The Search for Optimal Combination of Antiplatelet and Anticoagulation Regimens Following PCI

“The patient is given aspirin (1.0 g per day) for 3 days, starting the day before the procedure. Heparin and low molecular weight dextran are administered during dilatation; warfarin is started after the procedure and is continued until follow-up study 6–9 months later.”

— Gruentzig AR, Senning A, Siegenthaler WE. N Engl J Med 1979;301:61–68.

Since the introduction of percutaneous coronary angioplasty by Gruentzig in 1977, vast changes have transformed the field of interventional cardiology.^1,2 These changes have not only involved the development of new devices that have revolutionized the world of cardiology and our approach to the cardiovascular patient, but also in the adjuvant medical therapy. Intravenous unfragmented heparin has been used to prevent thrombus formation during the procedure at the site of arterial injury and on the equipment used during the procedure since the advent of coronary angioplasty. Despite the widespread routine use of heparin anticoagulation, the optimal dosing remains uncertain and there is large variability in its use.³ Furthermore, although activated clotting time (ACT) has often been used to guide heparin dosing, the optimal target ACT during percutaneous coronary intervention (PCI) remains uncertain. Empiric recommendations have derived from studies in patients undergoing coronary artery bypass surgery that demonstrated that an ACT between 300 and 400 seconds is required to prevent fibrin deposition within the extracorporeal circuit. Based on a series of retrospective, non-randomized studies that demonstrated an inverse relationship between the probability of ischemic events and the initial ACT measurement, the current American College of Cardiology/American Heart Association Guidelines for percutaneous coronary interventions recommend the use of sufficient unfractionated heparin to achieve an ACT between 250–300 seconds as measured with the Hemo Tec® device and between 300–350 seconds with the Hemochron® device.4 In patients treated with glycoprotein IIb/IIIa inhibitors during the procedure, the target ACT should be 200 seconds with either one of these devices. While high doses of unfractionated heparin and higher ACT levels may reduce the levels of periprocedural ischemic complications, they increase the risk of bleeding complications.

See Carnendran et al.

