Antithrombotic Therapy During Percutaneous Coronary Intervention (PCI)

James Lin, DO Internal Medicine Resident May 3, 2006.

Objectives:

 To review basic platelet physiology  To review mechanism of action of different Antithrombotic drugs.

 To compare different PCI treatments and PCI vs Surgery.

 To review different types of stents.

 To apply the current recommendations of Antithrombotic Therapy during PCI. ACCP vs ACC/AHA

Platelet Physiology

  Platelet is a circulating enucleate disc shaped cell, responsible for initiation of hemostatic mechanisms which repair injury to the vascular endothelium. 4 Major platelet functions: 1. Platelet adherence 2. Platelet activation and secretion 3. Platelet aggregation 4. Interaction with coagulation Factors

Platelet Physiology

   When a break within the integrity of vascular lining occurs, platelets are exposed to, and interact with collagen fibrils. Platelet not only provides a surface for platelet adhesion, but also serve as a strong stimulus for platelet activation. Activated platelets not only secrete thromboxane A2 and ADP, but also directly bind to the circulating coagulation protein fibrinogen, via the abundant platelet integrin, glycoprotein (GP)IIb/IIIa (also known as alphaIIb/beta3).

Platelet Physiology

     In addition to collagen, ADP, and Thromboxane A2, other agonist can activate platelets at sites of vascular injury. Tissue factor, which is expressed on all non-vascular cells, is exposed to circulating blood upon disruption of the protective endothelial layer of the vasculature. Tissue factor can interact with Factor VIIa to promote local coagulation, and ultimately the generation of thrombin, the most potent of the platelet agonist. Platelets facilitate this process by providing procoagulant phospholipids that accelerate thrombin generation. Platelet activation and fibrin deposition are intimately linked, maximizing the growth and strength of hemostatic plug.

Antiplatelet Drugs:

Oral antiplatelet drugs

 Aspirin  Clopidogrel (Plavix ® )  Ticlopidine (Ticlid ® )  Aspirin/Dipyridamole (Aggrenox ® )

Oral antiplatelet drugs

 Aspirin – Irreversible inhibitor of cyclooxygenase (COX) which prevents formation of the platelet aggregating substance thromboxane A 2 .

– Monitoring  Clopidogrel – Blocks platelet aggregation by inhibition of ADP receptor on the platelet membrane.

– Monitoring

Parenteral antiplatelet drugs

 Glycoprotein IIb/IIIa Inhibitors – Abciximab (Reopro ® ), eptifibatide (Integrilin ® ), tirofiban (Aggrastat ® ) – Prevent fibrinogen binding to Gly IIb/IIIa receptor and block platelet aggregation producing profound platelet inhibition.

– Used in conjunction with percutaneous coronary interventions (PCI).

Parenteral antiplatelet drugs

 Often administered with ASA, heparin/LMWH, clopidogrel.

 Monitoring – ACT – Platelet count

Antithrombin Drugs

 Vitamin K Antagonists - Warfarin (Coumadin ® )  Warfarin interferes with vitamin-K dependent carboxylation of several coagulation factors including II, VII, IX, and X, as well as anticoagulant proteins C and S.

 Full anticoagulant effect is delayed  Average daily dose 4-5mg.

Warfarin - monitoring

   International Normalized Ratio (INR) – The need for frequent testing and dose adjustments detracts from warfarin ’ s ease of use in clinical practice.

Anticoagulation Clinics Coagucheck S ®

Unfractionated Heparin

  Complex glycosaminoglycan isolated and purified from animal tissues (porcine intestinal mucosa). Bovine lung heparin no longer available.

Binds to endothelial cells and macrophages, as well as plasma proteins (platelet factor 4 and von Willebrand factor).

Unfractionated Heparin (UFH)

   Exerts its anticoagulant effect via antithrombin Heparin binds to and produces a conformational change in antithrombin.

Anticoagulant effect reversed with protamine.

Low Molecular Weight Heparin

 Low molecular weight heparins (LMWH) are prepared from UFH by enzymatic or chemical hydrolysis.

