Antithrombotic and Antiplatelet Therapy for Percutaneous Coronary Interventions

5 Antithrombotic and Antiplatelet Therapy for Percutaneous Coronary Interventionsimage



Morton J. Kern, Arnold H. Seto, Charles M. Parise


Familiarity with commonly used antithrombotic and antiplatelet agents is required in the management of interventional cardiology patients. This chapter outlines recommendations and uses of various antithrombotic and antiplatelet agents. Antithrombotic and antiplatelet agents for percutaneous coronary intervention (PCI) are summarized in Table 5-1, and recommendations from the ACC/AHA are summarized in Table 5-2.


Table 5-1 Antithrombotic and Antiplatelet Agents for PCI Intervention











Antithrombotic Therapy


• Heparin (unfractionated)


• Low-molecular-weight heparin


• Direct thrombin inhibitor


— Polypeptide inhibitors (hirudin [Lepirudin], bivalirudin [Angiomax])

— Low-molecular-weight inhibitors (argatroban [Acova])
Antiplatelet Therapy


• Cyclooxygenase inhibitors (aspirin)


• Adenosine diphosphate (ADP) receptor inhibitors (clopidogrel [Plavix], prasugrel [Effient], ticlopidine [Ticlid])


• Phosphodiesterase inhibitors (cilostazol [Pletal])


• Glycoprotein IIb/IIIa receptor inhibitors (abciximab [ReoPro], eptifibatide [Integrilin], tirofiban [Aggrastat])


• Adenosine reuptake inhibitors (dipyridamole [Persantine])


• CPTPs (cyclo-pentyl-triazolo-pyrimidines) [Ticagrelor (Brilinta)]


• Platelet glycoprotein IIb/IIIa antagonists


— Abciximab

— Eptifibatide

— Tirofiban


Table 5-2 ACC/AHA Recommendations for Pharmacologic Management of Patients Undergoing PCI Intervention

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Anticoagulants



Heparin


Heparin is given to PCI patients in doses between 40 and 70 U/kg intravenously. Unfractionated heparin (UFH) is a glycosaminoglycan widely used as an anticoagulant. It acts by accelerating the activity of antithrombin III (AT III), a molecule that breaks down the procoagulant factor IIa (thrombin) and factor Xa by forming a complex with AT III and thrombin. Figure 5-1 diagrams the coagulation cascade and role of antithrombins. In contrast, low-molecular-weight heparin (LMWH) is too small to participate in this ternary complex and exerts its effect primarily on factor Xa levels. Both UFH and LMWH are unable to significantly interact with thrombin that is already bound to clot. For this reason adjunctive antiplatelet agents (e.g., aspirin, thienopyridines, and glycoprotein IIb/IIIa receptor antagonists) are typically required for PCI procedures.


image

Figure 5-1 Diagrams of the coagulation cascade and role of antithrombins.


(Adapted from Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. from Conde ID, Kleiman NS. Arterial thrombosis for the interventional cardiologist: from adhesion molecules and coagulation factors to clinical therapeutics. Catheter Cardiovasc Interv 2003;60:236–246.) and Garg R, Uretsky BF, Lev EL. Anti-platelet and anti-thrombotic approaches in patients undergoing percutaneous coronary intervention. Catheter Cardiovasc Interv 2007;70:388–406.


The half-life of UFH is 1.5 hours, allowing for greater control of the anticoagulant effect. Discontinuation of a UFH IV drip can normalize the clotting cascade in a few hours. If there is a need to discontinue the anticoagulant effect of UFH emergently, protamine sulfate can be given, which forms an ion pair with UFH, neutralizing it. Protamine dosage for UFH reversal is 1 to 1.5 mg IV per 100 units of remaining active UFH, based on the time course of UFH administration (max 50 mg/dose at 5 mg/min). Although most of the protamine sulfate used today is recombinant, caution should be used in patients with fish allergies, as some proportion may still be derived from fish sperm. Typical protamine allergic reactions can include hypotension and bronchoconstriction due to histamine release. A slow IV infusion, while closely monitoring the patient, may mitigate the severity of the reaction. Care should also be observed in diabetic patients taking protamine-containing insulin preparations (e.g., NPH insulin), as they are at increased risk for severe protamine reactions, including anaphylaxis.



