Antithrombin therapy to support PCI

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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.

Unfractionated Heparin (UFH)

IV unfractionated heparin is the most common anticoagulant used in the cath lab.

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 level of anticoagulation varies widely between patients
• Inability to inactive clot-bound thrombin
• Does not prevent the platelet activation of thrombin
• Risk of HIT- Heparin Induced Thrombocytopenia

Low Molecular Weight Heparinoids (LMWH)

Mechanism of Action

• Unlike UFH or LMWH, Direct thrombin inhibitors (Lepirudin, Argatroban and Bivalirudin), these 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.

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.

Disadvantages

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

Trials with Bivalirudin

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 end points 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.

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)"