Accepted Manuscript

Anticoagulation in acute coronary syndrome-state of the art

Michel Zeitouni, Mathieu Kerneis, Tarek Nafee, Jean-Philippe

Collet, Johanne Silvain, Gilles Montalescot

PII: S0033-0620(18)30021-5
DOI: https://doi.org/10.1016/j.pcad.2018.01.004
Reference: YPCAD 861
To appear in:
Received date: 10 January 2018
Accepted date: 10 January 2018

Please cite this article as: Michel Zeitouni, Mathieu Kerneis, Tarek Nafee, Jean-Philippe
Collet, Johanne Silvain, Gilles Montalescot , Anticoagulation in acute coronary syndrome-
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 ACCEPTED MANUSCRIPT
Anticoagulation in Acute Coronary Syndrome-
State of the Art

Michel Zeitouni1, Mathieu Kerneis1,2, Tarek Nafee2, Jean-Philippe Collet1, Johanne Silvain1,
Gilles Montalescot1

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Sorbonne University, ACTION Group, INSERM UMRS 1166, Institut de Cardiologie, Hôpital

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Pitié-Salpêtrière (AP-HP), Paris, France

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2

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PERFUSE Study Group, Division of Cardiovascular Medicine, Department of Medicine, Beth
Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

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Short Title : Anticoagulation in ACS

Conflict of Interest/Disclosures: None

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Key Words: Anticoagulation, acute coronary syndrome, anticoagulants, anti-platelet therapy,

percutaneous coronary intervention
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Address for correspondence:

*Pr Gilles MONTALESCOT,
ACTION Group,
Institut de Cardiologie,
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Pitié-Salpêtrière Hospital,
47-83 bd de l'Hôpital,
75013 Paris,
Telephone: +33 142163007
Fax: +33 142162931
E-mail: gilles.montalescot@psl.aphp.fr
 ACCEPTED MANUSCRIPT
Abbreviations

ACS: acute coronary syndrome

AHA: American Heart Association

CV : Cardiovascular

ESC: European Society of Cardiology

LMWH: Low molecular weight heparin

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MI : Myocardial infarction

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NACE: net adverse clinical events

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NSTEMI: non-ST-segment elevation myocardial infarction

PCI: percutaneous coronary intervention

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STEMI: ST elevation myocardial infarction
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UFH: unfractionated heparin
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Short Abstract
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Early intravenous anticoagulation is the corner stone treatment of patients admitted with an acute
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coronary syndrome: it antagonizes the ongoing coronary thrombosis and facilitates the
percutaneous coronary intervention, hence a reduction of mortality and acute stent thrombosis.
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Unfractionated heparin, enoxaparin, bivalirudin and fondaparinux have been extensively studied
in large randomized control trials and meta-analyses with the same objective: reducing the
ischemic burden without hiking hemorrhagic events. This conundrum is evolving along the
generalization of the radial-artery access, the use of potent P2Y12 and the trend towards a
tailored approach regarding the ischemic and bleeding balance. In this systematic review, we
aimed at presenting the evidence based data and strategies for each anticoagulant in the setting of
acute coronary syndrome with and without ST-segment elevation.
 ACCEPTED MANUSCRIPT

Anticoagulation, in addition to antiplatelet therapy, is the first-line treatment of patients

admitted for an acute coronary syndrome (ACS) (1-4). The rationale for their use is two-fold: 1)

to antagonize the ongoing thrombosis cascade, and 2) to facilitate primary percutaneous coronary

intervention (PCI) by reducing procedure related complications (5-6). In the last two decades,

several large randomized controlled clinical trials have evaluated the efficacy and safety of pre-

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hospital and periprocedural administration of unfractionated heparin (UFH), enoxaparin,

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fondaparinux and bivalirudin among ACS patients to reduce cardiovascular (CV) mortality. The

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balance between the occurrence of ischemic and hemorrhagic events associated with the different

anticoagulant regimen remains a conundrum, since both are associated with increased short and

