|Year : 2009 | Volume
| Issue : 4 | Page : 145-155
Major bleeding in acute coronary syndrome
Douraid K Shakir1, Jassim Al Suwaidi2
1 MB CH B, F.R.C.P.; F.E. S. C., Department of Cardiology and Cardiovascular Surgery, Hamad Medical Corporation (HMC), Doha, Qatar
2 MB, ChB, F.A.C.C.; F.S.C.A.I.; F.E.S.C., Department of Cardiology and Cardiovascular Surgery, Hamad Medical Corporation (HMC), Doha, Qatar
|Date of Web Publication||17-Jun-2010|
Douraid K Shakir
Director of the Cardiac Catheterization Laboratory, Department of Cardiology and Cardiovascular Surgery, Hamad Medical Corporation, P.O Box 3050, Doha
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Acute coronary syndrome forms the vast majority of cases faced in daily cardiology clinical practice. It is usually managed by antiplatelates, antithrombotics and anticoagulants, all of which increase the risk of bleeding with associated increment in morbidity and mortality. Data gained from many studies and registries all over the world try to explore the magnitude of such problem as well as predictors and management. The definition of major bleeding in acute coronary syndrome is a dilemma by itself, as different definitions have led to inconsistency in its reported prevalence and magnitude of sequelae. Predicting the occurrence of major bleeding may help in saving lives, improving outcomes and cost-savings by preventing it. In this review, we try to explore these issues based on data extracted from large numbers of trials, studies and registries.
|How to cite this article:|
Shakir DK, Al Suwaidi J. Major bleeding in acute coronary syndrome. Heart Views 2009;10:145-55
| Introduction|| |
Acute coronary syndrome (ACS), which includes myocardial infarction (MI) and unstable angina (UA), forms the vast majority of cases seen in daily cardiology clinical practice. This syndrome is triggered by atherosclerotic plaque rapture, exposure of the arterial media, platelet activation and aggregation, thrombin activation, and occlusive thrombus formation  . Embolization of microthrombi to distal microvascular beds also leads to myocardial ischemia and its sequelae  . Interventions used in the management of ACS, such as antiplatelets, antithrombotics, or thrombolytic agents, are all associated with increased risk of bleeding. Addressing this complication is very important since major bleeding in ACS drastically worsens outcomes.
An estimated 785,000 Americans will have a new coronary artery event; approximately 470,000 will have a recurrent attack, and 195,000 will have a silent MI in 2010. The estimated annual incidence for MI is 610,000 new attacks and 325,000 recurrent ischemic attacks. Coronary heart disease (CHD) makes up more than half of all cardiovascular events in adults over 75 years of age. Every 25 seconds an American will suffer a coronary event, and each minute one patient will die from such an event  . The primary goal in managing ACS is to reduce the burden of ischemia, prevent recurrence, and minimize complications through the use of antiplatelet, anticoagulant, and antithrombotic agents. These agents are doubleedged swords, enhancing recovery, but with increased bleeding, which is associated with increased mortality and morbidity  . The use of these drugs as single agents, or in various combinations, duration of use, and the medical background of the patient all influence the incidence of major bleeding as a complication in ACS  . Increased awareness of the association between major bleeding and adverse outcomes in ACS has led to the development of new strategies and agents for management of ACS.
| Definitions of major bleeding in ACS|| |
The definition of major bleeding is of great importance since the incidence and magnitude of this complication are altered by the different classifications and definitions currently in use. There are two main definitions or classifications of major bleeding:
In the Thrombolysis In Myocardial Infarction (TIMI) study group  , "Hemorrhage was defined as "major" if there was a reduction of hemoglobin of 5 g/dl or more (or >15% in hematocrit) or any intracranial bleeding. Hemorrhage was classified as "minor" if there was an observed blood loss and a drop in hemoglobin of 3 to 5 g/dl (or in hematocrit from 10% to 15%) from study entry to the time of the lowest hemoglobin (hematocrit) and this was within 10 days; if there was spontaneous gross hematuria or hematemesis (>120 ml), even if the hemoglobin or hematocrit drop was less than 3 g or less than 10%, respectively; or if there was an unobserved loss 4 g/dl or more in hemoglobin or 12% or more in hematocrit. Blood loss attributable to revascularization or other surgical procedures was not classified as a TIMI hemorrhagic event."
