The role of anticoagulant therapies is to block the activity of coagulation factors. Anticoagulant agents may block specific targets in the coagulation cascade.

Approved anticoagulants for clinical use in the acute setting of acute coronary syndrome (ACS)/percutaneous coronary interventions (PCI) patients are classified according to their mechanism of action. Thrombin inhibitors are the most commonly used and are classified as indirect and direct thrombin inhibitors.

Anti-X inhibitors are also available, although there use is limited in patients undergoing PCI. Blockade of coagulation factors is pivotal as they are associated with enhanced platelet reactivity, thus increasing thrombotic risk.

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Indirect thrombin inhibitors (unfractionated heparin and low-molecular weight heparin)—generalities

Indirect thrombin inhibitors include unfractionated heparin (UFH) and low-molecular weight heparins (LMWH), which require a co-factor to fully exert their effects. This family binds to the enzyme inhibitor antithrombin (AT), causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop.

The activated AT then inactivates thrombin and other proteases involved in blood clotting (IXa and XIa), and most notably factor Xa. The rate of inactivation of these proteases by AT can increase by up to 1,000-fold due to the binding of heparin.

The conformational change in AT on heparin-binding mediates its inhibition of factor Xa. For thrombin inhibition, however, thrombin must also bind to the heparin polymer at a site proximal to the pentasaccharide. The highly negative charge density of heparin contributes to its very strong electrostatic interaction with thrombin.

UFH has been used in the management of acute coronary syndrome (ACS) and PCI patients for many years. Guideline recommendations for UFH use in ACS are based on meta-analyses of six relatively small randomized, placebo-controlled trials with UFH for treatment of unstable angina (UA)/non-ST elevation myocardial infarction (NSTEMI).

As an alternative, LMWH has been tested demonstrating the safety and efficacy in patients with UA/NSTEMI and ST-elevation myocardial infarction (STEMI), as well as patients undergoing PCI.

Although many different LMWH preparations have been developed, enoxaparin is the most widely studied in clinical trials of UA/NSTEMI, STEMI, and PCI. In addition, enoxaparin is the only U.S. Food and Drug Administration (FDA) approved LMWH.

Nine randomized trials directly compared LMWH with UFH in UA/NSTEMI patients presenting with substantial heterogeneity between the trials. However, in a meta-analysis of six trials evaluating 21,946 patients randomized to enoxaparin or UFH, a significant reduction in the combined end point of death or nonfatal MI at 30 days was observed favoring enoxaparin over UFH without showing any differences in major bleeding or blood transfusion within the first week of therapy.

In patients undergoing primary PCI, the largest evidence derives from the ATOLL (Acute Myocardial Infarction Treated with Primary Angioplasty and Intravenous Enoxaparin or Unfractionated Heparin to Lower Ischemic and Bleeding Events at Short- and Long-term Follow-up) trial. Although enoxaparin did not achieve a reduction in the primary ischemic endpoint, it did significantly reduce some clinical ischemic outcomes in comparison with UFH without differences in bleeding or procedural success.

Direct thrombin inhibitors (bivalirudin)

Direct thrombin inhibitors (DTIs) exert their anticoagulant effects by directly binding, without the need for a co-factor, to thrombin. Therefore, DTIs inhibit thrombin activity and thrombin-mediated activation of other coagulation factors (e.g. fibrin formation from fibrinogen) as well as thrombin-induced platelet aggregation. Importantly, DTIs inhibit clot-bound as well as fre thrombin.

Currently there are several DTI approved for use, including lepirudin, argatroban, and bivalirudin. Only bivalirudin has an indication a first-line anticoagulant in the setting of ACS and PCI.

Bivalirudin is a 20–amino acid polypeptide and is a synthetic version of hirudin. Its amino-terminal D-Phe-Pro-Arg-Pro domain, which interacts with the active site of thrombin, is linked via 4 Gly residues to a dodecapeptide analogue of the carboxy-terminal of hirudin (thrombin exosite).

Bivalirudin forms a 1:1 stoichiometric complex with thrombin, but once bound, the amino terminal of bivalirudin is cleaved by thrombin, thereby restoring thrombin activity. Bivalirudin is not immunogenic, although antibodies against hirudin can cross-react with bivalirudin with unknown clinical consequences.

Bivalirudin has a half-life of 25 minutes; proteolysis, hepatic metabolism, and renal excretion contribute to its clearance. The half-life of bivalirudin is prolonged with severe renal impairment, and thus dose adjustment is required in dialysis-dependent patients.