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long-term mortality (7). Therefore, the choice of anticoagulant is still an ongoing debate, as
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reflected in the most recent European Society of Cardiology (ESC) 2017 guidelines for STEMI

management: while the administration of UFH is a class I recommendation with the lowest level
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of evidence, bivalirudin and enoxaparin share the same IIa class of recommendation, with
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substantial evidence based support (1). The aim of this review was to provide a current state of

the art review of the literature regarding the different anticoagulation strategies available in ACS.
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Anticoagulation in ACS: Healing the Thrombosis and Optimizing the PCI

ACS is caused by an acute complete or incomplete coronary thrombosis resulting from a

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vascular, cellular and plasmatic response to atherosclerotic plaque rupture or erosion. Ulceration

of the coronary intima and media exposes the collagen and von Willebrand Factor from the

extracellular matrix of the injured endothelium, provoking vasoconstriction and platelet

activation. This phenomenon is self-sustained by continuous inter-platelet recruitment and leads

to the expression of glycoprotein IIb/IIIa, thromboxane A2, adenosine diphosphate and thrombin

(5-7). Thrombin converts fibrinogen into fibrin, which forms the framework of the clot, enabling
 ACCEPTED MANUSCRIPT
its growth and stabilization that will either lead to in-situ occlusion or distal embolization. Thus,

primary PCI is performed in a highly thrombotic setting, with an increased risk of early ischemic

complications, such as acute stent thrombosis. Further, by eroding and injuring the coronary

vessel, PCI itself is associated with activation of platelet aggregation and of the coagulation

cascade. This highlights the necessity of a rapid and efficient antithrombotic therapy, to prevent

platelet activation and adhesion with cyclooxygenase and P2Y12 inhibitors, and to block the

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thrombin pathway with anticoagulant drugs.

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UFH is a sulfated muco-polysaccharide with a molecular weight ranging from 4000 to

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30,000 Daltons that binds with anti-thrombin III (ATIII) and enables a direct inhibition of

thrombin and factor Xa . Of note, this inhibition of factor Xa prevents the activation of

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prothrombin into thrombin (8). Because of its chain weigh variability, UFH use requires the
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monitoring of the anti factor Xa activity or Activated Clotting Time. In contrast, enoxaparin,

synthesized by fractionation and depolymerization of heparin has a lighter structure (between

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3000 and 5000), with a longer half-life. It enables a more stable and predictable effect, and less
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heparin induced thrombocytopenia (9-10). The intravenous use of enoxaparin in PCI does not

need monitoring and the drug does not accumulate in case of renal insufficiency which is not a
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contraindication (11). Bivalirudin is a direct thrombin inhibitor administered by intravenous

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continuous perfusion during PCI, with a rapid anticoagulant effect that does not need monitoring

and disappears when the perfusion is stopped (12). Fondaparinux is a synthetic pentasaccharide
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derivated from cleavage of heparin sulfate, acting as a direct inhibitor of factor Xa inhibitor (13).

There is very limited experience with fondaparinux in PCI.

Heparin, Enoxaparin, Bivalirudin: Does the optimal treatment exist for STEMI patients?
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As the most affordable and oldest anticoagulant, UFH is the most used and preferred drug in ST

elevation myocardial infraction (MI; STEMI). However, here is no randomized controlled trial

evaluating UFH versus placebo among STEMI patients. The first evidence based benefits were

provided by trials that only enrolled patients with unstable angina or non-ST-segment elevation

MI (NSTEMI). Thus, UFH has been the controlled arm of all the anticoagulation trials evaluating

new drugs among STEMI patients, as an historical and practical gold standard. In fact, use of

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UFH in the acute phase of STEMI is still supported with the highest class recommendation by

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American and European guideline committees as a reflection of the common practice (1-4).

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However, UFH has some important limitations. First, high variability in chain weight and

manufacture characteristics lead to poorly defined optimal dosage, with activated clotting time

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frequently out of therapeutic range. This intra and inter-individual variability has direct
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consequences on both ischemic and bleeding outcomes (14-15). Second, after discontinuation,

UFH has demonstrated a pro-thrombotic effect, through a biological rebound in thrombin

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generation (16). Third, heparin-induced thrombocytopenia is a serious and life-threatening

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complication, particularly in the high risk context of MI.

