Abstract

Until recently, achievements in the treatment of acute coronary syndromes (ACS) could only be obtained with an increased risk of bleeding. Though long considered an unavoidable consequence of the treatment of ACS, recent data demonstrate that major bleeding has a serious impact on subsequent outcomes. These findings have brought a paradigm change to risk stratification that takes into account not only ischaemic risk, but also bleeding risk in the selection of an optimal management strategy. Strategies to reduce bleeding include assessment of the bleeding risk in each individual patient, appropriate dosing of antithrombotic drugs, and the use of drugs with proven reduced risk of bleeding in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

Background

In patients presenting with ST-segment elevation myocardial infarction (STEMI), primary percutaneous coronary intervention (PPCI) reduces ischaemic complications and improves survival compared with pharmacological reperfusion with a fibrinolytic.1,2 A quantitative analysis of 23 randomized trials found that while PPCI is more effective than fibrinolysis at reducing rates of mortality, non-fatal myocardial infarction (MI), recurrent ischaemia, total cerebrovascular accidents (CVA), and haemorrhagic CVA, an increased rate of major bleeding in patients occurs.1

Though long considered an unavoidable consequence of the treatment of acute coronary syndromes (ACS), recent data demonstrate that major bleeding has a serious impact on subsequent outcomes. In the Global Registry of Acute Coronary Events (GRACE), in-hospital mortality was almost three times higher in patients who experience major bleeding compared with those who do not (Figure 1), a finding that was consistent across the spectrum of ACS.3 These findings have brought a paradigm change to risk stratification that takes into account not only ischaemic risk, but also bleeding risk in the selection of an optimal management strategy. Until recently, achievements in the treatment of ACS could only be achieved at increased risk of bleeding.

Figure 1

In-hospital death rates in patients according to major bleeding in GRACE (Reprinted from Moscucci M et al.3 with permission from the European Society of Cardiology).

Figure 1

In-hospital death rates in patients according to major bleeding in GRACE (Reprinted from Moscucci M et al.3 with permission from the European Society of Cardiology).

Risk factors for bleeding

There are certain characteristics that may place patients at higher risk for bleeding complications (Table 1). A multivariate analysis from GRACE found that age (per 10-year increase), female sex, history of renal insufficiency, history of bleeding, use of glycoprotein (GP) IIb/IIIa inhibitors, and PCI were all associated with an increased risk of major bleeding in patients with STEMI.3 This was confirmed in the North American Registry of PCI, where an adjusted multivariate analysis identified female sex, age (per 10-year increase), glomerular filtration rate (GFR) (per 10 mL/min decrease), cardiogenic shock, emergency/salvage PCI, and chronic obstructive pulmonary disease as risk factors for bleeding.4

Table 1

Risk factors for major bleeding in patients with NSTEMI in GRACE and North American Registry of percutaneous coronary intervention

Variable Adjusted OR P-value 
Multivariate model for major bleeding in patients with NSTEMI   
Age (per 10-year increase) 1.22 0.0002 
Female sex 1.36 0.0116 
History of renal insufficiency 1.53 0.0062 
History of bleeding 2.18 0.014 
LMWH only 0.68 0.012 
LMWH and UFH 0.72 0.035 
GP IIb/IIIa inhibitors only 1.86 <0.001 
Percutaneous interventions 2.24 <0.0001 
Variable OR (95% CI)a χ2 
Adjusted analysis of risk factors for bleeding   
Female 1.74 (1.64–1.85) 319.3 
Age (per 10 year increase) 1.36 (1.31–1.42) 223.6 
GFR (per 10 mL/min decrease) 1.11 (1.10–1.13) 210.2 
Prior PCI 0.69 (0.64–0.73) 128.9 
Cardiogenic shock 1.87 (1.66–2.10) 104.7 
Emergent/salvage PCI 2.22 (1.98–2.49) 81.7 
COPD 1.31 (1.23–1.39) 70.6 
Variable Adjusted OR P-value 
Multivariate model for major bleeding in patients with NSTEMI   
Age (per 10-year increase) 1.22 0.0002 
Female sex 1.36 0.0116 
History of renal insufficiency 1.53 0.0062 
History of bleeding 2.18 0.014 
LMWH only 0.68 0.012 
LMWH and UFH 0.72 0.035 
GP IIb/IIIa inhibitors only 1.86 <0.001 
Percutaneous interventions 2.24 <0.0001 
Variable OR (95% CI)a χ2 
Adjusted analysis of risk factors for bleeding   
Female 1.74 (1.64–1.85) 319.3 
Age (per 10 year increase) 1.36 (1.31–1.42) 223.6 
GFR (per 10 mL/min decrease) 1.11 (1.10–1.13) 210.2 
Prior PCI 0.69 (0.64–0.73) 128.9 
Cardiogenic shock 1.87 (1.66–2.10) 104.7 
Emergent/salvage PCI 2.22 (1.98–2.49) 81.7 
COPD 1.31 (1.23–1.39) 70.6 

