Assessing Bleeding Risk in Acute Coronary Syndromes

Acute coronary syndromes (ACS) are usually caused by plaque rupture, platelet activation, and thrombus
formation leading to
coronary occlusion and myocardial damage. 1 Understanding the pathophysiology of ACS has led to the
development of highly
successful antithrombotic strategies, including acetylsalicylic acid, clopidogrel, and low molecular weight
heparin, which have
reduced the risk of death, myocardial infarction (MI) and recurrent ischaemia. 2 Early coronary revascularization
using percutaneous coronary intervention (PCI) with stent implantation has also improved the outlook for higher
risk patients with ACS.3 However, antithrombotic therapy and PCI increase the risk of bleeding and there is
growing evidence that major bleeding is independently associated with a higher risk of adverse outcomes
including death.4

Paper Bleeding

Prognostic implications of bleeding in acute coronary

syndrome
The clinical impact of bleeding has long been downplayed due to the availability of blood
transfusions and haemostatic agents, with bleeding often merely regarded as an unpleasant event,
increasing the length of hospital stay and costs, but not clearly impacting survival. It was only
recently recognized that major bleeding was associated with a subsequent increase in late
mortality, potentially negating the long-term benefits of ACS treatment. 10,24 26
Compared with patients without bleeding, patients who experience bleeding are more likely
to die not only early in-hospital but also late after discharge. 26 28 One possibility to explain the
relationship of bleeding with adverse outcomes in routine practice is that recognized predictors of
bleeding have much overlap with predictors of ischaemic events; bleeding acting as a marker for
increased ischaemic risk as well as contributing to death in some cases. A second possibility is that
bleeding has directly harmful consequences and also set in motion a number of adaptive changes,
in turn themselves leading to an adverse outcome. Consequences of bleeding include hypotension,
anaemia, and reduction in oxygen delivery (Figure 2). Experimental data suggest that a
haemoglobin level down to 7 g/dL is tolerated without myocardial ischaemia if there is no
obstructive coronary artery disease (CAD). 29 Anaemia per se is associated with an increased risk of
adverse outcomes in patients with ACS, or undergoing coronary revascularization. 30 32 However,
many patients with anaemia actually presented with anaemia prior to receiving any antithrombotic
therapy and without overt bleeding. In these patients, pre-existing anaemia may exacerbate the
consequences of subsequent bleeding, and certainly increases the probability of transfusion.
Discontinuation of antithrombotic therapy to minimize bleeding is an important trigger
ofACS.33,34 Itmay re-exacerbate the thrombotic risk allowing the accretion of new thrombus
material. In the face of bleeding, no general guideline can be given. Clinicians need to weigh the
respective risks related to ongoing bleeding, dose reduction, or temporary discontinuation of
antithrombotics, whenever possible, with rapid resumption of the initial antithrombotic therapy,
depending on the half life and reversibility of the effect and the possibility to treat bleeding (e.g.
compressible vs. Noncompressible bleeding site). Antithrombotic therapy should be, however,
discontinued if bleeding leads to hypotension or if bleeding is life-threatening and uncontrolled.
This should be followed by haemodynamic support with fluid repletion and vasopressor therapy as
necessary. All of these actions, however, place the patient at increased risk of recurrent ischaemia
and infarction.
Transfusion of whole blood or packed red blood cells might have appeared the simple and
ultimate solution to manage major bleeding, as it rapidly compensates for the volume loss
associated with the bleeding event, and as such is indicated when bleeding is associated with
haemodynamic instability or shock. However, when bleeding is less severe and haemodynamic
conditions remain stable, the effect of transfusions on mortality is at best neutral. Even in patients
with cardiovascular diseases or in the elderly, transfusion have no positive impact on outcome. 29,35
Furthermore, despite major bleeding with the loss of .5 g/dL haemoglobin, blood transfusion is
associated with increased mortality, and blood loss down to a nadir haematocrit as low as 25%
may be well tolerated.36 There are many potential mechanisms for the detrimental effects of
transfusions, including platelet activation and aggregation, impaired oxygen, and nitric oxide
delivery capabilities (Figure 3).37 As a matter of fact, in general, restrictive transfusion strategies
are associated with trends towards decreased mortality, myocardial infarction, and heart failure. 37

Therefore, transfusion may increase rather than decrease the risk of adverse events in patients
with ACS.38 Likewise, the common39 liberal use of blood transfusion to maintain predefined
haemoglobin levels in CAD patients without overt bleeding and with haematocrit .25% or
haemoglobin . 8 g/dL is not recommended.

