Advertisement

Anticoagulants and Primary PCI

  • Fahim H. Jafary
Open Access
Chapter

Abstract

Percutaneous coronary interventions (PCI) mandate usage of anticoagulants to facilitate a successful and safe procedure. This chapter reviews commonly used anticoagulant regimens used for PCI with tailored guidance for the acute setting, in particular primary PCI for ST-elevation myocardial infarction (STEMI).

9.1 Introduction

Percutaneous coronary interventions (PCI) mandate usage of anticoagulants to facilitate a successful and safe procedure. This chapter reviews commonly used anticoagulant regimens used for PCI with tailored guidance for the acute setting, in particular primary PCI for ST-elevation myocardial infarction (STEMI).

9.2 Rationale for the Use of Anticoagulant Therapy

PCI involves a variety of events that cumulatively increase the risk of intra and post procedure thrombosis. These include balloon-induced injury and dissection with exposure of the subendothelial tissue to blood, activation of platelets and the coagulation cascade and implantation of a potentially thrombogenic foreign body (stent) in the coronary circulation. These effects are, of course, more pronounced during PCI for acute coronary syndromes (ACS) where the thrombotic milieu is already “hot” at the outset. Therefore, anticoagulation with antiplatelet and antithrombotic therapy during PCI is considered obligatory. Of note, no placebo-controlled trials of antithrombotic therapy in PCI have ever been conducted, nor will there ever be such a trial. Indeed, the 2017 European Society of Cardiology (ESC) guidelines [1] give anticoagulation (antithrombotic therapy) a class I indication for routine use during STEMI PCI.

9.3 Classes of Anticoagulant

Several classes of anticoagulant regimens are available. Each of these is discussed in detail below.

9.3.1 Unfractionated Heparin and STEMI

Unfractionated heparin (UFH) has been available since the 1930s, and there is, therefore, an extensive generational physician experience with this drug in a variety of clinical settings. Derived from porcine intestine, a bag of UFH contains a heterogeneous mix of polysaccharides with a wide variety of molecular weights (Table 9.1). Only a third of the UFH molecules are biologically active as a result of possessing a key pentasaccharide sequence that is able to bind to antithrombin (AT) [2]. UFH attaches to AT to form a tertiary complex that binds to and inhibits both factor Xa and as IIa (thrombin), thereby inhibiting production and action of thrombin. As UFH inhibits both molecules, its anti Xa:IIa activity ratio is 1:1. In contrast, low molecular weight heparins (LMWH) by virtue of their predominantly shorter chains are only able to bind to AT and hence have primarily anti-Xa activity (Table 9.1).
Table 9.1

Comparative chart of characteristics of various anticoagulants used in the primary PCI setting

Drug

UFH

LMWH

Fondaparinux

Bivalirudin

Molecular weight (kDa)

3–30 (mean 15)

2–10

1.7

2.2

Action

Binds to AT, inhibits IIa and Xa

Binds to AT, inhibits Xa

Binds to AT, inhibits Xa

Directly binds to thrombin

Xa:IIa ratio

1:1

4:1

Pure Xa

Pure IIa

Plasma proteins binding

Extensive

Low

None

 

T ½ after dose

Variable (dose dependent)a

  

25 min

PCI dose

70–100 U/kg (no GPI planned)

50–70 U/kg IV (GPI planned). Target to therapeutic ACT

0.5 mg/kg IV bolus

 

0.75-mg/kg IV bolus, then 1.75-mg/kg/h infusion

Activates platelets

+++

+

HIT

0.5%

<0.1%

Negligible

Negligible

Monitoring

ACTb

Anti Xa levels

?ACT

Anti Xa levelsc

ACTd

Reversal

Protamine

Protamine (partial)

None

None

AT antithrombin, ACT activated clotting time, HIT heparin-induced thrombocytopenia

aHalf-life increases with dose

bACT reflects therapeutic effect

cNo point-of-care options

dACT does not reflect therapeutic effect, only reflects delivery of drug

Some well-known limitations of UFH include its inability to penetrate and bind to clot-bound thrombin, extensive binding by plasma proteins which limit bioavailability, an inherent platelet-activating effect of heparin and complex pharmacokinetics which make the anticoagulation response to a given dose somewhat unpredictable [2]. Despite these limitations unfractionated heparin remains the most widely used antithrombotic agent during PCI, and both the ACCF/AHA [3] and ESC [1] guidelines give UFH a class I recommendation in primary PCI.

