Practical Cardiovascular Medicine. Elias B. Hanna

poor clopidogrel response is particularly predictive of poor outcomes, tailored therapy was not superior to indiscriminate clopidogrel therapy.¹⁶⁴ TAILOR-PCI trial randomized PCI patients with ACS (~85% of patients) or stable CAD to clopidogrel or to escalating antiplatelet therapy based on genetic CYP2C19 testing (ticagrelor was given for mutation carriers, clopidogrel for non-carriers). Tailored therapy was not superior to clopidogrel, even among mutation carriers. Genetic testing may better serve to de-escalate from ticagrelor/prasugrel to clopidogrel in patients with good-function alleles (Popular genetics trial).

C. Anticoagulant therapy (Table 1.8)

      IV UFH has been shown to reduce early ischemic events and MI in patients with intermediate- or high-risk NSTE-ACS.¹⁶⁵ The starting bolus (60 U/kg) and drip (12 U/kg/h) used in ACS are lower than what is used in pulmonary embolism, with a conservative PTT goal of 46–70 seconds or 1.5–2× normal. Moderate rather than high-level anticoagulation is appropriate for ischemic reduction in ACS and minimizes the dreaded bleeding. Per ESC, it is the preferred anticoagulant in patients managed invasively (class I).

      SQ Enoxaparin. In NSTE-ACS managed medically, a therapeutic dose of SQ enoxaparin reduces ischemic events compared to UFH at a similar rate of major bleeding (1 mg/kg SQ twice daily, or once daily if GFR < 30).^166,167 In patients managed invasively, however, the SYNERGY trial failed to show any superiority of SQ enoxaparin over UFH, and there was a higher major bleeding risk with enoxaparin, particularly in patients who had crossover between heparin and enoxaparin.¹⁶⁸ A similar increase in bleeding risk with enoxaparin was seen in invasively treated patients in the A-to-Z trial.¹⁶⁹ Importantly, pharmacological studies have shown that the effect of SQ enoxaparin does not peak until a second dose is administered.¹⁷⁰ Thus, when two doses have already been administered, PCI may be performed within 8 hours of SQ enoxaparin without additional anticoagulation. However, when PCI is performed within a few hours of presentation, a single subcutaneous dose of enoxaparin does not provide appropriate anticoagulation for PCI and requires supplementation with 0.3 mg/kg of intravenous enoxaparin. The administration of a single SQ dose of enoxaparin is best avoided when PCI is planned in the next few hours; IV UFH is preferred in this case.

      IV UFH half-life increases with the dose used and is usually ~1.0–1.5 hours. SQ enoxaparin effect peaks at ~3–5 hours and is accelerated by the IV administration of enoxaparin 30 mg one-time dose in medically treated patients or 0.3 mg/kg in PCI. Its half-life is 4.5–7.0 hours, longer in renal failure. The short half-life of UFH may contribute to the “heparin rebound” phenomenon, wherein the abrupt cessation of UFH leads to a rebound increase in ischemia in the following 48 hours in medically treated patients (not PCI). Enoxaparin’s antithrombotic effect wanes much more slowly than that of UFH, and enoxaparin inhibits thrombin generation in addition to thrombin action, which attenuates the heparin rebound effect and explains some of the anti-ischemic benefits of enoxaparin in medically treated patients (but not PCI).

      SQ Fondaparinux (2.5 mg SQ daily, half-life ~20 hours). This low dose of fondaparinux, equivalent to a DVT prophylaxis dose, has proven to be as effective as a standard dose of enoxaparin (1 mg/kg twice daily) in reducing MI/ischemic events in NSTE-ACS, with a large reduction in major and fatal bleeding risk translating into a mortality reduction (OASIS 5 trial, where 40% of patients underwent PCI).¹⁷¹ This again corroborates the concept that only moderate-level anticoagulation is required in ACS, less than that required in pulmonary embolism (except during PCI). Patients who are managed invasively after receiving fondaparinux should receive full anticoagulation with heparin or bivalirudin during PCI, as the small fondaparinux dose does not provide the level of anticoagulation required during PCI. In contrast to the harmful enoxaparin–UFH switch, the switch from fondaparinux to UFH during PCI does not attenuate the benefit of fondaparinux on bleeding.¹⁷²

Table 1.8 Comparison of anticoagulants.

	Unfractionated heparin	Enoxaparin	Bivalirudin	Fondaparinux
Action	Binds to AT III in a way that inhibits thrombin > Xa	Is a small heparin derivative. Binds to AT III in a way that inhibits Xa > thrombin Inhibits thrombin generation	Direct thrombin inhibitor Inhibits both circulating and clot-bound thrombina	Is a small heparin derivative. Binds to AT III in a way that inhibits Xa only
Effect on platelets	Potential activation	± Activation	Neutral	Neutral
Elimination	Reticulo-endothelial system	Renal	Renal	Renal
Half-life	1–1.5 h	4–7 h. Increases if renal failure	25 min. Increases to 1 hour if GFR < 30 ml/min	17–21 h. Increases if renal failure
Time to peak effect	Immediate after IV bolus; few hours after infusion without bolus	3–5 h after SQ dose	Immediate	2–3 h after SQ dose
Dose	ACS: 60 U/kg bolus then 12 U/kg/h IV drip DVT/PE: 80 U/kg bolus then 15–18 U/kg/h PTT goal in ACS: 46–70 s (less than PE)	ACS and PE: 1 mg/kg SQ BIDb	During PCI: 0.75 mg/kg IV bolus then 1.75 mg/kg/h If started before PCI: 0.2 mg/kg/h	ACS: 2.5 mg SQ QD DVT/PE: 5–10 mg SQ QD (depending on weight)
Effect of renal failure on dosage	None	Change from 1mg/kg BID to 1 mg/kg QD if GFR<30 ml/min	Caution if GFR < 30 ml/mina	Avoid if GFR < 30 ml/min

      ^a Only bivalirudin inhibits fibrin-bound thrombin. Heparin and fondaparinux cannot act on fibrin-bound thrombin. Bivalirudin has not been studied in advanced renal failure (in ACUITY trial) but is not absolutely contraindicated.

      ^b If only one SQ dose was provided before PCI, give additional 0.3 mg/kg IV during PCI. SQ enoxaparin is not well studied in patients > 150 kg, where the 1 mg/kg dose is associated with a marked increase in bleeding risk compared to patients with a normal body weight. AT III, antithrombin III.

IV Bivalirudin. As opposed to UFH, bivalirudin does not activate platelets and inhibits both free and clot-bound thrombin. Bivalirudin is short-acting (half-life 25 min), which is both an advantage (bleeding reduction) but also an ischemic hazard, particularly in patients who have not received timely clopidogrel. Femoral-access studies suggested that bivalirudin is associated with less major bleeding than UFH (MATRIX), but this was partially due to higher GPI use in the UFH arm. A radial-access study with balanced and limited GPI use (VALIDATE-SWEDEHEART) showed an ischemic and bleeding