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Predictors of Bleeding Risk and Long-Term Mortality in Patients With Acute Coronary Syndromes

Posted on: Tuesday, 10 May 2005, 03:00 CDT

Key words: Acute coronary syndromes - Bleeding - Mortality - Myocardial infarction - ST-segment elevation MI - Unstable angina

ABSTRACT

Objective: The aim of this review was to collate the published evidence on independent predictors of bleeding and late mortality in acute coronary syndrome (ACS) patients, to compare the two sets of risk factors, and to investigate whether bleeding is reported as a predictor of late mortality.

Research design and methods: Computerized searches, covering the period from 1999 to July 2004, were performed on MEDLINE, EMBASE, and the Cochrane Library database. Studies were eligible for inclusion in the review if they related to patients with ACS and included an assessment of risk factors for bleeding, mortality, or both. Studies that did not meet these criteria were excluded.

Main outcome measures: A total of 937 studies were retrieved, of which 912 were excluded from the review because they did not meet the defined criteria.

Results: The available evidence suggests that any impact of bleeding on mortality is confined to the short term. In studies that showed a significant association between bleeding and risk of mortality, this was always related to in-hospital or 30-day mortality. By contrast, studies of long-term mortality consistently showed that bleeding was not an independent predictor. Furthermore, follow-up studies showed that adverse outcomes in hospital and within the first month were not related to 1-year mortality. This may reflect the beneficial impact of anticoagulant therapy on subsequent cardiovascular risk in patients with ACS, which outweighs any short-term detrimental effect of bleeding.

Conclusions: The available evidence suggests that any impact of bleeding on mortality in ACS patients appears to be confined to the short term, and long-term outcomes do not reflect the impact of in- hospital bleeding.

Introduction

Patients with acute coronary syndrome (ACS), a condition which includes unstable angina (UA), non-STsegment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI), constitute a diverse group with widely varying risks of subsequent cardiovascular events1. Current evidence-based management guidelines1-3 recommend that all such patients should receive anticoagulant therapy, and emphasize the importance of risk stratification when planning treatment. Risk factors for cardiovascular events in ACS patients include recurrent angina or ischemia at rest, ST-segment depression, and elevated troponin or diabetes. Patients without such risk factors may require only medical stabilization with antianginal and anti-thrombotic therapy, whereas invasive revascularization may be warranted in those at higher risk1,2. However, high-risk patients may also have risk factors that predispose them to an increased risk of bleeding during anticoagulant therapy, including advanced age and renal insufficiency4, while revascularization procedures are themselves associated with an increased bleeding risk5,6. Thus, while effective anticoagulant therapy can reduce the risk of thrombosis in patients with ACS, this may need to be balanced against a possible increase in the risk of bleeding. The situation is further complicated by the fact that there is currently uncertainty as to whether an increased risk of bleeding is associated with poorer long-term survival in ACS patients5.

This paper presents a systematic review of recent studies that have reported risk factors for bleeding, late (≥ 6 months) mortality, or both, in patients with ACS. The aim of this review was to collate the published evidence on independent predictors of bleeding and late mortality, to compare the two, and to investigate whether bleeding is reported as a predictor of late mortality.

Methods

Computerized searches, covering the period from 1999 to July 2004, were performed on MEDLINE, EMBASE, and the Cochrane Library database. Two groups of terms and keywords were used: (1) ACS, acute coronary syndrome, PCI, CABG, AMI, acute myocardial infarction, STEMI, NSTEMI, UA, ST-segment elevation myocardial infarction, non- ST-segment elevation myocardial infarction, or unstable angina; (2) risk factors, bleeding, or mortality. Bibliographies of retrieved articles and congress proceedings were also searched to identify further relevant articles. 1999 was chosen as a start date as it was the time when the spectrum of ischemic heart disease was redefined as acute coronary syndromes.

Studies were eligible for inclusion in the review if they related to patients with ACS and included an assessment of risk factors for bleeding, mortality, or both. Studies that did not meet these criteria were excluded.

Results

A total of 937 studies were retrieved, of which 912 were excluded from the review because they did not meet the defined criteria. Details of the studies included in the review are summarized in Table 1.