There are no comparative dosing trials of UFH in primary PCI and dosing recommendations are somewhat arbitrary. The 2017 ESC guidelines [1] recommend an UFH dose of 70–100 IU/kg intravenous bolus when no glycoprotein IIb/IIIa inhibitor is planned and 50–70 IU/kg bolus with planned glycoprotein IIb/IIIa inhibitor use. It remains unclear whether STEMI patients, given the ongoing thrombotic milieu, should receive the higher end of the dose spectrum of UFH.

9.3.2 Low-molecular Weight Heparins and STEMI

Unlike UFH, LMWH consist of a relatively more homogeneous mix of molecules and have better bioavailability and longer half-life. As a result, LMWH have the advantage of more predictable and consistent anticoagulation compared to UFH. Although extensively studied in the ACS population, there is limited data in the context of STEMI. In the randomized ATOLL trial [4], 910 STEMI patients were randomized to an intravenous bolus of 0.5 mg/kg enoxaparin or standard dose UFH. Although the trial had a strong trend towards benefit favouring enoxaparin (17% relative risk reduction; p = 0.068), it failed to meet the primary endpoint. Moreover, it should be recognized that this was an open label trial, and while a per-protocol analysis that excluded 13% of the study group (for protocol violations) suggested that enoxaparin was statistically superior to UFH, this can be regarded as hypothesis generating at best. Furthermore, > 70% of the study population received a glycoprotein IIb/IIIa inhibitor; therefore it is difficult to extrapolate the data to patients not receiving additional glycoprotein IIb/IIIa inhibitor therapy. Nevertheless, these results do imply that enoxaparin is at least as safe as UFH in the primary PCI setting. The ACCF/AHA guidelines make no recommendations on enoxaparin, but the 2017 ESC guidelines [1] give it a class IIa recommendation (level of evidence A) (Table 9.2). Both the ACCF/AHA [3] and ESC guidelines recommend against the use of fondaparinux, a synthetic pentasaccharide LMWH, during primary PCI given a higher risk of ischemic events and catheter thrombosis in the OASIS-6 trial [5].
Table 9.2

Summary of major societal guidelines on the use of various antithrombotic agents in primary PCI

Drug

ACCF/AHA

ESC

 

Rec.

LOA:

Rec.

LOA

UFH

I

C

I

C

Enoxaparin

No recommendation

IIa

A

Fondaparinux

III

B

III

B

Bivalirudin

I

B

IIa

Ia

A

C

ACCF/AHA American College of Cardiology Foundation/American Heart Association, ESC European Society of Cardiology, Rec recommendation, LOA level of evidence

aIn patients with heparin-induced thrombocytopenia

9.3.3 Direct Thrombin Inhibitors and STEMI

The most widely studied and used direct thrombin inhibitor (DTI) is bivalirudin. Bivalirudin binds reversibly to the catalytic site of thrombin and acts as a competitive inhibitor. Unlike heparins, bivalirudin can bind to clot-bound thrombin, is not bound by plasma proteins and, therefore, has excellent bioavailability. Bivalirudin also blocks thrombin-induced platelet aggregation. The dosing schedule of bivalirudin for STEMI patients undergoing PCI is outlined in Table 9.1. Despite its numerous theoretical advantages, recent randomized trials have failed consistently to demonstrate unequivocal superiority of bivalirudin over unfractionated heparin in the STEMI setting (Table 9.3). The studies do suggest a lowered risk of major bleeding, driven at least partially by reduced access site bleeding. Of note, several trials suggested an increased risk of early stent thrombosis (possibly ameliorated by prolonging the bivalirudin infusion post PCI).
Table 9.3

Summary of randomized trials of bivalirudin vs. heparin in primary PCI

Trial

Year

Treatment

Control

Radial

MACE

Bleeding

ST

HORIZONS-AMI [13]

2007

Bival + pGPI

Heparin + GPI

6%

EUROMAX[14]

2013

Bivala

Heparin

~50%

HEAT-PPCI [15]

2014

Bival

Heparin

80%

No diff

BRIGHT [16]

2015

Bivala

Heparin or heparin + GPI

78%

No diff

No diff

VALIDATE-SWEDEHEART[17]

2017

Bivala

Heparin

90%

No diff

No diff

No diff

Bival bivalirudin, pGPI provisional GP IIb/IIIa inhibitor, MACE major adverse cardiac events, ST stent thrombosis

aBivalirudin infusion continued post PCI

Given the lack of superiority and significantly higher costs, the role of bivalirudin in STEMI remains questionable. This is of particular importance in the current era of using more potent P2Y12 inhibitors (e.g. ticagrelor and prasugrel) and transradial access (which all but eliminates access site bleeding). Society guidelines are somewhat discordant, with the ACCF/AHA guidelines [3] awarding bivalirudin a class IB recommendation in STEMI, while the more updated 2017 ESC guidelines [1] give it a IIa recommendation unless there is a history of heparin-induced thrombocytopenia (class Ib).

