Antithrombin therapy to support PCI

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Anahita Deylamsalehi, M.D.[2]

Overview

Antithrombotic therapy is a centerpiece treatment in patients who are undergoing PCI. Selection of an optimal anticoagulant should be done by considering the patient’s clinical presentation such as stable ischemic disease, NSTE-ACS, or STEMI, and bleeding probability. Intravenous unfractionated heparin is the most common anticoagulant and has been the standard of care by default, nevertheless, other treatments such as direct thrombin inhibitor and low molecular weight heparins are also common options. Among low molecular weight heparins, enoxaparin is one of the most used treatments and is considered a safe alternative for UFH. Each treatment has its advantages and disadvantages which should be discussed in a patient-centered evaluation.

Antithrombin Therapy to Support PCI

• Antithrombotic therapy is a centerpiece treatment in patients who are undergoing PCI. Currently, the following three antithrombotic agents have been studied among patient who have undergone PCI:
  • Unfractioned Heparin (UFH)
  • Bivalirudin
  • Enoxaparin
• Using fondaparinux is not recommended as the only anticoagulant in PCI patients due to a higher incidence of guiding-catheter thrombosis.
• Selection of an optimal anticoagulant should be done by considering the patient’s clinical presentation such as stable ischemic disease, NSTE-ACS, or STEMI, and bleeding probability.
• The following table represents the dosing of parenteral anticoagulant during PCI:

Drug	For Patients Who Received Previous Anticoagulant Therapy	For Patients Who Did Not Received Any Anticoagulant Therapy
UFH	Additional UFH as needed (e.g., 2000 – 5000 U) to achieve the activated clotting time (ACT) of 250-300 seconds.	70–100 U/kg initial bolus to achieve the target ACT of 250–300 seconds.
Enoxaparin	*An intravenous dose of 0.3 mg/kg of enoxaparin for patients who received previous treatment with subcutaneous tissue enoxaparin within the last 8 –12 hours. If the last subcutaneous tissue dose was administered within the previous 8 hours, no additional enoxaparin should be given	0.5 – 0.75 mg/kg intravenous bolus
Bivalirudin	For patients who have received UFH, repeat ACT, if ACT is not in the therapeutic range, then give a 0.75 mg/kg intravenous bolus, then continue with a 1.75 mg/kg/h intravenous infusion.	0.75 mg/kg bolus, then continue with a 1.75 mg/kg/h intravenous infusion.
Argatroban	200 mg/kg intravenous bolus, then continue with a 15 mg/kg/min intravenous infusion.	350 mg/kg, then continue with a 15 mg/kg/min intravenous infusion.

_{HemoTec (GmbH, Switzerland) or I-Stat (Abbott) device can be used to check activated clotting time (ACT) for UFH dosing. However, activated clotting time (ACT) goals are 50 seconds higher for Hemochron ACT (Werfen) devices. Furthermore, it is recommended to consider the higher target ACT in patients with chronic total occlusion. On the other hand, target ACT should be 200-250 seconds if a intravenous glycoprotein IIb/IIIa inhibitors is selected.}

Unfractionated Heparin (UFH)

• Intravenous unfractionated heparin is the most common anticoagulant and has been the standard of care by default.
• Since studies on UFH dosing were done years ago, there is no evidence that previously recommended doses can be used in the modern coronary stent era. Therefore, the effectiveness of UFH dosing based on activated clotting time in modern practice is uncertain.
• Furthermore, the routine use of full dose anticoagulation therapy after PCI is no longer indicated.

Mechanism of action

Heparin is a glycosaminoglycan of 12-15 kDa that binds Anti-thrombin 3 and facilitates its ability to inhibit coagulation factors 2a (thrombin) and 10a by a factor of 1000. Thrombin plays a central role not only in plasma coagulation (by catalysing fibrinogen to fibrin as well as activating several coagulation factors) but platelet activation as well.