All ACS patients

Five studies4-8 investigated risk factors for bleeding, and nine9- 17 investigated risk factors for late mortality, in patients with ACS. It should be noted that bleeding was not always considered as a risk factor when modeling the risk of mortality.

These studies identified a variety of risk factors for bleeding or mortality, with considerable overlap between the two (Tables 1 and 2). The most common risk factors for both bleeding and late mortality were age over 65 years, female sex, renal insufficiency, and the use of an intra-aortic balloon pump (IABP). In studies where odds ratios (ORs) were reported, these factors were associated with ORs of approximately 1.2-3.0 for bleeding, and 1.4-4.3 for late mortality.

The influence of bleeding on the risk of mortality was investigated in two studies using data from the Global Registry of Acute Coronary Events (GRACE)4,9. These studies showed that major bleeding was a significant predictor of in-hospital mortality (adjusted OR 1.64, 95% confidence interval [CI] 1.18-2.28)4, but not of 6-month mortality9.

Patients undergoing percutaneous coronary intervention

Six studies5,6,13,18-20 involved patients undergoing percutaneous coronary intervention (PCI). Age, renal insufficiency, use of an IABP, and procedural hypotension were found to be independent predictors of bleeding during PCI, with reported ORs of 1.9-3.0 for bleeding and 1.05-3.9 for mortality. In the one study which evaluated bleeding as a risk factor for mortality, major bleeding was found to be an independent predictor of inhospital mortality, with an OR of 3.5 (95% CI 1.9-6.7, p < 0.0001)5. There was, however, no association between bleeding and 1-year mortality. Independent predictors of long-term mortality included age, renal insufficiency, a history of congestive heart failure or angina, and diabetes mellitus, which were associated with an OR of 1.05-3.10 at 1 year)18. In addition, age, a history of congestive heart failure, and diabetes remained highly significant (p < 0.0001) predictors of mortality at 3 years19.

Patients undergoing coronary artery bypass grafting

Two studies21,22 reported risk factors for mortality or bleeding in patients undergoing coronary artery bypass grafting (CABG). Only one of these investigated risk factors for bleeding. This study found that increasing age (OR 1.03, 95% CI 1.01-1.05, p = 0.041), body mass index below 25 kg/m^sup 2^ (OR 2.1, 95% CI 1.3-3.5, p = 0.003), nonelective surgery (OR 1.7, 95% CI 1.1-2.8, p = 0.022) and five or more distal anastomoses (OR 1.8, 95% CI 1.1-3.0, p = 0.035) were significant predictors of bleeding22. The risk factors for late mortality were similar to those in patients undergoing PCI and included age, diabetes, hypertension, and a history of myocardial infarction or heart failure. The OR associated with these risk factors was 0.8-2.42 at 1 month, and 1.1-1.5 at 6 months and beyond21. One study concluded that although females have worse outcome, it is the overall prevalence of risk factors, rather than sex, which determines the risk of mortality, and that there were no significant differences in mortality between men and women after adjustment for other risk factors (OR 0.9, p = 0.573)21.

Patients with UA or NSTEMI

Five reports16,17,23-25 were confined to patients with UA or NSTEMI (i.e. patients without persistent ST-segment elevation). With the exception of one report from the PURSUIT (Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy) study17, none of these investigated risk factors for bleeding. Significant predictors of mortality in patients with UA or NSTEMI included age, previous myocardial infarction or angina, and diabetes, which were generally associated with ORs of 1-2. In the PURSUIT study, risk factors for bleeding or 30-day mortality included previous CABG or percutaneous transluminal coronary angioplasty (PTCA), the use of an IABP, and thrombocytopenia17. The presence of moderate or severe bleeding was a significant predictor of mortality or myocardial infarction at 30 days (OR 2.0, 95% CI 1.6- 2.5)17. A further study in patients treated with the low-molecular- weight heparin (LMWH) enoxaparin showed that low anti-Xa activity (< 0.5 IU/mL) was as powerful a predictor of 30-day mortality as age, left ventricular dysfunction, and renal dysfunction, with an OR of 3.45 (95% CI 1.34-8.86) compared with patients with an anti-Xa activity in the target r\ange23. This finding underlines the fact that inadequate anticoagulation can result in a poor outcome in patients with ACS, and highlights the importance of careful consideration of both the bleeding risk and the risk of under- treatment.