Available products  Fragmin ® (dalteparin)  Lovenox ® (enoxaparin)  Innohep ® (tinzaparin

LMWH

 Binds to antithrombin and inactivates thrombin to a lesser extent than UFH because the smaller molecule fragments cannot bind thrombin and antithrombin simultaneously

LMWH

 Advantages – Better bioavailability – Longer half-life – Administered subcutaneously either once or twice daily – More predictable dose response – HIT Type II occurs less often with LMWH  Disadvantages – Protamine only partially reverses anticoagulant response.

Direct Thrombin Inhibitors (DTI)

Available Agents  Refludan ® (lepirudin)  Argatroban  Angiomax ® (bivalirudin)  Exanta ® (ximelagatran)* *Awaiting FDA approval

Direct Thrombin Inhibitors

   Thrombin is the central effector of coagulation and amplifies its own production, it is a natural target for pharmacologic intervention.

Target sites on the thrombin molecule responsible for substrate recognition and/or cleavage.

By blocking either the active site alone or both the active site and exosite I, DTIs specifically inhibit thrombin activity.

Argatroban

   Small molecule that binds reversibly to the active site of the thrombin molecule.

Approved for patients with HIT or HIT with thrombosis and patients undergoing percutaneous transluminal coronary angioplasty (PTCA) in conjunction with aspirin.

No reversal agent available.

Argatroban - Monitoring

 normal value is used.

 Argatroban synergistically interferes with the INR; the PT or INR cannot always be reliably used to monitor warfarin therapy in patients receiving argatroban. Effect dependent on argatroban dose and ISI of thromboplastin used.

 Argatroban alone also interferes with the INR and is dependent upon the ISI of the thromboplastin used.

Angiomax® (bivalirudin)

  Synthetic molecule designed on the basis of structural studies of hirudin; formerly known as hirulog.

Undergoes reversible binding may lead to less bleeding.

 No antidote available for reversal.

Angiomax® (bivalirudin)

 Therapeutic use – FDA- approved • Anticoagulation in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) in conjunction with aspirin.

– Other • Treatment of patients with HIT and unstable angina.

• Anticoagulation for patients with HIT undergoing CABG (on pump or off-pump).

Angiomax® (bivalirudin)

 Monitoring – ACT for patients undergoing PTCA.

– ACT for patients undergoing CABG.

– aPTT for patients with HIT or unstable angina.

TYPES OF STENTS

 These can be categorized as: – Balloon-expandable (eg, Palmaz-Schatz, Multilink family (currently the Penta), NIR, Bx Velocity) vs Self expandable (eg, Wallstent, RADIUS). – Tublar Vs Coil or Hybrid – Premounted vs. Unmounted (The latter are not in use in the US).

– Bifurcated stents – Covered Stents, Nonbiodegradable (usually PTFE) polymeric or autologous vein graft coverint to serve as an impermeable barrier as might be sesired to seal a coronary perforation, a passive coating to modify platelet adhesion or an active coating (heparin – coated stents).

– Drug-Eluting stents, which relase antiprofliferative agents (eg, Sirolimus, paclitaxel) These stents are now used in the mjaority of procedures. – Small vessel stents, which are engineered to provide less emtal and smaller strut thickness while maintaining optimal scaffolding for vessels <2.5mm in diameter.

Stents

 Wallstents

Risks of Stents:

Bad things can happen • • • • • • • • • • Acute myocardial infarction (heart attack) Arrhythmias (abnormal heart rhythms) Death Dissection Drug reactions to anti-platelet agents Emboli (blood clotting) Emergent Coronary Artery Bypass Surgery Hemorrhage (bleeding) Hypotension/Hypertension (low/high blood pressure) Infection and pain at insertion site www.guidant.com

Risks of Stents2:

More bad things can happen • • • • • • • • • Ischemia (low oxygen state) Perforation Pseudoaneurysm Restenosis Spasm Stent emobilization Stent thrombosis/occlusion Stroke/cerebrovascular accident Total occlusion of the coronary artery www.guidant.com

Stent vs. Angioplasty

 Bare metal stents , despite leading to a higher thrombosis rate, are less risky than balloon angioplasty because it results in a lower rate of restenosis and lower overall number of adverse effects.