Therefore, the ATOLL trial (Acute ST-elevation myocardial infarction Treated with
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primary angioplasty and intravenous enoxaparin Or unfractionated heparin to Lower ischemic

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and bleeding events at short- and Long-term follow-up) has compared the efficacy of intravenous

enoxaparin to UFH among primary PCI patients (n=910) (17). Investigators reported a non-
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significant reduction of the primary composite endpoint of death, complication of MI, procedure

failure, or major bleeding at 30 days (RR=0.83, 95% [0.68-1.01], p=0·06). Enoxaparin also

provided a 40 % reduction on the secondary composite endpoints of death, recurrence and

complication of MI (RR = 0.59, 95 % [0.38 – 0.91], p=0.015). Head to head per-protocol analysis

found that the primary endpoint, the mortality rate and the bleeding events were reduced in the

enoxaparin group (18) (RR=0.76 95%CI [0.62 – 0.94], p=0.012). These findings were confirmed
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by other randomized controlled trials, where enoxaparin administration was associated with a

reduced rate of death and re-infarction without an increased rate of bleeding events (19-20)

(Figure 1a and 1b). Thus, there is strong evidence that routine use of intravenous enoxaparin for

patients admitted with STEMI could improve both ischemic and bleeding outcomes. As a result,

it is currently supported by a level IIa in latest ESC guidelines (1).

In 2003, the REPLACE-2 trial (Randomized Evaluation in PCI Linking Angiomax

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to Reduced Clinical Events) was one of the first to compare bivalirudin to UFH plus glycoprotein

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platelet inhibitors (GPI). This trial demonstrated a similar efficacy among treatment arms, with a

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significant reduction of bleeding in the bivalirudin group at 30 days (21). Subsequently, the

HORIZONS-AMI trial (Harmonizing Outcomes with Revascularization and Stents in Acute

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Myocardial Infarction) compared bivalirudin to UFH plus systematic GPI in 3600 patients.
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Bivalirudin significantly reduced the rate of net adverse clinical events (NACE) at one month

(RR = 0.76, 95 %CI [0.63–0.92], p = 0.005). This finding was primarily driven by a reduction in
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major bleeding events in the bivalirudin group (RR=0.60, 95% CI [0.46–0.77], P <0.001) and a
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slight reduction in cardiovascular death, persistent at 1 and 3 years (21-22). Importantly, patients

of the bivalirudin group suffered from a four-fold increase in acute stent thrombosis (23).
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Nonetheless, these results led to a class I recommendation with a B level of evidence in the
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subsequent update to the European and American STEMI guidelines in 2012 and 2013 (2)(24).

The EUROMAX trial (European Ambulance Acute Coronary Syndrome Angiography) published
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in 2013 was the first to compare bivalirudin to UFH in the era of radial-artery PCI access and

stronger P2Y12 inhibition. GPI was optional for both groups, but was used in 11 % of bivalirudin

patients versus 69 % of UFH patients. Bivalirudin significantly reduced the primary endpoint of

death and major bleeding. Again, this was primarily driven by a 50 % reduction in bleeding

events, without significant differences in secondary ischemic outcomes of death, re-infarction,

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and target vessel revascularization. As observed in the HORIZON-AMI Trial, patients in the

bivalirudin arm suffered from a five-fold increase of acute stent thrombosis.

In 2014, the HEAT-PPCI (How Effective Are Antithrombotic Therapies in Primary

Percutaneous Coronary Intervention) was the first trial to report superiority of UFH over

bivalirudin on NACE, with less ischemic events and similar bleedings (25). In this study,

investigators assigned 1800 patients to receive either bivalirudin or UFH, with optional and

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unfrequent use of GPI in both groups (13 % in bivalirudin group and 15 % in UFH group). The

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primary efficacy outcome was the proportion of major adverse cardiovascular events, and the

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primary safety outcome was the rate of major bleeding at 28 days. Patients receiving bivalirudin

suffered from an increased rate of ischemic events (RR = 1.52, 95 %CI [1.09–2.13]), which was

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primarily driven by significant increase in recurrent MI and, again, an increased rate of stent
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thrombosis. In the BRIGHT trial (Bivalirudin in Acute Myocardial Infarction vs Heparin and

