What’s new in cardiology?

PREOPERATIVE ANTITHROMBOTIC THERAPY – WHAT DO WE STOP AND WHY?

View Slides

T Painter
Royal Adelaide Hospital, Adelaide, SA

This paper will consider both anticoagulant and antiplatelet therapy as they are closely interlinked and present similar clinical dilemmas. The issue of antithrombotic therapy and regional anaesthesia will not be addressed (covered later in the week), nor will the use of these agents in pregnancy.

When considering preoperative cessation of antithrombotic agents, a number of factors have relevance, namely: surgical urgency, duration of surgical bleeding risk and the risk and consequences of perioperative bleeding and thromboembolism.

This can be a complex decision making process and requires a sound understanding of the pharmacologic profiles of an ever increasing number of antithrombotic agents. To make matters more complicated, there is a general lack of information available in the literature addressing the risks of ceasing, substituting or continuing these agents preoperatively.

Anticoagulant therapy

Recent literature suggests that there is a significant variation among clinicians in their preoperative management of chronically anticoagulated patients, especially those with mechanical heart valves.There appear to be several reasons for this:

• The spectrum of indications for anticoagulant therapy is broad.
• The risks and consequences of stopping therapy and subsequent thromboembolic events range widely and can be fatal.
• There is a lack of consensus regarding how to stratify an individual’s perioperative thromboembolic risk.
• There is limited trial based evidence for any particular preoperative thrombophylaxis regimen and this is reflected in the lack of agreement found in recent guidelines.
• There is ongoing pressure to manage patients in the community.

It is clear that at present, there can be no standardized approach. Some generalisations can be made:

1. Certain procedures have a low risk of surgical bleeding and can be performed under full or slightly reduced anticoagulation, especially cataract and minor dental and dermatologic operations.
2. Most other surgeries can be safely carried out provided the INR ? 1.5. Warfarin should be ceased 4-5 days preoperatively to permit this.
   • Patients at high risk of a primary or recurrent thromboembolic event - (e.g. recent venous thromboembolism) should have consideration given to deferral of surgery if possible. If not, the patient should be fully anticoagulated with intravenous unfractionated heparin (UH) 1-2 days following warfarin cessation3, 4. Intravenous UH should be ceased 5-6 hours preoperatively4.
   • Patients who have high risk factors for thromboembolism – (e.g. mechanical mitral valve) have traditionally received intravenous UH. However, there is increasing evidence for the safety and efficacy of low molecular-weight heparin (LMWH) in this setting, which would facilitate outpatient treatment5,6. These patients should receive a full anticoagulant dose (e.g. enoxaparin 1.5 mg/kg/d) from one day after warfarin cessation. As there is no specific antidote to LMWH, this should be ceased 24 hours pre-operatively, and would not be appropriate for those requiring emergency operations5.
   • Patients at intermediate or low-risk of thromboembolism – (e.g. mechanical aortic valve) have proven more difficult to manage. Some have advocated no preoperative thrombophylaxis unless the patient is already hospitalized 3. This has generated some controversy, but there are no clear indications from the literature how best to proceed with these patients. In light of the emerging evidence of the safety of LMWH in the outpatient population, some authors have advocated the institution of preoperative prophylactic outpatient LMWH (e.g. 20-40 mg/d enoxaparin)5 or UH (5000 u/d subcutaneously)4. It would appear that it has become less acceptable to treat this group on an inpatient basis.

Antiplatelet therapy

Antiplatelet therapy is now firmly established in everyday clinical practice and has conclusively been shown to reduce adverse events in those with cardiovascular (CV) disease7. As well as an expanding list of indications for antiplatelet therapy, there is an ever increasing range of agents available.

Unnecessary cessation of antiplatelet agents may place patients at increased risk of adverse perioperative CV events, especially in those having CV surgery or who have had a recent acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI)7. Most data regarding bleeding complications when these agents are continued relate to patients on aspirin undergoing cardiac surgery where there may be an increase in bleeding, although no increase in mortality7. Preoperative clopidogrel for those undergoing coronary artery bypass surgery appears to have a stronger association with increased bleeding complications. For patients undergoing non-cardiac surgery, data is extremely sparse but may point to an increase in bleeding, especially where antiplatelet agents are used in combination.