Low molecular weight heparins (LMWHs) have a series of advantages when compared to unfractionated heparin. The antithrombotic action of heparin is totally dependent on the presence of cofactors; it mandates intensive and meticulous laboratory monitoring due to the individual response; it can be inactivated by platelet factor 4, and most important, it does not inactivate clot-bound thrombin. Conversely, LMWHs, such as enoxaparin, may offer important advantages because of a higher anti-factor Xa:IIa ratio, resistance to neutralization by platelet factor 4, ease of administration and a more predictable bioavailability. The NICE (National Investigators Collaborating on Enoxaparin) trials have evaluated a series of algorithms that have tried to integrate the use of LMWH alone or in combination with glycoprotein IIb/IIIa inhibitors during PCI (NICE 1 and 4, respectively).⁵ Despite all these advantages and its proven efficacy in the NICE trials, its use in the cath lab is still limited; the ideal dose has not been determined and current guidelines do not recommend the use of LMWH as the sole anticoagulant or in conjunction with glycoprotein IIb/IIIa inhibitors during PCI.⁴ The NICE 1 registry established that a dose of 1 mg/kg of intravenous enoxaparin could be safely used during PCI, while the NICE 4 trial was the first large-scale study to show that the use of a reduced dose of enoxaparin (0.75 mg/kg intravenous bolus) and a glycoprotein IIb/IIIa inhibitor (abciximab) in patients undergoing PCI provides safe and effective anticoagulation and is associated with a low incidence of bleeding and periprocedural ischemic complications.⁵ Vascular access sheaths in the NICE 4 trial were removed 4 hours after the enoxaparin bolus and vascular access closure devices were not used. The incidence of overall major bleeding complications was 1.1% and the incidence of minor bleeding complications was 6.2%. These results were very similar to previous studies with glycoprotein IIb/IIIa inhibitors and unfractionated heparin. Unfortunately, NICE 4 was not a randomized study and did not use different dose regimens of enoxaparin.⁵ A recently published study by Choussat et al. showed that PCI can safely be performed with a low dose of intravenous enoxaparin (0.5 mg/kg) irrespective of patient age, weight, renal function or the concomitant use of the glycoprotein IIb/IIIa inhibitor eptifibatide.6 A total of 242 consecutive patients were enrolled in this study. Vascular sheaths were removed immediately after the procedure in patients not treated with eptifibatide (74%) or 4 hours later when administered (26%). Vascular closure devices were not used in this study. At 1-month clinical follow-up, major bleeding complications were seen in only 1 patient (0.4%) and minor bleeding complications in 3 patients (1.2%). Interestingly, there were 3 cases of myocardial infarction (1.2%) and 1 death (0.4%). Therefore, the authors concluded that a low dose of enoxaparin appears to be safe and effective and allows immediate sheath removal when used alone and does not require adjustment when used in conjunction with eptifibatide. The recently published results from the CRUISE (Coronary Revascularization Using Integrilin and Single Bolus Enoxaparin Study) trial compared the use of enoxaparin versus unfractionated heparin in 261 patients undergoing urgent or elective PCI who were treated concomitantly with eptifibatide.⁷ At the time of the procedure, patients were randomized in an open-label fashion to either intravenous enoxaparin (0.75 mg/kg) or intravenous unfractionated heparin (60 IU/kg followed by additional boluses in order to maintain an ACT > 200 seconds). All patients were treated with a standard dose of eptifibatide before the intervention and continued for 18–24 hours after PCI. Access sheaths were removed 4 hours after the last dose of enoxaparin or when ACT was 7 In the current issue, Carnendran et al.⁸ assess the safety and feasibility of the concomitant administration of intravenous enoxaparin (0.5 mg/kg) and a glycoprotein IIb/IIIa inhibitor in 75 patients who underwent PCI. All patients were treated in a standard fashion with clopidogrel and aspirin and the vast majority were treated with eptifibatide for an average of 18 hours. Femoral access sheaths were removed at the end of the procedure with the use of a closure device (Angio-Seal®). Procedural success was high, with a minimal incidence of periprocedural bleeding complications. Only 1 patient had a self-contained retroperitoneal hematoma (1.3%) and 1 patient had mild thrombocytopenia. None of the patients had life-threatening bleeding episodes, bleeding requiring surgical intervention, hemorrhagic stroke, access site hematoma, severe thrombocytopenia or need for blood transfusion. Furthermore, there were no ischemic events during hospitalization or at 30-day follow-up. While these data support the proposed strategy of the combined use of enoxaparin and IIb/IIIa inhibitors, the study is limited by its non-randomized design, the lack of an appropriate control group and by the small number of patients. However, several questions have arisen that have no precise answers. What are the economic implications of changing the current approach to LMWH? Can we extrapolate these results to all closure devices and all glycoprotein IIb/IIIa inhibitors? What will be the role of direct thrombin inhibitors during PCI? What about patients pre-treated with LMWH before their arrival to the cath lab? Is a single intravenous bolus of 0.5 mg/kg sufficient or should patients receive 0.75 mg/kg? And finally, going back to our original question, how low can we go with the enoxaparin dose? Nevertheless, the present study provides further support for the safety of a single, low-dose bolus of enoxaparin in combination with glycoprotein IIb/IIIa inhibitors in patients who undergo PCI and early access sheath removal with the aid of a closure device. A more definitive answer will be provided when the results of the NICE-5 and SYNERGY trials become available. These prospective studies include patients presenting with acute coronary syndromes undergoing PCI who will be randomized to unfractionated heparin or enoxaparin and will be concomitantly treated with a glycoprotein IIb/IIIa inhibitor. The current study by Carnendran et al., in conjunction with the aforementioned studies in patients undergoing PCI, advocates a strategy of combined low-dose enoxaparin and eptifibatide with early sheath removal. The potential advantage over current strategies will only be determined by the randomized studies that are currently underway. Undoubtedly, future guidelines will have to address the issue of LMWH during PCI in a way to simplify and optimize current techniques.

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