CLINICAL RESEARCH: COAGULATION
A Comparison of the Clinical Impact of Bleeding Measured by Two Different Classifications Among Patients With Acute Coronary Syndromes
Sunil V. Rao, MD*,*,
Kristi O’Grady, MS*,
Karen S. Pieper, MS*,
Christopher B. Granger, MD, FACC*,
L. Kristin Newby, MD, MHS, FACC*,
Kenneth W. Mahaffey, MD, FACC*,
David J. Moliterno, MD, FACC ,
A. Michael Lincoff, MD, FACC ,
Paul W. Armstrong, MD, FACC ,
Frans Van de Werf, MD, FACC||,
Robert M. Califf, MD, FACC* and
Robert A. Harrington, MD, FACC*
* Duke Clinical Research Institute, Durham, North Carolina
University of Kentucky, Lexington, Kentucky
Cleveland Clinic Foundation, Cleveland, Ohio
University of Alberta, Edmonton, Alberta, Canada
|| Universitaire Ziekenhuizen Leuven, Leuven, Belgium.
Manuscript received February 17, 2005;
revised manuscript received August 26, 2005,
accepted September 9, 2005.
* Reprint requests and correspondence: Dr. Sunil V. Rao, The Duke Clinical Research Institute, P.O. Box 17969, Durham, North Carolina 27715. (Email: sunil.rao{at}duke.edu).
 |
Abstract
|
|---|
OBJECTIVES: The goal of this study was to determine the association between Thrombolysis In Myocardial Infarction (TIMI) and Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding and clinical outcomes.
BACKGROUND: There are limited data on the relative utility of either scale at predicting clinical outcomes in patients with non–ST-segment elevation acute coronary syndromes (ACS).
METHODS: Pooled data from two randomized trials of patients with ACS (n = 15,454) were analyzed to determine the association between TIMI and GUSTO bleeding and 30-day and 6-month death/myocardial infarction (MI) using Cox proportional hazards modeling that included bleeding as a time-dependent covariate.
RESULTS: There was a stepwise increase in the adjusted hazard of 30-day death/MI with worsening GUSTO bleeding (hazard ratio [95% confidence interval], GUSTO mild 1.20 [1.05 to 1.37]; moderate 3.28 [2.88 to 3.73]; severe 5.57 [4.33 to 7.17]), and an increased risk with all three levels of TIMI bleeding (TIMI minimal 1.84 [1.63 to 2.08]; TIMI minor 1.64 [1.31 to 2.04]; major 1.45 [1.23 to 1.70]). When both bleeding scales were included in the same model, the risk with GUSTO bleeding persisted; however, the association between TIMI bleeding and outcome was no longer significant.
CONCLUSIONS: Both scales identify ACS patients with bleeding complications at risk for adverse outcomes. In a model that included both definitions, the risk with GUSTO bleeding persisted while the risk with TIMI bleeding did not. This suggests that bleeding assessed with clinical criteria is more important than that assessed by laboratory criteria in terms of outcomes. Future clinical trials should consider using a combination of the GUSTO bleeding scale and the need for transfusion to assess bleeding complications.
|
Abbreviations and Acronyms
| | ACS = acute coronary syndrome | | CABG = coronary artery bypass grafting | | GUSTO = Global Use of Strategies to Open Occluded Coronary Arteries | | MI = myocardial infarction | | PARAGON = Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network trial | | PURSUIT = Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy trial | | TIMI = Thrombolysis In Myocardial Infarction |
|
Contemporary therapy for the treatment of acute ischemic heart disease includes anti-thrombotic medications and the use of early invasive risk stratification (1). While this combination of treatments has improved the outcomes of patients with acute coronary syndromes (ACS), the risk of bleeding remains a significant issue (2,3). Cognizant of this fact, clinical investigators systematically identify bleeding events that occur during the course of randomized clinical trials. Although guidelines exist for classifying bleeding events (4), many clinical trials utilize one of two bleeding classifications: the Thrombolysis In Myocardial Infarction (TIMI) classification, and/or the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) classification. The existence of these two systems often leads to disparities in the reported incidence of bleeding events within the same clinical trial. For example, in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, the rate of TIMI major bleeding among patients assigned to the platelet inhibitor eptifibatide was 3.0%, yet the rate of GUSTO severe bleeding in this same group was 1.1%. Moreover, the proportion of patients receiving eptifibatide deemed to have no TIMI bleeding was 84.2%, but the proportion deemed to have no GUSTO bleeding was 68.8%. There are limited data on the relative merits of either scale at predicting clinical outcomes. We analyzed data from two large multicenter randomized clinical trials to compare the association between the different degrees of in-hospital TIMI and GUSTO bleeding and short- and intermediate-term clinical outcomes.
|
Methods
|
|---|
Patient population and treatments.