GPI Plus Heparin), 2400 patients were randomized to one of 3 groups: 1) bivalirudin 2) heparin
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alone and 3) heparin plus tirofiban (26). The rate of NACE was lower in the bivalirudin group,
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mainly driven by a reduction in bleeding events. Interestingly, in this study, patients in the

bivalirudin group did not experience an increase in acute stent thrombosis. Finally, in the
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MATRIX trial (Minimizing Adverse Hemorrhagic Events by Transradial Access Site and
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Systemic Implementation of Angiox), 7200 patients with ACS were randomized to receive either

UFH or bivalirudin. The two primary outcomes (major adverse CV events and net adverse
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clinical events) were unchanged with bivalirudin as compared with UFH. Patients on bivalirudin

had a reduction of the secondary endpoint of major bleeding and mortality (27). These conflicting

results led to a downgrade of the class of recommendation to IIa in the most recent update of the

ESC guidelines (1).

Following the update to the ESC guidelines, the results of VALIDATE-SWEDEHEART

trial (Bivalirudin versus Heparin in ST-Segment and Non–ST-Segment Elevation Myocardial

 ACCEPTED MANUSCRIPT
Infarction in Patients on Modern Antiplatelet Therapy in the Swedish Web System for

Enhancement and Development of Evidence-based Care in Heart Disease Evaluated according

to Recommended Therapies Registry Trial) were released. This was a registry-based randomized

open-label clinical trial which evaluated the efficacy and safety of bivalirudin compared to UFH

in patients with acute MI (STEMI and NSTEMI). This trial demonstrated no significant

difference in ischemic or bleeding events between the treatment arms at 180 days. The treatment

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effect was consistent among subjects with STEMI and NSTEMI (28).

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The observed treatment benefit of Bivalirudin in reducing bleeding events was postulated to be

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associated with the use of GPI in the control arms. In trials where GPIs were not used with UFH,

no reduction in bleeding was observed with bivalirudin treatment (28-29) (figure 2a and 2b).

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Meta-Analyses Clear the Debate (Central Figure)

In an updated meta-analysis of 10,350 patients from five randomized clinical trials,

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investigators showed that bivalirudin failed to show any benefits on mortality, whereas a
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concerning trend of increased MI and increased acute stent thrombosis was noted (30 – 31). Of

note, the MATRIX trial demonstrated that this hike of ischemic events could not be overcome by
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post-PCI bivalirudin infusion (32).

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In contrast, two meta-analyses brought clarity to the comparison of enoxaparin with UFH. In

2011, Navarese et al. performed a meta-analysis including 10 studies that enrolled 16 000
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patients admitted for primary PCI. Low molecular weight heparin (LMWH) use was associated

with a significant reduction in mortality (RR = 0.51 95%CI [0.41-0.64]) and major bleeding (RR

= 0.68, 95%CI[0.49-0.94]) (33). Similarly, in 2012, Silvain et al. performed a meta- analysis of

23 studies that enrolled 30 000 patients admitted for both elective and primary PCI. In this

analysis, enoxaparin was associated with efficacy and safety benefits particularly among patients

who underwent primary PCI with a significant reduction in mortality (RR = 0.52 95% CI(0.42 -
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0.64)) and major bleeding (RR= 0.72, 95% CI[0.56 - 0.93]) (34). In spite of many arguments

currently supporting use of intravenous enoxaparin – including the medical cost - the optimal

anticoagulation for primary PCI is still an ongoing debate. Only a direct and head to head

comparison between intravenous enoxaparin and intravenous bivalirudin could answer this

crucial question.

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Anticoagulation in NSTEMI: Same Rationale, More Evidence.

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Unfractionated Heparin

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UFH remains the most commonly used anticoagulant in NSTEMI, in the setting of medical

treatment or differed early PCI in the 24 – 48 hours. In 1996, a meta-analysis of 6 randomized

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trials performed by Oler et al. demonstrated that addition of heparin to aspirin in patients with
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unstable angina and elevated cardiac enzymes resulted in a 33 % reduction of death and ischemic

outcomes (35). This was confirmed by a second meta-analysis of 12 trials, involving a total of
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17157 patients assessing both UFH and LMWHs in NSTEMI that showed similar results (RR =
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0.53 [0.38-0.73]) (36). Thus, prescription of UFH is a class IB recommendation of both American

and European 2014 and 2015 NSTEMI guidelines (3) (4).

