Anticoagulant Agents for NSTEACS and PCI
Jorge Magallon MD
Ajay J. Kirtane MD, SM, FACC, FSCAI
Acute coronary syndromes (ACS) are typically characterized by thrombosis superimposed over rupture, erosion, or mechanical disruption of a thin fibrous cap overlying lipid-laden plaque within a culprit coronary artery. Exposure of plaque contents to the bloodstream initiates the activation and upregulation of various mediators of the thrombotic cascade, which further contribute to luminal compromise, resulting in worsening ischemia and reinfarction. Anticoagulant and antiplatelet therapies help minimize and placate the thrombotic process, which is the hallmark of ACS. As such, these agents are the cornerstones of adjunctive pharmacology for ACS. Additionally, anticoagulant and antiplatelet agents can more safely facilitate mechanical therapies such as percutaneous coronary intervention (PCI), which, while aiming to mechanically stabilize the plaque responsible for ACS, are at the same time prothrombotic and constitute an iatrogenic form of plaque rupture similar to natively occurring ACS. This chapter covers the indications and usage of various anticoagulant therapies in the setting of non-ST segment acute coronary syndromes (NSTEACS) and during PCI.
OVERVIEW OF ACC/AHA/SCAI GUIDELINE RECOMMENDATIONS
Anticoagulants in NSTEACS
The ACC/AHA guidelines summarizing the recommendations for the use of anticoagulant therapy in NSTEACS patients separate anticoagulant management of these patients on the basis of whether treating physicians will pursue an invasive management strategy (early diagnostic catheterization to then triage patients for further medical therapy, PCI, or coronary artery bypass grafting [CABG]) or a conservative management strategy (medical therapy followed by noninvasive risk stratification) (1). Once the diagnosis of ACS has been made, patients should be immediately started on anticoagulant therapy regardless of the management strategy—a Class I recommendation in the ACC/AHA guidelines (Table 4-1). The notable exception to this is for those patients whose ACS is not a consequence of an atherothrombotic process, but is rather a secondary event (e.g., as a result of severe blood loss, trauma, or sepsis).
There are several classes of anticoagulants that have been shown to be effective in treating patients with ACS: unfractionated heparin (UFH), low-molecular-weight heparins, direct thrombin inhibitors, and Factor Xa inhibitors. The primary function of these agents is to inhibit the coagulation cascade, thereby preventing or minimizing thrombosis in order to alleviate the ischemic effects of ACS. A critical management issue related to the use of anticoagulant agents in ACS is the potential tradeoff of more potent anticoagulation (aimed at maximizing anti-ischemic efficacy) for an increase in bleeding complications. The association between ischemic events and late mortality has been recognized historically and well described in studies of ACS; in fact, this is one of the fundamental principles behind the use of anticoagulant therapy in ACS. More recently, a strong linkage between nonfatal bleeding events and subsequent mortality has also emerged in both randomized clinical trials and observational studies on ACS (2, 3 and 4). Thus, the treating physician must be acutely aware of the joint importance of both ischemic and bleeding complications when selecting the optimal anticoagulant strategy for patients with NSTEACS.
TABLE 4-1 ACC/AHA Guideline Recommendations for NSTEACS | ||||||||||||||
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Anticoagulant Use with an Invasive Management Strategy
Patients presenting with NSTEACS who are being treated with an invasive management strategy are usually started on anticoagulant therapy at the time of diagnosis, and typically taken to the catheterization lab within 48 hours of presentation. Anticoagulant agents that have been shown to be effective in this setting include intravenous bivalirudin, intravenous UFH, subcutaneously administered fondaparinux, or subcutaneously administered enoxaparin. As stated in the guidelines, there are limited comparative data among the various Class I agents in this setting, and across-study comparative assessments based upon historical data are often confounded by changes in adjunctive therapies (e.g., antiplatelet agents) over time. Thus, the specific choice of an anticoagulant agent may be a physician- or an institution-dependent decision, modified by patient-specific factors.