Avoidance of bleeding in acute coronary syndrome and

percutaneous coronary intervention
The role of overdosing
Overdosing is a frequent situation associated with established increased major bleeding
risk and in-hospital death. 20,21 Using the minimal effective dose and adjusting the dose, when
appropriate, to body weight, age, and to renal function are sensible steps to minimize the risk of
bleeding.
Fondaparinux, low-molecular-weight heparins (LMWH), hirudin, argatroban, bivalirudin, and
GP IIb/IIIa blocker are largely cleared by the kidneys, and should therefore not be used or need to
be down-titrated in patients with severe renal failure, defined as a creatinine clearance ,30
mL/min.20,21 Unfractionated heparin remains the anticoagulant of choice in this particular situation,
but does not totally protect against bleeding complications. With worsening renal function, there is
a gradual increase in the risk of bleeding with UFH, similar to that seen with LMWH. 51
Unfractionated heparin, LMWH, intravenous direct thrombin inhibitors, TNK-tPA, and GP
IIb/IIIa blockers all require careful weight-adjusted dosing. 28,46,47,51,52 The use of high loading and
maintenance doses of clopidogrel to speed up its efficacy and overcome high residual-on treatment
platelet reactivity, especially in the setting of PCI, may be beneficial in terms of clinical outcomes,
although in the CURRENT/OASIS 7 trial this was only seen in patients going on to PCI, 53 but not
when the trial was analysed by intention-to-treat54 and was achieved at the expense of increased
major bleeding.

Use for the shortest possible duration

In determining the duration of antithrombotic therapy, it is important always to balance the
bleeding-related risks with the antithrombotic benefits, and therefore adopt the shortest possible
course of therapy. As an example, dual therapy with aspirin and clopidogrel is recommended for 1
month after bare metal stenting in stable patients, and for 6 up to 12 months after an ACS
(regardless of stenting) and after implantation of drug eluting stents (regardless of clinical
diagnosis). Continuation of dual antiplatelet therapy beyond these intervals should be considered
an exception rather than the rule. So far, there is a single randomized study showing no hazard of
clopidogrel discontinuation 1 year after drug-eluting stent implantation. 55 There are currently 11
randomized trials ongoing comparing various duration of dual antiplatelet therapy in this setting
(Table 6).

Choice of drugs
Antithrombotic agents shown to produce less bleeding while maintaining anti-ischaemic efficacy in
randomized trials should be preferred, particularly for those for whom bleeding reduction was
associated with reduced mortality or improved clinical outcomes. This is the case of fondaparinux
against enoxaparin in the medical management of patients with NSTE-ACS 26 and of bivalirudin vs.
UFH+GPIIb/IIIa blockers in primary PCI for ST-segment elevation myocardial infarction. 25 Agents
which lower bleeding rates while achieving non-inferior efficacy are also of interest, although
consideration of the individual patient risk profile for bleeding and MI becomes an important factor
in the decisionmaking process. This is the case for bivalirudin vs. UFH + GpIIb/IIIa blockers in NSTEACS28,56 and, possibly, of enoxaparin vs. UFH in patients undergoing elective or primary
angioplasty.41,57

Reducing gastrointestinal bleeding

The risk of gastrointestinal haemorrhage increases two- to threefold even with low-dose aspirin
monotherapy compared with
placebo, and all doses of aspirin are associated with an increased risk of gastrointestinal bleeding.
The risk of aspirin-related ulcer complications is significantly increased in patients aged more than
60 years, patients with serious comorbidities, concomitant use of non-steroidal anti-inflammatory
drugs (NSAIDs), systemic corticosteroids, anticoagulants, or other antiplatelet agents. Overall,
there is no evidence of decreased efficacy, but clear evidence of increased safety with lower doses
of aspirin.54 Proton-pump inhibitors display a high capacity to reduce recurrent gastrointestinal
bleeding in patients at high risk for gastrointestinal side effects under chronic aspirin therapy,
although they are not effective in preventing lower gastro-intestinal bleeding. 58 Adding a protonpump inhibitor to reduce gastrointestinal bleeding events in patients at high risk of gastrointestinal

