from computerized, long-term mortality records from the Dutch National Death Index between January 1, 2012, and April 30, 2012.
Study Design, Bleeding Definitions, and Adjudication
The study cohort consisted of all STEMI patients included in our study database who were alive at the end of the procedure. The primary outcome of this study was 1-year all-cause mortality. All hospitalizations were reviewed for the presence of bleeding by 1 author (W.J.K.) who had full access to the patient's clinical and laboratory records. Complicated cases were discussed and adjudicated with 2 other authors (J.G.P.T. and J.P.S.H.). For each bleeding event, the following items were recorded in the study database: the date and source of the bleeding, the hemoglobin decrease associated with the bleeding event (adjusted for the amount of transfusions), the amount of blood transfusions attributable to the bleeding event, the discontinuation of antithrombotic therapy associated with bleeding (as well as the use of aspirin, thienopyridine, vitamin K antagonists, heparin, and glycoprotein IIb/IIIa inhibitors before and after the bleeding was recorded), use of diagnostic procedures (including imaging techniques), surgery to control bleeding, the use of vasoactive agents for bleeding, and other medical and nonmedical interventions. In addition, for all patients who underwent coronary artery bypass graft (CABG), we recorded the need for reoperation because of bleeding after closure of the sternum, the amount of blood transfusions within a 48-h window post-CABG, and the chest tube output in the first 24 h after CABG.
Bleeding events occurring during the initial hospitalization were assessed and classified according to TIMI (Thrombolysis In Myocardial Infarction), GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries), ISTH (International Society on Thrombosis and Haemostasis), and BARC criteria (7,12–14). A detailed description of these bleeding classifications is given in Online Table 1. If a patient experienced multiple in-hospital bleeding events, the most severe was classified rather than the first event. The occurrence of BARC type 1 bleeding was not considered in the present paper.
For each bleeding classification, 1-year mortality rates for the various bleeding categories were estimated using Kaplan-Meier analyses. A landmark was set at 30 days. BARC type 5 bleeding (fatal bleeding) was not assessed as a separate bleeding category because it is not possible to associate fatality itself with mortality. To ensure a fair comparison with the other bleeding classifications, patients with fatal bleedings were excluded from the analyses. We calculated hazard ratios for 1-year mortality for the different bleeding categories of the TIMI, ISTH, GUSTO, and BARC bleeding classifications by using univariable and multivariable Cox regression analyses adjusting for baseline predictors of mortality. To identify baseline variables with a significant unadjusted association with 1-year mortality, univariable Cox regression analyses were first performed for the variables listed in Tables 1 and 2 (with the exception of in-hospital hemoglobin decrease and procedural data specific to CABG). To identify independent baseline predictors of 1-year mortality, we next performed a stepwise backward selection Cox regression analysis including variables with a significant association according to univariable analysis (p < 0.10). The entry criterion was set at p < 0.05, and the exit criterion was set at p = 0.10.
The increased discriminative value of the models after addition of in-hospital bleeding (according to the different bleeding definitions) to the baseline predictors of 1-year mortality was estimated by using 3 measures: change in Harrell's c-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) (15,16). Bootstrapping (400 runs) was used to compare these measures among the different multivariable models. To investigate the prognostic value of the individual data elements of the different bleeding classifications for 1-year mortality, we developed additional Cox models. Details regarding these models are described in the Online Appendix.
Data were complete for mortality and for 19 of 40 variables. Missing patient-level covariates were assumed to be missing at random and were imputed with the use of multiple imputations. The imputation procedure and subsequent Cox proportional hazards regression estimation, estimation of Harrell's c-index, NRI, and IDI were performed according to Rubin's protocol (17,18). Analyses were performed with SPSS version 19.0 (IBM SPSS Statistics, IBM Corporation, Armonk, New York) and R (R Foundation for Statistical Computing, Vienna, Austria).
Of the 2,009 STEMI patients recorded in our database, 7 patients died during the index PPCI. Baseline, procedural, and angiographic characteristics of the remaining 2,002 patients included in the present analysis are given in Tables 1 and 2. A total of 596 (29.8%) were women, and 277 (13.8%) had diabetes. Their mean age was 62 years, median total ischemic time was 3 h, and cardiogenic shock was present in 7.7% of patients. Sixty-two patients underwent CABG during the index admission. Of the 1,938 patients who did not undergo CABG and in whom hemoglobin measurements were available, 389 (20.1%) had a decrease in hemoglobin of at least 3 g/dl; 143 (36.8%) of these patients had no observed blood loss. The incidence of BARC bleeding types is shown in Table 3. Incidence of in-hospital bleeding complications according to other bleeding definitions is shown in Table 4. Of the 62 patients who underwent CABG during the index admission, 27 (43.5%) developed BARC type 4 bleeding and 1 (1.6%) developed BARC type 5 bleeding. In patients with BARC type 4 bleeding, the median amount of days from presentation until CABG was 0 (interquartile range: 0 to 6), whereas in patients without CABG-related bleeding, the median amount of days until CABG was 6 (interquartile range: 1.5 to 13).