NSTEACS patients undergoing PCI frequently require uptitration of anticoagulant dosing at the time of PCI in order to minimize the additional thrombogenicity associated with the procedure (Table 4-2). Consistency in anticoagulant choice should be maintained in most circumstances as several studies have demonstrated
an associated increased risk of bleeding when switching anticoagulant agents, particularly if enoxaparin is used as the initial anticoagulant (5). In rare cases (for example in the treatment of intraprocedural thrombotic complications), patients may require the use of more than one anticoagulant agent during PCI. Additionally, because of an increased rate of catheter-related thrombotic complications observed during PCI performed with fondaparinux (2), many operators have adopted a strategy of intraprocedural treatment with UFH in patients initially treated with this agent (6).
an associated increased risk of bleeding when switching anticoagulant agents, particularly if enoxaparin is used as the initial anticoagulant (5). In rare cases (for example in the treatment of intraprocedural thrombotic complications), patients may require the use of more than one anticoagulant agent during PCI. Additionally, because of an increased rate of catheter-related thrombotic complications observed during PCI performed with fondaparinux (2), many operators have adopted a strategy of intraprocedural treatment with UFH in patients initially treated with this agent (6).
TABLE 4-2 Dosing of Anticoagulant Agents | ||||||||||||||||||||||||||||||||||||
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Anticoagulant therapy is typically discontinued immediately following PCI because continued administration has demonstrated limited additional anti-ischemic benefits and an increased risk of bleeding.
Anticoagulant Use with a Conservative Management Strategy
The goal of anticoagulant therapy in patients with NSTEACS is first to placate the activated prothrombotic state. Appropriate patients can then be further risk-stratified with noninvasive testing, which may lead to a more selective use of angiography and/or revascularization. Conservatively managed patients with NSTEACS may be treated with various anticoagulants, including UFH, enoxaparin, or fondaparinux. According to the current ACC/AHA guidelines, bivalirudin is not considered part of the armamentarium for a conservative management strategy because of the limited data with this agent in conservatively managed patients. A Class IIa recommendation is given to the use of either fondaparinux or enoxaparin over UFH for the treatment of ACS in conservatively managed patients.
There are limited data regarding the exact duration of anticoagulant therapy in conservatively managed patients; however, it is generally accepted practice to continue these agents for at least 48 hours after initial presentation.
Anticoagulants during PCI
Anticoagulation is generally administered during PCI in order to suppress the thrombotic process that may be precipitated by the introduction of foreign objects into the coronary vasculature (i.e., catheters, wires, balloons, stents). Further, anticoagulants can help suppress activation of the thrombotic cascade following vessel injury during PCI. There are several classes of anticoagulants that have shown to be effective in treating patients undergoing PCI, including UFH; enoxaparin, a low-molecular-weight heparin; and direct thrombin inhibitors such as bivalirudin.
Anticoagulants are typically not administered during diagnostic catheterization procedures with the exception of radially performed diagnostic procedures. If the radial artery is chosen as the access site for angiography, it is recommended that parenteral
anticoagulation be started immediately after the arterial sheath is placed in order to reduce the risk of radial artery occlusion. Spaulding et al. demonstrated a correlation between the dose of UFH therapy used following radial access and the rate of radial artery occlusion post procedure in 415 patients; occlusion occurred in 71% of patients with no UFH therapy, 24% in patients treated with 2,000 to 3,000 U of UFH, and 4.3% in those treated with 5,000 U of UFH (7). Whether the use of more modern hydrophilic sheaths, smaller catheter sizes, and shorter procedure times can completely mitigate this effect is unknown.
anticoagulation be started immediately after the arterial sheath is placed in order to reduce the risk of radial artery occlusion. Spaulding et al. demonstrated a correlation between the dose of UFH therapy used following radial access and the rate of radial artery occlusion post procedure in 415 patients; occlusion occurred in 71% of patients with no UFH therapy, 24% in patients treated with 2,000 to 3,000 U of UFH, and 4.3% in those treated with 5,000 U of UFH (7). Whether the use of more modern hydrophilic sheaths, smaller catheter sizes, and shorter procedure times can completely mitigate this effect is unknown.
Once the decision is made to pursue PCI (irrespective of the access site), the ACC/AHA/SCAI guidelines give a Class I recommendation to administer parenteral anticoagulation at the time of the procedure (Table 4-3) (8). Specific recommendations regarding the choice of agent depend upon the clinical scenario. For elective PCI (or in patients not previously on parenteral anticoagulants), an anticoagulant agent is chosen and typically administered as a parenteral bolus, with an infusion lasting for the duration of the PCI. For patients with NSTEACS treated with upstream therapy, the dose of anticoagulation is typically higher during PCI than during maintenance upstream therapy, and several therapies used upstream are not indicated for PCI; thus, specific decisions regarding switching anticoagulants, further bolus dosing, and/or increasing the dose of infusion are required (Table 4-2). Of the anticoagulants used during PCI, UFH is one agent for which intraprocedural monitoring of levels of anticoagulant activity is recommended.