Patients with STEMI

Six studies11,13,14,26-28 investigated patients with STEMI. These studies found that age, low body mass index, high Killip class, female sex, previous myocardial infarction, and diabetes were significant predictors of late mortality. In studies where ORs were reported, age, female sex, high Killip class and previous myocardial infarction were associated with ORs of 1.60-1.80(27,28). Two studies found that major bleeding was not an independent risk factor for late mortality13,27.

Discussion

The results of this systematic review appear to show that in patients with ACS the most common risk factors for both bleeding and late mortality are age over 65, female sex, renal insufficiency, and the use of an IABR Table 1 shows that the most common risk factors that were specific for bleeding were a history of bleeding and previous invasive procedures (CABG or PCI). For late mortality, the most common specific risk factors were diabetes, previous myocardial infarction, a history of heart failure, myocardial damage, and impaired ventricular function (as manifested by elevated cardiac enzymes), high Killip class, or low systolic blood pressure.

The available evidence suggests that any impact of bleeding on mortality is confined to the short term. In studies that showed a significant association between bleeding and risk of mortality, this was always related to in-hospital or 30-day mortality4,5,17,18. By contrast, studies of long-term mortality consistently showed that bleeding was not an independent predictor9,18. This may reflect the beneficial impact of anticoagulant therapy on subsequent cardiovascular risk in patients with ACS, which outweighs any short- term detrimental effect of bleeding. Data from UA/NSTEMI patients enrolled in the Thrombolysis in Myocardial Infarction (TIMI) 11B and Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and Non-Q-wave Myocardial Infarction (ESSENCE) studies suggested that the risk of major cardiovascular events (mortality, nonfatal myocardial infarction, or urgent revascularization) was highest during the 6 weeks after discharge from hospital, and that enoxaparin treatment significantly reduced the risk of such events during this period29. By contrast, a recent study has reported that major bleeding associated with excessive anticoagulation is a significant, independent predictor of mortality at 60 days30. This study, however, was performed in a consecutive series of hospitalized patients, and its generalizability to patients with ACS is uncertain. Nevertheless, such findings suggest that the risks associated with inadequate anticoagulation may outweigh any deleterious short-term effect of bleeding. Interestingly, a recent study of over 24 000 ACS patients enrolled in the GUSTOIIb, PURSUIT and PARAGON B studies has shown that blood transfusion in ACS patients appears to be an independent predictor of early mortality31. This is in contrast to other such studies. Clearly the relationship between disease severity, anemia, and outcome warrants further investigation.

The present study does have certain limitations, because it was a hypothesis-generating systematic review, rather than a prospective study, and, furthermore, of the studies included, not all collected or reported all necessary data. In addition, this is a qualitative systematic review limited to three databases and the studies included cover a wide range of designs, which makes comparisons difficult. Further prospective studies, and perhaps meta-analyses, are needed to establish the impact of excessive bleeding on long- term mortality in ACS patients.

Table 1. Summary of studies included in the review

Table 1. Summary of studies included in the review

Table 2. Risk factors for bleeding and late mortality in all ACS patients3-16

Conclusions

The available evidence suggests that any impact of bleeding on mortality in ACS patients appears to be confined to the short term, and long-term outcomes do not reflect an impact of in-hospital bleeding.

Acknowledgements

Supported by a grant from sanofi-aventis. The author would like to thank Jacqueline Mason for editorial help in preparing this manuscript.