Prognostic value of bleeding complications according to the different bleeding definitions
One-year survival status was complete in 1,997 patients (99.8%). Multivariable predictors of 1-year mortality determined by using a stepwise backward selection Cox proportional hazards model are shown in Online Table 2. Figure 1 presents Kaplan-Meier curves for 1-year mortality according to the different bleeding classifications (with a landmark set at 30 days). Table 3 presents the 30-day and 1-year mortality rates for the separate BARC bleeding types. In patients undergoing CABG during the index admission, 1-year mortality was 25.9% among those who developed BARC type 4 bleeding and 5.9% among those who did not. Table 4 shows 1-year mortality rates and unadjusted and adjusted hazard ratios for 1-year mortality according to the different bleeding classifications. Online Table 3 presents the 30-day mortality rates and unadjusted and adjusted hazard ratios for 30 days' mortality according to the different bleeding classifications. Bleeding complications were associated with higher cumulative mortality, irrespective of the applied bleeding definition. However, after adjustment for baseline predictors of mortality, only TIMI major bleeding and BARC type 3b or 3c bleeding continued to be associated with a higher risk of 1-year mortality. Figure 2 displays the rates of temporary and indefinite cessation of antithrombotic therapy in response to bleeding according to the different BARC types.
Predictive value of bleeding complications according to different bleeding definitions
The predictive value of the multivariable model including baseline predictors was excellent (Harrell's c-index: 0.836). Adjusted receiver-operating characteristic curves for the multivariable models, including the baseline predictors of mortality and bleeding complications according to the different bleeding definitions, are shown in Figure 3. There was no statistically significant improvement in Harrell's c-index after addition of any of the bleeding scales to the multivariable model (Table 5). Nevertheless, classification of patients who died or were alive at 1-year follow-up significantly improved after addition of either TIMI (NRI: 0.222), ISTH (NRI: 0.339), GUSTO (NRI: 0.305), or BARC (NRI: 0.181) to the multivariable model with baseline predictors of mortality. However, the IDIs of the multivariable models including TIMI, ISTH, and BARC bleeding complications were below zero, indicating that the improvement in predicted probability of those correctly reclassified was smaller than the worsening in predicted probability of those incorrectly reclassified. Online Table 4 presents Harrell's c-indices, NRIs, and IDIs of the multivariable models for 30-day mortality.
Prognostic value of the individual data elements of bleeding definitions
Table 6 displays the incidence, mortality rates, and unadjusted and adjusted hazard ratios for 1-year mortality of the individual data elements of the BARC, TIMI, GUSTO, and ISTH bleeding classifications. Bleeding complications with a large hemoglobin decrease (≥5 g/dl) and bleeding complications resulting in the need for vasoactive agents were associated with a high risk of subsequent mortality, although the latter did not reach conventional statistical significance (p = 0.083). Intracranial and hemopericardial bleeding complications were associated with a high unadjusted mortality rate. For intracranial hemorrhage, a hazard ratio for 1-year mortality was not computable because there was only 1 patient with intracranial bleeding.
The main findings of the present analysis can be summarized as follows. First, the incidence of BARC types 2, 3, 4, and 5 bleeding was 4.4%, 14.2%, 1.4%, and 0.3%, respectively. Second, BARC type 3b or 3c bleeding and TIMI major bleeding were associated with a 2-fold higher risk of 1-year mortality. Addition of BARC, TIMI, GUSTO, or ISTH bleeding classifications to a multivariable model with baseline predictors of mortality improved the reclassification (NRI) but did not improve Harrell's c-index or the IDI of the multivariable models. Thus, the additive predictive value of bleeding beyond conventional cardiovascular risk factors is limited. Finally, data elements of bleeding definitions associated with high mortality were intracranial and hemopericardial bleeding, bleeding requiring the use of vasoactive agents, and bleeding complications associated with a large decrease in hemoglobin (≥5 g/dl).