In general, anticoagulant therapy is discontinued immediately following PCI. Decisions regarding management of the vascular access site depend upon several factors: the site of access (e.g., femoral vs. radial), whether use of a vascular closure device is planned, and the particular anticoagulant used. For femoral access, if use of a vascular closure device is planned, it is typically deployed immediately after PCI. For manual compression of a femoral access site, sheaths are usually removed when the activated clotting time (ACT) falls below 150 to 180 seconds in patients treated with UFH; for patients treated with bivalirudin, sheaths are typically removed 2 hours after termination of the infusion. For radial access, sheath removal is typically performed immediately after PCI by applying nonocclusive pressure, typically with a specialized pressure device (to achieve patent hemostasis).
TABLE 4-3 ACC/AHA/SCAI PCI Guideline Recommendations | ||||||||||||||||||||
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SPECIFIC ANTICOAGULANTS
Unfractionated Heparin
UFH is a mixture of polysaccharide chains with molecular weights ranging from 3,000 to 30,000 Da, which exerts its major anticoagulant effect by indirectly inactivating thrombin and the coagulation cascade. UFH facilitates activation of antithrombin III, which then inactivates Factors IIa (thrombin), IXa, and Xa. Bioavailability of UFH varies from patient to patient because of its nonspecific binding to plasma proteins and cells. As a consequence, the anticoagulant response to UFH varies among patients and necessitates the monitoring of the activated partial thromboplastin time (aPTT) or ACT in order to achieve the optimally desired level of anticoagulation.
Summary of Trial Data
NSTEACS
One of the oldest anticoagulants used to treat ACS, UFH has been studied in numerous trials involving NSTEACS patients. In a metaanalysis comparing the effect of aspirin plus UFH with that of UFH alone, aspirin plus UFH was shown to reduce early ischemic events, with borderline significance noted in the reduction of early death or myocardial infarction (MI) (Fig. 4-1) (9). It should be noted that the effects of UFH regarding the endpoint of death/MI were not significant in any of the individual trials included in this meta-analysis. Furthermore, antiplatelet agents such as adenosine diphosphate (ADP) receptor blockers, which provide an additional anti-ischemic effect, were not included in these trials, so the “true” effect of UFH when used in conjunction with more potent antiplatelet agents compared with no UFH is poorly understood from clinical trials.
 FIGURE 4-1 Meta-analysis of UFH plus aspirin vs. aspirin alone in ACS (Adapted from: Oler et al. JAMA. 1996;276:811-815, with permission.) |
Additional information on the use of UFH with or without other antiplatelet agents (ADP receptor antagonists and glycoprotein [GP] IIb/IIIa inhibitors) is covered in Chapter 3 describing the use of antiplatelet agents.
Elective PCI
UFH was the sole anticoagulant used in PCI for many years, and because of its widespread and early acceptance, there are limited trial data examining its efficacy and safety compared with a background of no UFH. Clinical experience with the use of UFH suggests that the optimal intensity of anticoagulation is generally greater in patients undergoing PCI than in those who are being medically managed with ACS. Early on in the PCI experience, UFH was given at the beginning of the procedure as a standard dose of 10,000 U intravenously, with further bolus doses administered hourly. However, because of variable anticoagulant effects observed with these fixed dosing regimens of UFH, as well as the observation of an increased rate of bleeding complications in patients treated with UFH plus potent antiplatelet agents such as GP IIb/IIIa inhibitors, the measurement of ACT has become integrated as part of the PCI procedure (see below).
Although the administration of UFH during PCI is a Class I recommendation, whether UFH is needed at all during PCI for low-risk patients, particularly in the era of adjunctive antiplatelet pharmacotherapy, is unknown. A modestly sized but underpowered randomized trial, the CIAO trial, prospectively enrolled 700 patients undergoing elective PCI and assigned patients to UFH versus no UFH on a background of aspirin and a thienopyridine (10). The primary endpoint of death, MI, or urgent target vessel revascularization was achieved more frequently in the UFH than in the no UFH arm (2.0% vs. 3.7%, p = 0.17). Procedures without UFH were performed without adverse events, no stent thromboses were observed, and absence of UFH was associated with a decrease in postprocedural MI and bleeding events. Despite these findings, larger randomized studies with more complex patients will be needed before it can be concluded definitively that PCI procedures can be done safely without anticoagulation.
