Antithrombin therapy to support PCI

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

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 catalyzing fibriongen to fibrin as well as activating several coagulation factors) but platelet activation as well.

Advantages

• Physician familiarity with use
• Level of anticoagulation can be titrated with 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

Formed by cleavage of UFH molecules to derive compounds 1/3 the size. This shorter molecule does not bind AT3 and Thrombin well but can bind AT 3 to Factor 10a. The most used LMWH Enoxaparin (Lovenox) has a 10a/2a ratio of 3.8.

Advantages

• Longer half life so can be given SQ instead of IV continuous infusion. However, depending on when last dose of SQ heparin given, may need to give small booster dose of IV Lovenox prior to PCI.
• Less protein binding and much lower incidence of HIT
• Several trials have shown lower rates of ischemic complications in spectrum of ACS (not just pts treated invasively) as compared to Heparin (STEMI trials ENTIRE/TIMI 23, CREATE, ExTRACT TIMI 25). Advantage less clear for NSTEMI/UA managed with early invasive strategy with recent large SYNERGY TRIAL failing to meet primary end point. However a meta-analysis by Murphy et al. EHJ 2007 showed decrease in MI at 8% vs 9.1% favoring LMWH. In recent PCI-ExTRACT trial (the 4676 pts out of 20,479 in ExTRACT-TIMI 25 who underwent angioplasty after fibrinolysis) there was reduction in death or reinfarction at 30 days of 10.7% vs 13.8% P=.001 with no excess bleeding and fewer strokes.

Disadvantages

• More difficult to reverse than Heparin.
• Although dosing more reliable than Heparin, without a monitoring system it can be difficult to dose appropriately for pts that are elderly, morbidly obese, or have renal insufficiency
• No clear advantage in elective PCI over Heparin in reducing ischemic complications but may reduce bleeding (CRUISE n=261 and STEEPLE n=3528) in selected populations

Clinical Use

• Enoxaparin is a superior antithrombin in patients with STEMI especially if they are initially treated with a fibrinolytic, as long as they are not morbidly obese, or have renal insufficiency.
• Enoxaparin likely better choice than heparin in pts with UA/NSTEMI initially managed medically/conservatively.
• Enoxaparin is a reasonable choice in elective PCI.

Dosing

If given SQ therapeutic anticoagulation is reached by 60 minutes. With a half life or around 6 hours the level of anticoagulation can wane if PCI is done several hours after last dose.

• If last SQ Enoxaparin given less than 8 hrs ago proceed to PCI
• If last SQ Enoxaparin given 8-12 hrs ago rebolus with 0.3mg/kg
• If last SQ Enoxaparin given more than 12 hrs ago rebolus with 0.75mg/kg

When switching from Enoxaparin to heparin per SYNERGY trial

If last SQ Enoxaparin given less than 8 hrs ago no heparin bolus start drip at 12 u/hr If last SQ Enoxaparin given 8-12 hrs ago give half bolus (30u/kg) then start drip If last SQ Enoxaparin given more than 12 hrs ago give full bolus then start drip

Direct Thrombin Inhibitors

Mechanism of Action

• Unlike UFH or 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 Afib 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 bival obviates need for 2b/3a)

Trials with BIVALIRUDIN

Replace 2-Compared Bivalirudin plus provisional 2b/3a (which ended up being given in 7.2% of pts) vs heparin with planned 2b/3a. In this study of 6010 pts 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 .8% absolute increase in peri-procedural MI's in the bivalirudin group. Importanly 85% of pts were pre-treated with plavix or ticlid. In Replace 2 Bival strategy 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 pts undergoing early invasive strategy comparing Bivalirudin alone vs Bivalirudin with 2b/3a vs Heparin or Lovenox with 2b/3a. Found the ischemic composite endpoint (death, MI, revasc) at 30 days to be the same in all 3 arms. However, major bleeding was significantly less with Bival alone at 3.1% vs Bival+2b3a at 5.3% and Heparin/Lovenox+2b3a at 5.7%. Again this was driven mostly by access site complications, but unlike in REPLACE 2 the bleeding endpts were significant whether one used the study definition or TIMI definition. A major caveat is also that pts who did not get plavix had increased ischemic events in the bival only arm.

CONCLUSION- Bivalirudin is an excellent choice in most NSTEMI/UA pts 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.