Clinical data from the multicenter international PURSUIT trial (n = 10,798) and the Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON) B trial (n = 5,225) were pooled. The details of the trials have been published elsewhere (5,6). Briefly, patients with acute non–ST-segment elevation ACS enrolled in the PURSUIT trial were randomly assigned to receive the intravenous glycoprotein IIb/IIIa inhibitor eptifibatide or placebo. Patients with non–ST-segment elevation ACS enrolled in the PARAGON B trial were randomly assigned to receive the intravenous glycoprotein IIb/IIIa inhibitor lamifiban or placebo. For the current study, the analysis was limited to the patients from the two trials that had complete data on end points.
Concomitant treatment with aspirin (dose ranges between 80 and 325 mg daily) and antithrombin agents was recommended by protocol in both trials. The use of other medications and procedures was at the discretion of the treating physicians.
Definitions and end points.
Bleeding
The TIMI bleeding classification is a laboratory-based scale (7) while the GUSTO bleeding classification is a clinically based scale (8) (Table 1). The TIMI definition of bleeding uses four categories: major, minor, minimal, and none. The GUSTO bleeding definition also uses four categories: severe or life-threatening, moderate, mild, and none. The PURSUIT investigators used both definitions to classify bleeding events. The PARAGON investigators defined bleeding complications as major or life-threatening, and intermediate. Major or life-threatening bleeding was defined as any intracranial hemorrhage or bleeding leading to hemodynamic compromise requiring intervention. Intermediate bleeding was defined as bleeding requiring transfusion or a decrease in hemoglobin 5 g/dl or more (or decrease in hematocrit  15% when hemoglobin was unavailable). For the purpose of this analysis, the TIMI and GUSTO classifications were reconstructed from the detailed clinical data ().
Data on the date, time, severity, and location (including "unidentifiable") of each in-hospital bleeding event were collected prospectively. Detailed clinical data, including treatments (such as blood transfusion), baseline, and nadir hemoglobin or hematocrit values after each bleeding event, and hemodynamic status during each bleeding event, were collected on all patients in both trials. For patients who experienced more than one bleeding episode, only the most severe bleeding episode was considered.
End points
The primary end point of our study was the occurrence of death or recurrent myocardial infarction (MI) at 30 days. The secondary end point was the occurrence of death or recurrent MI at six months. Myocardial infarction was defined according to the protocol of each trial (5,6). All death and MI events for each trial were adjudicated by an independent blinded events committee.
Statistical analysis.
Patients were grouped according to the presence or absence of a bleeding event. Patients who experienced a bleeding event were further classified based on bleeding severity according to the TIMI and GUSTO scales. Categorical variables are expressed as percentages, and continuous variables are expressed as medians and interquartile ranges. Baseline characteristics were compared using chi-square tests for categorical variables and the non-parametric Kruskal-Wallis test for continuous variables. Baseline differences with p values <0.01 were considered significant.
We compared unadjusted rates of the primary and secondary end points among patients with no bleeding and those within the various categories of TIMI and GUSTO bleed severity. To determine the association between bleeding severity as defined by the two scales and the primary and secondary outcomes, we constructed separate models for each bleeding definition. Because bleeding is a post-randomization event that can change over time, and can influence and be influenced by treatments (e.g., procedures) and adverse events (e.g., MI), both models incorporated bleeding as a time-dependent covariate in a Cox regression. This technique minimizes confounding by considering only those bleeding events that transpired before the occurrence of the end points (9). Variables entered into both models were based on a comprehensive set of baseline variables from a validated model of outcome among patients with non–ST-segment elevation ACS (10) (c-index = 0.81) and included patient characteristics, presenting signs and symptoms, and treatments, including blood transfusion.