aAll P-values < 0.001.

COPD, chronic obstructive pulmonary disease; GFR, glomerular filtration rate; GP, glycoprotein; LMWH, low-molecular weight heparin; PCI, percutaneous coronary intervention; UFH, unfractionated heparin; OR, odds ratio; CI, confidence interval; NSTEMI, non-ST segment myocardial infarction.

The Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) National Quality Improvement Initiative Registry5 Investigators developed a risk score that can be used to calculate the risk of major bleeding for an individual patient. The programme is available online and allows for input of characteristics including baseline haematocrit, GFR, heart rate, systolic blood pressure, prior vascular disease, diabetes mellitus, signs of congestive heart failure, and sex.6 Based on the input variables, the programme will provide a CRUSADE bleeding score as well as the risk of in-hospital major bleeding, thereby allowing for individualization of treatment.

Some argue that major bleeding is related to incorrect dosing in many patients. In CRUSADE, there was evidence of increased major bleeding if there was a major excess in dosing of unfractionated heparin (UFH), low-molecular weight heparin (LMWH), and GP IIb/IIIa inhibitors.5 However, the observation that even patients who were under-dosed had the same bleeding risk as those who had received an excess dose suggests that other contributing factors are evident.

The relationship between bleeding and increased long-term mortality has not been fully elucidated. However, it is likely multi-factorial and may include factors such as haemodynamic compromise through hypovolaemia, triggering a hyperadrenergic state induced by blood loss, and transfusion-induced microcirculatory disorder, nitric oxide depletion, immunological effects, and inflammatory response. Importantly, discontinuation of antithrombotics can have severe consequences including increased risk of thrombosis and subsequent mortality.7

Methods to minimize the risk of bleeding

Several procedural and pharmacological modifications can be made to reduce the risk of bleeding while preserving ischaemic protection.

Procedural measures

There are procedural preventive methods, such as the use of smaller size guides and use of the radial rather than femoral approach. There are only scarce data in ACS patients. A recent publication showed that as catheter size was reduced from an 8 French in 1994–1995 to a 7 French during 1996–1999 to a 5 or 6 French during 2000–2005, the percentage of major femoral bleeding was significantly reduced (P < 0.001 for trend).8 In the ESPRIT trial in patients with ACS, access site bleeding was cut in half (14.2% vs. 6.3%) and access site complications nearly disappeared (6.6% vs. 0.7%) when the radial approach was used.9 However, there was still quite a high percentage of any bleeding even when the radial approach is used during PPCI (11.8%). A similar finding was observed in the ACUITY trial.10

Pharmacological measures

Aside from procedural modifications, there is room for improvement regarding the selection of an antithrombotic regimen. Both anticoagulant and antiplatelet treatments are required, and usually at least two antiplatelet agents are needed (aspirin and clopidogrel), and in high-risk cases, a GP IIb/IIIa inhibitor must also be added. The use of multiple adjunctive antiplatelet agents increases the risk of bleeding, and since none of the agents can replace the other, it is critical to focus on the choice of anticoagulants and select a drug that is known to reduce the risk of bleeding.

The Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention Patients (STEEPLE) trial demonstrated in stable patients that replacing UFH with low-dose enoxaparin (0.5 mg/kg) resulted in a reduced rate of the combined endpoint of major and minor bleeding events (8.7% vs. 6.0%, P = 0.014), though the risk of bleeding still exists.11 In the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction 25 (ExTRACT-TIMI 25) trial, enoxaparin vs. UFH reduced death/non-fatal MI (16.7% vs. 13.0%, P = 0.002); however there was no significant reduction in bleeding in patients undergoing PCI after fibrinolysis (3.0% vs. 2.1%, P = 0.30).12 The Sixth Organization to Assess Strategies in Acute Ischaemic Syndromes (OASIS-6) trial investigated fondaparinux, a compound that is associated with a lower risk of bleeding, in patients with STEMI.13 Although there was a lower risk of severe haemorrhage, the difference was not statistically significant [1.0% vs. 1.3%, HR (95% CI)=0.77 (0.55–1.08), P = 0.13]. Furthermore, closer inspection of the data show that the reduction in death or re-infarction at 30 days associated with fondaparinux vs. UFH/placebo was limited to patients who received no reperfusion therapy (12.2% vs. 15.1%) or thrombolytic therapy (10.9% vs. 13.6%), but not in patients undergoing PPCI (6.0% vs. 4.9%, interaction P-value = 0.04).

Bivalirudin, a direct thrombin inhibitor, is another agent that is consistently associated with a significant reduction in the risk of bleeding across the spectrum of ACS. In the ACUITY trial, the risk of major bleeding in patients with NSTEMI was significantly reduced with bivalirudin (with provisional use of GP IIb/IIIa inhibitors in approximately 9% of patients) compared with UFH/LMWH plus GP IIb/IIIa inhibitors (3.0% vs. 5.7%, P < 0.001).10 The reduction in major bleeding translated into better net clinical outcomes (10.1% vs. 11.7%, P = 0.02), with non-inferior rates of composite ischaemia in bivalirudin-treated patients (7.8% vs. 7.3%, P = 0.32).

In the recent Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, 3602 patients with STEMI undergoing PPCI were randomized in an open-label fashion to treatment with either bivalirudin (with provisional use of GP IIb/IIIa inhibitors in approximately 7% of patients) or UFH plus routine use of GP IIb/IIIa inhibitors.14 At 30 days, major bleeding was significantly reduced with bivalirudin compared with UFH plus GP IIb/IIIa inhibitors, with a resultant significantly lower rate of net adverse clinical events (NACE), and no difference in the overall major adverse cardiac event (MACE) rate (Figure 2). Furthermore, cardiac-related mortality at 30 days was significantly reduced with bivalirudin; no difference was observed in non-cardiac-related mortality (Figure 3). This was maintained over 1 year, with a 31% risk reduction in all-cause mortality [3.4% vs. 4.8%, HR (95% CI) = 0.69 (0.50, 0.97), P = 0.029] and a 43% risk reduction in cardiac mortality [2.1% vs. 3.8%, HR (95% CI) = 0.57 (0.38, 0.84), P = 0.005] in patients treated with bivalirudin vs. UFH plus GP IIb/IIIa inhibitors.15 Based on the results of this trial, bivalirudin has recently received a Class IIa recommendation as an adjunct to PPCI in the recently updated 2008 European Society of Cardiology guidelines for the management of patients with STEMI.16

Figure 2

Primary 30-day outcomes of the HORIZONS-AMI trial. MACE, major adverse cardiac events (all-cause death, re-infarction, ischaemic target vessel revascularization, or stroke).

Figure 2

Primary 30-day outcomes of the HORIZONS-AMI trial. MACE, major adverse cardiac events (all-cause death, re-infarction, ischaemic target vessel revascularization, or stroke).

Figure 3

Thirty-day cardiac and non-cardiac mortality in the HORIZONS-AMI trial (Reprinted from Stone GW et al.14 with permission from Massachusetts Medical Society. All rights reserved.).

Figure 3

Thirty-day cardiac and non-cardiac mortality in the HORIZONS-AMI trial (Reprinted from Stone GW et al.14 with permission from Massachusetts Medical Society. All rights reserved.).