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Enoxaparin
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In 2000, the ESSENCE trial (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave

Coronary Events) was one of the first to randomize patients that were admitted for unstable
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angina or non-Q-wave MI to receive either UFH or enoxaparin (37). While this study was

performed in a period with limited access to PCI, treatment with enoxaparin reduced the

composite of death, recurrent MI and invasive procedures at 30 days (OR = 0.80, 95% CI [0.67 to

0.96]), with a sustained benefit at one year. In the A-to-Z trial performed in the setting of

NSTEMI with early PCI, no significant differences in efficacy and safety outcomes were

observed between the enoxaparin and UFH arms (38). In 2006, the large scale randomized trial
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SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization and

Glycoprotein IIb/IIIa Inhibitors) enrolled 10 000 moderate risk patients with NSTEMI who

underwent early PCI (39). Although no difference in ischemic outcomes was observed,

enoxaparin was associated with a significant increase in bleeding complications among patients

who also received UFH prior to PCI. The SYNERGY trial taught us that, in general, switching

anticoagulant strategies should be avoided.

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Eventually, in a systematic overview totaling 20 000 patients from 6 randomized trials, Petersen

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et al described a reduction of combined death and myocardial infraction in patients treated with

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enoxaparin compared to UFH, with similar major bleeding outcomes (40). Those results were

confirmed by a meta-analysis published in 2007, showing a significant reduction of death and net

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adverse events for NSTEMI patients treated by enoxaparin versus UFH (41). Finally, since the
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development of stronger P2Y12 and modern PCI techniques, a meta-analysis of 23 trials that

enrolled 30,966 patients demonstrated superiority of enoxaparin regarding ischemic outcomes

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and bleeding prevention (34). As a result of these studies, prescription of enoxaparin in NSTEMI
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patients is recommended with a class I-A in AHA 2014 guidelines and I-B in 2015 ESC

guidelines. (3-4)
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Fondaparinux
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The OASIS-5 (The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes) trial is

one of the rare randomized trials directly comparing two modern anticoagulants: enoxaparin and
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fondaparinux. Investigators reported that fondaparinux led to a reduction of bleeding

complications (HR =0.62[0.54-0.72]) and mortality (HR = 0.83[0.71 – 0.97]) in patients with

NSTE-ACS (42). However, it was associated with an increase in catheter and periprocedural

thrombosis, requiring adjuvant infusion of UFH during PCI in patients pre-treated with

fondaparinux (43). Those results led to a class I-B of recommendation in 2014 and 2015 AHA

and ESC guidelines for NSTEMI (3-4).

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Of interest, fondaparinux, was also evaluated among patients with STEMI. In 2006, investigators

of the OASIS-6 randomized 12 000 subjects with STEMI to receive either UFH or fondaparinux

whatever the type of reperfusion. Importantly, only 30 % of the study population was treated by

primary PCI. While fondaparinux reduced the rate of death and bleeding in the overall study

population, it showed an alarming rate of periprocedural catheter thrombosis (0 vs 22; P<0.001)

and coronary complication including new acute thrombosis and no reflow (225 vs 270; P=0.04)

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in the subgroup treated by primary PCI (44). As a result, the use of fondaparinux is a class III

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recommendation in international guidelines for STEMI, and should not be used.

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Bivalirudin

In 2007, the ACUITY trial (the Acute Catheterization and Urgent Intervention Triage Strategy)

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compared three anticoagulation strategies for NSTEMI patients: 1) bivalirudin monotherapy 2)
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bivalirudin plus GPI and 3) UFH plus GPI (45). The three groups had similar rates of ischemic

outcomes, and despite a reduction of major bleedings in bivalirudin group (RR= 0.52, [0.40–
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0.66], bivalirudin failed to show a significant reduction of adverse events at 30 days (RR = 0.87
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[0.75–1.00]. In 2011, ISAR REACT 4 (the Intracoronary Stenting and Antithrombosis

Research) randomized trial showed similar results when comparing bivalirudin to UFH plus
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Abciximab. Those results led to a class I-B recommendation for bivalirudin use in AHA 2014
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guidelines and I-A in ESC 2015 guidelines for NSTEMI.