In the Global Use Of Strategies To Open Occluded Coronary Arteries (GUSTO) trial  , "Bleeding complications were classified as severe or life-threatening if they were intracerebral or if they resulted in substantial hemodynamic compromise requiring treatment. Moderate bleeding was defined by the need for transfusion. Minor bleeding referred to other bleeding, not requiring transfusion or causing hemodynamic compromise."
Rao et al  compared these two major definitions. The median time from the ACS event to the most severe TIMI bleeding was one day compared to two days in GUSTO. There were 1151 patients who met the GUSTO criteria but did not meet TIMI criteria, while 765 patients met the TIMI criteria but did not meet the GUSTO bleeding criteria. Using the TIMI bleeding classification, 12.7% had minimal bleeding, 8.5% had minor bleeding, and 8.2% had major bleeding, while in GUSTO classification 19.2% had mild bleeding, 11.4% had moderate bleeding, and only 1.2% had major bleeding. There was a graded increase in short and intermediate-term adverse outcomes for GUSTO classification but not for TIMI classification after adjusting for certain risk factors. There was also a graded increase in 30-day and 6-month mortality and MI, with worsening GUSTO classification but no significant association with the TIMI classification. The authors concluded that, in predicting outcomes, assessment of major bleeding based on clinical criteria is more important than laboratory-based criteria .
There are other less commonly used definitions such as those used by the PARAGON study  , Acuity trial  , Oasis-2  , and the Cure study.
To provide consistency, the Academic Bleeding Consensus proposed a standardized reporting of bleeding complications for clinical investigations in acute coronary syndromes  . They analyzed existing evidence on bleeding in ACS and its impact on clinical outcomes. Criteria for the assessment of bleeding were then developed by an expert panel that suggested dividing the bleeding-related events to be reported in the clinical trials into three categories [Table 1].
Red category includes clinical data on bleeding events, laboratory parameters, and the consequences of bleeding that is essential for all studies. Orange category includes everything in the red category plus bleeding resulting in discontinuation or alteration of therapy (recommended for all studies). Green category includes the red and orange criteria plus bleeding resulting in hemodynamic instability, disability, increased length of stay or a decrease in hemoglobin (optional for all studies).
| Mechanism and Magnitude of the problem|| |
The incidence of major bleeding in the ACS varies among different trials, and ranges from 0.7 to 19.2% , . The incidence was 3.9% in the GRACE study  , 15% in TIMI 1  , and 4.1% in TIMI 2  . The death rate in ACS with major bleeding also varied widely from 0.1% to 38% in different trials , . These huge discrepancies are primarily due to the different definitions used in the trials. Another contributing factor is the different drug regimens used such as single agent versus combination therapy, dosing with or without loading, and the duration of use. The availability of interventional facilities at the site also plays a role in increasing bleeding complications. Patient characteristics such as co-morbidities, age, renal function, Killip class at presentation, GRACE score, and the type of ACS event also play a role [Table 2] and [Table 3].
Many mechanisms by which major bleeding affects patient outcome have been suggested. Anemia results in a decrease of the oxygen delivery to the vital organs including the already vulnerable myocardium, thereby exacerbating ischemia. Hypotension resulting from large amount of blood loss also compounds hypoxemia and hypo-perfusion of the vital organs, including the myocardium. Activation of the sympathetic nervous system, release of endogenous noradrenalin, endothelin, vasopressin, and exaggeration of inflammatory response all contribute to worse outcomes.
| Predictors of major bleeding|| |
A large number of trials have studied the predictors of major bleeding that can be used to anticipate and prevent this complication in daily clinical practice [Table 3].