Incidence of BARC-defined bleeding complications in STEMI
The incidence of the different BARC bleeding types reported in the present study was higher than those reported in a recently published pooled analysis of patients with stable and unstable coronary artery disease undergoing PCI (8). The fact that BARC-defined bleeding complications occur more frequently in STEMI patients compared with unstable angina/non–ST-segment elevation myocardial infarction patients or patients undergoing elective PCI is consistent with previous studies showing higher bleeding rates in STEMI patients according to traditional bleeding definitions (19). Factors contributing to the higher bleeding rate in STEMI patients include the emergent setting of PCI, greater prevalence of cardiogenic shock and renal failure, more aggressive antithrombotic therapy, and use of an intra-aortic balloon pump for hemodynamic support (20). The lower BARC bleeding rates in the study by Ndrepepa et al. (8) can also be explained by the fact that their study population consisted of a clinical trial population, whereas the present study population consisted of a real-world patient cohort. These real-world populations generally consist of a sicker population compared with those of randomized controlled trials (21).
Comparison of the prognostic value of bleeding events according to the BARC, TIMI, GUSTO, and ISTH bleeding classifications
Consistent with the study by Ndrepepa et al. (8), we found mortality to be increasing with increasing BARC type. Regardless of the applied bleeding classification, in-hospital bleeding was associated with mortality according to univariable analysis, but after multivariable adjustment, ISTH, GUSTO, TIMI minor, and BARC types 2, 3a, and 4 bleeding were no longer associated with 1-year mortality. Thus, most of the excess mortality in patients with bleeding could be explained by factors associated with high mortality in patients with bleeding, such as cardiogenic shock and acute renal insufficiency (22). Both TIMI major bleeding and BARC type 3b or 3c bleeding were associated with a 2-fold higher risk of 1-year mortality according to multivariable analysis. Both these definitions include bleeding with a hemoglobin decrease ≥5 g/dl, which was the data element with the strongest association with mortality. Both the BARC 3b and ISTH major bleeding definition include hemopericardial bleeding as a data element, and all bleeding definitions include intracranial hemorrhage as a data element. Clearly, intracranial and hemopericardial bleedings can have a direct fatal outcome (22,23). These bleeds are rare, however, and it is therefore possible that we could not demonstrate a significant relationship between these bleeding complications and subsequent mortality. BARC type 3b bleeding is also defined by the use of vasoactive agents to control hypotension. Although nonsignificant by conventional statistical standards, this data element was associated with a 2-fold higher risk of mortality in the present study. It is conceivable that this data element identifies bleeds characterized by severe blood loss, and it is intuitive that this condition is associated with high mortality (24,25). Interestingly, bleeding resulting in hemodynamic compromise but not requiring the use of intravenous vasoactive agents (part of the GUSTO severe bleeding definition) was not associated with mortality. This finding suggests that bleeding complications which could be stabilized without the need for inotropes are not associated with mortality. Data elements that identified smaller bleeding complications (e.g., bleeding complications with a modest declines in hemoglobin [between 2 and 5 g/dl]) were not associated with mortality. This is consistent with the ExTRACT–TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment–Thrombolysis In Myocardial Infarction 25) study in which a TIMI minor bleeding (hemoglobin decrease of 3 to 5 g/dl) was not associated with mortality (22).
Bleeding definitions in the context of STEMI
BARC type 3b is defined by blood loss resulting in hemodynamic compromise requiring the use of vasoactive agents. Up to 5% to 8% of STEMI patients undergoing PPCI (7.7% in the present study) develop cardiogenic shock, and these patients are often treated with intravenous vasoactive agents (26). When a patient with cardiogenic shock treated with intravenous vasoactive agents coincidentally develops a bleeding complication, it can be challenging to determine whether the vasoactive agents were administered for cardiogenic shock or for the bleeding complication, or for both. Thus, in the setting of PPCI for STEMI, the association between BARC type 3b bleeding and mortality may be confounded by the prescription of vasoactive agents for cardiogenic shock. Likewise, a hemoglobin decrease not related to bleeding occurs frequently in STEMI patients, especially in patients with cardiogenic shock and patients admitted to an intensive care unit (27–29). In the present study, up to 20% of patients had a hemoglobin decrease of at least 3 g/dl, and almost 40% of these patients had no observed blood loss. Possible explanations for the hemoglobin decrease in these patients include hemodilution, frequent blood sampling, and treatment with nitroglycerin (27–32). In critically ill STEMI patients admitted to an intensive care unit who experience a hemoglobin drop caused by the aforementioned nonbleeding causes and who coincidentally develop minor bleeding (e.g., an access site hematoma <5 cm in diameter), one cannot determine whether the hemoglobin decrease was the result of bleeding or of nonbleeding causes. Consequently, in the setting of STEMI, the high mortality after bleeding with a large hemoglobin decrease (≥5 g/dl) can be attributed in part to the high mortality of critically ill STEMI patients with a hemoglobin decrease not related to bleeding.