In the PCI setting, bivalirudin has been tested in comparison with UFH ± GP (glycoprotein) IIb/IIIa inhibitors in several trials, showing noninferiority in terms of ischemic events with significantly less bleeding complications. This has been confirmed in several trials, across the spectrum of coronary artery disease (CAD) manifestations, including patients with stable CAD, UA/NSTEMI, and STEMI.

The benefits of bivalirudin are enhanced in patients at greater risk of bleeding, including elderly, diabetics, and patients with chronic kidney disease. The ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial is the largest study assessing the net clinical benefit of bivalirudin versus GP IIb/IIIa inhibitors in UA/NSTEMI patients, showing that the net benefit was driven by a significant reduction in bleeding complications without any trade-off in efficacy.

Importantly, prerandomization treatment with UFH or enoxaparin in ACUITY did not abrogate the net clinical benefit of bivalirudin.

Direct thrombin inhibitors (bivalirudin)

These findings were more recently confirmed in the ISAR-REACT (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment)-4 trial. Importantly, in the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarctions) trial, bivalirudin reduced cardiac mortality and all-cause mortality among STEMI patients undergoing primary PCI compared with UFH + GP IIb/IIIa inhibitors after 3 years of follow-up.

The only concern that emerged from bivalirudin therapy was an early (first 24 hours) excess in stent thrombosis rates. Posthoc analysis showed, however, that pretreatment with UFH and clopidogrel mitigated this early thrombotic risk.

Early thrombotic risk has now become less of a concern with the use of the more potent P2Y12 receptor antagonists, such as prasugrel and ticagrelor, as well as with prolonging bivalirudin infusion, even though there are no large-scale studies that specifically assess this aspect.

Differences between drugs within the class

Indirect thrombin inhibitors

Indirect thrombin inhibitors require a cofactor to fully exert their effects. UFH is a heterogeneous mixture of variable molecular weight (2,000 to 30,000 Da) polysaccharide molecules.

UFH has two structural components that are pivotal in determining its function: (1) a unique pentasacharide sequence responsible for factor Xa inhibition) and (2) saccharide chain lengths >18 units long (needed to achieve thrombin inhibition). The pentasaccharide sequence is required for binding of UFH at AT, thereby increasing the potency of AT by up to 1,000 fold.

LMWHs are produced through depolymerization of the polysaccharide chains of UFH, producing fragments ranging from 2,000 to 10,000 Da. These shorter chain lengths contain the unique pentasaccharide sequence necessary to bind to AT (<18 saccharides), but its lengths are too short to form the ternary complex cross-linking AT and thrombin.

Thus the primary inhibitory effects of LMWHs are mostly on factor Xa (e.g., enoxaparin anti-Xa:anti-IIa activity is 4:1). LMWHs have reduced binding to plasma proteins and cells compared with UFH, thereby providing a more favorable and predictable pharmacokinetic profile. Following subcutaneous injection, LMWHs have a bioavailability higher than 90% and a predictable anticoagulant response; they do not require monitoring due to more rapid and predictable absorption.

Anti-Xa levels peak 3 to 5 hours after a subcutaneous dose of LMWH. The elimination the half-life of LMWHs is largely dose-dependent and occurs 3 to 6 hours following a subcutaneous dose, being cleared by the kidney and leading to prolonged anti-Xa effect and linear accumulation of anti-Xa activity in patients with a creatinine clearance <30 ml/min.

The LMWHs also produce fewer platelet agonist effects and are less often associated with heparin-induced thrombocytopenia (HIT).

Direct thrombin inhibitors

Currently there are several DTI approved for use, including lepirudin, argatroban, and bivalirudin. Lepirudin and argobatran are indicated only for the treatment of HIT, while bivalirudin has an indication as a first-line anticoagulant in the setting of ACS and PCI.


Indirect thrombin inhibitors

UFH: An initial IV bolus of 60 to 70 U per kg (maximum 4,000 U). Continuous infusion of 12 to 15 U/kg/ hr (maximum 1,000 U/hr). In the setting of PCI without GP IIb/IIIa inhibitors, UFH is recommended at a dose of 70 to 100 IU/kg; a dose of 50 to 70 IU/kg is recommended in patients undergoing PCI with GP IIb/IIIa inhibitor use.

LMWH (enoxaparin): A 30 mg IV bolus,1 mg/kg subcutaneously (sc) every 12 hr. If creatinine clearance is <30 mL/min, the dose should be reduced to 1 mg/kg sc every 24 hr.

