Anticoagulation and antiplatelet therapy in acute coronary syndromes

Bivalirudin, a direct thrombin inhibitor

Bivalirudin is a synthetic direct thrombin inhibitor of fluid-phase and clot-bound thrombin (Figure 4). It also inhibits platelets directly.

The ACUITY trial³² randomized 13,819 patients with moderate to high-risk ACS scheduled for invasive treatment into three treatment groups:

• Heparin (either unfractionated heparin or enoxaparin) plus a glycoprotein IIb/IIIa inhibitor (either eptifibatide, tirofiban, or abciximab)
• Bivalirudin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin alone.

The bivalirudin-alone treatment was as sociated with noninferior rates of composite ischemia end points and significantly lower rates of major bleeding, adding up to a significant reduction in the net clinical outcome end point. An important caveat is that bivalirudin’s noninferiority was mostly in the group of patients already receiving a thienopyridine before angiography and percutaneous coronary intervention (RR 0.97 vs 1.27, P = .054). There was less major, nonmajor, minor, CABG-related, and non-CABG-related bleeding as well as need for transfusion in the bivalirudin-alone group, making bivalirudin monotherapy an attractive option in ACS patients with or without ST-segment elevation undergoing a percutaneous coronary intervention.^1,31

The ISAR-REACT trial³⁴ later compared bivalirudin alone vs unfractionated heparin and abciximab in patients with non-ST-elevation myocardial infarction undergoing percutaneous coronary intervention pretreated with aspirin and clopidogrel. The composite rate of ischemia was similar in the two treatment groups, with significantly lower rates of bleeding in the bivalirudin group.

HORIZONS-AMI³⁵ randomized 3,602 patients with ST-elevation myocardial infarction receiving aspirin and clopidogrel either to unfractionated heparin and a glycoprotein IIb/IIIa inhibitor or to bivalirudin. As in the ACUITY trial, there was no difference in ischemic end points and a 40% to 45% lower rate of major bleeding end points in the bivalirudin group, translating into an overall lower rate of death.

Enoxaparin, a low-molecular weight heparin

Enoxaparin is a low-molecular-weight heparin that inhibits factor IIa and factor Xa via antithrombin, roughly in a ratio of 1:3 (Figure 4). It has a time to peak effect of 10 minutes when given intravenously³⁶ and 3 to 5 hours when given subcutaneously.³⁷ Its half-life is 4.5 hours, but it is longer in patients with renal dysfunction, requiring dose adjustments in this population.

Its anticoagulant effect is partially reversible. If it is to be reversed between 0 and 8 hours after dosing, the recommended reversal regimen is 1 mg of protamine sulfate for every 1 mg of enoxaparin used. At 8 to 12 hours, it is 0.5 mg of protamine for every 1 mg of enoxaparin. After 12 hours, no protamine is required.

Compared with unfractionated heparin, enoxaparin has less plasma protein binding and a more consistent anticoagulant effect. Its high bioavailability also allows for subcutaneous dosing. Its greater anti-Xa activity inhibits thrombin generation more effectively, and it causes lower rates of thrombocytopenia and heparin-induced thrombocytopenia.

de Lemos et al³⁸ found that, in ACS patients in whom an early conservative approach of medical management was planned, enoxaparin was more efficacious than unfractionated heparin and caused a similar rate of bleeding.

Murphy et al,³⁹ in a meta-analysis of 12 trials in 49,088 ACS patients, also found that enoxaparin had a net clinical benefit compared with unfractionated heparin in reducing rates of myocardial infarction and death despite more bleeding.

The ESSENCE trial⁴⁰ compared enoxaparin vs unfractionated heparin in 3,171 patients with ACS. It found fewer ischemic events with enoxaparin in the early phase, more minor bleeding, but no increase in major bleeding.

The SYNERGY trial,⁴¹ in 10,027 patients with high-risk non-ST-elevation ACS undergoing percutaneous coronary intervention, compared subcutaneous enoxaparin with intravenous heparin. Enoxaparin was found to be noninferior to heparin but caused more bleeding, including major bleeding, drops in hemoglobin, and intracranial hemorrhage.

The EXTRACT-TIMI 25 trial.⁴² In patients with ST-elevation myocardial infarction, enoxaparin has been shown to be beneficial both in patients treated with fibrinolysis and in those who underwent primary percutaneous coronary intervention. The EXTRACT-TIMI 25 trial randomized 20,749 patients to receive either enoxaparin (an intravenous bolus and maintenance subcutaneous dosing based on renal function) or intravenous heparin in addition to thrombolysis within 6 hours of the diagnosis of ST-elevation myocardial infarction. Although the enoxaparin group had more bleeding end points, they had fewer primary and secondary efficacy end points, translating into an overall net clinical benefit in favor of enoxaparin.

The ATOLL trial⁴³ examined the use of enoxaparin (0.5 mg/kg intravenously) or unfractionated heparin in 910 patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention (via the radial artery in 66% to 69%). Although there was a trend towards benefit in terms of the primary end point of death, myocardial infarction complications, procedure failure, and major bleeding favoring enoxaparin, it was not statistically significant (95% CI 0.68–1.01, P = .06).

However, there was a 37% to 42% lower rate of the secondary end point of death, recurrent myocardial infarction or ACS, or urgent target-vessel revascularization in the enoxaparin group, with a 40% reduction in death from any cause, death from a cardiac cause, or shock. The safety profiles of the two drugs were similar, and the net clinical benefit significantly favored enoxaparin.

