Anticoagulation in ACS

16-11-2015

• Introduction• Coagulation cascade• Need for anticoagulation in ACS• Anticoagulant Agents • Evidences• Guidelines

• Acute coronary syndromes represent a spectrum of disease ranging from unstable angina to non-ST segment myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI).

• Acute coronary syndromes are characterized by the formation of atherosclerotic plaque.

• Plaque disruption or erosion is the final step in the activation of the platelet system and the coagulation cascade in the coronary vessels.

• The resulting labile thrombus causes a transient occlusion of the coronary arteries resulting in the clinical presentation of ACS.

Coagulation cascade

Pathogenesis

Anticoagulant agents

• UFH

• LMWH

• Fondaparinux

• Direct Thrombin Inhibitors (Bivalirudin)

Unfractionated heparin (UFH)

• Heparin is an indirect thrombin inhibitor which complexes with antithrombin (AT), formerly known as AT III.

• It converts AT from a slow to a rapid inactivator of thrombin, factor Xa, and to a lesser extent, factors XIIa, XIa, and IXa.

• The binding of heparin to the heparin binding site on AT produces a conformational change in AT, accelerating the inactivating function of AT 1000- to 4000-fold.

• Unfortunately, only one third of the UFH molecules have antithrombin III activity and UFH non-specific binding to protein and cells results in a less predictable dose-response curve

The acute phase of unstable angina, either Aspirin or Heparin treatment is associated with a reduced incidence of myocardial infarction, and there is a trend favoring heparin over aspirin.

Heparin treatment is also associated with a reduced incidence of refractory angina.

Heparin had no significant influence on event rate, although the group treated with aspirin and heparin had the lowest number of events during the initial 5 days.

Treatment had few side-effects and high patient compliance.

Limitations

• Heparin has a number of limitations –

– A narrow therapeutic window of adequate anticoagulation without bleeding

– A highly variable dose-response relation requiring laboratory monitoring.

– Reduced ability to inactivate thrombin bound to fibrin as well as factor Xa bound to activated platelets within a thrombus

– Heparin-induced thrombocytopenia, HIT– Heparin resistance

LMW HEPARIN

• Unfractionated heparin is a heterogeneous mixture of polysaccharide chains with a mean molecular weight of 15000.

• LMWH consists of fragments of UFH with a mean molecular weight of 5000.

• Both bind to anti-thrombin via a unique pentasaccharide sequence that is randomly dispersed on one-third and one-fifth of the chains of UFH and LMWH, respectively.

• LMWH preparations have greater activity against factor Xa than thrombin, with anti-Xa:anti-IIa ratios that range from 2:1 to 4:1.

• LMWH produces a more predictable anticoagulant response and has a longer plasma half-life than UFH.

• Greater bioavailability than UFH when given by subcutaneous injection.

• They do not increase osteoclast number and activity as much as UFH.

• The incidence of HIT is lower with LMWH.• LMWH is more convenient to use than unfractionated heparin

and this factor alone has led to the widespread use of LMWH in both arterial and venous thrombosis.

• Can be given even on OPD basis.

Fondaparinux

• Fondaparinux , a synthetic pentasaccharide, selectively binds antithrombin and causes rapid and predictable inhibition of factor Xa. (Indirect Inhibitor)

• Neutralization of factor Xa interrupts the blood coagulation cascade and inhibits thrombin formation and thrombus development.

• In contrast to heparin, fondaparinux does not inhibit thrombin.

OASIS-5

Direct Thrombin Inhibitors (DTI)

• Bivalirudin (Angiox™, AngiomaxR) is a synthetic 20-amino acid peptide analogue of hirudin.

• It is a direct thrombin inhibitor that binds specifically and reversibly to both fibrin-bound and unbound thrombin.

• Bivalirudin directly inhibits thrombin by binding to the active site and exosite 1 of thrombin.

• This binding is specific, noncompetitive and initially irreversible. • The inhibition is reversed as bivalirudin is slowly cleaved by

thrombin, freeing the active site and allowing thrombin to regain its activity.

• In patients with normal renal function, bivalirudin is rapidly cleared from plasma and has a terminal half-life of 25 minutes.

ACUITY Trial

2013 AHA/ACC STEMI Guidelines

• Patients with STEMI undergoing reperfusion with fibrinolytic therapy should receive anticoagulant therapy for a minimum of 48 hours, and preferably for the duration of the index hospital hospitalization, up to 8 days or until revascularization if performed. (Level of Evidence: A) Recommended regimens include

2014 AHA/ACC NSTEMI Guidelines