The driving force behind the reduction in mortality appears to be the 41% risk reduction in 30-day non-CABG-related major bleeding with bivalirudin [5.0% vs. 8.4%, HR (95% CI) = 0.59 (0.45, 0.76), P < 0.0001]. One may argue that a potential explanation for the increased bleeding in the UFH plus GP IIb/IIIa inhibitor arm is because of an increase in thrombocytopenia, which is more frequently associated with GP IIb/IIIa inhibitors. And while it does have some influence on bleeding, particularly in patients with profound thrombocytopenia, the occurrence was rare in both the UFH plus GP IIb/IIIa inhibitor and the bivalirudin arm (moderate = 3.9% and 1.8%; severe = 1.1% and 0.5%; profound = 0.5% and 0.1%, respectively). Therefore, the reduction in major bleeding evidenced with bivalirudin treatment cannot be explained only by a reduction in thrombocytopaenia, but rather is likely because of its unique mechanism of action. Bivalirudin binds to both exosite 1 and the active site of thrombin, forming a bivalirudin:thrombin complex that is slowly cleaved by thrombin. Recovery of thrombin's active site functions allows for a return to haemostasis, thereby providing bivalirudin with a safety advantage.17

Conclusions

Although long considered a consequence of the treatment of patients with ACS, it is now evident that bleeding has a strong impact on subsequent adverse outcomes. Therefore, a paradigm change has occurred. The optimal management of patients with STEMI must focus on prevention of bleeding as much as prevention of further ischaemic events. Strategies to reduce bleeding include assessment of the bleeding risk in each individual patient, appropriate dosing of antithrombotic drugs, and the use of drugs with proven reduced risk of bleeding in patients with STEMI undergoing PPCI.

Conflict of interest: Advisory Boards and speaker honorarium: The Medicines Company, Lilly, Daiichi Sankyo, GlaxoSmithKline, SanofiAventis, Merck, Iroko.

References

1
Keeley
EC
Boura
JA
Grines
CL
Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials
Lancet
 , 
2003
, vol. 
361
 (pg. 
13
-
20
)
2
Schömig
A
Neumann
FJ
Kastrati
A
Schühlen
H
Blasini
R
Hadamitzky
M
Walter
H
Zitzmann-Roth
EM
Richardt
G
Alt
E
Schmitt
C
Ulm
K
A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents
N Engl J Med
 , 
1996
, vol. 
334
 (pg. 
1084
-
1089
)
3
Moscucci
M
Fox
KA
Cannon
CP
Klein
W
López-Sendón
J
Montalescot
G
White
K
Goldberg
RJ
Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE)
Eur Heart J
 , 
2003
, vol. 
24
 (pg. 
1815
-
1823
)
4
Anderson
HV
Shaw
RE
Brindis
RG
McKay
CR
Klein
LW
Krone
RJ
Ho
KK
Rumsfeld
JS
Smith
SC
Jr
Weintraub
WS
Risk-adjusted mortality analysis of percutaneous coronary interventions by American College of Cardiology/American Heart Association Guidelines Recommendations
Am J Cardiol
 , 
2007
, vol. 
99
 (pg. 
189
-
196
)
5
Alexander
KP
Chen
AY
Roe
MT
Newby
LK
Gibson
CM
Allen-LaPointe
NM
Pollack
C
Gibler
WB
Ohman
EM
Peterson
ED
CRUSADE Investigators
Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment elevation acute coronary syndromes
JAMA
 , 
2005
, vol. 
294
 (pg. 
3108
-
3116
)
6
CRUSADE Bleeding Score
 