If LMWH has been started as the upstream anticoagulant, then it should be continued without stacking of UFH. If patients undergo PCI, enoxaparin can be administered in several ways:

  • The first dosing regimen option is 1 mg/kg subcutaneously twice daily; when this route is used, it is important to ensure that the last dose of subcutaneous LMWH is administered within 8 hours of the procedure and that at least two subcutaneous doses of LMWH are given before the procedure to ensure a steady state.

  • If the last dose of enoxaparin was given 8 to 12 hours before PCI, then a 0.3 mg/kg bolus of IV enoxaparin is recommended at the time of PCI.

  • The third dosing regimen option is 1 mg/kg enoxaparin intravenously (if no GP IIb/IIIa inhibitor is used) or 0.75 mg/kg (if a GP IIb/IIIa inhibitor is used) at the time of PCI. For elective PCI, an intravenous dose of 0.5 mg/kg was found to be safe in the STEEPLE (SafeTy and Efficacy of Enoxaparin in PCI patients, an international randomized Evaluation) study.


PCI: IV: Initial: 0.75 mg/kg bolus, followed by 1.75 mg/kg/hr for the duration of the procedure; may continue postprocedure at a reduced dose if clinically indicated. For patients who received UFH prior to the procedure, it is recommended to wait 30 minutes before administering a bivalirudin bolus dose.

UA/NSTEMI (moderate-high risk) undergoing early invasive strategy (unlabeled dose): IV: Initial: 0.1 mg/kg bolus, followed by 0.25 mg/kg/hr. Once PCI is determined to be necessary, give an additional bolus of 0.5 mg/kg and increase infusion rate to 1.75 mg/kg/hr; may discontinue at end of procedure or continue for up to 4 hours postprocedure if necessary. If cardiac surgery is deemed necessary, discontinue bivalirudin 3 hours prior to surgery and dose with unfractionated heparin per institutional practice.

Patients with moderate renal impairment (30 to 59 mL/min) should receive an infusion of 1.75 mg/kg/hr. If the creatinine clearance is less than 30 mL/min, reduction of the infusion rate to 1 mg/kg/hr should be considered.

If a patient is on hemodialysis, the infusion rate should be reduced to 0.25 mg/kg/hr. The infusion may be continued for 4 hours after the procedure at the discretion of the operator.

Indications and contraindications

Indirect thrombin inhibitors

UFH: Class IA therapy when it is used with platelet inhibitors in all settings.

LMWH (enoxaparin): Class IA indication in NSTEMI and in STEMI treated with fibrinolytic therapy. In the PCI setting, LMWHs are allowed, although the use of UFH is preferred (class 1B).


Bivalirudin is currently approved for use during PCI as an alternative to UFH. The benefit of bivalirudin as an anticoagulant in patients undergoing PCI has been demonstrated across the spectrum of CAD manifestations (stable CAD, UA/NSTEMI, and STEMI).

Undesirable effects

Indirect thrombin inhibitors

Bleeding remains an undesired effect of indirect thrombin inhibitors, the risk of which varies according to the dosage used and the risk profile of the population. The risk of bleeding increases with higher heparin doses, concomitant use of antiplatelet drugs or oral anticoagulants, and increasing age (>70 years old).

Patients with renal dysfunction have increased risk of bleeding with LMWHs, underscoring the importance of adjusted dosing in these patients. Reversal of the anticoagulant effect of UFH can be achieved rapidly with an IV bolus of protamine using 1 mg of protamine to neutralize 100 IU of UFH, however the degree to which the anti‐Xa activity of LMWH is neutralized by protamine is variable and uncertain. Another adverse effect described with heparin is the development of HIT, which usually between 5 and 15 days after the initiation of therapy.

In the setting of HIT, a direct antithrombin drug must be selected. Patients treated with LMWH can develop HIT, and these drugs are not recommended for use in patients with documented or suspected HIT. Less commonly, long-term use of heparin can be associated with the development of osteoporosis and rare allergic reactions.


Bleeding events may occur, although they are less common with bivalirudin than with UFH + GPIIb/IIIa inhibitors as showed in all trials dedicated to this compound.

Recombinant factor VIIa can reverse the anticoagulant effect of DTIs in healthy volunteers, although the short half-life of these agents typically precludes the need for active reversal.

Alternative approaches

  • Direct thrombin inhibitors are appropriate treatment alternatives for ACS/PCI patients.

  • Indirect thrombin inhibitors are alternatives to bivalirudin in ACS/PCI patients.