9.4 Monitoring of Intensity of Anticoagulation in the Cardiac Catheterization Laboratory

9.4.1 Unfractionated Heparin

The anticoagulation response of UFH is variable and unreliable. Therefore, monitoring the level of anticoagulation using a point-of-care testing device is inherently attractive. The most widely used test to measure the anticoagulant effect of high doses of heparin (levels at which the aPTT would be “immeasurable”) is the activated clotting time (ACT) which has a linear dose-response to heparin concentrations in the very high 1–5 U/mL range and is available as a point-of-care assay. That said, there is lack of robust data to suggest that ACT testing and monitoring is necessary and beneficial. Several studies have questioned the relationship between ACT levels achieved and ischemic complications [6, 7]. Despite its limitations, ACT remains widely used in the cardiac catheterization laboratory to gauge the intensity of heparinization. Indeed, the ACCF/AHA guidelines [3] give monitoring ACT levels and titrating UFH dosing during primary PCI a class I recommendation, though the ESC guidelines are silent on the subject. The ACCF/AHA/SCAI PCI guidelines [8] recommend titrating UFH dosing to target ACT levels (Table 9.4) although these “targets” are largely based on consensus and experience rather than systematic study.
Table 9.4

Effect of various antithrombotic drugs on activated clotting time

Drug

Xa:IIa activity

Effect on ACT

Target ACT (s)

UFH

1:1

Linear ↑

GPI, 300–350 (Hemochron), 250–300 (HemoTech)

No GPI, 200–250 (any device)

Enoxaparin

4:1

Modest ↑

None defineda

Fondaparinux

Pure Xa

No effect

No recommendation

Bivalirudin

Pure IIa

Disproportionate ↑

No recommendationb

UFH unfractionated heparin, ACT activated clotting time, GPI glycoprotein IIb/IIIa inhibitor

aSee text for recommendations

bACT levels do not correlate with therapeutic efficacy; only an indicator of drug delivery

9.4.2 Low Molecular Weight Heparin

Monitoring anticoagulation with enoxaparin is difficult because the ACT does not follow a linear dose-response unlike with UFH. The most definitive assay of enoxaparin’s anticoagulant effect (measuring anti factor Xa activity) is not a readily available laboratory or point-of-care assay. Nevertheless, enoxaparin does moderately prolong the ACT, and several authors have suggested a role of ACT testing to guide enoxaparin therapy in the cardiac catheterization laboratory. One group has proposed a target ACT of 175 s for PCI performed with and 200 s for PCI performed without a glycoprotein IIb/IIIa inhibitor [9]. They also propose that every additional 0.1 mg/kg bolus of intravenous enoxaparin may be expected to increase the ACT by 10 s [10]. Of note, this has not been systematically studied for outcomes and remains a rough guide at most.

9.4.3 Bivalirudin

Bivalirudin raises the ACT usually in the “super therapeutic” range (often >300 s). However, studies with bivalirudin have reproducibly demonstrated no relationship between ACT levels and either bleeding or ischemic complications, quite in contrast to heparin. Thus, it may be reasonable to check an ACT once following the bolus of bivalirudin to confirm that the drug was delivered, thereby avoiding inadvertent failure of drug administration (e.g. intravenous line occlusion and other errors which may easily occur in the emergency setting). However, there is no role of sequentially testing ACT for the above-mentioned reasons. It is important to note, though, that the pivotal bivalirudin trials gave an additional dose of 0.3 mg/kg bolus if the post bolus ACT was <225 s. However, the ACCF/AHA or ESC guidelines do not specifically recommend this practice.