The first model incorporated TIMI bleed severity as a time-dependent covariate and used "no TIMI bleeding" as the reference. The second model incorporated GUSTO bleed severity as a time-dependent covariate and used "no GUSTO bleeding" as the reference. Due to the potential influence of blood transfusion on outcomes (11), we repeated the analysis after adjusting for transfusion by creating a dichotomous time-dependent variable that coded transfusion of at least 1 U of blood. We also repeated the analysis by constructing a model that included both bleeding scales as time-dependent covariates. Additional models were generated to evaluate the effect of each bleed scale in the presence or absence of the other scale. The models were adjusted for baseline covariates and included the scale of interest (e.g., the GUSTO scale) plus an indicator for any bleed according to the other scale (e.g., any type of TIMI bleed) versus no bleed according to the other scale (e.g., no TIMI bleed of any sort). Another set of models included the interaction of these two variables. Because coronary artery bypass surgery (CABG) can influence the severity of bleeding as well as outcomes, we repeated the analysis again for the entire patient cohort with censoring at the time of CABG. Finally, we used interaction terms to explore the effect of patient age, gender, weight, and renal function on TIMI and GUSTO bleeding levels in predicting short- and intermediate-term death or MI. All analyses were performed using SAS Version 8.2 (SAS Institute, Cary, North Carolina).
Ethics of protocol.
The institutional review boards of all participating institutions reviewed and approved the protocols of the PURSUIT and PARAGON B trials. All enrolled patients gave written informed consent.
|
Results
|
|---|
Timing of events and baseline characteristics.
A total of 15,454 patients from the two trials had complete data on end points. Among patients with a bleeding event, the median time from randomization to the most severe TIMI bleeding event was 1.0 days (25th, 75th percentile: 1.0, 2.0). The median time to the most severe GUSTO bleeding event was 2.0 days (1.0, 6.0). The median times to PCI and CABG procedures were 3.8 days (1.2, 9.8) and 9.9 days (4.1, 30.3), respectively. There were 1,151 patients who met criteria for GUSTO bleeding that did not meet criteria for TIMI bleeding, and 765 patients who met criteria for TIMI bleeding that did not meet criteria for GUSTO bleeding. There were 3,758 patients who met criteria for both TIMI and GUSTO bleeding.
With regard to TIMI bleeding, 12.7% of patients experienced a TIMI minimal bleed, 8.5% of patients experienced a TIMI minor bleed, and 8.2% experienced a TIMI major bleed. Table 1 shows the baseline characteristics of the patients who developed TIMI bleeding by the severity of the bleeding event. There were significant differences in baseline characteristics across the TIMI bleeding categories so that patients with a TIMI minor bleed were older, more often of non-white race and female, more often had cardiac risk factors, and were sicker at presentation compared with those having either a TIMI minimal or major bleed. In addition, a higher proportion of patients with TIMI minor bleeding had undergone in-hospital PCI compared with those with TIMI minimal or major bleeding. In contrast, a higher proportion of patients who experienced a TIMI major bleed had prior hyperlipidemia, prior MI, prior congestive heart failure, and prior stroke. A higher proportion of patients with TIMI minimal bleeding had undergone cardiac catheterization and CABG compared with those who experienced TIMI minor or major bleeding. Approximately one-third of the patients with TIMI minimal, minor, and major bleeding underwent blood transfusion during the hospitalization. Significantly more patients with TIMI bleeding who underwent CABG were transfused compared with patients with TIMI bleeding who did not undergo CABG (18% vs. 4.6%, p < 0.001).
The proportion of patients with GUSTO mild, moderate, and severe bleeding was 19.2%, 11.4%, and 1.2%, respectively. Table 2 shows the baseline characteristics of patients by worsening GUSTO bleed severity. As the GUSTO bleeding severity worsened, there was a gradient of increasing age, increasing proportion of patients of non-white race, and an increasing proportion of patients with hypertension, diabetes mellitus, prior MI, prior stroke, prior PCI, chronic renal insufficiency, and patients presenting with higher Killip class and higher heart rate. Patients who experienced a GUSTO moderate bleed had undergone cardiac catheterization and/or CABG during hospitalization more often than those experiencing mild or severe bleed, while patients who experienced a GUSTO mild bleed had undergone PCI more often than those who experienced a moderate or severe bleed. Very few patients with GUSTO mild bleeding underwent blood transfusion while a large proportion of patients with GUSTO moderate and severe bleeding received blood transfusion. Significantly more patients with GUSTO bleeding who underwent CABG received transfusion compared with patients with GUSTO who did not undergo CABG (53.5% vs. 10.0%, p < 0.001).