Likeliness of Occurrence:

No, really, will it happen?

  Very low risk of most complications However…restenosis in: – Balloon angioplasty: 30-50% – Bare metal stents: 20-30% – Drug-eluting stents: <10%  Goal: minimize restenosis rate while keeping all other risks in check  (Note: Restenosis is defined as >50% narrowing of blood vessel diameter)

Stents vs. Balloon Angioplasty

 1991-1996 Restenosis Stent trial (REST) of patients with heart disease due to a lesion in a coronary artery  1/3 patients are high-risk  6 month follow-up  383 patients assigned to undergo: – Standard balloon angioplasty or – Stenting with the Palmaz-Shatz stent New England Journal of Medicine

Frequency of Complications

Event Death Minimal luminal diameter Myocardial infarction Restenosis Revascularization needed Thrombosis No major adverse event Angioplasty Stent 1.7% 1.85mm

4.4% 32.0% 27.0% 0.6% 72.0% 2.2% 2.04mm

8.4% 18.0% 10.0% 3.9% 84.0% New England Journal of Medicine

Stent vs. Angioplasty Verdict

 Bare metal stents , despite leading to a higher thrombosis rate, are less risky than balloon angioplasty because it results in a lower rate of restenosis and lower overall number of adverse effects.

Stents vs. Bypass Surgery

 1997-2001 trial of patients with high grade lesions  1/2 patients are high-risk  6 month follow-up  220 patients assigned to undergo: – Minimally invasive bypass surgery or – Stenting with a variety of bare metal stents New England Journal of Medicine

Frequency of Complications

Event Death Minimal luminal diameter Myocardial infarction Restenosis Revascularization needed Thrombosis No major adverse event Surgery 2.0% 0.38mm

5.0% 18.0% 8.0% ?

85.0% Stent 0.0% 1.70mm

3.0% 33.0% 29.0% ?

69.0% New England Journal of Medicine

Stent vs. Surgery Verdict

 Bare metal stents , while giving good short-term results, are more risky than minimally invasive bypass surgery because the risk of restenosis is much higher and so is the need for repeated intervention.

Bare Metal vs. Drug-Eluting Stents

 2000-2001 RAVEL trial of patients with angina  2/5 patients are high-risk  6 month follow-up  238 patients assigned to undergo: – Stenting with sirolimus-eluting stent or – Stenting with bare metal Bx Velocity stent New England Journal of Medicine

Frequency of Complications

Event Death Minimal luminal diameter Myocardial infarction Restenosis Revascularization needed Thrombosis No major adverse event Drug-Eluting Stent 1.7% 2.42mm

3.3% 0.0% 0.0% 0.0% 94.1% Bare Metal Stent 1.7% 1.64mm

4.2% 26.6% 22.9% 0.0% 70.9% New England Journal of Medicine

Bare Metal vs. Drug-Eluting Stent Verdict

 Drug-eluting stents are a great deal less risky than bare metal stents because they almost completely prevent restenosis, and similar to the surgery case, there is no longer a need for repeated intervention.

Drug-Eluting Stent vs. Bypass Surgery Complications

Event Death Minimal luminal diameter Myocardial infarction Restenosis Revascularization needed Thrombosis No major adverse event Drug-Eluting Stent 1.7% 2.42mm

3.3% 0.0% 0.0% 0.0% 94.1% Bypass Surgery 2.0% 0.38mm

5.0% 18.0% 8.0% ?

85.0% New England Journal of Medicine

Drug-Eluting Stent vs. Bypass Surgery Verdict

 • • • • •  Drug-eluting stents are more effective, safer, and pose less risk than bypass surgery because they have practically no restenosis or other adverse complications.

REFERENCES: Coronary Stent System Potential Adverse Effects. www.guidant.com.

De Luna AB, O’Neill WW. Drug-coated stents – for everyone or for selected use in high-risk populations. www.cardiosource.com

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Diegeler A, Thiele H, Falk, V, et al. Comparison of stenting with minimally invasive bypass surgery for stenosis of the left anterior descending coronary artery. N Engl J Med 2002 Aug 22;347:561-6.