9.5 Approach to the Patient Who Has Received Anticoagulation Prior to Primary PCI

Although relatively unusual for a patient to receive parental anticoagulation prior to arrival to the cardiac catheterization laboratory for primary PCI, historically, some emergency room (ER) physicians have routinely administered UFH in the ER to STEMI patients. Also, in a “rescue” or “salvage” PCI setting, a patient may have received full-dose thrombolytic therapy prior to arriving to the laboratory. Furthermore, a situation may arise in which a patient admitted with an acute coronary syndrome “heats up” and progresses to STEMI despite receiving some sort of anticoagulation therapy. Table 9.5 shows the therapeutic options for the patient who arrives to the cardiac catheterization laboratory with anticoagulant therapy on board. Table 9.6 summarizes the approach to dosing if prior therapy has been administered.
Table 9.5

Therapeutic options for anticoagulation during primary PCI based on pretreatment status

Pretreatment

Therapeutic options during primary PCI

None

UFH

Enoxaparin

Bivalirudin

UFHa

UFH

Bivalirudin

Enoxaparin

Enoxaparina

Fondaparinux

UFH

GPI

UFH—check ACT and adjust dose (see Table 9.1)

Thrombolyticb

UFH—check ACT and adjust dose

UFH unfractionated heparin, GPI glycoprotein IIb/IIIa inhibitors

aNo good “formula” to convert dosing of UFH to enoxaparin and vice versa

bSalvage” PCI setting

Table 9.6

Dosing of anticoagulation therapy in the cardiac catheterization laboratory in patients receiving anticoagulation prior to arrival

Drug

On treatment

Not on treatment

UFH

Check ACT on arrival

“Top-up” UFH according to ACT

70–100 U/kg (no GPI planned)

50–70 U/kg IV (GPI planned). Target to therapeutic ACT

Enoxaparin

Last SC dose <8 h—no additionala

Last SC dose >8 h—additional bolus 0.3 mg/kg IV bolus

0.5 mg/kg IV bolus

Fondaparinux

70–100 U/kg (no GPI planned)

50–70 U/kg IV (GPI planned)

Target to therapeutic ACT [18]

Bivalirudin

0.5 mg/kg bolus; ↑ drip to 1.75 mg/kg/h

0.75 mg/kg bolus; 1.75 mg/kg/h drip

ACT activated clotting time, UFH unfractionated heparin, SC subcutaneous, GPI glycoprotein IIb/IIIa inhibitor

aIf patient received <2 doses, assume no steady state and administer additional bolus

As a rule of thumb, if a patient has been on therapy, then a “booster” dose of the anticoagulant is recommended. On the other hand, if a patient has received no prior therapy, then the full dose of the anticoagulant should be administered. It is important to note that “on therapy” for these purposes assumes a steady state of the drug. For enoxaparin, which is commonly used in the acute coronary syndrome setting, this means at least two doses have been administered. Hence if a patient arrives to the cardiac catheterization laboratory after receiving one dose of enoxaparin in the ward, it is safer to administer an additional dose of enoxaparin (Table 9.6). Note that no good “formula” exists to switch previous therapy with UFH to enoxaparin and vice versa when a patient arrives to the cardiac catheterization laboratory.

9.6 Role of Anticoagulation Following Successful PCI

By and large, anticoagulation should be stopped after a successful procedure. Data suggests that extending the anticoagulation with post procedure UFH or LMWH does not reduce ischemic complications but does increase bleeding risks [11, 12]. Therefore barring some compelling indication (very high thrombus burden or left ventricular thrombus) UFH or LMWH should not be continued after primary PCI. Similarly routine ACT check post procedure likely has little cumulative value other than to determine when the access sheath may be removed in the case of femoral access. In the case of bivalirudin, trials have suggested an increased risk of acute stent thrombosis following drug cessation at the end of the procedure (Table 9.3). This may be related to the very short half-life of the drug with a rapid wash-out. Prolonging the infusion may help mitigate that risk, although the data shows mixed results.

9.7 Summary

Anticoagulation with an antithrombotic drug is considered mandatory during PCI. UFH remains the most widely used antithrombotic agent during primary PCI and ideally should be dosed to a target therapeutic ACT. Enoxaparin may be a reasonable alternative in primary PCI, although advantage for this over heparin is debatable. Bivalirudin has many theoretical advantages over the heparins; however, trials in the primary PCI setting have failed to show superiority of bivalirudin for ischemic events, although bleeding events (driven partially by access site bleeding) are reduced. Furthermore, acute stent thrombotic events may be increased with bivalirudin, and consequently use of this drug is less widespread. Anticoagulation dosing in the cardiac catheterization laboratory needs to be tailored according to prior therapy and titrated (at least in the case of UFH) either empirically or to a therapeutic ACT where monitoring is available.

