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The golden rule is to avoid crossover especially between UFH and low molecular weight heparin (LMWH) [ 60 ] and to discontinue antithrombins after PCI except in specific individual situations (e.g. thrombotic complication).

Risk stratification in NSTE-ACS patients determines the use of specific agents and doses.

Patients at very high ischaemic risk (e.g. persistent angina, haemodynamic instability, refractory arrhythmias) should immediately be referred to the catheterization laboratory and receive UFH 60 IU/kg i.v. bolus, followed by infusion until PCI, combined with DAPT. In patients at high risk of bleeding, bivalirudin monotherapy with 0.75mg/kg bolus followed by 1.75 mg/kg/h can be used.

In medium-to-high ischaemic risk patients (e.g. troponin positive, recurrent angina, dynamic ST changes) for whom an invasive strategy is planned within 24 (−48) h, options for anticoagulation are:

In patients ≪75 years

UFH 60 IU/kg i.v. bolus, then infusion until PCI, controlled by activated partial thromboplastin time (aPTT)

Enoxaparin 1 mg/kg subcutaneous (s.c.) twice daily until

Fondaparinux 2.5 mg daily s.c. until PCI

Bivalirudin 0.1 mg/kg i.v. bolus followed by infusion of 0.25 mg/kg/h until PCI

In patients ≥ 75 years

UFH 60 IU/kg i.v. bolus, then infusion (aPTT controlled) until PCI

Enoxaparin 0.75 mg/kg twice daily until PCI

Fondaparinux 2.5 mg daily s.c.

Bivalirudin 0.1 mg/kg i.v. bolus followed by infusion of 0.25 mg/kg/h until PCI.

In low ischaemic risk patients (troponin negative, no ST-segment changes), a primarily conservative strategy is planned. Anticoagulation is maintained until PCI using fondaparinux 2.5mg s.c. daily or enoxaparin 1 mg/kg s.c. twice daily (0.75 mg in patients ≥ 75 years) or UFH 60 IU/kg i.v. bolus followed by infusion (aPTT controlled).

The golden rule is to continue the initial therapy and avoid switching between antithrombins (with the exception of adding UFH to fondaparinux).

UFH . Continue infusion, activated clotting time measurement can be used: target range: 200–250s with GPIIb-IIIa inhibitors; 250–350s without GPIIb-IIIa inhibitors.

Enoxaparin . Less than 8 h since last s.c. application: no additional bolus; within 8–12 h of last s.c. application: add 0.30mg/kg i.v. bolus; > 12 h since last s.c. application: 0.75 mg/kg i.v. bolus.

Bivalirudin . Add an additional i.v. bolus of 0.5 mg/kg and increase the infusion rate to 1.75 mg/kg/h before PCI.

Fondaparinux . Add UFH 50–100 IU/kg when PCI is performed.

Fondaparinux, an indirect factor Xa inhibitor, has been tested against enoxaparin in the OASIS-5 trial [ 250 ]. While the combined ischaemic event rate was similar, severe bleeding complications were highly significantly reduced with fondaparinux. This favourable net clinical outcome with fondaparinux included reduced long-term mortality and stroke rates. Because of a higher rate of catheter thrombosis when fondaparinux alone was used, UFH should be added for patients referred for angiography and PCI.

In contrast to the highly selective patient populations of previous RCTs, SYNTAX is a 5-year ‘all comers’ trial of patients with the most severe CAD, including those with LM and/or three-vessel CAD, who were entered into either the trial or a parallel nested registry if ineligible for randomization [ 4 ]. By having two components, SYNTAX therefore captured real treatment decisions in a trial of 1800 patients randomized to PCI or CABG and in a registry of 1077 CABG patients (whose complexity of CAD was deemed to be ineligible for PCI) and 198 PCI patients (considered to be at excessive surgical risk). At 1 year, 12.4% of CABG and 17.8% of PCI patients reached the respective primary composite endpoint ( P ≪ 0.002) of death (3.5% vs. 4.4%; P = 0.37), MI (3.3% vs. 4.8%; P = 0.11), CVA (2.2% vs. 0.6%; P= 0.003), or repeat revascularization (5.9% vs. 13.5%; P ≪0.001) [ 4 ]. Unpublished data at 2 years showed major adverse cardiac and cerebral event (MACCE) rates of 16.3% vs. 23.4% in favour of CABG ( P ≪0.001). Because PCI failed to reach the pre-specified criteria for non-inferiority, the authors concluded at both 1 [ 4 ] and 2 years that ‘CABG remains the standard of care for patients with three-vessel or LM CAD although the difference in the composite primary endpoint was largely driven by repeat revascularization’. Whether the excess of CVA in the CABG group in the first year was purely periprocedural or also due to lower use of secondary preventive medication (DAPT, statins, antihypertensive agents, and ACE inhibitors) is not known.

Failure to reach criteria for non-inferiority therefore means that all other findings are observational, sensitive to the play of chance, and hypothesis generating. Nevertheless, in 1095 patients with three-vessel CAD, the MACCE rates were 14.4% vs. 23.8% in favour of CABG ( P ≪ 0.001). Only in the tercile of patients with the lowest SYNTAX scores (≪23) was there no significant difference in MACCE between the two groups. It is also noteworthy that the mortality and repeat revascularization rates were similar in the 1077 CABG registry patients, even though these patients had more complex CAD.

Taking together all 1665 patients with three-vessel CAD (1095 in the RCT and 570 in the registry), it appears that CABG offers significantly better outcomes at 1 and 2 years in patients with SYNTAX scores > 22 (79% of all patients with three-vessel CAD). These results are consistent with previous registries [ 32–37 ] reporting a survival advantage and a marked reduction in the need for repeat intervention with CABG in comparison with PCI in patients with more severe CAD.

CABG is still conventionally regarded as the standard of care for significant LM disease in patients eligible for surgery, and the CASS registry reported a median survival advantage of 7 years in 912 patients treated with CABG rather than medically [ 54 ]. While ESC guidelines on PCI state that ‘Stenting for unprotected LM disease should only be considered in the absence of other revascularization options’ [ 55 ], emerging evidence, discussed below, suggests that PCI provides at least equivalent if not superior results to CABG for lower severity LM lesions at least at 2 years of follow-up and can justify some easing of PCI restrictions. However, the importance of confirming that these results remain durable with longer term follow-up (at least 5 years) is vital.