View this table:
[in this window]
[in a new window]
|
Table 2. Baseline Characteristics of Patients by TIMI Bleeding Severity (Numbers Shown Are Percentages Unless Otherwise Noted)
|
|
Outcomes.
Tables 2 and 3 show the unadjusted rates of 30-day and 6-month death or MI for patients who experienced various levels of TIMI and GUSTO bleeding. After multivariable adjustment, there was a stepwise increase in the adjusted hazard of the primary and secondary end points as GUSTO bleeding severity worsened (Figs. 1A and 1B). There was also an increased adjusted risk with each level of TIMI bleeding, but the point estimates of the hazard ratios for each level of TIMI bleeding were similar to each other. After adjustment for blood transfusion, the stepwise increase in the risk of short- and intermediate-term outcomes with worsening GUSTO bleeding persisted; however, the association between TIMI bleeding severity and six-month adverse outcomes was no longer statistically significant (Figs. 2A and 2B). When both bleeding scales were included in the same model, the stepwise increase in the risk for 30-day and 6-month death or MI with worsening GUSTO bleeding was evident, but there was no significant increase in risk with any level of TIMI bleeding (Figs. 3A and 3B). The analysis was repeated with censoring at the time of CABG, and the results were nearly identical (data not shown). There were no significant interactions between patient age, gender, weight, or renal function and TIMI bleeding. There was a significant interaction between age and GUSTO moderate bleeding such that the increased risk of death or MI with GUSTO moderate bleeding was more pronounced among younger patients. There was a significant interaction between GUSTO and TIMI bleeding (p < 0.0001). The risk for the 30-day and 6-month end points for GUSTO bleeding without TIMI bleeding was higher than the risk with GUSTO bleeding with any degree of TIMI bleeding.
View this table:
[in this window]
[in a new window]
|
Table 3. Baseline Characteristics of Patients by GUSTO Bleeding Severity (Numbers Shown Are Percentages Unless Otherwise Noted)
|
|
View larger version (16K):
[in this window]
[in a new window]
|
Figure 1 (A) Adjusted hazard ratios of 30-day death or myocardial infarction (MI) by worsening Global Strategies for Opening Occluded Coronary Arteries (GUSTO) and Thrombolysis In Myocardial Infarction (TIMI) bleeding severity. Separate models constructed for each bleeding scale. Adjusted for age, gender, weight, site, diabetes mellitus, smoking status, prior angina, peripheral vascular disease, pre-randomization therapy, MI at enrollment, systolic blood pressure at randomization, diastolic blood pressure at randomization, heart rate at randomization, Killip class, and assigned treatment. (B) Adjusted hazard ratios for six-month death or MI by worsening GUSTO and TIMI bleeding severity. Separate models constructed for each bleeding definition. Separate models constructed for each scale. Adjusted for age, gender, weight, site, diabetes mellitus, smoking status, prior angina, peripheral vascular disease, pre-randomization therapy, MI at enrollment, systolic blood pressure at randomization, diastolic blood pressure at randomization, heart rate at randomization, Killip class, and assigned treatment.
|
|
View larger version (14K):
[in this window]
[in a new window]
|
Figure 2 (A) Hazard ratios of 30-day death or myocardial infarction (MI) by Global Strategies for Opening Occluded Coronary Arteries (GUSTO) and Thrombolysis In Myocardial Infarction (TIMI) bleeding severity after adjustment for blood transfusion. Separate models constructed for each scale. Adjusted for age, gender, weight, site, diabetes mellitus, smoking status, prior angina, peripheral vascular disease, pre-randomization therapy, MI at enrollment, systolic blood pressure at randomization, diastolic blood pressure at randomization, heart rate at randomization, Killip class, assigned treatment, and blood transfusion. (B) Hazard ratios of six-month death or MI by worsening GUSTO and TIMI bleeding severity after adjustment for blood transfusion. Separate models constructed for each scale. Adjusted for age, gender, weight, site, diabetes mellitus, smoking status, prior angina, peripheral vascular disease, pre-randomization therapy, MI at enrollment, systolic blood pressure at randomization, diastolic blood pressure at randomization, heart rate at randomization, Killip class, assigned treatment, and blood transfusion.