Dosing Strategies and Therapeutic Targets
NSTEACS
In ACS, unfractionated heparin is administered as an intravenous bolus followed by a continuous intravenous infusion. Traditionally, UFH is given as a 5,000-U bolus followed by a 1,000 U/h infusion, with further adjustments made according to the aPTT. However, more predictable anticoagulation can be effected through weightbased dosing, which is the current recommendation in the ACC/AHA guidelines. These guidelines recommend an intravenous bolus dose of UFH (60 U/kg not to exceed 4,000 U), followed by an initial 12 U/kg/h infusion (not to exceed 1,000 U/h). Further dosing is dictated by monitoring of the aPTT or ACT (the latter for patients undergoing PCI).
Measurement of the aPTT can vary from institution to institution, so it is important to implement an institution-specific nomogram and/or protocol for UFH. Ideally, patients maintained on UFH should have a target aPTT in the range of 1.5 to 2.0 times control. This dosing is thought to optimize the anti-ischemic effects of UFH while minimizing bleeding that can occur at higher achieved levels of anticoagulation (11). For patients undergoing PCI, additional intravenous boluses are typically administered.
The ACC/AHA guidelines recommend the administration of UFH up until the time of angiography for those patients undergoing an early invasive management strategy, but the optimal duration of UFH in ACS patients beyond angiography is unknown. Patients who undergo PCI should have UFH discontinued after PCI; those undergoing CABG should continue UFH. Patients being treated medically or those not undergoing an invasive management strategy are typically treated with UFH through their hospitalization (at least 48 hours), at which point it can be discontinued.
UFH is a reversible anticoagulant whose effect dissipates over time when the infusion is stopped. In more emergent settings, protamine sulfate can be administered for rapid reversal. A test dose is usually given prior to administering a full dose of protamine to prevent anaphylaxis-type reactions, which have been known to occur in patients with prior exposure to long-acting insulins.
During PCI
For PCI, UFH is administered as an intravenous bolus with therapeutic levels monitored by ACT. Because the intensity of anticoagulation during PCI is greater than during upstream medical therapy, heparin infusions are typically discontinued 30 minutes prior to PCI, and full dosing of UFH is given at the time of PCI. Weightbased dosing should be employed, with doses of 50 to 70 U/kg with a target ACT of 200 to 250 seconds if GP IIb/IIIa inhibitors are used and 70 to 100 U/kg with a target ACT of 300 to 350 seconds if no GP IIb/IIIa inhibitors are used (Table 4-2). Patients undergoing PCI with UFH should have the anticoagulant stopped at the end of the procedure.
Chew and colleagues pooled the results from the UFH-only arms of six randomized control trials enrolling 5,216 patients primarily treated with balloon angioplasty alone and examined the association between ACT and outcomes after PCI (12). In this analysis, patients with ACT values ranging from 350 to 375 seconds had the lowest ischemic event rates (Fig. 4-2, Left Panel); however, major or minor bleeding rates were lowest with ACT values between 300 and 350 seconds (Fig. 4-2, Right Panel). A pooled analysis of four more recent randomized trials, which included patients treated primarily with stents and GP IIb/IIIa inhibitors, demonstrated no significant correlation between maximal ACT and ischemic complications, with a monotonically increasing risk of bleeding at increasing levels of ACT (13). Based upon these and other studies, current guidelines recommend ACT-based titration of UFH during PCI, with lower levels of ACT for patients treated with concomitant potent antiplatelet therapies.
Adverse Consequences
As an anticoagulant, UFH is associated with bleeding complications, which must be weighed against the potential anti-ischemic effects of the agent. While bleeding complications can occur despite a therapeutic range aPTT, higher aPTT values are associated with increased bleeding complications. Appropriate dosing and monitoring of UFH should be performed in order to maximize UFH’s risk-benefit ratio, as higher doses of both the bolus and infusion have been associated with adverse outcomes (14). In a large observational registry of ACS patients, excess dosing of UFH was found in almost one third of patients (15).
In addition to bleeding complications, exposure to UFH has also been associated with the development of heparin-induced thrombocytopenia, which can occur with or without thrombosis (1
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