toxicity who receive long-term treatment with low-dose aspirin is recommended. 59 On the other
hand, there is a pharmacologic interaction between omeprazole and clopidogrel, 60 which is some
observational cohorts appeared to be associated with higher cardiovascular event rates. However,
the jury is still out regarding the clinical significance of this interaction, which did not appear to
impact clinical outcomes in one prospective, albeit somewhat underpowered, randomized trial 61 or
in other large observational cohorts. 62 64 Whether proton pump inhibitors should be routinely
added to the already long list of medications needed after an ACS or PCI requires testing, given the
implications in terms of cost, adherence to polypharmacy, and cost-effectiveness, and is not at the
moment recommended. Instead, a recent consensus document on the concomitant use of proton
pump inhibitors and thienopyridines highlights that proton pump inhibitors are appropriate in
patients with risk factors for gastrointestinal bleeding who require antiplatelet therapy, 65 such as
patients with prior history of upper gastro-intestinal tract bleeding, advanced age; concomitant use
of warfarin, steroids, or NSAIDs; or H. pylori infection.

Preventing access site bleeding

Numerous devices have been developed to obtain efficient arterial closure immediately at the end
of a PCI procedure performed with the femoral approach, but have failed to abolish major access
site bleeds or improve clinical outcomes. 45 Consistent results indicate that a reduced arterial
sheath size, timely sheath removal, and the use of radial (instead of femoral) artery access for PCI
are associated with a frank reduction in peri-PCI bleeding rates. Using a radial approach, as
opposed to femoral access for angiography and PCI appears remarkably effective in preventing
access site bleeding43,44: pooled results from 17 randomized studies indicate a 78% reduction in
entry site complications when a radial approach is used, with a number need to treat of only 39
patients.43 Whether using radial access for PCI in ACS patients can improve clinical outcomes is
being tested in the 7000 patient RIVAL randomized trial. 66 In the interim, a large observational
database analysis has suggested that in patients at higher risk for bleeding, use of vascular closure
devices and bivalirudin for PCI were associated with lower bleeding rates. 67

Patients on chronic oral anticoagulation

Given the concerns with increased bleeding risk in patients receiving protracted triple
antithrombotic therapy with oral anticoagulants (atrial fibrillation, venous thrombosis, pulmonary
embolism, mechanical prosthetic valves),68 aspirin, and thienopyridines, it makes sense to
minimize the overlap between these agents, and therefore to prefer bare metal stents over drugeluting stents in order to allow safe early discontinuation of clopidogrel. The selection of a post-PCI
antithrombotic strategy in this context should probably be based on individual patient
characteristics, as retrospective analyses suggest that triple therapy provides the best benefit-risk
ratio, provided that clopidogrel co-treatment is kept as short as possible. 63 In general, if the patient
is at high risk of thromboembolic events requiring oral anticoagulants (e.g. because of a prosthetic
mitral valve, recent venous thrombosis or pulmonary embolism, or atrial fibrillation with a CHADS 2
score.1), triple oral antithrombotic therapy (aspirin + clopidogrel + oral anticoagulants) should be
used until clopidogrel can be safely discontinued. Once the risk of stent thrombosis is lower,
consideration should be given to oral anticoagulants alone, 69 although contemporary studies on
this important topic are lacking. This is, in fact, an incentive to use bare metal stents during PCI
procedures in these patients in order to discontinue clopidogrel after 4 weeks. In patients with a
lower thromboembolic risk in whom oral anticoagulation is optional (e.g. atrial fibrillation with
CHADS2 score 01)especially if they have an increased bleeding risk (e.g. age .75 years, severe
renal dysfunction, recent gastrointestinal bleeding, prior stroke, uncontrolled hypertension)
physicians may consider using dual antiplatelet therapy for several weeks before resuming oral
anticoagulants and discontinuing one oral antiplatelet agent or maintaining dual antiplatelet
therapy in the long term as it has a better efficacy profile than aspirin alone at least in patients
with atrial fibrillation considered unsuitable for vitamin K antagonists (Figure 3).69 For long-term
use, after the need of clopidogrel has waned, we concur with the recent ESC Atrial Fibrillation
guidelines in recommending VKA alone rather than the combination of VKA + aspirin.69,70 For
patients who develop ACS while being on chronic oral anticoagulation, adding antiplatelet therapy
to oral anticoagulation should be considered, but the optimal duration of tripleantithrombotic
therapy in these patients is unknown and should probably be minimized, particularly in patients
who do not undergo placement of a stent, in order to minimize bleeding risks.