Advantages

• Physician familiarity with the use
• Level of anticoagulation can be titrated with activated clotting time (ACT). Target ACT typically 200-250 with 2b/3a and 250-350 without 2b/3a (these levels have been empirically derived and target ACT's have fallen in the stent era as the risk for acute vessel closure has diminished).
• Can be reversed with protamine (1mg of protamine for 100u of heparin acutely) in case of coronary artery perforation or vascular access complication.
• No dose adjustment needed for renal dysfunction
• Inexpensive

Disadvantages

• Significant protein binding
• Monitoring required as the level of anticoagulation varies widely between patients
• Inability to inactive clot-bound thrombin
• Does not prevent the platelet activation of thrombin
• Risk of Heparin Induced Thrombocytopenia (HIT).

Low Molecular Weight Heparinoids (LMWH)

• The following medicines belong to the low molecular weight heparins:
  • Enoxaparin
  • Parnaparin
  • Dalteparin
  • Ardeparin
  • Certoparin

Enoxaparin

• Enoxaparin is considered a safe alternative for UFH.
• More complication is seen in patients who were given upstream enoxaparin and then have switched to UFH. This effect is seen even when heparin is administered within a 10-hours period after the last dose of enoxaparin.
• In almost all patients who are undergoing PCI and have received 0.5 mg/kg intravenous enoxaparin, a peak anti-Xa level more than 0.5 IU/mL will be seen.

Clinical Trials with Enoxaparin

• SYNERGY: This trial showed no inferiority in enoxaparin compared to UFH. Furthermore, this trial showed no difference in the rate of death, MI, or major bleeding among patients with NSTE-ACS who were treated with enoxaparin compared to UFH.
• AtoZ: This trial showed no inferiority in enoxaparin compared to UFH. Furthermore, this trial showed no difference in the rate of death, MI, or major bleeding among patients with NSTE-ACS who were treated with enoxaparin compared to UFH.
• ATOLL: This trial compared intravenous enoxaparin with UFH, and reported a reduction in death, recurrent ACS, urgent revascularization, and bleeding among those who received enoxaparin.
  • This finding is supported by a large meta-analysis which studied patients undergoing PCI for STEMI and NSTE-ACS.

Direct thrombin inhibitor

Mechanism of Action

• Unlike UFH or low molecular weight heparin (LMWH), direct thrombin inhibitors (Lepirudin, Argatroban and Bivalirudin) don't require the help of AT-3 to exert their anticoagulation effect.
• These medicines are IV only, but there is great interest in developing safe oral DTI to replace coumadin in the DVT/PE and atrial fibrillation population.
• The following are some of the medications belong to this group:
  • Bivalirudin
  • Desirudin
  • Argatroban
  • Dabigatran
  • Lepirudin
• Bivalirudin (Angiomax) is the only DTI used commonly in the cath lab although the others have been studied.

Advantages

• Short half life. This facilitates early sheath removal after PCI
• Can inhibit fibrin-bound thrombin
• Simplified dosing regimen. Can be adjusted for patients with renal insufficiency.
• Fewer bleeding complications especially at access site. This advantage increases as bleeding risk increases due to age and renal insufficiency.
• Best regimen for patients with known HIT. Both argatroban and bivalirudin are acceptable alternatives for use in patients with heparin-induced thrombocytopenia.

Disadvantages

• Cost (however this is offset if use of bivalirudin obviates need for 2b/3a)