Erbel R, Haude M, Hopp HW, et al. Coronary-artery stenting compared with balloon angioplasty for restenosis after initial balloon angioplasty. N Engl J Med 1998 Dec 3;339:1672-8.

Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002 Jun 6;346:1773-80.

Recommendations: 2004 Seventh ACCP Antithrombotic Therapy During PCI   Grade 1: Recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2: suggests that individual patients ’ choices.

values may lead to different

CHEST 2004; 126:179S-187S

Recommendations: 2004 Seventh ACCP Antithrombotic Therapy During PCI  Aspirin: – For pt undergoing PCI, ACCP recommends pretreatment with aspirin, 75mg to 325 mg (grade 1A) Mufson et al, total of 495 pts were randomly assigned to low-dose (80mg/d) or high-dose (1500 mg/d) aspirin starting 24 h before balloon angioplasty. No differences between the two groups respects to occurrence of MI(3.6% vs 3.9%), or need for CABAG (3.6% vs 3.7%) A longer pretreatment period (up to 24 h) should be considered if a lower dose of aspirin (75 to 100mg) is used because of potential delay in bioavailability and attainment of a platelet inhibtory effect. ACC/AHA 2005 guidelines state the same (level Evidence A)  ACC/AHA recommends pt not already taking daily chronic aspirin therapy should be given 300 to 325 mg of aspirin at least 2 hours and preferably 24 hours before the PCI Procedure is performed (level C evidence)

Recommendations: 2004 Seventh ACCP Antithrombotic Therapy During PCI  Aspirin: – For long-term treatment after PCI, ACCP recommends aspirin 75 to 162 mg/d (grade 1A).

Schwartz et al, 376 pts were randomized to treatment with the combination of ASA(990 mg/d) and dipyridamole (75mg/d) or with placebo for 6 months after balloon angioplasty. There was no difference in the rate of binary restenosis in the two treatment groups (37.7% vs 38.6%, respectively). Taylor et al, 212 pts to 6 months of treatment with ASA (100mg/d) vs placebo within 2 weeks of successful angioplasty. Angiographic restenosis occurred in 25% of aspirin treated pts and in 38% of those receiving placebo. However, there were no significant difference in clinical outcomes between the two groups. Although these trials suggest that aspirin has little or no effect on angiographic or clinical re-stenosis, long-term aspirin therapy is useful for secondary prevention of cardiovascular events (death, MI, or stroke).

Recommendations: 2004 Seventh ACCP Antithrombotic Therapy During PCI  Aspirin – For long-term treatment after PCI in pts who receive antithrombotic agents such as clopidogrel or warfarin, we recommend lower-dose aspirin, 75mg to 100 mg/d (Grade 1 C+).

When aspirin is administered in combination with other antiplatelet agents or with anticoagulants, it is reasonable to use a daily dose of 75 to 162 mg, rather than 325 mg, to minimize bleeding complications. Concept is supported by CURE study. CURE: Three groups, <100mg, 101-199mg, >200mg. The combined incidence of major bleeding increased as function of the aspirin dose, both in patients receiving aspirin plus placebo (1.9%, 2.8%, and 3.7% respectively).

Recommendations: 2004 Seventh ACCP Antithrombotic Therapy During PCI  Thienopyridine Derivatives: – Ticlopidine vs Clopidogrel Clopidogrel is safer than ticlopidine and easier to administer. Clopidogrel does not cause neutropenia, thereby obviating the need for blood count monitoring. Futhermore, hemolytic uremic syndrome and thrombotic thrombocytopentic purpura are rare complications of clopidogrel. Finally, unlike ticlopidine, which requires BID dosing, clopidogrel is Q daily. Similar efficacy, clopidogrel fewer side effects.

For pts who undergo stent placement, ACCP recommends the combination of aspirin and a thienopyridine over systemic anticoagulation therapy.

Recommendations: 2004 Seventh ACCP Antithrombotic Therapy During PCI  ACCP recommend a loading dose of 300mg of clopidogrel at least 6 hrs prior to planned PCI (Grade 1B). If clopidogrel is started < 6 h prior to planned PCI, suggest 600 mg loading dose of clopidogrel. – ACC/AHA recommends the same loading dose at least 6 hours before PCI, and/or GP IIb/IIIa antagonists, administered at the time of PCI.  If ticlopidine is administered, they recommend that a loading dose of 500 mg at least 6 h before planned PCI. (grade 2c).

Recommendations: 2004 Seventh ACCP Antithrombotic Therapy During PCI  Aspirin intolerant patients: – For PCI pts who cannot tolerate aspirin, ACCP recommends that the loading dose of clopidogrel (300mg) or ticlopidine (500mg) be adminstered at least 24 h prior to planned PCI (Grade 2c).

– Clopidogrel is given at the time of procedure, supplementation with GPIIb/IIIa receptor antagonists can be beneficial to facilitate earlier platelet inhibition than with clopidogrel alone.

– When a loading dose of clopidogrel is administered, a regimen of greater than 300mg is reasonable to achieve higher levels of antiplatelet activity more rapidly, but the efficacy and safety compare with a 300 mg loading dose are less established.

Recommendations: 2004 Seventh ACCP Antithrombotic Therapy During PCI   Duration of thienopyridine therapy after stent placement – After PCI, ACCP recommends, in addition to aspirin, clopidogrel (75mg/d) for at least 9 to 12 months. (Grade 1A) – If ticlopidine is used in place of clopidogrel after PCI, we recommend ticlopidine for 2 weeks after placement of a bare metal stent in addition to aspirin. (grade 1b) – In pts with low atherosclerotic risk such as those isolated coronary lesions, ACCP recommends clopidogrel for at least 2 weeks after placement of a bare metal stent (Grade 1A), for 2 to 4 months after placement of sirolimus-eluting stent (grade 1c+) and 6 months after placement of paclitaxel-eluting stent. (Grade 1C).

ACC/AHA recommends after the PCI procedure, in pts with neither aspirin resistance, allergy, nor increased risk of bleeding, aspirin 325 mg daily should be given at least 1 month after bare-metal stent, 3 months after sirolimus-eluting stent implantation, and 6 months after paclitaxel-eluting stent implantation, after which daily chronic aspirin use should be continued indefinitely at a dose of 75mg to 162 mg.

Recommendations: 2004 Seventh ACCP Antithrombotic Therapy During PCI  Recommendations use of GP IIb – IIIa – For all pts undergoing PCI, particularly those undergoing primary PCI, or those with refractory UA or other high-risk features, ACCP recommends use of a GP IIb-IIIa antagonist (abciximab or eptifibatide) grade 1A. – In pts undergoing PCI for STEMI, ACCP recommends abciximab over epifibatide for now.(CADILLAC trial) (This is because large randomized trial have not yet been performed. However, smaller studies shows favorable outcome). – ACC/AHA recommends that STEMI undergoing PCI, it is reasonable to administer abciximab as early as possible.

Recommendations: 2004 Seventh ACCP Antithrombotic Therapy During PCI – ACCP recommends adminsitration of abciximab as a 0.25 mcg/min (grade 1A) and eptifibatide as a double bolus (each of 180mcg/kg adminstered 10 min apart) followed by an 18-h infusion of 2.0 mcg/kg/min. (Grade 1A). – In pts undergoing PCI, ACCP recommends against the use of tirofiban as an alternative to abciximab (grade 1A) RESTORE trial, Major bleeding occurred in 5.8% of those receiving tirofiban and in 3.7% in placebo.

Recommendations: 2004 Seventh ACCP Antithrombotic Therapy During PCI – For pts with NSTEMI/UA who are designated as moderate to-high risk based on TIMI score, ACCP recommends that upstream use of GP IIb-IIIa antagonist (either eptifibatide or tirofiban) be started as soon as possible prior to PCI (grade 1A). ACC/AHA especially feels that GP IIb-IIIa is especially efficacious when clopidogrel is not given .

– In NSTEMI/UA pts who receive upstream treatment with tirofiban, ACCP recommends PCI be deferred for at least 4 h after initiating the tirofiban infusion (grade 2c) – With planned PCI in NSTEMI/UA pts with an elevated troponin level, we recommend that abciximab be started within 24 h prior to intervention (grade 1A).

Recommendations: 2004 Seventh ACCP Antithrombotic Therapy During PCI  Unfractionated Heparin: – In pts receiving a GP IIb-IIIIa inhibitor, ACCP recommends a heparin bolus of 50 to 70 IU/kg to achieve a target ACT> 200s (grade 1C) – In pts not receiving a GP IIb-IIIa inhibitor, ACCP recommends that heparin be administered in doses sufficient to produce an ACT of 250 to 350 s (Grade 1 C+). ACC/AHA agrees with this.

– In pts after uncomplicatred PCI, we recommend against routine postprocedural infusion of heparin (grade 1A).

Recommendations: 2004 Seventh ACCP Antithrombotic Therapy During PCI  LMWH: – In pts who have received LMWH prior to PCI, ACCP recommends that administration of additional anticoagulant therapy is dependent on the timing of the last dose of LMWH (grade 1 C). If the last dose of enxaparin is administered between 8 hours and 12 hours before PCI, ACCP suggests a 0.3mcg/kg bolus of IV enoxaparin at the time of PCI (grade 2c). If the last enoxaparin dose is adminstered >12 h before PCI, ACCP suggest conventional anticoagulation therapy during PCI. (0.5mg-1mg/kg).

Recommendations: 2004 Seventh ACCP Antithrombotic Therapy During PCI  Direct thrombin Inhibitors: Hirudin, bivalirudin, argatroban.

– For pts undergoing PCI who are not treated with a GP IIb-IIIa antagonist or heparin, ACCP recommend bivalirudin (0.75mg/kg bolus followed by an infusion of 1.75 mg/kg/h for the duration of PCI0 during PCI (Grade 1A).

– In PCI pts who are at low risk for complications, ACCP recommend bivalirudin as an alternative to heparin as an adjunct to GP IIb-III a antagonists (grade 1b). ACC/AHA agrees with this recommendation.

– In PCI pts who are at high risk for bleeding, ACCP recommends bivalirudin over heparin as an adjunct to GP IIb-III a antagonists (Grade 1B).

Recommendations: 2004 Seventh ACCP Antithrombotic Therapy During PCI  Warfarin: Vitamin K antagonist – In pt undergoing PCI with no other indication for systemic anticoagulation therapy, ACCP recommends Against routine use of warfarin after PCI. (grade 1A).

CASE:

 A 47 year old male presented to MCH ED with c/o of chest pain. Pain is described as crushing chest pain that radiated to his left arm and neck for 1 hour. He has hx of hypertension. Smokes 2 packs a day for 30 years. The only medication that Pt takes is the metoprolol 50mg BID. On physical exam, his blood pressure is 130/80, HR 86 bpm. There is no JVD ’ s and his lungs were clear. Initial Troponin I is high at 3 ng/mL. ECG:

Question #1

     Decision was made by ER physician to transfer the patient down to CIC for immediate PCI. It will be another 3 hours before the pt will have PCI.

  1.

According to the 2004 ACCP guidelines, what would be the appropriate antiplatelet drug combination that the ER physician could give prior to transferring the patient down in addition to the unfractionated heparin: A) B) C) D) ASA 325 mg, Plavix 75mg ASA 650 mg, Plavix 300 mg ASA 325mg, Plavix 300mg/ or 600 mg ASA 81 mg, Plavix 150mg.

Answer C.

Question #2:

  Pt arrived at the Heart Center, in the cath. Lab, the Cardiologist found that pt had an 75% RCA blockage, decision was made to place a paclitaxel- stent in patient. According to the guidelines, how long should this patient be on the plavix?

A) At least 3 months  B)  C)  D) At least 6 months At least 9 months indefinite

Answer C

Question 3:

 According to the guidelines, how long should this patient be on ASA, and at what dosage?

 A) ASA 81 mg for 3 months then 325mg chronically   B) ASA 325 for at least 9 months, then 81-160mg chronically C) stop ASA 160 for at least 6 months, then  D) ASA for 325mg then Stop.

Answer B.