Inhibiting Coagulation
Rapid inhibition of the coagulative cascade by an injectable agent is recommended by ESC in all settings of PCI.4 Anticoagulants should be used in ACS patients undergoing PCI to reduce thrombus-related complications and minimise periprocedural thrombotic risks. Metaanalytic data suggest advantages of combination antithrombotic therapy with both antiplatelet and anticoagulant agents in ACS patients.57 Anticoagulation may be achieved indirectly or directly. Indirect anticoagulation typically requires antithrombin activation that acts as a suppressor of thrombin (UFH, LMWHs) or factor Xa (fondaparinux and partially LMWHs). Similarily, direct anticoagulation is obtained by direct inhibiton of thrombin (bivalirudin, dabigatran) or factor Xa (apixaban, rivaroxaban, otamixaban).
UFH, LMWH, fondaparinux and bivalirudin are currently used in ACS (see below) and, as a general rule, switching anticoagulants in ACS patients undergoing PCI is not recommended (ESC class:III; LOE:B) except in specific cases.5,6
Unfractioned Heparin
UFH is a sulphate-polysaccharide with a mean molecular weight of 15 kDa, which is also naturally secreted by several cells such as basophils and mast cells. Almost one-third of the heparin molecules contain a pentasaccharide with high affinity for antithrombin III (AT) that binds to this molecule causing more efficient exposure of the active site, thus increasing by up to 1,000-fold the AT ability to inactivate thrombin and factor Xa.58 This anticoagulant activity may be pharmacologically reverted: in fact, protamine sulphate, originally isolated by salmon sperm, is a cationic polypeptide that forms stable ion-pair with heparin, inactivating it.59 The use of UFH for the treatment of ACS has been validated in several dated randomised trials. In the ATACS trial,60 214 ACS patients were randomised to receive either ASA 160 mg daily alone or in combination with anticoagulant therapy (i.v. UFH in the acute phase followed by a warfarin maintenance). The combination strategy significantly reduced ischaemic events (electrocardiogram [ECG] changes, MI and/or death) at 14 days (10.5 % versus 27 %; p=0.004). A meta-analysis considering six studies of NSTE-ACS patients treated with ASA plus UFH versus ASA alone found a 33 % risk reduction of death or AMI in heparin-treated patients.61 As the anticoagulant effect of UFH is quite variable between individuals, strict monitoring of the activated partial thromboplastin time (aPTT) is required to avoid lack of efficacy or haemorragic complications (recommended aPTT 1.5–2.5 times UNL). More recent data from the FUTURA/OASIS-8 trial suggest that in NSTEACS patients treated with PCI, low (50 IU/kg) versus standard (85 IU/kg) doses of UFH do not significantly reduce major peri-PCI bleeding and vascular access-site complications.62
The ESC recommends the use of i.v. bolus UFH in NSTEMI patients proceeding to PCI (Class:I; LOE:C) at doses of 70–100 IU/Kg (or 50–60 IU/Kg in combination with GPIs) to acheive aPTT 50–70 seconds and intra-procedural activated clotting times (ACT) of 250– 350 seconds (or 200–250 seconds in combination with GPIs).5 In STEMI patients undergoing primary PCI not pre-treated with bivalirudin or enoxaparin, Class I level C recommendation is given to UFH at the same dosages than NSTEMI.6
Low Molecular Weight Heparins
LMWHs are 2–10 KDa heparin derivates with different pharmacological effects on thrombin (more marked in greater molecular weight molecules) or factor Xa (especially lighter molecules). These drugs are well-absorbed after subcutanous injections, bear a prolonged plasmatic half-life and bind much less than UFH to plasmatic proteins, therefore providing a more predictable anticoagulant effect.63 The most studied and clinically used molecule of this class is enoxaparin. In an A to Z trial, enoxaparin met the non-inferiority criteria in respect to UFH in NSTE-ACS patients treated with ASA and tirofiban.64 The larger SYNERGY trial64 randomised 10,027 high-risk NSTE-ACS patients to either receive UFH or enoxaparin. Again, enoxaparin proved non-inferior to UFH for a composite of death and non-fatal AMI at 30 days. However, both studies demonstrated a modest but significant increment of TIMI major bleedings in the enoxaparin group. In the randomised open-label ATOLL trial,65 enoxaparin did not reduce the primary endpoint of 30-day death, complications of MI, procedural failure and major bleeding (28 % versus 34 %; p=0.063),but the main secondary endpoint of death, recurrent ACS, or urgent revascularisation was significantly reduced (30 % versus 52 %; p=0.015), without evidence of increase in major bleedings. ESC guidelines recommend b.i.d. subcutaneous administration of 1 mg/kg enoxaparin for NSTEMI patients when fondaparinux is not available (Class:I; LOE:B), with no need for adjunctive anticoagulant therapy during PCI if the last dose of enoxaparin was administered less than 8 hours earlier.5 In the primary PCI for STEMI setting, the use of enoxaparin may be considered, with fewer robust evidences (Class:IIb; LOE:B).