Advanced age is one of the strongest predictors of major bleeding in ACS. Increased risk of major bleeding with age was seen in the GRACE trial  , with an age distribution of 61.5 - 79.5 years (mean 71.1), and in Spencer et al.  with ages 64-81 years (mean 74, P value < 0.001). The REAL LIFE study reported the same with age group of 68 ± 12.4 years of age  and the German ACOS trial the mean age was 74.6 years with a range of 66 -79 years  . Other studies that support this include the Interact trial  with a mean age of 71 years and SWEDEHEART study .
Gender was found to be a predictor of major bleeding in different trials. In the GRACE trial  , females had a higher bleeding tendency, at 5% compared to 3.3% in males (P < 0.001). The same was reported in SWEDEHEART  and by Spencer et al  . The Acuity trial  reported more major bleeding in males with P value < 0.0001 as did Ferguson et al.  who reported male sex predominance with P value < 0.001. These differences could be explained by differences in socio-economic status and the population demographics [Table 3].
Previous history of bleeding
Prior history of bleeding was also identified as a risk for major bleeding in patients with ACS. This was reported in the GRACE trial  , in which the incidence of major bleeding in those who had a bleeding history was 11.5% compared to 3.8% in those with no previous history (P value of < 0.0001). Spencer et al.  also reported increased risk of bleeding in patients with ACS from 1.1% in non-bleeders to 3.7% in previous bleeders. The authors suggest that reporting history of bleeding in ACS trials may draw more attention to this risk factor [Table 3].
Renal impairment is another important predictor of major bleeding in ACS patients. The GRACE trial  reported an increase in major bleeding from 3.8% in patients with normal renal function to 11.5% in patients with renal impairment (P < 0.001) and Spencer et al.  reported a similar increase from 7.7% to 14% respectively. Fox et al.  reported an increase in major bleeding in those who received enoxaparin over fondaparinux for non-ST-segment elevation ACS among patients with renal dysfunction especially in those with GFR lower than 58 ml/min per 1.7 m2. The INTERACT trial  , Acuity trial , , German ACOS trial  , Eikelboom et al.  and Mortensen et al.  reported an increase in major bleeding in cases of ACS with renal impairment. Renal impairment is an independent risk factor for major bleeding with odds ratios of 1.48-1.53 in different trials ,,.
ST-Elevation Myocardial infarction
Most clinical trials report that STEMI is a strong predictor of major bleeding over other conditions since it is usually treated more aggressively. Thrombolytic therapy is often combined with loading doses of antiplatelet agents, and more invasive interventional procedures, leading to higher incidence of major bleeding. The GRACE trial  reported a significant increase in major bleeding in patients with STEMI compared to NSTEMI and UA (4.8%, 4.7%, and 2.3% respectively with P < 0.001). Spencer et al.  reported that 58% of bleeders had STEMI versus 42% for the NSTEMI with P value of <0.001.
The cardiopulmonary status at the time of ACS event plays a big role in predicting major bleeding as evidenced by the fact that advanced Killip class (III or IV) correlates with increased major bleeding events. This is seen in the GRACE trial  , in which 13.1% of patients with major bleeding were classified as advanced Killip class. The Canadian ACS registry  reported 28.9% of patients with major bleeding had advanced Killip class compared to 15.4% (P value 0.01) in those with no major bleeding, with odds ratio of 1.61 for major bleeding in advanced Killip class. Other studies such as the INTERACT trial  , Budaj et al.  , and Rao et al.  also support a role for Killip class In increased risk of major bleeding [Table 3].