STEMI AHA 2013

Bleeding Complications
Despite variable definitions for major and minor bleeding used in clinical trials, bleeding that
complicates the course of an ACS, including STEMI, is independently associated with recurrent

MI, stroke, death, longer hospital stay, and increased cost. The risk of death increases as a
function of the severity of bleeding, independent of the success or failure of reperfusion
therapy. In a pooled analysis from 4 ACS trials, the adjusted hazard ratio for death within 30
days ranged from 1.6 with mild bleeding to 10.6 with severe bleeding (535). Most bleeding is
procedure related, although gastrointestinal and intracerebral bleeding may be more life
threatening. Factors likely to contribute to adverse outcomes with ACS related bleeding
include patient comorbidities (536,537), discontinuation of antiplatelet or anticoagulant
therapy in response to bleeding (536,538), and blood transfusion (539,540). Additional
considerations include types of antiplatelet or anticoagulant agent at time of PCI
(248,541,542), number of antithrombotic agents used (533), dosing (543), duration of
therapy, crossover from low-molecular-weight heparin to UFH, HF or shock, diabetes mellitus,
peripheral artery disease, and prior warfarin use. If triple antithrombotic therapy is required
after discharge, the risk of bleeding increases (Figure 4) (533).
Risk factors for bleeding in patients with ACS have been identified from several clinical
trials (535,544546) (Table 13). Predictive models for major bleeding in patients with ACS and
in patients undergoing PCI have been reported from the NCDR ACTION RegistryGWTG
(547,548). An analysis from the ACTION RegistryGWTG suggests that the CRUSADE bleeding
risk score, developed in patients with nonST-elevation MI, may be extended to the STEMI
population (549). Major bleeding occurred in 2.8% of _40,000 patients with acute MI in the
GRACE Registry (536). Patients who experienced a major bleeding episode were more likely to
die in hospital than were those who did not bleed (20.9% versus 5.6%; p_0.001), even after
adjustment for several relevant demographic and clinical
variables. One in 5 patients with a major bleed did not survive to hospital discharge; these
patients accounted for 10% of all hospital deaths and were older, more severely ill, and more
likely to undergo invasive procedures. In ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis
Reperfusion for Acute Myocardial Infarction TreatmentThrombolysis In Myocardial Infarction
25), high 30-day mortality rates after major bleeding in patients with STEMI treated with
fibrinolysis and either unfractionated or low-molecular-weight heparin were driven largely by
the very poor prognosis associated with ICH (65% mortality rate) (537). The overall incidence
of ICH in this study was 0.6%
(332). The relationship between non-ICH bleeding and death in both ExTRACT-TIMI 25 and
TRITON-TIMI 38 may have been confounded by patient attributes, severity of illness, and
treatment protocols (537,550). To minimize the risk of bleeding complications, an assessment
of patient, procedural, and pharmacological risk factors should be performed at time of
presentation with STEMI and continuously thereafter. As an example, a longer time to PCI may
be justifiable if the risk of hemorrhage with fibrinolysis is considered prohibitive.
Evidence suggests that although anemia is a risk factor for bleeding, the threshold for
transfusion should be high (551). Absent ongoing ischemia, transfusion should be avoided
unless the hemoglobin level is _8 mg/dL. The optimal hemoglobin level in the transfused
patient is not known, but the number of units provided should be minimized (539,552).

9.7.2.1.