Fondaparinux
Fondaparinux is a synthetic pentasaccharide similar to that contained in other glycosaminoglycanes and heparinsulphates, causing reversible, indirect and selective inhibition of factor Xa by allosteric activation of AT.66 Unlike UFH, it does not affect thrombin and bears 100 % bioavailability after subcutaneous administration, long elimination half-life (17 hours) permitting one daily administration and predictable antithrombotic effects also due to low association with plasmatic proteins. Fondaparinux does not seem to induce heparininduced thrombocytopenia (HIT), but due to its renal elimination it is contraindicated when the glomerular filtration rate is low (<20 ml/ minute). The PENTUA study67 was a dose-finding trial that randomised ACS patients to enoxaparin or fondaparinux at different daily dosages (2.5, 4, 8 or 12 mg), reporting no dose-related differences in death, MI or recurrent ischaemia after 9 days, thus suggesting the use of the lower dose. Per-protocol analysis suggested potential reduction of the endpoint in respect to enoxaparin. In the ASPIRE trial,68 350 patients undergoing elective or urgent PCI were randomised to fondaparinux 2.5 or 5 mg or to UFH. No significant differences in terms of bleeding in fondaparinux versus the UFH group were found (6.4 % versus 7.7 %; p=0.61), while a 2.5 mg dose of fondaparinux tended to have fewer bleeding events, but the study may have been undersized for adequate statistical power. The large OASIS-5 study randomised 20,078 NSTEACS patients to either Fondaparinux 2.5mg once daily or enoxaparin 1 mg/kg b.i.d. for an average of 5 days of enrolment.69 Fondaparinux was non-inferior to enoxaparin for a composite efficacy endpoint of death, AMI or refractory ischaemia at 9 days (5.8 % versus 5.7 %) with significantly fewer major bleedings in the fondaparinux group (2.2 % versus 4.1 %; p<0.001). Bleeding was an independent predictor for mortality and, as a consequence, hard endpoints at 6 months (death, AMI, strokes) were lower in patients treated with fondaparinux (11.3 % versus 12.5 %; p=0.007). As expected, in PCI patients treated with fondaparinux there were fewer major bleeding complications at 9 days (2.4 % versus 5.1 %; p<0.001). Although more catheter-related thrombosis were seen in the fondaparinux group, this difference disappeared with the addition of an UFH bolus at the beginning of PCI. Overall, OASIS-5 demonstrated a net clinical benefit of fondaparinux over enoxaparin in the balance of death, AMI, stroke and major bleeding (8.2 % versus 10.4 %; p=0.004). Conversely, the OASIS-6 randomised trial,70 designed to evaluate fondaparinux in the setting of STEMI, was not able to provide definitive results and raised multiple criticisms, mainly due to the heterogeneity in the medical and invasive treatment of the enrolled patients. Particularily, even if the authors concluded for mortality and reinfarction reduction at 30 days in the fondaparinux group, no benefits were observed in the PCI population with significantly higher guiding catheter thrombosis and other coronary complications (abrupt closure, no-reflow, dissection, new thrombus formation).
ESC recommendations for fondaparinux are therefore strong in NSTEMI patients and administration of a daily dose of 2.5 mg subcutaneously seems associated with the most favourable efficacy–safety profile among other anticoagulants (Class:I; LOE:A). In case of fondaparinux pre-treatment, in order to lower the risk of intraprocedural thrombosis, a single bolus of UFH (85 IU/kg adapted to ACT, or 60 IU in the case of concomitant use of GP IIb/IIIa receptor inhibitors) should be added at the time of PCI (Class:I; LOE:B).5 Conversely, fondaparinux is not recommended in patients with STEMI undergoing PCI (Class:III; LOE:B).6