|
|
View larger version (13K):
[in this window]
[in a new window]
|
Figure 3 (A) Hazard ratios of 30-day death or myocardial infarction (MI) by worsening Global Strategies for Opening Occluded Coronary Arteries (GUSTO) and Thrombolysis In Myocardial Infarction (TIMI) bleeding severity after including both scales in the same model. Adjusted for age, gender, weight, site, diabetes mellitus, smoking status, prior angina, peripheral vascular disease, pre-randomization therapy, MI at enrollment, systolic blood pressure at randomization, diastolic blood pressure at randomization, heart rate at randomization, Killip class, assigned treatment, and blood transfusion. (B) Hazard ratios of six-month death or MI by worsening GUSTO and TIMI bleeding severity after including both scales in the same model. Adjusted for age, gender, weight, site, diabetes mellitus, smoking status, prior angina, peripheral vascular disease, pre-randomization therapy, MI at enrollment, systolic blood pressure at randomization, diastolic blood pressure at randomization, heart rate at randomization, Killip class, assigned treatment, and blood transfusion.
|
|
|
Discussion
|
|---|
Our study has several important findings. First, we have shown that both the GUSTO and TIMI bleeding scales identify patients at increased risk for adverse clinical events. This risk was manifest primarily within 30 days after the bleeding event. Second, we found that each scale identifies patients with bleeding events that are missed by the other scale. Third, after adjustment for blood transfusion, the stepwise increase in risk with worsening GUSTO bleeding persisted while the risk with TIMI bleeding was no longer statistically significant. Finally, when both bleeding definitions were included in the same model only GUSTO bleeding was associated with a worse prognosis. When exploring interaction terms between the two bleeding scales, we found that TIMI bleeding did not affect the risk among patients who also met criteria for GUSTO bleeding. This suggests that in terms of adverse outcomes, assessment of bleeding using clinical criteria is more important than using laboratory criteria.
Our study has important implications for both clinical care and clinical research. Both bleeding definitions were developed to classify bleeding complications of thrombolytic therapy (7,8), and have not been previously validated in the setting of non–ST-segment elevation ACS. Other investigators have explored the incidence and predictors of bleeding complications in this population (2,12,13), but the bleeding definitions used varied across studies, and outcomes were not specifically examined. Our results add to these previous studies by demonstrating that that bleeding complications, regardless of severity, are associated with worse clinical outcomes among patients with acute ischemic heart disease in whom thrombolytic therapy is not used. While this increased risk persisted for all levels of GUSTO bleeding even after adjusting for blood transfusion, it did not persist for TIMI bleeding after accounting for transfusion. Because one difference between the TIMI and GUSTO scales is whether transfusion is necessary, our results suggest that patients who experience TIMI bleeding who do not require transfusion (i.e., asymptomatic decreases in hemoglobin) are not at risk for adverse outcomes. Therefore, liberal use of blood transfusion in these patients may expose them to the risks of transfusion (11,14) without any clear benefit. These data also provide support for clinical practice guidelines that discourage the use of blood transfusions in patients who are clinically stable regardless of their nadir hemoglobin or hematocrit value (15).
Although our study is the first to provide evidence for the association between bleeding as measured by both the GUSTO and TIMI bleeding classifications and clinical outcomes in the setting of non–ST-segment elevation ACS, these definitions have been used either alone or in combination in cardiovascular clinical trials over the last two decades (5,16–24). This has resulted in wide variation in the rates of bleeding complications that have been reported with various antithrombotic agents. For example, in the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial of enoxaparin versus unfractionated heparin, the rate of TIMI major bleeding was 9.7% among patients assigned to enoxaparin, but the rate of GUSTO severe bleeding was only 2.7% (24). In the context of this disparity, our study suggests that the guidelines for measuring bleeding among patients with ACS (4) should be amended to include a more optimal metric—a combination of the clinically-based GUSTO scale and need for blood transfusion. Bleeding complications with limited prognostic value as determined by the laboratory-based TIMI scale may continue to have a role in guiding dosing decisions for new anticoagulants that are in development.
