Anticoagulation in the Cardiac Catheterization Laboratory

The safety of switching antithrombins among patients undergoing Percutaneous Coronary Intervention (PCI) in the setting of Acute Coronary Syndromes (ACS)
One question that frequently confronts the clinician is whether it is safe to switch antithrombins in the setting of acute coronary syndromes (ACS), particularly among patients undergoing percutaneous coronary interverntion (PCI). In the SYNERGY study, switching between unfractionated heparin and enoxaparin before randomization was not associated with excess bleeding. However, crossing over to the other antithrombin after randomization was associated with excess bleeding. In these instances crossover after randomization, it not clear whether bleeding or ischemia caused the patient to crossover, or alternatively whether the crossover caused the patient to have a bleeding or ischemic event. In other words, the direction of causality could not be determined.

A recent substudy from REPLACE 2 evaluated whether a hazard existed when either unfractionated heparin or low molecular weight heparin were administered in the 48 hours prior to bivalirudin administration in the REPLACE-2 trial. The REPLACE 2 substudy analyzed the phenomenon of pre-randomization “switching” rather than post-randomization “crossover”.

There was no difference in protocol major or minor bleeding, TIMI bleeding, or non-coronary artery bypass graft blood transfusions between the patients receiving preceding antithrombin therapy and patients without prior antithrombin therapy (p=NS) among patients treated with bivalirudin. These findings extend prior observations from the SWITCH trial in which patients with ACS were treated with enoxaparin and subsequently switched to bivalirudin for the percutaneous coronary intervention procedure after varying durations of time (0-4 hours, 4-8 hours or 8-12 hours from last enoxaparin dose to percutaneous coronary intervention). Switching from enoxaparin to bivalirudin among patients undergoing percutaneous coronary intervention was not associated with an increase in major bleeding, regardless of the duration from last enoxaparin administration to percutaneous coronary intervention in the SWITCH trial.

The method of switching or transition in the REPLACE 2 substudy involved the following:
 * Administration of bivalirudin > 8 hours after last low molecular weight heparin dose or
 * > 6 hours after unfractionated heparin, unless in the case of unfractionated heparin therapy the activated partial thromboplastin time was ≤ 50 seconds or the activated clotting time was ≤ 175 seconds.

When switching was undertaken in this fashion, preceding therapy with either low molecular weight heparin or unfractionated heparin was not associated with an excess of bleeding or transfusions compared with bivalirudin therapy alone in the cardiac catheterization laboratory.

Potential explanations for the safety of switching to Bivalirudin include the fact that bivalirudin has a half-life of 25 minutes while both unfractionated heparin and low molecular weight heparin have relatively long half-lives. Bivalirudin becomes biologically inactive when it is cleaved by and subsequently dissociates from thrombin, allowing thrombin to return to normal hemostatic activity. In contrast unfractionated heparin may remain active after it is cleaved from thrombin. Bivalirudin specifically inhibits Factor IIa (thrombin), while unfractionated heparin and low molecular weight heparin have some activity against both Factor IIa (thrombin) and Factor Xa. Since the anti-IIa activity of unfractionated heparin is reduced more rapidly than the anti-Xa activity, it may be possible that the additive effect of 2 heparinoids may increase the levels of anti-Xa activity to supra-therapeutic levels, while adding only anti-IIa activity (bivalirudin) on top of any residual anti-Xa activity would not result in increased anti-Xa levels.

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

 * 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

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
 * when pts receive LMWH prior to cath and then UFH at time of PCI (switching) their bleeding complications increase significantly (SYNERGY and OASIS-5)

Summary
Lovenox likely better choice in pts with STEMI especially if they are initially treated with lytics as long as they are not aged, morbidly obese, or have renal insufficiency. LMWH likely better choice than heparin in pts with UA/NSTEMI initially managed medically/conservatively. Lovenox reasonable choice in elective PCI especially if radial approach used.

Dosing

 * As no monitoring, the dosing of Lovenox can be more difficult.
 * 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 lovenox given less than 8 hrs ago proceed to PCI
 * If last SQ lovenox given 8-12 hrs ago rebolus with .3mg/kg
 * If last SQ lovenox given more than 12 hrs ago rebolus with .75mg/kg

When switching from lovenox to heparin per SYNERGY trial


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

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 (and makes interventional fellows happy)
 * Can inhibit fibrin-bound thrombin
 * Easy 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)
 * no benefit over heparin if a 2b/3a needs to be added.

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 a excellent choice in most NSTEMI/UA pts managed with an early invasive strategy if they have been pre-treated with plavix. If this has not been done then 2b/3a will need to be used and the benefits of bivalirudin are greatly attenuated.

Bivaluridin use
In patients with known heparin-induced thrombocytopenia, it is reasonable to consider bivalirudin as a useful alternative to heparin to be used in conjunction with streptokinase. Dosing according to the HERO 2 regimen (a bolus of 0.25 mg/kg followed by an intravenous infusion of 0.5 mg/kg/h for the first 12 hours and 0.25 mg/kg/h for the subsequent 36 hours) is recommended, but with a reduction in the infusion rate if the partial thromboplastin time is above 75 seconds within the first 12 hours. (Class IIa Level of Evidence: B)

UFH use

 * Patients undergoing percutaneous or surgical revascularization should receive UFH. (Class I, Level of Evidence: C)


 * Unfractionated heparin should be given intravenously to patients undergoing reperfusion therapy with alteplase, reteplase, or tenecteplase with dosing as follows: bolus of 60 U/kg (maximum 4000 U) followed by an infusion of 12 U/kg/hr (maximum 1000 U) initially adjusted to maintain activated partial thromboplastin time (aPTT) at 1.5 to 2.0 times control (approximately 50 to 70 seconds). (Class I, Level of Evidence: C)


 * Unfractionated heparin should be given intravenously to patients treated with non-selective fibrinolytic agents (streptokinase, anistreplase, urokinase) who are at high risk for systemic emboli (large or anterior MI, atrial fibrillation (AF), previous embolus, or known LV thrombus). ( Class I, Level of Evidence: B)


 * Platelet counts should be monitored daily in patients taking UFH. (Class I, Level of Evidence: C)


 * It may be reasonable to administer UFH intravenously to patients undergoing reperfusion therapy with streptokinase. (Class IIb, Level of Evidence: B)

LMWH use

 * Low-molecular-weight heparin might be considered an acceptable alternative to UFH as ancillary therapy for patients aged less than 75 years who are receiving fibrinolytic therapy, provided that significant renal dysfunction (serum creatinine greater than 2.5 mg/dL in men or 2.0 mg/dL in women) is not present. Enoxaparin (30-mg IV bolus followed by 1.0 mg/kg SC every 12 hours until hospital discharge) used in combination with full-dose tenecteplase is the most comprehensively studied regimen in patients aged less than 75 years of age. (Class IIb, Level of Evidence: B)


 * Low-molecular-weight heparin should not be used as an alternative to UFH as ancillary therapy in patients aged more than 75 years who are receiving fibrinolytic therapy. (Class III, Level of Evidence: B)


 * Low-molecular-weight heparin should not be used as an alternative to UFH as ancillary therapy in patients less than 75 years who are receiving fibrinolytic therapy but have significant renal dysfunction (serum creatinine greater than 2.5 mg/dL in men or 2.0 mg/dL in women). (Class III, Level of Evidence: B)