The antiplatelet agents fall into three main groups:

1. Aspirin – irreversibly acetylates platelet cyclooxygenase and thus production of thromboxane A2, weakly inhibiting platelet aggregation and vasoconstriction. Restoration of activity requires release of new platelets from the bone marrow and thus 10-12 days for full activity, although some is restored at 2-4 days. For patients with a low CV risk profile and/or where normal platelet activity is essential, aspirin should be ceased for 7-10 days. Otherwise, most would not recommend aspirin cessation.
2. Thienopyridines – Clopidogrel-selectively and irreversibly prevents adenosine diphosphate induced platelet aggregation, from which the partially inhibited platelet takes 7-10 days to fully recover. As with aspirin, clopidogrel may not need to be ceased for elective non-cardiac surgery if it is being given as monotherapy. It will act synergistically with aspirin and if feasible should be ceased in this context7. However, it should be noted that those on combined therapy may well have had a recent ACS or PCI (within 6 weeks) with a stent deployed. These patients are at much increased risk of perioperative CV complications and serious consideration should be given to delaying surgery or devising an alternative anticoagulation regimen if this is not possible. It is recommended that patients who have received a drug-eluting stent be given 3-6 months of combined aspirin/clopidogrel therapy8. Consultation with the responsible cardiologist would seem prudent should these patients require surgery during this time. Ticlopidine – has an unfavourable side effect profile and has largely been replaced by clopidogrel1.
3. Glycoprotein IIb/IIIa receptor inhibitors – act by preventing fibrinogen adherence to aggregating platelets. Powerful inhibitors of platelet function, they are usually given to patients after PCI or ACS, and therefore those on these agents generally require emergent and/or cardiac surgery.

Abciximab – an antibody fragment which has a high affinity to the receptor. While abciximab’s plasma half life is only 26 minutes, its effective half life is 12 hours and effects on the platelet can still be seen at 7 days after cessation. However, as there is marked improvement in platelet aggregation at 12 hours, surgery should be delayed if at all possible.

Tirofiban/Eptifibatide – both low molecular weight agents which have much higher dissociation constants than abciximab and thus an effective half life of only 2 hours. Restoration of full platetet activity takes 3-4 hours.

No specific antidote is available for any of the above agents. Platelet transfusions have been suggested as the only possible antidote should excessive bleeding occur perioperatively, although there is limited data to support this practice. Platelet transfusions are not effective for tirofiban and eptifibatide. Blood conservation techniques and the use of antifibrinolytics may help minimize perioperative bleeding.

Direct thrombin inhibitors (DTIs) – such as the recombinant hirudins (lepirudin, desirudin), bivalirudin and argatroban are parenteral agents that bind thrombin (free and clot-bound) and inhibit its actions. They provide a predictable anticoagulant response and are marketed as heparin alternatives in thrombophylaxis and ACS and for the treatment of heparin induced thrombocytopenia. Restoration of clotting activity following treatment cessation takes between 1-2 hrs for argatroban, 2-3 hours for bivalirudin and 8-18 hours for recombinant hirudin1, 9.

Herbal remedies – may interact with conventional anticoagulant or antiplatelet drugs and/or have intrinsic activity. Herbal remedies such as garlic, ginko biloba and ginseng are common examples. Physicians should be aware of these (and other) effects of these remedies which are, for the most part, considered safe by consumers.

Future agents – Factor Xa inhibitors

Fondaparinux – a parenteral pentasaccharide which binds with very high affinity to antithrombin III and thus indirectly inactivates Factor Xa. An important emerging anticoagulant, it has a half life of 14-16 hours and has no antidote. Protamine is ineffective.

DX-9065a/Razaxaban – directly inhibit Factor Xa and are currently in development and phase II and III testing. Razaxaban is orally bioavailable.

Time of Presentation
Saturday 13 May 2006 - 1030-1200

References

1. Harder S, Klinkhardt U, Alvarez JM. Avoidance of bleeding during surgery in patients receiving anticoagulant and/or antiplatelet therapy: pharmacokinetic and pharmacodynamic considerations. Clin Pharmacokinet. 2004;43(14):963-81
2. Garcia DA, Ageno W, Libby EN, Bibb J, Douketis J, Crowther MA. Perioperative anticoagulation for patients with mechanical heart valves: a survey of current practice. J Thromb Thrombolysis. 2004 Dec;18(3):199-203.
3. Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med. 1997 May 22;336(21):1506-11.
4. Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep;126(3 Suppl):204S-233S.
5. Watts SA, Gibbs NM. Outpatient management of the chronically anticoagulated patient for elective surgery. Anaesth Intensive Care. 2003 Apr;31(2):145-54.
6. Douketis JD, Johnson JA, Turpie AG. Low-molecular-weight heparin as bridging anticoagulation during interruption of warfarin: assessment of a standardized periprocedural anticoagulation regimen. Arch Intern Med. 2004 Jun 28;164(12):1319-26.
7. Merritt JC, Bhatt DL. The efficacy and safety of perioperative antiplatelet therapy. J Thromb Thrombolysis. 2004 Feb;17(1):21-7.
8. Popma JJ, Berger P, Ohman EM, Harrington RA, Grines C, Weitz JI. Antithrombotic therapy during percutaneous coronary intervention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep;126 (3 Suppl):576S-599S.
9. Vandermeulen E. Anaesthesia and new antithrombotic drugs. Curr Opin Anaesthesiol 2005;18:353-9.
10. Samuels N. Herbal remedies and anticoagulant therapy. Thromb Haemost. 2005 Jan;93(1):3-7.