Summary of Heparin Mode of Action




1. Heparin is a mixture of glycosaminoglycans (mucopolysaccharides) that combine with a plasma protein called antithrombin III (AT III) to make the AT III a highly effective inhibitor of thrombin and several other clotting factors.


2. Heparin requires the presence of AT III to be effective.


3. Unfractionated heparin (UFH) is a heterogeneous polysaccharide that binds to antithrombin to inhibit thrombin and factor Xa.



Monitoring


Heparin therapy is usually monitored by the activated clotting time (ACT), which is the time for whole blood to form a firm clot. When blood levels of heparin have been measured directly, antithrombotic efficacy occurs between 0.2 and 0.4 U/mL. It is common practice to maintain the Hemochron ACT at 300 to 350 seconds and the HemoTec ACT at 250 to 300 seconds, although some interventionalists may prefer higher values. When used with glycoprotein IIb/IIIa antagonists (abciximab, eptifibatide, tirofiban), the recommended heparin bolus is reduced to 40 U/kg to achieve a target ACT of between 200 and 250 seconds. The activated partial thromboplastin time (aPTT) is not used in the catheterization laboratory as it saturates at the doses of heparin used for PCI.



Indications




1. Angina for PCI, unstable angina, acute myocardial infarction


2. Following anterior wall myocardial infarction, 7 to 10 days until warfarin (Coumadin) increases international normalized ratio (INR) to therapeutic levels


3. Prevention and treatment of deep venous thrombosis


4. Treatment of pulmonary embolism



Side Effects



Heparin-Induced Thrombocytopenia (HIT)


Heparin can cause an immune-mediated thrombocytopenia that can lead to thrombosis, stroke, loss of limb, or other ischemic events (e.g., heparin-induced thrombocytopenia with thrombosis [HITT]). If heparin is given after the procedure, monitor platelet count daily. If platelets fall below 100,000 or by more than 50%, discontinue heparin and consider the possible etiologies of thrombocytopenia.


There are two types of heparin-induced thrombocytopenia (HIT) (Table 5-3). Type I HIT (HIT-1) is due to direct (non–immune-mediated) platelet activation, with mild thrombocytopenia and a benign clinical course. Type II HIT (HIT-2) is due to immune-mediated platelet activation, with moderate or severe thrombocytopenia and serious thromboembolic complications. Platelet transfusions should not be used to treat HIT due to increased risk of thrombotic complications. Anticoagulation to prevent thrombosis is the main treatment of HIT-2 patients; typical drugs are the direct-acting thrombin antagonists, lepirudin and argatroban. Compared with UFH, LMWH carries a reduced risk of HIT.


Table 5-3 Heparin-Induced Thrombocytopenia



































  Type I Heparin-Induced Thrombocytopenia Type II Heparin-Induced Thrombocytopenia
Incidence 10% Rare
Mechanism Direct platelet aggregating effect of heparin Autoantibody (IgG or IgM) directed against platelet factor IV–heparin complex
Onset Early (1–5 days) Later (>5 days); may occur sooner if prior heparin exposure
Platelet count 50,000–150,000/mm3 <50,000/mm3
Duration Transient; often improves even if heparin is continued Requires discontinuation of all heparin; gradual recovery in platelet count over 1–5 days in most patients
Clinical Benign Recalcitrant venous and arterial course thromboses and thromboembolism; may be fatal
Heparin Unfractionated or low-molecular-weight heparin may be continued Argatroban and lepirudin are FDA-approved

Modified from Safian R, Grines C, Freed M. The new manual of interventional cardiology. Birmingham, MI: Physicians’ Press, 1999.



Minor Bleeding (Puncture Site, Gums, etc.)


Discontinue heparin. Monitor vital signs, aPTT, hemoglobin, hematocrit, platelet count, ACT.



Major Bleeding (Retroperitoneal, Gastrointestinal)


After bolus only, give protamine sulfate (1% solution) at 1 mg/100 U heparin or approximately 25 mg slow IV infusion over 10 minutes. Monitor vital signs, aPTT, hemoglobin, hematocrit, platelet count, ACT. Give blood transfusions as necessary according to transfusion guidelines. Assess site of bleeding and need for therapeutic interventions.


For patients receiving intravenous heparin infusion, discontinue infusion. Give protamine sulfate (1% solution) at 1 mg/100 U heparin or approximately 25 mg slow IV infusion over 10 minutes. Repeat ACT in 20 minutes.