Study limitations.
Our study has some limitations. First, our study was not designed to evaluate the definitions of bleeding per se. Rather, we sought to delineate the association between bleeding defined by two of the most commonly used bleeding scales and clinical outcomes. Second, our results could be the result of ascertainment bias. The identification of TIMI bleeding events could be limited if hemoglobin or hematocrit values are not obtained. This could lead to an underestimation of the number of TIMI bleeds. Third, our study was a post-hoc analysis of pooled clinical trial data that was collected prospectively. Therefore, despite our robust statistical methods, there could be residual confounding. Fourth, we reclassified bleeding events from the PARAGON B trial into the relevant GUSTO and TIMI categories on the basis of the detailed clinical data that was available. Nevertheless, because PARAGON B used a definition of bleeding that was slightly modified from either the GUSTO or TIMI classification, this may limit our ability to draw firm conclusions on the relationship between both definitions and clinical outcomes. Fifth, despite the strength of the associations we found, we cannot definitively state causality between bleeding and death or MI due to the retrospective nature of our study. Finally, our study population was comprised of patients enrolled in clinical trials and may not be fully representative of patients seen in clinical practice (25). Because the study population did not include higher-risk patients, such as those who are older and have more comorbidities, the risks may be underestimated.
Conclusions.
In conclusion, the results of our study indicate that both the GUSTO and TIMI scales identify patients with bleeding complications who are at risk for short- and intermediate-term death or MI. However, after adjusting for transfusion and when both scales were included in the same model, the increased risk with worsening GUSTO bleeding persisted while the risk with TIMI bleeding did not. These results suggest that asymptomatic decreases in hemoglobin and/or hematocrit that do not require transfusion may not be associated with a worse prognosis. Therefore, the issue of whether asymptomatic decreases in hemoglobin or hematocrit require aggressive transfusion deserves further scrutiny. This study also suggests that a combination of the GUSTO scale and need for transfusion should be used to assess bleeding complications in subsequent clinical trials of patients with ACS.
|
Appendix
|
|---|
For the reconstruction of TIMI and GUSTO bleeding events from the PARAGON B dataset, please see the online version of this article.
|
Footnotes
|
|---|
This analysis was supported by the Duke Clinical Research Institute, Durham, North Carolina.
|
References
|
|---|
1. Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban N Engl J Med 2001;344:1879-1887.[Abstract/Free Full Text]2. Moscucci M, Fox KA, Cannon CP, et al. Predictors of major bleeding in acute coronary syndromesthe Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2003;24:1815-1823.[Abstract/Free Full Text] 3. Kinnaird TD, Stabile E, Mintz GS, et al. Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions Am J Cardiol 2003;92:930-935.[CrossRef][Web of Science][Medline] 4. Cannon CP, Battler A, Brindis RG, et al. American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes. A report of the American College of Cardiology task force on clinical data standards (Acute Coronary Syndromes Writing Committee) J Am Coll Cardiol 2001;38:2114-2130.[Free Full Text] 5. The PURSUIT Trial Investigators Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes: Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy N Engl J Med 1998;339:436-443.[Abstract/Free Full Text] 6. The PARAGON B Investigators Randomized, placebo-controlled trial of titrated intravenous lamifiban for acute coronary syndromes Circulation 2002;105:316-321.[Abstract/Free Full Text] 7. Chesebro JH, Knatterud G, Roberts R, et al. Thrombolysis In Myocardial Infarction (TIMI) trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge Circulation 1987;76:142-154.[Abstract/Free Full Text] 8. The GUSTO Investigators An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction N Engl J Med 1993;329:673-682.