Diabetes mellitus (DM) has been studied extensively as it is a growing problem globally. DM complications include nephropathy, hypertension, and atherosclerosis, which in turn lead to increased risk for major bleeding in ACS. A large number of studies report this association between DM and major bleeding in ACS, but there are discrepancies in the results as to whether the presence of DM significantly affects outcomes for ACS patients [Table 3].
| Choice of antiplatelet, antithrombotic, glycoprotein IIb/IIIa inhibitor, or fibrinolytic agent|| |
All medications used in the management of ACS, inhibit thrombosis and platelet function, thus increase the risk of bleeding. Most trials studied the impact of different agents on incidence of major bleeding. Although the protocols used, doses and duration of use, and different combinations of these agents all seem to play a role in precipitating major bleeding. The significance of this impact is unclear due to discrepancies among different clinical trials [Table 3].
| Invasive procedures|| |
Coronary interventions and right heart catheterizations increase major bleeding as reported by many clinical trials. This is either from the medications used in the procedures such as heparins or glycoprotein (GP) IIb/IIIa inhibitors, the use of higher loading doses of antiplatelet agents, or from the puncture site wound.
| Major bleeding and hospital outcomes|| |
Outcomes for patients hospitalized with ACS are greatly affected by the occurrence of major bleeding. Mortality of ACS at 1, 3, and 6 months and 1 year increases as major bleeding increases ranging from 0.1% to 38% [Table 2] and [Table 4], with odds ratios of 1.64 to 3.92. Both major and minor bleeding are associated with increased mortality and with worse outcomes in those with higher degrees of bleeding , . Both congestive heart failure and re-infarction rates are increased in ACS patients with major bleeding 21-48% and 8-50% respectively; all the increases were statistically significant; [Table 4].
| Prevention and management|| |
The main goal in the management of major bleeding in ACS is to minimize the adverse effects of bleeding on total body hemodynamic integrity and oxygenation. Appropriate antithrombotic or antiplatelet agent selection with proper dose and dosing protocol adjustment, in conjunction with careful patient selection may help to reduce the incidence major bleeding.
In many trials, hemodynamic stability was achieved by blood transfusions, but this in turn increases morbidity and mortality , . Aggressive transfusion is thus not recommended for low hemoglobin in ACS  . Although erythropoietin increases the RBC mass when used in renal failure, it does not help in the acute setting, and was associated with increased cardiovascular events  , hence there is no enthusiasm for its use in ACS in general.
Dosing and combination of antithrombotic therapies plays a significant role in the incidence of major bleeding. Peters et al.  in his review of the CURE trial found a dose-dependent increase in major bleeding as aspirin dose increased with no increase in efficacy of aspirin at the higher doses.
The same review found that post CABG bleeding was only reduced when clopidogrel was stopped 5 days prior to the procedure. Triple therapy with aspirin, clopidogrel, and heparin increases the incidence of major bleeding  . The ISAR-REACT 2 randomized trial  used quadruple strategy with aspirin, clopidogrel, heparin, and GP IIb/IIIa inhibitor (abciximab) in high risk PCI patients. At 30 days, the mortality, MI, and urgent target vessel revascularization rates were significantly lower in abciximab group than placebo group, with no significant difference in major bleeding as measured by blood transfusion requirements.
The TARGET trial  also used quadruple therapy and showed no significant differences in the rate of major bleeding complications between abciximab and tirofiban. The CRUSADE Trial  however reported that excessive dosing of unfractionated heparin (UFH), low molecular weight heparin (LMWH), or GP IIb/IIIa inhibitor led to increased major bleeding, increased mortality in those receiving GP IIb/IIIa inhibitor, and increased hospital stay in those on high doses of LMWH and GP IIb/IIIa inhibitor.
UFH is probably the most commonly used antithrombotic agent in ACS. Its effect is measured by monitoring activated clotting time (ACT). In a meta-analysis of UFH use in PCI, higher doses were associated with increased incidence of post-procedure minor and major bleeding with linear increments as ACT increases. Weight-indexed dosing was independently associated with higher bleeding rates for each 10 U/kg with / OR = 1.04 and P = 0.00139. Intensive use of LMWH in ACS has recently become more widespread. SYNERGY studied the effect on major bleeding and found no difference between LMWH and UFH in all cause mortality at 30 days, and higher rates of major bleeding.