www.crusadebleedingscore.org (accessed on 13 January 2009)
7
Rao
SV
Eikelboom
JA
Granger
CB
Harrington
RA
Califf
RM
Bassand
JP
Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes
Eur Heart J
 , 
2007
, vol. 
28
 (pg. 
1193
-
1204
)
8
Doyle
BJ
Ting
HH
Bell
MR
Lennon
RJ
Mathew
V
Singh
M
Holmes
DR
Rihal
CS
Major femoral bleeding complications after percutaneous coronary intervention: incidence, predictors, and impact on long-term survival among 17,901 patients treated at the Mayo Clinic from 1994 to 2005
JACC Cardiovasc Intervent
 , 
2008
, vol. 
1
 (pg. 
202
-
209
)
9
Kinnaird
T
Anderson
R
Hill
J
Thomas
M
Bleeding during percutaneous intervention: tailoring the approach to minimise risk
Heart
 , 
2009
, vol. 
95
 (pg. 
15
-
19
)
10
Stone
GW
McLaurin
BT
Cox
DA
Bertrand
ME
Lincoff
AM
Moses
JW
White
HD
Pocock
SJ
Ware
JH
Feit
F
Colombo
A
Aylward
PE
Cequier
AR
Darius
H
Desmet
W
Ebrahimi
R
Hamon
M
Rasmussen
LH
Rupprecht
HJ
Hoekstra
J
Mehran
R
Ohman
EM
ACUITY Investigators
Bivalirudin for patients with acute coronary syndromes
N Engl J Med
 , 
2006
, vol. 
355
 (pg. 
2203
-
2216
)
11
Montalescot
G
White
HD
Gallo
R
Cohen
M
Steg
PG
Aylward
PE
Bode
C
Chiariello
M
King
SB
3rd
Harrington
RA
Desmet
WJ
Macaya
C
Steinhubl
SR
STEEPLE Investigators
Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention
N Engl J Med
 , 
2006
, vol. 
355
 (pg. 
1006
-
1017
)
12
Gibson
CM
Murphy
SA
Montalescot
G
Morrow
DA
Ardissino
D
Cohen
M
Gulba
DC
Kracoff
OH
Lewis
BS
Roguin
N
Antman
EM
Braunwald
E
ExTRACT-TIMI 25 Investigators
Percutaneous coronary intervention in patients receiving enoxaparin or unfractionated heparin after fibrinolytic therapy for ST-segment elevation myocardial infarction in the ExTRACT-TIMI 25 trial
J Am Coll Cardiol
 , 
2007
, vol. 
49
 (pg. 
2238
-
2246
)
13
Yusuf
S
Mehta
SR
Chrolavicius
S
Afzal
R
Pogue
J
Granger
CB
Budaj
A
Peters
RJ
Bassand
JP
Wallentin
L
Joyner
C
Fox
KA
OASIS-6 Trial Group
Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial
JAMA
 , 
2006
, vol. 
295
 (pg. 
1519
-
1530
)
14
Stone
GW
Witzenbichler
B
Guagliumi
G
Peruga
JZ
Brodie
BR
Dudek
D
Kornowski
R
Hartmann
F
Gersh
BJ
Pocock
SJ
Dangas
G
Wong
SC
Kirtane
AJ
Parise
H
Mehran
R
HORIZONS-AMI Trial Investigators
Bivalirudin during primary PCI in acute myocardial infarction
N Engl J Med
 , 
2008
, vol. 
358
 (pg. 
2218
-
2230
)
15
Mehran
R
for the HORIZONS-AMI Investigators
HORIZONS AMI: A prospective, randomized comparison of bivalirudin vs. heparin plus glycoprotein IIb/IIIa inhibitors during primary angioplasty in acute myocardial infarction. One year results
Paper presented at: Transcatheter Cardiovascular Therapeutics (TCT) Conference
12–17 October 2008
Washington DC
16
Van de Werf
F
Bax
J
Betriu
A
Blomstrom-Lundqvist
C
Crea
F
Falk
V
Filippatos
G
Fox
K
Huber
K
Kastrati
A
Rosengren
A
Steg
PG
Tubaro
M
Verheugt
F
Weidinger
F
Weis
M
Vahanian
A
Camm
J
De Caterina
R
Dean
V
Dickstein
K
Filippatos
G
Funck-Brentano
C
Hellemans
I
Kristensen
SD
McGregor
K
Sechtem
U
Silber
S
Tendera
M
Widimsky
P
Zamorano
JL
Silber
S
Aguirre
FV
Al-Attar
N
Alegria
E
Andreotti
F
Benzer
W
Breithardt
O
Danchin
N
Di Mario
C
Dudek
D
Gulba
D
Halvorsen
S
Kaufmann
P
Kornowski
R
Lip
GY
Rutten
F
ESC Committee for Practice Guidelines (CPG)
Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology
Eur Heart J
 , 
2008
, vol. 
29
 (pg. 
2909
-
2945
)
17
Weitz
JI
Bates
SM
Acute coronary syndromes: a focus on thrombin
J Invas Cardiol
 , 
2002
, vol. 
14
 
Suppl. B
(pg. 
2B
-
7B
)