Inhibiting Coagulation

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Inhibiting Coagulation

Bivalirudin

Bivalirudin is a synthetic peptide congener of the natural compound hirudine, found in the saliva of the medicinal leech Hirudo medicinalis. The drug acts as a potent, rapid and reversible inhibitor specific for thrombin that binds both to the catalytic site and to the substraterecognition site of circulating and clot-bound thrombin, inactivating it. Thrombin itself has the ability to slowly cleave the bond with bivalirudin, restoring its procoagulant properties. The molecule does not bind to plasmatic proteins, therefore producing predictable anticoagulant effects that may also be monitored with routine coagulative tests (aPTT, ACT).⁷¹ Furthermore, bivalirudine does not seem to induce HIT. The increasing awareness of the detrimental effects of bleeding on outcome of ACS patients represents the premise to appreciate these characteristics of bivalirudine, especially in invasively treated subjects. In the REPLACE-2 trial⁷² bivalirudine (0.75 mg/kg followed by 1.75 mg/kg/ hour during the intervention) plus provisional GPI was compared with UFH plus planned GPI over DAPT in 6,010 patients undergoing elective or urgent PCI (45 % of the patients had unstable angina). Non-significant differences were seen in the primary composite 30-day endpoint of death, MI, urgent repeated revascularisation or in-hospital major bleeding (9.2 % bivalirudine versus 10.0 % UFH). However, bivalirudine treatment reduced both in-hospital major bleeding (2.4 % versus 4.1 %; p<0.001) and minor bleeding (13.4 % versus 25.7 %; p<0.001). In the setting of ACS, the ACUITY trial⁷³ randomised 13,819 patients planned for invasive strategy to one of three anticoagulant regimens: unfractionated heparin or enoxaparin plus a GP IIb/IIIa inhibitor, bivalirudin plus a GP IIb/IIIa inhibitor or bivalirudin alone. Bivalirudin was started with an i.v. bolus of 0.1 mg/kg and subsequent infusion of 0.25 mg/kg/h, followed by an additional bolus of 0.5 mg/kg and infusion of 1.75 mg/kg/h, stopping infusion after PCI. The composite main endpoint of death, MI or unplanned revascularisation for ischaemia at 30 days was not different between bivalirudine/GPI and heparin/GPI (7.7 % versus 7.3 %), as was major bleeding (5.3 % versus 5.7 %) or net clinical benefit. The therapy with bivalirudine alone proved non-inferior to heparin/GPI in terms of the composite main endpoint (7.8 % versus 7.3 %), while significantly reducing major bleeding (3.0 % versus 5.7 %; p<0.001) and improving the net clinical outcome (10.1 % versus 11.7 %; p=0.02; RR=0.86). The rate of major bleeding was mildly raised in patients with <60 ml/minute creatinine clearance, but similar for all anticoagulant regimens. One sub-study of ACUITY investigated the therapy switch from UFH/LMWH to Bivalirudin at the time of PCI, reporting similar incidence of ischaemic events (6.9 % versus 7.4 %, p=0.52), less major bleeding (2.8 % versus 5.8 %; p<0.01) and improved net clinical outcomes (9.2 % versus 11.9 %; p<0.01), thus suggesting that shifting to Bivalirudin may be favorable to improve prognosis.⁷⁴ In the setting of STEMI, the HORIZON- AMI⁷⁵ trial randomised 3,602 primary-PCI patients presenting within 12 hours of symptoms onset to receive either UFH+GPI or bivalirudine alone. Major bleeding was substantially reduced with bivalirudin (4.9 % versus 8.3 %; p<0.001), as were 30-day rates of cardiac (1.8 % versus 2.9 %; p=0.03) and all-cause death (2.1 % versus 3.1 %; p=0.047). Although the authors reported an increment of acute stent thrombosis with bivalirudine alone, this difference disappeared at 30-day analysis. Possible advantages of early therapy with bivalirudin over UFH plus optional GPIs, administered during the transportation to a HUB centre for primary PCI, were investigated in the EUROMAX randomised open-label trial⁷⁶ enrolling 2,218 patients with STEMI presenting within 12 hours. This study confirmed the reduction in major bleedings in the bivalirudin arm, driving the composite primary endpoint (death and major non-CABG related bleedings at 30 days) towards significance (5.1 % versus 8.5 %; RR 0.60; p<0.001), despite the persisting increment in acute stent thrombosis (1.1 % versus 0.2 %; p=0.007). Conflicting evidence arise from the single-centre HEAT PPCI study recently presented at the 2014 American College of Cardiology congress, which randomised 1,829 patients with STEMI receiving primary angioplasty in Liverpool between 2012 and 2013 to either bivalirudin or UFH before the procedure. The primary endpoint, a composite of all-cause mortality, stroke, reinfarction and target lesion revascularisation (TLR), was higher in the bivalirudin group (8.7 % versus 5.7 %; p=0.01), with more stent thrombosis (3.4 % versus 0.9 %; p=0.001), but no difference in terms of major or minor bleedings between the two strategies. Concerns were raised about the value of these monocentric data in comparison with the discussed larger multicentric trials that may deserve more credit, but the topic is object of current interest and debate.

To date, ESC guidelines for STEMI recommend Bivalirudin with bailout GPIs over UFH plus GPIs (Class:I; LOE:B). In NSTEMI patients, bivalirudin is recommended as an alternative to UFH plus GPIs in subjects undergoing early PCI especially if at high bleeding risk (Class:I; LOE:B).^5,6

Novel Anticoagulant Agents

Lowering thrombotic complications of ACS and modulating the effects of thrombin on both coagulative cascade and platelets aggregation represent the rationale for potential use of oral anticoagulants in the therapy of ACS-patients. In fact, several studies and meta-analyses have been conducted in the past to test the efficacy of warfarin for the improvement of clinical outcomes of these patients.^77,78 However, although these studies almost consistently found significant reductions in death, AMI or ischaemic stroke, major bleedings were markedly increased by two to threefold in warfarin-treated subjects, or even more when DAPT was started.⁷⁹ The relatively high incidence of cardiovascular death and AMI at 5 years after an ACS, which is approximately 25 to 30 % even in the DAPT era, pushes the research towards trying novel oral anticoagulants (NOA) in secondary prevention of ischaemic events.⁸⁰ Factor Xa direct inhibitors rivaroxaban and apixaban have been challenged in ACS phase II^81,82 trials, but produced inconsistent effects on hard endpoints while clearly raising the risk of major bleeding. The apixaban phase III APPRAISE-2 trial was prematurely stopped due to excess of bleeding in the treatment group. In the ATLAS ACS-2 trial, 2.5/5 mg of Rivaroxaban twice daily combined with ASA or ASA plus clopidogrel demonstrated a statistically significant reduction of death from cardiovascular causes, MI or stroke compared with placebo at 13.1 months. The authors also descibed a reduction in all-cause and cardiovascular mortality with an increase in the risk of major bleeding and intracranial haemorrhage, but no increase in the risk of fatal bleeding.⁸³ The direct thrombin inhibitor dabigatran was also tested in the unpublished RE-DEEM phase II trial, but no further development of its ACS-indication are planned by the producing industry. Another phase III study on the i.v. factor Xa inhibitor otamixaban is currently ongoing.

Therefore, despite the consistent physiopathological rationale, the use of NOA is not routinely recommended in ACS patients by current ESC guidelines and deserves more in-depth evaluation.