For patients receiving large doses (>5000 U) of subcutaneous heparin, give protamine sulfate (1%) solution (1 mg/100 U heparin) slow IV infusion over 10 minutes. Repeat aPTT/ACT in 20 minutes and 1 hour. It may be necessary to repeat the protamine sulfate infusion after 1 hour because of the slow absorption of subcutaneous heparin. Observe for protamine reaction. Use protamine only when severe bleeding warrants it. Have resuscitation equipment available. Morphine (2–4 mg IV) is helpful for chills.



Use of Heparin as a Bridge to Warfarin Therapy




1. Give heparin 40–70 U/kg IV bolus followed by 1000–1700 U/hr IV infusion.


2. Obtain ACT at 4–6 hr and keep aPTT at 50–90 sec.


3. Start warfarin on day 1 at no more than 10 mg a day.


4. Obtain INR and platelet count.


5. Give heparin and warfarin jointly with heparin for 3 to 5 days, and until INR is between 2.0 and 3.0, then stop heparin.


6. Continue warfarin at an INR of 2.0 to 3.0.



Low-Molecular-Weight Heparin


LMWHs are fractionated heparins with molecular weights between 3000 and 7000 daltons (UFH is 3000–30,000 daltons). The therapeutic dose of the most commonly used LWMH, enoxaparin, is 1 mg/kg subcutaneously every 12 hours. Patients requiring PCI require additional intravenous bolus doses of enoxaparin to ensure adequate anti-Xa activity for the procedure. Table 5-4 describes suggested doses for PCI.


Table 5-4 Suggested Dosing of Enoxaparin Prior to PCI



























Preprocedure Enoxaparin IV Bolus Enoxaparin Dose at Time of PCI
No prior enoxaparin 0.75 mg/kg IV
Prophylactic doses of enoxaparin only 0.5 mg/kg IV
One-two 1 mg/kg SQ doses, last <8 hrs prior 0.3 mg/kg IV
One-two SQ doses, last 8–12 hrs prior 0.3–0.5 mg/kg IV
Adequate (>3) SQ doses, last <8 hrs prior No additional enoxaparin
Adequate (>3) SQ doses, last 8–12 hrs prior 0.3 mg/kg IV
Any doses, >12 hours Can use alternative antithrombin

LMWHs have features distinct from UFH, including:



1. More predictable anticoagulation effect


2. Lack of inhibition by platelet factor 4


3. Lack of need for monitoring


4. Lower risk of HIT


5. Subcutaneous bolus administration


Table 5-5 compares features of LMWHs with UFH.


Table 5-5 Comparison of Low-Molecular-Weight and Unfractionated Heparin






























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Jun 5, 2016 | Posted by in CARDIAC SURGERY | Comments Off on Antithrombotic and Antiplatelet Therapy for Percutaneous Coronary Interventions

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Characteristic Unfractionated Heparin Low-Molecular-Weight Heparin
Composition Heterogeneous mix of polysaccharides; molecular weight 3000–30,000 Homogeneous glycosaminoglycans; molecular weight 4000–6000
Mechanisms Activates antithrombin III*; equivalent activity against factor Xa and thrombin; releases TFPI from endothelium; unable to inactivate clot-bound thrombin or FDP; inactivates fluid phase thrombin Less activation of antithrombin III; greater activity against factor Xa than thrombin; releases TFPI for endothelium; unable to inactivate clot-bound thrombin or FDP; weaker inactivation of fluid-phase thrombin
Pharmacokinetics Variable binding to plasma proteins, endothelial cells, and macrophages leads to unpredictable anticoagulant effects (less available to interact with antithrombin III); short half-life Minimal binding to plasma proteins, endothelial cells, and macrophages leads to predictable anticoagulation; longer half-life
Laboratory monitoring Unpredictable anticoagulant effects; use aPTT or ACT Unable to use aPTT or ACT except in renal failure to body weight <50 kg or >80 kg; use anti-factor-Xa levels
Clinical uses Venous thrombosis; unstable angina, acute myocardial infarction, ischemic stroke, PCI Venous thrombosis in surgery and trauma patients, unstable angina, ischemic stroke. No advantage during PCI
Reversal Protamine neutralizes antithrombin activity