Trials with Bivalirudin

• There are numerous studies that compared bivalirudin and heparin. Almost all of them did not report any difference in ischemic endpoints; however, less bleeding was reported with bivalirudin.
• Although complications such as bleeding is lower with bivalirudin based on clinical trials, in real practice, this benefit may be less pronounced with routine use of radial artery intervention and low rates of glycoprotein IIb/IIIa inhibitor use.
  • Replace 2: This trial compared bivalirudin plus provisional 2b/3a (which ended up being given in 7.2% of patients) vs heparin with planned 2b/3a. In this study of 6010 patients, ischemic events were similar but major bleeding (mostly vascular access site) was reduced by about 40%. There was no mortality difference at one year despite a 0.8% absolute increase in peri-procedural MI's in the bivalirudin group. Importantly ,85% of patients were pre-treated with plavix or ticlid. In Replace 2, bivalirudin strategy was found to be less expensive because of savings on 2b/3a as well as less bleeding.
  • ACUITY: Complex trial of 13,819 high risk UA or NSTEMI patients undergoing early invasive strategy comparing bivalirudin alone vs Bivalirudin with 2b/3a vs Heparin or Lovenox with 2b/3a. It was found that the ischemic composite endpoint (death, MI, revascularization) at 30 days was the same in all 3 arms. However, major bleeding was significantly less with bivalirudin alone at 3.1% vs bivalirudin and 2b/3a at 5.3% vs Heparin, Lovenox and 2b/3a at 5.7%. Again this was driven mostly by access site complications, but unlike in REPLACE 2 the bleeding endpoints were significant whether one used the study definition or TIMI definition. A major caveat is also that patients who did not get plavix had increased ischemic events in the bivalirudin only arm.
  • VALIDATE- SWEDEHEART: This clinical trial evaluated a prolonged bivalirudin infusion versus UFH. Result did not show any improvement in rates of major adverse cardiovascular events, major bleeding, or stent thrombosis with bivalirudin within a 6-month follow up.
• In conclusion, bivalirudin is an excellent choice in most NSTEMI/UA patients managed with an early invasive strategy if they have been pre-treated with clopidogrel. If this has not been done then 2b/3a will need to be used and the benefits of bivalirudin are greatly attenuated.

2021 ACA Revascularization Guideline

Class 1 Recommendation, Level of Evidence: C-EO

Administration of intravenous unfractionated heparin (UFH) is useful in reducing ischemia events in patients undergoing PCI.

Class 1 Recommendation, Level of Evidence: C-LD

Bivalirudin or argatroban should be used instead of UFH in patients with heparin-induced thrombocytopenia who are undergoing PCI.

Class 2b Recommendation, Level of Evidence: A

Bivalirudin could be used as a reasonable alternative to UFH in order to reduce bleeding in patients undergoing PCI.

Class 2b Recommendation, Level of Evidence: B-BR

In patients who have been treated with upstream subcutaneous enoxaparin for either unstable angina or NSTE-ACS, intravenous enoxaparin could be considered at the time of PCI in order to reduce ischemic events.

Class 3 Recommendation (HARM), Level of Evidence: B-R

UFH should be avoid in patients who are on therapeutic subcutaneous enoxaparin, and have received the last dose within 12 hours of PCI due to higher rate of bleeding.

ACCF/AHA/SCAI 2011 Guidelines for Percutaneous Coronary Intervention (DO NOT EDIT)

Use of Parenteral Anticoagulants during PCI (DO NOT EDIT)

Class I

"1. An anticoagulant should be administered to patients undergoing PCI. (Level of Evidence: C)"

Unfractionated Heparin (DO NOT EDIT)

Class I

"1. Administration of intravenous UFH is useful in patients undergoing PCI. (Level of Evidence: C)"

Enoxaparin (DO NOT EDIT)

Class I

"1. An additional dose of 0.3 mg/kg intravenous enoxaparin should be administered at the time of PCI to patients who have received fewer than 2 therapeutic subcutaneous doses (e.g., 1 mg/kg) or received the last subcutaneousenoxaparin dose 8 to 12 hours before PCI.(Level of Evidence: B)"

Class III (Harm)

"1. Unfractionated heparin (UFH) should not be given to patients already receiving therapeutic subcutaneous enoxaparin.(Level of Evidence: B)"

Class IIb

"1. Performance of PCI with enoxaparin may be reasonable in patients either treated with upstream subcutaneous enoxaparin forUA/NSTEMI or who have not received prior antithrombin therapy and are administered intravenous enoxaparin at the time ofPCI. (Level of Evidence: B)"

Bivalirudin and Argatoban (DO NOT EDIT)

Class I

"1. For patients undergoing PCI, bivalirudin is useful as an anticoagulant with or without prior treatment with unfractionated heparin (UFH).(Level of Evidence: B)"

"2. For patients with heparin-induced thrombocytopenia, it is recommended that bivalirudin or argatroban be used to replace unfractionated heparin (UFH). (Level of Evidence: B)"

Fondaparinux (DO NOT EDIT)

Class III (No Benefit)

"1. Fondaparinux should not be used as the sole anticoagulant to support PCI. An additional anticoagulant with anti-IIa activity should be administered because of the risk of catheter thrombosis.(Level of Evidence: C)"