References

  1. 1.
    Ibanez B, James S, Agewall S, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119–77.CrossRefPubMedGoogle Scholar
  2. 2.
    De Caterina R, Husted S, Wallentin L, et al. Parenteral anticoagulants in heart disease: current status and perspectives (section II). Position paper of the ESC Working Group on thrombosis-task force on anticoagulants in heart disease. Thromb Haemost. 2013;109(5):769–86.CrossRefPubMedGoogle Scholar
  3. 3.
    O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;127(4):529–55.CrossRefPubMedGoogle Scholar
  4. 4.
    Montalescot G, Zeymer U, Silvain J, et al. Intravenous enoxaparin or unfractionated heparin in primary percutaneous coronary intervention for ST-elevation myocardial infarction: the international randomised open-label ATOLL trial. Lancet. 2011;378(9792):693–703.CrossRefPubMedGoogle Scholar
  5. 5.
    Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006;295(13):1519–30.CrossRefPubMedGoogle Scholar
  6. 6.
    Brener SJ, Moliterno DJ, Lincoff AM, Steinhubl SR, Wolski KE, Topol EJ. Relationship between activated clotting time and ischemic or hemorrhagic complications: analysis of 4 recent randomized clinical trials of percutaneous coronary intervention. Circulation. 2004;110(8):994–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Chew DP, Bhatt DL, Lincoff AM, et al. Defining the optimal activated clotting time during percutaneous coronary intervention: aggregate results from 6 randomized, controlled trials. Circulation. 2001;103(7):961–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124(23):2574–609.CrossRefPubMedGoogle Scholar
  9. 9.
    Cavusoglu E, Lakhani M, Marmur JD. The activated clotting time (ACT) can be used to monitor enoxaparin and dalteparin after intravenous administration. J Invasive Cardiol. 2005;17(8):416–21.PubMedGoogle Scholar
  10. 10.
    Marmur JD, Bullock-Palmer RP, Poludasu S, Cavusoglu E. Avoiding intelligence failures in the cardiac catheterization laboratory: strategies for the safe and rational use of dalteparin or enoxaparin during percutaneous coronary intervention. J Invasive Cardiol. 2009;21(12):653–64.PubMedGoogle Scholar
  11. 11.
    Riaz IB, Asawaeer M, Riaz H, et al. Optimal anticoagulation duration of unfractionated and low molecular weight heparin in non-ST elevation acute coronary syndrome: a systematic review of the literature. Int J Cardiol. 2014;177(2):461–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Ducrocq G, Steg PG, Van ‘t Hof A, et al. Utility of post-procedural anticoagulation after primary PCI for STEMI: insights from a pooled analysis of the HORIZONS-AMI and EUROMAX trials. Eur Heart J Acute Cardiovasc Care. 2017;6(7):659–65.CrossRefPubMedGoogle Scholar
  13. 13.
    Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008;358(21):2218–30.CrossRefPubMedGoogle Scholar
  14. 14.
    Steg PG, Van ‘t Hof A, Hamm CW, et al. Bivalirudin started during emergency transport for primary PCI. N Engl J Med. 2013;369(23):2207–17.CrossRefPubMedGoogle Scholar
  15. 15.
    Shahzad A, Kemp I, Mars C, et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet. 2014;384(9957):1849–58.CrossRefPubMedGoogle Scholar
  16. 16.
    Han Y, Guo J, Zheng Y, et al. Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial. JAMA. 2015;313(13):1336–46.CrossRefPubMedGoogle Scholar
  17. 17.
    Erlinge D, Koul S, Eriksson P, et al. Bivalirudin versus heparin in non-ST and ST-segment elevation myocardial infarction-a registry-based randomized clinical trial in the SWEDEHEART registry (the VALIDATE-SWEDEHEART trial). Am Heart J. 2016;175:36–46.CrossRefPubMedGoogle Scholar
  18. 18.
    Alfonso F. Comments on the 2017 ESC guidelines for the Management of Acute Myocardial Infarction in patients presenting with ST-segment elevation. Rev Esp Cardiol. 2017;70(12):1039–45.CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s) 2018

<SimplePara><Emphasis Type="Bold">Open Access</Emphasis> This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.</SimplePara> <SimplePara>The images or other third party material in this book are included in the book's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the book's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.</SimplePara>

Authors and Affiliations

  1. 1.Tan Tock Seng HospitalSingaporeSingapore

Personalised recommendations