References

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2. Bertrand ME, Simoons ML, Fox KA, et al. The Task Force on the Management of Acute Coronary Syndromes of the European Society of Cardiology. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2002;23:1809-40

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14. Stenestrand U, Wallentin L. Register of Information and Knowledge About Swedish Heart Intensive Care Admissions (RIKS-HIA). Fibrinolytic therapy in patients 75 years and older with STsegment- elevation myocardial infarction: one-year follow-up of a large prospective cohort. Arch Intern Med 2003;163:965-71

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17. McClure MW; Berkowitz SD, Sparapani R, et al. Clinical significance of thrombocytopenia during a non-ST-elevation acute coronary syndrome. The Platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial experience. Circulation 1999;99:2892-900

18. Lincoff AM, Kleiman NS, Kereiakes DJ, et al. REPLACE-2 Investigators. Long-term efficacy of bivalirudin and provisional glycoprotein Ilb/IIIa blockade vs heparin and planned glycoprotein Ilb/IIIa blockade during percutaneous coronary revascularization. REPLACE-2 randomized trial. JAMA 2004;292:696-703

19. Kereiakes DJ, Lincoff AM, Anderson KM, et al. Abciximab survival advantage following percutaneous coronary intervention is predicted by clinical risk profile. Am J Cardiol 2002;90:628-30

20. Nikolsky E, Mehran R, Mintz GS, et al. Impact of symptomatic peripheral arterial disease on 1-year mortality in patients undergoing percutaneous coronary interventions. J Endovasc Ther 2004; 11:60-70

21. Koch CG, Weng Y-S, Zhou SX, et al. Ischemia Research and Education Foundation; Multicentre Study of Perioperative Ischemia Research Group. Prevalence of risk factors, and not gender per se, determines short- and long-term survival after coronary artery bypass surgery. J Cardiothorac Vase Anesth 2003;17:585-93

22. Karthik S, Grayson AD, McCarron EE, Pullan DM, Desmond MJ. Reexploration for bleeding after coronary artery bypass surgery: risk factors, outcomes, and the effect of timedelay. Ann Thorac Surg 2004;78:527-34

23. Montalescot G, Collet JP, Tanguy ML, et al. Anti-Xa activity relates to survival and efficacy in unselected acute coronary syndrome patients treated with enoxaparin. Circulation 2004;110:392- 8

24. Boersma E, Pieper KS, Steyerberg EW, et al. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. The PURSUIT Investigators. Circulation 2000;101:2557-67

25. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI. A method for prognostication and therapeutic decision making. JAMA 2000;284:835- 42

26. Sinnaeve PR, Alexander JH, Bogaerts K, et al. Efficacy of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: one-year follow-up results of the Assessment of the Safety of a New Thrombolytic-3 (ASSENT-3) randomized trial in acute myocardial infarction. Am Heart J 2004; 147:993-8

27. Califf RM, Pieper KS, Lee KL, et al. Prediction of 1-year survival after thrombolysis for acute myocardial infarction in the global utilization of streptokinase and TPA for occluded coronary arteries trial. Circulation 2000;101:2231-8

28. Thiemann DR, Coresh J, Schulman SP, Gerstenblith G, Oetgen WJ, Powe NR. Lack of benefit for intravenous thrombolysis in patients with myocardial infarction who are older than 75 years. Circulation 2000;101:2239-46

29. Sabatine MS, McCabe CH, Morrow DA, et al. Identification of patients at high risk for death and cardiac ischemic events after hospital discharge. Am Heart J 2002;143:966-70

30. Koo S, Kucher N, Nguyen PL, Fanikos J, Marks PW, Goldhaber SZ. The effect of excessive anticoagulation on mortality and morbidity in hospitalized patients with anticoagulant-related major hemorrhage. Arch Intern Med 2004; 164:1557-60

31. Rao Sy Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004;292:1555-62

CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2871_3, Accepted for publication: 25 January 2005

Published Online: 04 March 2005

doi: 10.1185/030079905X30725

Marc Cohen

Cardiac Catheterization Laboratory, Newark Beth Israel Center, Newark, NJ, USA

Address for correspondence: Dr Marc Cohen, Cardiac Catheterization Laboratory, Newark Beth Israel Center, 201 Lyons Avenue, Newark, NJ 07112, USA. Tel.: +1-973-926-7852; Fax: +1-973- 282-0839; email: marcohen@sbhcs.com

Copyright Librapharm Mar 2005

Source: Current Medical Research and Opinion

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