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Choosing the Best Anticoagulant for the Right ACS patient: a Need for Tailored Strategies

Radial or femoral access

The choice of access for PCI is important in immediate and short term consequences, and should

be taken into account for choosing the right anticoagulant. In a meta-analysis totaling 12 trials

and 5,055 patients treated by all regimens of anticoagulants, radial approach was associated with
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decreased risk of 50 % of both mortality and major bleeding (46). According to a large meta-

analysis including patients treated by bivalirudin and UFH with or without GPI, bivalirudin use

could counter-balance the excess of hemorrhagic risk when PCI is performed via femoral access.

In contrast, the safety benefit of bivalirudin on hemorrhagic events is less obvious when radial

access is used or in the absence of GPIs (47).

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Delay to the Catheterization Laboratory & Fibrinolysis

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Similarly, delay before revascularization or impossibility to perform a PCI should be taken into

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account in the choice of anticoagulation regimen. Enoxaparin has been the most studied

anticoagulant on top of fibrinolysis for STEMI patients, and provided strong evidence of

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efficiency and safety (48-49). As a result, intravenous followed by sub-cutaneous enoxaparin is
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highly recommended (class I-A) by latest European and American guidelines for patients treated

by fibrinolysis for STEMI. Interestingly, in OASIS-6, fondaparinux significantly reduced the

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composite of death or myocardial re-infarction in the subgroup of patients who could not benefit
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from PCI without increasing severe bleedings or strokes compared to UFH (50).
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Vision for the Future

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The lesson taught by recent large randomized trials and meta-analyses is the crucial need to

develop trials evaluating strategies and not just drugs, especially in the current setting of modern
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techniques and stronger P2Y12 inhibitors. Of note, trials evaluating ticagrelor and prasugrel in

STEMI mostly used UFH and enoxaparin as periprocedural anticoagulants, while bivalirudin was

used in less than 5 % of patients (51-52). In contrast with dual antiplatelet therapy management,

tailored strategies for procedural anticoagulation in STEMI are poorly developed and their

applicability needs improvement and modernization. While several scores are available to guide

physicians within the ischemic and bleeding balance none of them have been prospectively
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validated (53-54). These scores mainly include age, renal function and admission characteristics.

This pathway should be developed in the future, to enable a more accurate, efficient and safe

anticoagulant therapy for MI.

Conclusion

Intravenous anticoagulation is the standard of care and first line treatment of patients admitted for

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a myocardial infraction with and without ST elevation. Its objective is to control the ongoing

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coronary thrombosis, and facilitate PCI. In STEMI, unfractionated heparin, enoxaparin and

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bivalirudin are the three commonly used anticoagulants, with the higher class of recommendation

for UFH. In NSTEMI, Fondaparinux is an additional choice, but with the need of a

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periprocedural UFH dose during PCI. Bivalirudin prescription might lead to less bleeding events,
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but more acute stent thrombosis, and its evidence based benefits are unclear in the current setting

of modern therapies. Enoxaparin use has been constantly associated with better ischemic and
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bleeding outcomes in both STEMI and NSTEMI settings. Development of trials comparing
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strategies that take into account the antiplatelet regimen and the ischemic-bleeding balance are

warranted to allow a tailored approach of periprocedural anticoagulant therapies for primary PCI
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in myocardial infarction.
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FIGURES

Central Figure: Relative percentage of adverse clinical events according to anticoagulation

strategies in patients admitted for STEMI and NSTEMI. * indicates p value < 0.05

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Figure 1a: Major adverse cardiovascular events in trials comparing enoxaparin to UFH in
STEMI

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Figure 1b: Major bleeding events in trials comparing enoxaparin to UFH in STEMI

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Figure 2a: Major adverse cardiovascular events in trials comparing bivalirudin to UFH with or
without GPI in STEMI

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Figure 2b: Major bleeding events in trials comparing bivalirudin to UFH with or without GPI in
STEMI

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