[Abstract/Free Full Text] 9. Fisher LD, Lin DY. Time-dependent covariates in the Cox proportional-hazards regression model Annu Rev Public Health 1999;20:145-157.[CrossRef][Web of Science][Medline] 10. Boersma E, Pieper KS, Steyerberg EW, et al. The PURSUIT Investigators Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients Circulation 2000;101:2557-2567.[Abstract/Free Full Text] 11. Rao SV, Jollis JG, Harrington RA, et al. The relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes JAMA 2004;292:1555-1562.[Abstract/Free Full Text] 12. Lenderink T, Boersma E, Ruzyllo W, et al. Bleeding events with abciximab in acute coronary syndromes without early revascularizationan analysis of GUSTO IV-ACS. Am Heart J 2004;147:865-873.[CrossRef][Web of Science][Medline] 13. Berkowitz SD, Stinnett S, Cohen M, Fromell GJ, Bigonzi F. Prospective comparison of hemorrhagic complications after treatment with enoxaparin versus unfractionated heparin for unstable angina pectoris or non–ST-segment elevation acute myocardial infarction Am J Cardiol 2001;88:1230-1234.[CrossRef][Web of Science][Medline] 14. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care N Engl J Med 1999;340:409-417.[Abstract/Free Full Text] 15. American College of Physicians Practice strategies for elective red blood cell transfusion Ann Intern Med 1992;116:403-406.[Abstract/Free Full Text] 16. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non–Q-wave myocardial infarction N Engl J Med 1998;338:1488-1497.[Abstract/Free Full Text] 17. Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina N Engl J Med 1998;338:1498-1505.[Abstract/Free Full Text] 18. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes N Engl J Med 1996;335:775-782.[Abstract/Free Full Text] 19. Gilchrist IC, Berkowitz SD, Thompson TD, Califf RM, Granger CB. Heparin dosing and outcome in acute coronary syndromes: the GUSTO-IIb experience. Global Use of Strategies to Open Occluded Coronary Arteries Am Heart J 2002;144:73-80.[CrossRef][Web of Science][Medline] 20. The EPIC Investigators Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty N Engl J Med 1994;330:956-961.[Abstract/Free Full Text] 21. The EPILOG Investigators Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization N Engl J Med 1997;336:1689-1696.[Abstract/Free Full Text] 22. The RESTORE Investigators Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplastyRandomized Efficacy Study of Tirofiban for Outcomes and REstenosis. Circulation 1997;96:1445-1453.[Abstract/Free Full Text] 23. The ESPRIT Investigators Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT)a randomised, placebo-controlled trial. Lancet 2000;356:2037-2044.[CrossRef][Web of Science][Medline] 24. The SYNERGY Trial Investigators Enoxaparin vs unfractionated heparin in high-risk patients with non–ST-segment elevation acute coronary syndromes managed with an intended early invasive strategyprimary results of the SYNERGY randomized trial. JAMA 2004;292:45-54.[Abstract/Free Full Text] 25. Lee PY, Alexander KP, Hammill BG, Pasquali SK, Peterson ED. Representation of elderly persons and women in published randomized trials of acute coronary syndromes JAMA 2001;286:708-713.[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
V. Serebruany, S. V. Rao, M. A. Silva, J. L. Donovan, A. O. Kannan, L. Makarov, S. Goto, and D. Atar
Correlation of inhibition of platelet aggregation after clopidogrel with post discharge bleeding events: assessment by different bleeding classifications
Eur. Heart J.,
October 23, 2009;
(2009)
ehp434v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-P. Bassand, R. Afzal, J. Eikelboom, L. Wallentin, R. Peters, A. Budaj, K. A.A. Fox, C. D. Joyner, S. Chrolavicius, C. B. Granger, et al.
Relationship between baseline haemoglobin and major bleeding complications in acute coronary syndromes
Eur. Heart J.,
October 12, 2009;
(2009)
ehp401v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
APPRAISE Steering Committee and Investigators
Apixaban, an Oral, Direct, Selective Factor Xa Inhibitor, in Combination With Antiplatelet Therapy After Acute Coronary Syndrome: Results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) Trial
Circulation,
June 9, 2009;
119(22):
2877 - 2885.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Mehran, S. J. Pocock, G. W. Stone, T. C. Clayton, G. D. Dangas, F. Feit, S. V. Manoukian, E. Nikolsky, A. J. Lansky, A. Kirtane, et al.
Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes: a risk model from the ACUITY trial
Eur. Heart J.,
June 2, 2009;
30(12):
1457 - 1466.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Z. Potsis, C. Katsouras, and J. A. Goudevenos
Avoiding and Managing Bleeding Complications in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes
Angiology,
April 1, 2009;
60(2):
148 - 158.
[Abstract]
[PDF]
|
|
|
|
|
|
|
C Pristipino, C Trani, M S Nazzaro, A Berni, G Patti, R Patrizi, B Pironi, P Mazzarotto, G Gioffre, G G L Biondi-Zoccai, et al.
Major improvement of percutaneous cardiovascular procedure outcomes with radial artery catheterisation: results from the PREVAIL study
Heart,
March 15, 2009;
95(6):
476 - 482.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Cohen
Expanding the Recognition and Assessment of Bleeding Events Associated With Antiplatelet Therapy in Primary Care
Mayo Clin. Proc.,
February 1, 2009;
84(2):
149 - 160.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T Kinnaird, R Anderson, J Hill, and M Thomas
Bleeding during percutaneous intervention: tailoring the approach to minimise risk
Heart,
January 1, 2009;
95(1):
15 - 19.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Marzocchi, A. Manari, G. Piovaccari, C. Marrozzini, S. Marra, P. Magnavacchi, P. Sangiorgio, L. Marinucci, N. Taglieri, G. Gordini, et al.
Randomized comparison between tirofiban and abciximab to promote complete ST-resolution in primary angioplasty: results of the facilitated angioplasty with tirofiban or abciximab (FATA) in ST-elevation myocardial infarction trial
Eur. Heart J.,
December 2, 2008;
29(24):
2972 - 2980.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. V. Rao and S. Y.H. Kim
Informing the Consent Process
Circ Cardiovasc Qual Outcomes,
September 1, 2008;
1(1):
7 - 8.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. J. Applegate, M. T. Sacrinty, M. A. Kutcher, F. R. Kahl, S. K. Gandhi, R. M. Santos, and W. C. Little
Trends in Vascular Complications After Diagnostic Cardiac Catheterization and Percutaneous Coronary Intervention Via the Femoral Artery, 1998 to 2007
J. Am. Coll. Cardiol. Intv.,
June 1, 2008;
1(3):
317 - 326.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-P. Bassand
Bleeding and transfusion in acute coronary syndromes: a shift in the paradigm
Heart,
May 1, 2008;
94(5):
661 - 666.
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. L. Dauerman
Percutaneous Coronary Intervention Pharmacology From a Triangle to a Square.
J. Am. Coll. Cardiol.,
February 19, 2008;
51(7):
698 - 700.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. B. Berger and S. V. Manoukian
Bleeding Is Bad.... Isn't It?
Circulation,
December 11, 2007;
116(24):
2776 - 2778.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. V. Rao, J. A. Eikelboom, C. B. Granger, R. A. Harrington, R. M. Califf, and J.-P. Bassand
Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes
Eur. Heart J.,
May 2, 2007;
28(10):
1193 - 1204.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. V. Manoukian, F. Feit, R. Mehran, M. D. Voeltz, R. Ebrahimi, M. Hamon, G. D. Dangas, A. M. Lincoff, H. D. White, J. W. Moses, et al.
Impact of Major Bleeding on 30-Day Mortality and Clinical Outcomes in Patients With Acute Coronary Syndromes: An Analysis From the ACUITY Trial
J. Am. Coll. Cardiol.,
March 27, 2007;
49(12):
1362 - 1368.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. W. Mahaffey and R. A. Harrington
Optimal Timing for Use of Glycoprotein IIb/IIIa Inhibitors in Acute Coronary Syndromes: Questions, Answers, and More Questions
JAMA,
February 14, 2007;
297(6):
636 - 639.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. W. Eikelboom and J. Hirsh
Bleeding and management of bleeding
Eur. Heart J. Suppl.,
October 1, 2006;
8(suppl_G):
G38 - G45.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. W. Eikelboom, S. R. Mehta, S. S. Anand, C. Xie, K. A.A. Fox, and S. Yusuf
Adverse Impact of Bleeding on Prognosis in Patients With Acute Coronary Syndromes
Circulation,
August 22, 2006;
114(8):
774 - 782.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods