Antithrombin therapy to support PCI

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

Overview

ACCF/AHA/SCAI 2011 Guidelines for Percutaneous Coronary Intervention: Use of Parenteral Anticoagulants during PCI[1] (DO NOT EDIT)

Class I
"1. An anticoagulant should be administered to patients undergoing PCI. (Level of Evidence: C)"

Unfractionated Heparin (UFH)

IV unfractionated heparin is the most common anticoagulant used in the cath lab.

ACCF/AHA/SCAI 2011 Guideline for Percutaneous Coronary Intervention: Unfractionated Heparin [1] (DO NOT EDIT)

Class I
"1. Administration of intravenous UFH is useful in patients undergoing PCI. (Level of Evidence: C)"

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)

ACCF/AHA/SCAI 2011 Guideline for Percutaneous Coronary Intervention: Enoxaparin[1] (DO NOT EDIT)

Class I
"1. An additional dose of 0.3 mg/kg intravenous enoxaparin should be administered at the time of PCI to patients who have received fewer than 2 therapeutic subcutaneous doses (e.g., 1 mg/kg) or received the last subcutaneous enoxaparin dose 8 to 12 hours before PCI.[2][3][4][5][6] (Level of Evidence: B)"
Class III (Harm)
"1. Unfractionated heparin (UFH) should not be given to patients already receiving therapeuticsubcutaneous enoxaparin.[2][7] (Level of Evidence: B)"
Class IIb
"1. Performance of PCI with enoxaparin may be reasonable in patients either treated with upstreamsubcutaneous enoxaparin for UA/NSTEMI or who have not received prior antithrombin therapy and are administeredintravenous enoxaparin at the time of PCI.[8][9][2][10] (Level of Evidence: B)"

ACCF/AHA/SCAI 2011 Guideline for Percutaneous Coronary Intervention: Fondaparinux[1] (DO NOT EDIT)

Class III (No Benefit)
"1. Fondaparinux should not be used as the sole anticoagulant to support PCI. An additional anticoagulant with anti-IIa activity should be administered because of the risk ofcatheter thrombosis.[11][12](Level of Evidence: C)"

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

ACCF/AHA/SCAI 2011 Guideline for Percutaneous Coronary Intervention: Bivalirudin and Argatoban[1] (DO NOT EDIT)

Class I
"1. For patients undergoing PCI, bivalirudin is useful as an anticoagulant with or without prior treatment with unfractionated heparin (UFH).[13][14][15][16][17][18][19][20][21] (Level of Evidence: B)"
"2. For patients with heparin-induced thrombocytopenia, it is recommended thatbivalirudin or argatroban be used to replace unfractionated heparin (UFH).[22][23] (Level of Evidence: B)"

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.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, Chambers CE, Ellis SG, Guyton RA, Hollenberg SM, Khot UN, Lange RA, Mauri L, Mehran R, Moussa ID, Mukherjee D, Nallamothu BK, Ting HH (2011). "2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: Executive Summary A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions" (PDF). Journal of the American College of Cardiology. 58 (24): 2550–83. doi:10.1016/j.jacc.2011.08.006. PMID 22070837. Retrieved 2011-12-08. Text "PDF" ignored (help); Unknown parameter |month= ignored (help)
  2. ↑ 2.0 2.1 2.2 Ferguson JJ, Califf RM, Antman EM, Cohen M, Grines CL, Goodman S, Kereiakes DJ, Langer A, Mahaffey KW, Nessel CC, Armstrong PW, Avezum A, Aylward P, Becker RC, Biasucci L, Borzak S, Col J, Frey MJ, Fry E, Gulba DC, Guneri S, Gurfinkel E, Harrington R, Hochman JS, Kleiman NS, Leon MB, Lopez-Sendon JL, Pepine CJ, Ruzyllo W, Steinhubl SR, Teirstein PS, Toro-Figueroa L, White H (2004). "Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial". JAMA : the Journal of the American Medical Association. 292 (1): 45–54. doi:10.1001/jama.292.1.45. PMID 15238590. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  3. ↑ Cohen M, Levine GN, Pieper KS, Lan L, Antman EM, Aylward PE, White HD, Kleiman NS, Califf RM, Mahaffey KW (2010). "Enoxaparin 0.3 mg/kg IV supplement for patients transitioning to PCI after subcutaneous enoxaparin therapy for NSTE ACS: a subgroup analysis from the SYNERGY trial". Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 75 (6): 928–35. doi:10.1002/ccd.22340. PMID 20432399. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  4. ↑ Collet JP, Montalescot G, Golmard JL, Tanguy ML, Ankri A, Choussat R, Beygui F, Drobinski G, Vignolles N, Thomas D (2004). "Subcutaneous enoxaparin with early invasive strategy in patients with acute coronary syndromes". American Heart Journal. 147 (4): 655–61. doi:10.1016/j.ahj.2003.10.019. PMID 15077081. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  5. ↑ Levine GN, Ferrando T (2004). "Degree of anticoagulation after one subcutaneous and one subsequent intravenous booster dose of enoxaparin: implications for patients with acute coronary syndromes undergoing early percutaneous coronary intervention" (PDF). Journal of Thrombosis and Thrombolysis. 17 (3): 167–71. doi:10.1023/B:THRO.0000040484.99422.77. PMID 15353913. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  6. ↑ Martin JL, Fry ET, Sanderink GJ, Atherley TH, Guimart CM, Chevalier PJ, Ozoux ML, Pensyl CE, Bigonzi F (2004). "Reliable anticoagulation with enoxaparin in patients undergoing percutaneous coronary intervention: The pharmacokinetics of enoxaparin in PCI (PEPCI) study". Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 61 (2): 163–70. doi:10.1002/ccd.10726. PMID 14755805. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  7. ↑ Drouet L, Bal dit Sollier C, Martin J (2009). "Adding intravenous unfractionated heparin to standard enoxaparin causes excessive anticoagulation not detected by activated clotting time: results of the STACK-on to ENOXaparin (STACKENOX) study". American Heart Journal. 158 (2): 177–84. doi:10.1016/j.ahj.2009.05.022. PMID 19619692. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  8. ↑ Brieger D, Collet JP, Silvain J, Landivier A, Barthélémy O, Beygui F, Bellemain-Appaix A, Mercadier A, Choussat R, Vignolles N, Costagliola D, Montalescot G (2011). "Heparin or enoxaparin anticoagulation for primary percutaneous coronary intervention". Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 77 (2): 182–90. doi:10.1002/ccd.22674. PMID 20578166. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  9. ↑ Choussat R, Montalescot G, Collet JP, Vicaut E, Ankri A, Gallois V, Drobinski G, Sotirov I, Thomas D (2002). "A unique, low dose of intravenous enoxaparin in elective percutaneous coronary intervention". Journal of the American College of Cardiology. 40 (11): 1943–50. PMID 12475453. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  10. ↑ Montalescot G, Gallo R, White HD, Cohen M, Steg PG, Aylward PE, Bode C, Chiariello M, King SB, Harrington RA, Desmet WJ, Macaya C, Steinhubl SR (2009). "Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention 1-year results from the STEEPLE (SafeTy and efficacy of enoxaparin in percutaneous coronary intervention patients, an international randomized evaluation) trial". JACC. Cardiovascular Interventions. 2 (11): 1083–91. doi:10.1016/j.jcin.2009.08.016. PMID 19926048. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  11. ↑ Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, Budaj A, Peters RJ, Bassand JP, Wallentin L, Joyner C, Fox KA (2006). "Comparison of fondaparinux and enoxaparin in acute coronary syndromes". The New England Journal of Medicine. 354 (14): 1464–76. doi:10.1056/NEJMoa055443. PMID 16537663. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  12. ↑ Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, Budaj A, Peters RJ, Bassand JP, Wallentin L, Joyner C, Fox KA (2006). "Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial". JAMA : the Journal of the American Medical Association. 295 (13): 1519–30. doi:10.1001/jama.295.13.joc60038. PMID 16537725. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  13. ↑ De Luca G, Cassetti E, Verdoia M, Marino P (2009). "Bivalirudin as compared to unfractionated heparin among patients undergoing coronary angioplasty: A meta-analyis of randomised trials". Thrombosis and Haemostasis. 102 (3): 428–36. doi:10.1160/TH09-05-0287. PMID 19718462. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  14. ↑ Lincoff AM, Steinhubl SR, Manoukian SV, Chew D, Pollack CV, Feit F, Ware JH, Bertrand ME, Ohman EM, Desmet W, Cox DA, Mehran R, Stone GW (2008). "Influence of timing of clopidogrel treatment on the efficacy and safety of bivalirudin in patients with non-ST-segment elevation acute coronary syndromes undergoing percutaneous coronary intervention: an analysis of the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial". JACC. Cardiovascular Interventions. 1 (6): 639–48. doi:10.1016/j.jcin.2008.10.004. PMID 19463378. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  15. ↑ Kastrati A, Neumann FJ, Mehilli J, Byrne RA, Iijima R, Büttner HJ, Khattab AA, Schulz S, Blankenship JC, Pache J, Minners J, Seyfarth M, Graf I, Skelding KA, Dirschinger J, Richardt G, Berger PB, Schömig A (2008). "Bivalirudin versus unfractionated heparin during percutaneous coronary intervention". The New England Journal of Medicine. 359 (7): 688–96. doi:10.1056/NEJMoa0802944. PMID 18703471. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  16. ↑ Lincoff AM, Kleiman NS, Kereiakes DJ, Feit F, Bittl JA, Jackman JD, Sarembock IJ, Cohen DJ, Spriggs D, Ebrahimi R, Keren G, Carr J, Cohen EA, Betriu A, Desmet W, Rutsch W, Wilcox RG, de Feyter PJ, Vahanian A, Topol EJ (2004). "Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial". JAMA : the Journal of the American Medical Association. 292 (6): 696–703. doi:10.1001/jama.292.6.696. PMID 15304466. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  17. ↑ Mehran R, Lansky AJ, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Wong SC, Nikolsky E, Gambone L, Vandertie L, Parise H, Dangas GD, Stone GW (2009). "Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial". Lancet. 374 (9696): 1149–59. doi:10.1016/S0140-6736(09)61484-7. PMID 19717185. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  18. ↑ Schulz S, Mehilli J, Ndrepepa G, Neumann FJ, Birkmeier KA, Kufner S, Richardt G, Berger PB, Schömig A, Kastrati A (2010). "Bivalirudin vs. unfractionated heparin during percutaneous coronary interventions in patients with stable and unstable angina pectoris: 1-year results of the ISAR-REACT 3 trial". European Heart Journal. 31 (5): 582–7. doi:10.1093/eurheartj/ehq008. PMID 20150324. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  19. ↑ Stone GW, McLaurin BT, Cox DA, Bertrand ME, Lincoff AM, Moses JW, White HD, Pocock SJ, Ware JH, Feit F, Colombo A, Aylward PE, Cequier AR, Darius H, Desmet W, Ebrahimi R, Hamon M, Rasmussen LH, Rupprecht HJ, Hoekstra J, Mehran R, Ohman EM (2006). "Bivalirudin for patients with acute coronary syndromes". The New England Journal of Medicine. 355 (21): 2203–16. doi:10.1056/NEJMoa062437. PMID 17124018. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  20. ↑ Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Dangas G, Wong SC, Kirtane AJ, Parise H, Mehran R (2008). "Bivalirudin during primary PCI in acute myocardial infarction". The New England Journal of Medicine. 358 (21): 2218–30. doi:10.1056/NEJMoa0708191. PMID 18499566. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  21. ↑ Dangas G, Mehran R, Guagliumi G, Caixeta A, Witzenbichler B, Aoki J, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Rabbani LE, Parise H, Stone GW (2009). "Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: results from the HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial". Journal of the American College of Cardiology. 54 (15): 1438–46. doi:10.1016/j.jacc.2009.06.021. PMID 19796737. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  22. ↑ Lewis BE, Matthai WH, Cohen M, Moses JW, Hursting MJ, Leya F (2002). "Argatroban anticoagulation during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia". Catheterization and Cardiovascular Interventions :Official Journal of the Society for Cardiac Angiography & Interventions. 57 (2): 177–84. doi:10.1002/ccd.10276. PMID 12357516. Retrieved 2011-12-15. Unknown parameter |month= ignored (help)
  23. ↑ Mahaffey KW, Lewis BE, Wildermann NM, Berkowitz SD, Oliverio RM, Turco MA, Shalev Y, Ver Lee P, Traverse JH, Rodriguez AR, Ohman EM, Harrington RA, Califf RM (2003). "The anticoagulant therapy with bivalirudin to assist in the performance of percutaneous coronary intervention in patients with heparin-induced thrombocytopenia (ATBAT) study: main results". The Journal of Invasive Cardiology. 15 (11): 611–6. PMID 14608128. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)

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