Coronary Anticoagulant Therapy
Figure 1: Tissue Factor Pathway – Current Anticoagulants Target Multiple Factors, New Agents Target Factor IIa or Factor Xa
Tissue factor pathway
Factor XII Factor XI Factor IX Factor VIII
Unfractionated heparin
Dabigatran AZD0837 Bivalirudin Argatroban
Factor X Factor V Factor II
Fibrin clot Factor I
Factor VII Warfarin
Rivaroxaban Apixaban Edoxaban Betrixaban Eribaxaban YM150 TAK442
LY 517717
the haemoglobin level of at least 20g per litre, transfusion of at least two units of blood, or symptomatic bleeding in a critical area or organ” was met in 3.36% per year in patients taking warfarin, 2.71 and 3.11% in patients taking the low and high dosage of dabigatran respectively. As a result of the superior effectiveness and comparable safety of the 150mg dose, dabigatran was approved by the US Food and Drug Administration (FDA) in the US in October 2010 for patients with AF. Also available is a 75mg twice daily dose for patients with severe renal failure, after which a debate has arisen. RE-LY did not investigate the use of dabigatran in such a low dose and no other data on the efficacy of this dose is available. Moreover, the dose of 110mg showed to be non-inferior to warfarin in both the efficacy and safety end-points, but was not approved.
and new anticoagulant treatment might be effective in reducing the incidence of postoperative stroke. New anticoagulant agents aiming at reducing both early graft thrombosis and postoperative stroke would mean a major evolution.
Anticoagulants
Several new anticoagulants have been or are currently evaluated to prevent adverse events in patients with atrial fibrillation (AF) and/or acute coronary syndrome (ACS) (see Table 1).8–18
introduced agents walk the same path. After trials have evaluated new agents for stroke prevention in AF or as treatment for deep-vein thrombosis, subsequent trials will likely evaluate its efficacy and safety in patients with ACS. Eventually, many of these patients will undergo CABG and the use of anticoagulant medication then becomes an issue regarding whether they will result in bleeding complications.
Agents AVE5026, idrabiotaparinux, otamixaban and RB006 are less suitable for long-term use in patients with mechanical heart valves because of their parental administration. Oral anticoagulants (see Figure 1 and Table 1) are easier to use in patients postoperative of cardiac surgery, but need to show their effectiveness and safety against existing therapies.
Dabigatran Etexilate
Dabigatran is taken orally as a prodrug called dabigatran etexilate (see Table 1). An oral bioavailability of approximately 6% is fully converted into dabigatran. In plasma, the peak level of the drug occurs after two hours. Eight per cent is excreted by the kidneys and the drug has a half-life of 14–17 hours.19–20
After initially being evaluated in hip and
knee surgery, this factor IIa (fIIa) inhibitor was introduced as an anticoagulant in the field of cardiovascular diseases to prevent stroke in high-risk patients with AF. The Randomized evaluation of long-term anticoagulant therapy (RE-LY) trial21
Many of these newly
Many discuss the possibility of dabigatran replacing VKAs in patients with mechanical heart valves. Although no studies have yet compared the two in such a setting, it is speculated that similar outcomes as the RE-LY trial would be the result. The international multicentre double-blind randomised RE-ALIGN study is currently in the start-up phase to compare the efficacy and safety in valvular surgery and start of enrolment is anticipated in June 2011.
Rivaroxaban
Rivaroxaban targets factor Xa (fXa) and has a half-life of seven to 11 hours (see Table 1).22
It has shown to be effective in the prevention
of thromboembolisms in patients undergoing orthopaedic surgery before it was evaluated in a phase II trial including patients with ACS.16
Results showed that rivaroxaban dose-dependently increased the rate of clinically significant bleeding for all doses. The primary efficacy end-point of death, myocardial infarction (MI), stroke, or severe ischaemia requiring revascularisation was 5.6% for rivaroxaban compared to 7% for placebo patients (p=0.10). The composite end-point without severe ischaemia was, however, significantly improved compared to aspirin alone (3.9 versus 5.5%). The authors rightly stated that rivaroxaban increases bleeding and might reduce major adverse events. Recently presented results from the Randomized double blind study comparing once-daily oral rivaroxaban with adjusted dose oral warfarin for the prevention of stroke in patients with nonvalvular atrial fibrillation (ROCKET-AF) study at the 2010 American Heart Association (AHA) Scientific Sessions showed a reduction in the primary composite end-point of stroke or non-central nervous system embolisation by 21% in a per protocol analysis.23 Patients treated with rivaroxaban also had statistically significant fewer intracranial haemorrhages, critical organ bleeds and bleeding-related deaths compared to the warfarin group, but did, however, have an increased rate of haemoglobin/haematocrit drop and transfusions.
Rivaroxaban has a potential role in cardiac surgery as an adjunct to aspirin post-CABG, or as a replacement of VKAs in patients with mechanical heart valves.
Apixaban compared two doses of
dabigatran (110mg and 150mg twice daily) to the conventional adjusted dose (INR 2–3) of warfarin in >18,000 patients. After a median follow-up period of two years, the primary end-point of stroke and systemic embolism was reached in 1.69% per year for warfarin, 1.53% for dabigatran 100mg (p<0.001 for non-inferiority) and 1.11% for the high dosage of dabigatran (p<0.001 for superiority). The primary safety end-point of major bleeding defined as “a reduction in
72
Apixaban is administered in an active form, resulting in a rapid absorption with peaking plasma levels after three hours (see Table 1).20 Apixaban showed encouraging results in the Apixaban for prevention of acute ischemic and safety events (APPRAISE) trial as an additional therapy to aspirin and/or clopidogrel compared to a placebo in patients with ACS.18
There was a non-significant trend to a decrease of ischaemic events in both an apixaban 2.5mg twice daily and 10mg once daily dose. This did however come with a cost of increased
INTERVENTIONAL CARDIOLOGY
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