Fondaparinux, a factor Xa inhibitor

Fondaparinux is a synthetic pentasaccharide that indirectly inhibits factor Xa through the action of antithrombin (Figure 4). After a 2.5-mg subcutaneous dose, it has a time to peak concentration of 2 hours and a half-life of 17 to 21 hours.

The OASIS-5 trial⁴⁴ compared fondaparinux and enoxaparin in 20,078 patients treated for non-ST-elevation ACS. Although the rates of death, myocardial infarction, and refractory ischemia at 9 days were similar for both drugs, the fondaparinux group had a significantly (almost 50%) lower rate of bleeding at 30 days, translating into significantly fewer deaths at 30 days. However, patients receiving fondaparinux who underwent percutaneous coronary intervention had a threefold higher rate of catheter-related thrombosis.

The OASIS-6 trial⁴⁵ compared fondaparinux vs usual care (placebo in those in whom unfractionated heparin was not indicated or unfractionated heparin for up to 48 hours followed by placebo for up to 8 days) in 12,092 patients with ST-elevation myocardial infarction. There was a 1.5% absolute risk reduction in death and reinfarction without an increase in bleeding at 30 days, with trends persisting 6 months into the study. However, fondaparinux was not superior to heparin in the 3% of patients who underwent primary percutaneous coronary intervention. As in OASIS-5, there was more catheter-related thrombosis in the fondaparinux group.

Although the use of supplemental unfractionated heparin appears to have mitigated this risk, fondaparinux remains a less-than-ideal option in the era of primary percutaneous coronary intervention for ST-elevation myocardial infarction and has therefore found limited use in this group of patients. It should, however, be considered in patients for whom a conservative strategy is planned, especially if bleeding risk is deemed to be high.

ORAL ANTICOAGULANTS

Oral anticoagulants provide ischemic benefit in selected patients with ACS—at the price of a higher risk of significant bleeding.

Warfarin

Warfarin was investigated after myocardial infarction in the WARIS II,⁴⁶ CARS,⁴⁷ and CHAMP⁴⁸ trials.

WARIS II⁴⁶ looked at the use of aspirin alone, warfarin alone, and aspirin and warfarin in combination. The rates of the primary end points of stroke, nonfatal infarction, and death were lower in the warfarin group.

CARS⁴⁷ found no difference in the rate of the primary end point of fatal infarction, nonfatal ischemic stroke, or cardiovascular death with aspirin vs warfarin plus aspirin.

CHAMP⁴⁸ saw similar trends, ie, no difference in the rate of death, recurrent myocardial infarction, or stroke with warfarin plus aspirin vs aspirin alone.

All three studies showed increases in major bleeding with warfarin use.

Putting these trials into context, the significant net clinical benefit of dual antiplatelet therapy in the current era compared with the significant bleeding and questionable conflicting evidence supporting benefit with warfarin has limited its use in ACS patients.

Rivaroxaban, an oral factor Xa inhibitor

Rivaroxaban is a novel oral direct reversible factor Xa inhibitor.

The ATLAS ACS 2-TIMI 51 trial⁴⁹ found rivaroxaban 2.5 mg or 5 mg to yield a significantly lower rate of the primary outcome of cardiovascular death, myocardial infarction, ischemic stroke, and in-stent thrombosis compared with placebo, but significantly more major non-CABG bleeding and intracranial hemorrhage.

The dose used in this trial was much lower than the dose used in trials investigating the role of this drug in stroke prophylaxis in atrial fibrillation.

Apixaban, an oral factor Xa inhibitor

Apixaban is another direct factor Xa inhibitor.

The APPRAISE-2 trial⁵⁰ compared apixaban 5 mg twice daily vs placebo in ACS. There was no difference in the rate of cardiovascular death, myocardial infarction, or stroke, but there was significantly more bleeding in the apixaban group, prompting early termination of this study.

Dabigatran, an oral thrombin inhibitor

Dabigatran is an oral direct thrombin inhibitor.

The RE-DEEM trial⁵¹ compared four doses of dabigatran (50, 75, 110, and 150 mg twice daily) and placebo in ACS patients. The dabigatran groups had more major and minor bleeding, and the higher the dose, the higher the incidence of bleeding. In addition, the rates of ischemic end points were no lower with dabigatran, although this trial was not powered to show differences in clinical events.

REDUCING THE RISK OF BLEEDING

In the treatment of ACS, the benefits of restoring perfusion by preventing further propagation of thrombus and platelet aggregation come at a significant price of higher bleeding risk. This in turn increases the risk of death through various mechanisms, including shock, worsening ischemia, discontinuation of antiplatelet and anticoagulation therapy causing stent thrombosis, and anemia leading to transfusion, which propagates the underlying inflammatory milieu.⁵²

Giugliano and Braunwald⁵³ provide practical suggestions to reduce this risk, advising physicians to:

• Avoid inappropriately high dosing, particularly in patients with renal insufficiency
• Preferentially use agents that cause less bleeding (eg, bivalirudin, fondaparinux) without compromising anti-ischemic efficacy
• Minimize the concomitant use of other drugs that cause bleeding (eg, NSAIDs)
• Use drugs that protect against bleeding (eg, proton pump inhibitors) in patients at high risk
• Prevent access-site bleeding by using the radial artery, smaller sheaths, and appropriate sheath and closure device management. Indeed, the use of radial interventions in ACS has been shown to reduce access-site-related bleeding, even in patients at high risk.⁵⁴

The reduction in bleeding risk may provide future trials the opportunity to increase antithrombotic efficacy of different agents with goals of reducing ischemic end points.