GP IIb/IIIa inhibitors have been proved superior over UFH in reducing the adverse effects of ongoing ischemia. Aguirre et al.  compared the use of abciximab as an infusion or bolus doses to placebo on a base of UFH and aspirin. There were more major bleeding events in the infusion group than the bolus dose strategy, with lowest incidence in the placebo group, P < 0.001. The need for blood transfusions was also significantly increased in the abciximab group (40). These complications can be avoided if lower doses of UFH are used as in the EPILOG (Evaluation in PTCA to Improve Long Term Outcome with Abciximab GP IIb/IIIa Blockade) study  . Minor bleeding was lower in GP IIb/IIIa group, also depending on the dose and protocol used for UFH.
Newer drugs may help in decreasing major bleeding. Use of the direct thrombin inhibitor bivalirudin is associated with lower risk of bleeding in ACS than heparin and GP IIb/IIIa inhibitor combination, with non-inferior ischemic outcomes for bivalirudin. In the REPLACE -2 trial, bivalirudin and GP IIb/IIIa was compared to UFH and GP IIb/IIIa in a PCI protocol, with significant reduction in major bleeding and a lower 1-year mortality in patients who received bivalirudin ,,,, . OASIS -2 investigators  studied lepirudin (a hirudin) in the management of NSTEMI in comparison to UFH. The lepirudin group had significantly lower cardiovascular mortality, re-infarction rates, and refractory angina, but there was a significantly increased risk of major bleeding that required blood transfusion in the lepirudin group.
Fondaparinux sodium is a synthetic pentasaccharide that inhibits activated factor X. This agent was evaluated in OASIS-5 , in patients with UA or NSTEMI and showed significantly decreased incidence of major bleeding rates, with better short-term outcomes as measured by MI, recurrent ischemia, or mortality.
New antiplatelet agents are now emerging. Prasugrel is a thienopyridine pro-drug that requires conversion to an active metabolite before binding to the platelet P2Y12 receptor. It inhibits adenosine diphosphate more rapidly and consistently than clopidogrel. In TRITON-TIMI 38, a double-blinded randomized trial for PCI planned patients  , prasugrel 60-mg loading dose was compared to clopidogrel 300-mg loading dose with maintenance doses of 10 mg prasugrel and 75 mg clopidogrel with up to 15 months follow-up. The prasugrel group had significantly lower rates of MI, urgent target vessel revascularization, and stent thrombosis, but there was an increase in major bleeding events with HR 1.32 and P = 0.03. There was also a significant increase in life-threatening bleeding, including both fatal and nonfatal bleeding.
Ticagrelor is a reversible and direct acting oral P2Y12 receptor antagonist, which provides greater and more consistent platelet inhibition than clopidogrel. The PLATO trial  , a double-blinded study, compared ticagrelor (180-mg loading dose followed by 90 mg twice daily) and clopidogrel (300- to 600-mg loading dose with 75 mg daily maintenance dose) in the management of ACS with 12-month follow-up. Cardiovascular mortality, MI, and stroke were significantly lower in ticagrelor group with HR = 0.84 and P = 0.0025, with no difference in major bleeding complications.
Cangrelor, an adenosine triphosphate analogue, is an intravenous platelet inhibitor that reversibly binds to and inhibits the P2Y12 ADP receptor. In the CHAMPION PLATFORM trial  , a randomized, double-blinded, placebo-controlled trial, in the setting of PCI, the rate of stent thrombosis and mortality from any cause were both significantly decreased in cangrelor group. There was an increase in major bleeding due to groin hematomas in the cangrelor group.
Procedural protocols in different institutions also affect the rates of major bleeding. Increased risk of bleeding with femoral puncture versus a radial approach , has prompted certain centers to move to using the radial approach in more than 98% of PCI cases. Bigger puncture sites also lead to more site bleeding  . Use of arterial puncture closing devices did not decrease the risk of puncture site bleeding, but increased the hematoma size and pseudo-aneurysm formation  . Longer procedures significantly increase risk of developing major bleed  , as does use of devices such as intra-aortic balloon counter pulsation  .
To address the issue of major bleeding and improve outcomes in ACS, there is a large number of ongoing trials, trying to find powerful antiplatelet and antithrombotic agents with lower side effects.
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[Table 1], [Table 2], [Table 3], [Table 4]