TREATMENT OF ICH

Older age, female sex, low body weight (_70 kg [female] and _80 kg [male]), prior stroke, and
hypertension on presentation (with a graded increase beginning at _160 to 170 mm Hg
systolic) are the major risk factors for ICH. Once ICH is recognized, all antiplatelet and
anticoagulant therapy should be stopped. Brain imaging with emergency neurological and
neurosurgical consultation is required. Consideration Consideration can be given to the use of
protamine, fresh frozen plasma, prothrombin complex concentrates, activated factor VII (555),
and platelets as indicated. Resumption and timing of anticoagulant and/or antiplatelet
therapy after ICH should be individualized and guided by neurosurgical consultation (556).

9.7.2.2.

VASCULAR ACCESS SITE BLEEDING

Vascular access site bleeding is the most common type of bleeding after STEMI, particularly
after PCI. PCI trials have identified female sex, advanced age, renal insufficiency, anemia,
IABP, use of GP IIb/IIIa antagonists, and lowmolecular-weight heparin within 48 hours of PCI as
risk factors for femoral access site bleeding (557). Larger sheath size, postprocedural heparin
use, higher activated clotting times, and late postprocedural sheath removal increases the
risk of access site bleeding and should be avoided. Radial artery access may decrease
bleeding complications and should be considered whenever feasible (558), but procedural
success with this technique is dependent on operator experience (559,560). Among patients

with STEMI in the RIVAL (Radial Versus Femoral Access for Coronary Angiography and
Intervention in Patients with Acute Coronary Syndromes) trial, radial artery access appeared
to reduce the rate of the primary composite outcome (death, MI, stroke, nonCABGrelated
major bleeding) and the individual secondary outcomes of death, MI, stroke, and overall
mortality. However, rates of major bleeding were not lower with radial versus femoral access
in patients with STEMI, though rates of major vascular complications were significantly
reduced (561).
Although arterial closure devices have been associated with decreased femoral access
site bleeding, more rapid hemostasis, and shorter duration of bed rest (251,562,563), their
routine use cannot be advocated specifically to reduce vascular complications after PCI, given
the lack of robust, directionally consistent data on their efficacy and safety compared with
manual compression (564566). Retroperitoneal bleeding should be suspected when the
following are seen: unheralded intraprocedural or postprocedural hypotension and
bradycardia (or tachycardia), high vascular puncture site, and an otherwise unexplained
decrease in hemoglobin. Prompt computed tomographic imaging of the abdomen and pelvis
may be helpful. Conservative management usually suffices, but early vascular interventional
or surgical consultation should be obtained (219).
7.8. Anemia, Bleeding, and Transfusion: Recommendations
CLASS I

1. All patients with NSTE-ACS should be evaluated for the risk of bleeding. (Level of Evidence: C)
2. Anticoagulant and antiplatelet therapy should be weightbased where appropriate and should be adjusted when
necessary for CKD to decrease the risk of bleeding in patients with NSTE-ACS (522,697,698). (Level of Evidence: B)
CLASS III: NO BENEFIT