Prognostic value of CABG-related bleeding
We found that as many as 45% of patients undergoing CABG during the index admission developed a BARC- or TIMI-defined, CABG-related bleeding event (of which 1 was fatal). Thus, in patients undergoing CABG in whom dual or triple antiplatelet therapy often cannot be discontinued in a timely manner before surgery, the occurrence of CABG-related bleeding is a frequent complication. Mortality was 4 to 5 times higher in those who experienced a CABG-related bleed compared with those undergoing CABG without bleeding. Most of the patients who developed a CABG-related bleeding event underwent CABG on the day of presentation (i.e., they underwent emergency CABG), whereas those who did not develop a CABG-related bleed underwent CABG in a more elective setting. After adjustment for timing of CABG and other confounders, in-hospital CABG-related bleeding was no longer associated with mortality. Therefore, it is likely that the high mortality after CABG-related bleeding is at least in part attributable to the high-risk circumstances associated with emergency CABG and to the indication for which patients underwent emergency CABG (e.g., ongoing ischemia, cardiogenic shock, PCI failure, mechanical complications) (33).
Data collection occurred retrospectively. Prospective evaluation of the BARC bleeding classification might have yielded systematic serial hemoglobin measurements. However, we had at least 2 hemoglobin measurements in >1,900 of 2,002 patients. In addition, we believe that in patients with observed blood loss, physicians are more inclined to perform frequent hemoglobin measurements because this test is clinically indicated. Therefore, ample hemoglobin measurements were available in those with bleeding complications. Source documentation available for adjudication of events consisted of data recorded as part of routine clinical care. Prospective data collection might have yielded better source documentation to better classify BARC bleeding complications. Nevertheless, even in prospective studies, many bleeding complications occur in local (referring) hospitals (or in other settings) where the trial protocol often is not applied and the source documentation available to the clinical event committee consists of data collected in the setting of routine clinical care.
The present analysis demonstrated a significant 2-fold higher risk of 1-year mortality after BARC type 3b or 3c bleeding or TIMI major bleeding in STEMI patients undergoing PPCI. This high risk, however, did not translate into a substantial improvement in overall measures of mortality prediction. ISTH- and GUSTO-defined bleeding complications were not significantly associated with mortality. Data elements associated with high mortality were intracranial or hemopericardial bleeding, bleeding requiring the use of intravenous vasoactive agents, and bleeding resulting in a large decrease in hemoglobin levels.
The authors greatly acknowledge the staff of the Departments of Cardiology of the following hospitals for their assistance during data collection (alphabetical order): BovenIJ Ziekenhuis, Bronovo, Diakonessenhuis Utrecht, Flevoziekenhuis, Gelre Ziekenhuizen, Gemini Ziekenhuis, HagaZiekenhuis, Kennemer Gasthuis, MC Zuiderzee, Meander Medisch Centrum, Medisch Centrum Alkmaar, Medisch Centrum Haaglanden, Onze Lieve Vrouwe Gasthuis, Rode Kruis Ziekenhuis Beverwijk, Sint Lucas Andreas Ziekenhuis, Slotervaartziekenhuis, Spaarne Ziekenhuis, St. Antonius Ziekenhuis, Tergooiziekenhuizen, Vrije Universiteit Medisch Centrum, Westfriesgasthuis, Ziekenhuis Amstelland, and Zuwe Hofpoort Ziekenhuis.
This work was supported by The Nuts OHRA Foundation (SNO-T-0702-61). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- activated partial thromboplastin time
- Bleeding Academic Research Consortium
- coronary artery bypass graft
- Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries
- integrated discrimination improvement
- International Society on Thrombosis and Haemostasis
- net reclassification improvement
- percutaneous coronary intervention
- primary percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- Thrombolysis In Myocardial Infarction
- Received November 7, 2013.
- Revision received January 14, 2014.
- Accepted January 17, 2014.
- American College of Cardiology Foundation
- ↵(2002) Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324:71–86.
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