1. A strategy of routine blood transfusion in hemodynamically stable patients with NSTE-ACS and hemoglobin levels
greater than 8 g/dL is not recommended (699703). (Level of Evidence: B)
Anemia in patients with ACS is associated with an increased risk for Holter monitor _detected recurrent ischemia and for
MACE, with greater anemia correlating with greater risk (704708). In 1 large analysis of multiple studies, the risk of
adverse outcome was higher in patients with NSTE-ACS with hemoglobin levels <11 g/dL (704). The potentially
detrimental effects of severe anemia include decreased myocardial oxygen delivery and increased MVO 2 related to
maintenance of a higher cardiac output (704,709,710). Patients with anemia are less likely to be treated with aspirin,
and patients with ACS and anemia are likely to have more bleeding complications with PCI (711). This has been
correlated with increased short-term risk of MACE outcomes, including mortality; long-term risk remains controversial
(712717). The ACUITY study suggests that the risk of mortality associated with bleeding is at least as great as that
associated with procedure-related or spontaneous MI (718).
Major bleeding is a coprimary endpoint in many trials and is a consideration when assessing the net clinical benefit
of a new drug. A universal definition of bleeding has been proposed to assist clinicians (547,719721). The incidence
of major bleeding in patients with ACS varies widely (0.4% to 10%) (715,722) owing to differing definitions of major
bleeding, patient populations, anticoagulation regimens, and PCI or CABG. Factors in patients with ACS related to an
increased bleeding risk include older age, female sex, lower body weight, history of prior bleeding and/or invasive
procedures, anemia, use of GP IIb/IIIa inhibitors or thrombolytics, and CKD (522,711,713715,722,723). Nonweightbased dosing of anticoagulants and dosing of antithrombin and antiplatelet medications that are not adjusted for CKD
are associated with an increased risk of bleeding (522,697,698). Bleeding is related to adverse outcomes because it
may be a marker of underlying disease, such as occult malignancy; leads to cessation of antithrombin and antiplatelet
therapy; may prompt transfusion, which itself may have adverse effects; can cause hypotension; and, if intracranial,
can be fatal (724). Proton pump inhibitors decrease the risk of upper GI bleeding, including in patients treated with
DAPT. Proton pump inhibitors are used in patients with a history of prior GI bleeding who require DAPT and are an
option in patients at increased risk of GI bleeding
(26,430).
Evaluation of the risk of bleeding includes a focused history of bleeding symptoms, identification of predisposing
comorbidities, evaluation of laboratory data, and calculation of a bleeding risk score (688,716,725). Approximately 15%
of all patients with NSTE-ACS and 3% to 12% of those not undergoing CABG receive blood transfusion (702). Rates vary
widely and are closer to the lower figure but increase in association with factors such as coronary intervention,
anticoagulant/antithrombotic therapy, older age, female sex, anemia, renal insufficiency, and frailty. Tissue
oxygenation does not change or may actually decrease with transfusion (722). Blood transfusion in patients with ACS is
associated with an increased risk of adverse outcome, including death (702704). A restrictive transfusion strategy
leads to an outcome that is at least as good, if not better, than a
liberal transfusion strategy (699,700). An analysis of a large ACS registry found no benefit from blood transfusion in
patients with a nadir hematocrit >24% (702). In a meta-analysis of 10 studies of patients with AMI, transfusion versus
no transfusion was associated with an increase in all-cause mortality (18.2% versus 10.2%; p<0.001) and subsequent
MI rate (RR: 2.0; 95% CI: 1.06 to 3.93; p0.03) (726). A restrictive approach to transfusion generally consists of no
routine transfusion for a haemoglobin level >7 g/dL to 8 g/dL (699,700,727). A restrictive approach to blood transfusion
is advocated by the American Association of Blood Banks (700) and the European Society of Cardiology (727). On the
basis of data available at the time of publication, a strategy of routine liberal blood transfusion in hemodynamically
stable patients with NSTE-ACS and mild to moderate anemia is not recommended.
7.9. Thrombocytopenia
The incidence of thrombocytopenia in patients with ACS varies from 1% to 13%. In 1 large prospective registry, one
third of patients treated with prolonged heparin therapy developed some degree of thrombocytopenia (728).
Independent risk factors for the development of thrombocytopenia include lower baseline platelet count, older age,

ACS, cardiac or vascular surgery, intravenous UFH or both UFH and LMWH, duration of heparin therapy, and low body
mass index (728730). The risk of thrombocytopenia is increased in patients treated with abciximab and, to a lesser
degree, with eptifibatide or tirofiban (731734).
Thrombocytopenia on presentation or related to antithrombotic therapy is associated with significantly increased risk of
thrombotic events, MI, major bleeding, and in-hospital mortality in patients with and without ACS (728731,735739).
The OR for development of these endpoints with thrombocytopenia (compared to without thrombocytopenia) is 2 to 8.
Data from the CATCH (Complications After Thrombocytopenia Caused by Heparin) registry identi fied a platelet count
nadir of 125 _109/L as a threshold, below which there is a linear augmentation in probability of bleeding (740). Results
from CATCH highlighted that thrombocytopenia and heparin-induced thrombocytopenia are often not diagnosed (728).
Thrombocytopenia is generally a contraindication for GP IIb/IIIa inhibitor therapy; direct thrombin inhibitors are often
considered in preference to UFH or LMWH in patients with thrombocytopenia.