Introduction
Myocardial infarction (MI) includes patients presenting with ST-elevation MI (STEMI) and those without ST-segment MI (NSTEMI), and although these types of MI share a common physiopathology and principles of treatment (see Chapter 13 ), the approaches to management of anticoagulant therapy for these conditions differ by MI type and overall management strategy (invasive vs. conservative).
Rationale for Anticoagulant Therapy in Acute Coronary Syndrome
The rationale for administering anticoagulant therapy acutely in STEMI patients is strong and includes the following treatment goals :
- 1.
Establishing and maintaining patency of the infarct-related artery whatever the reperfusion strategy used (fibrinolysis, primary angioplasty, or no reperfusion therapy).
- 2.
Prevention of ventricular thrombus formation and cerebral embolization.
- 3.
Prevention of complications related to percutaneous coronary intervention (PCI), such as catheter thrombosis, distal embolization of fragmented thrombus, slow or no flow post-PCI, ischemic stroke, abrupt vessel closure, and acute stent thrombosis.
Other objectives are common to acute medical conditions and bed rest, such as prevention of deep venous thrombosis and possible consequent pulmonary embolism.
In NSTEMI, the objectives are similar, although the artery is rarely fully occluded :
- 1.
Maintaining patency of the infarct-related artery whatever strategy is decided by the treating physician (invasive strategy or medical therapy).
- 2.
Prevention of PCI-related complications.
- 3.
Prevention of complications or bed rest.
Containing Thrombus Formation and Propagation
Successful and durable myocardial reperfusion is the goal of the initial antithrombotic therapy, including anticoagulation and antiplatelet therapy (see Chapter 19 ). After the initial disruption or rupture of vulnerable plaque (see Chapter 3 ), the common pathophysiological substrate of acute coronary syndrome (ACS), the damaged endothelium, and the exposition of the lipid core leads to platelet adhesion and aggregation, followed almost instantly by activation of the coagulation cascade and formation of an initial platelet-rich thrombus ( Figure 18-1A ).
A key step in this process is the activation of prothrombin to thrombin (factor IIa), which transforms the circulating fibrinogen into fibrin fibers, forming the scaffold of the coronary thrombus and leading to its stabilization (see Figures 18-1B and 18-1C ). The evolution of the thrombus may culminate in resolution with asymptomatic healing, a subtotal coronary artery occlusion leading to a NSTEMI, or to fully occlusive thrombus presenting as a STEMI. As a result, initial anticoagulant therapy is indicated in all patients with MI, in the absence of contraindications. The class of anticoagulant and dose regimen depends on the type of MI and whether the anticoagulant is to be used as an adjunct to PCI or fibrinolysis.
Although treatment with heparin, as the prototypical parenteral anticoagulant, has a strong pathobiological rationale and has become entrenched in the clinical management of MI, the evidence from clinical studies directly demonstrating the efficacy of heparin in MI is modest. However, the rationale for use of anticoagulants in MI has been bolstered by subsequent trials of newer anticoagulants, such as the low–molecular-weight heparins (LMWHs).
Overview of Available Anticoagulant Drugs
Although adjuvant anticoagulant therapy may result in a small improvement in initial restoration of flow in the thrombotic coronary artery, its main roles are maintaining patency after successful reperfusion, preventing reocclusion, and reducing the risk of thrombotic complications of PCI. The options for initial anticoagulant therapy include four main drugs: unfractionated heparin (UFH), the LMWHs (e.g., enoxaparin), fondaparinux, and bivalirudin. UFH and enoxaparin are the most frequently used anticoagulants worldwide. They are both biological products that are derived from mucosal tissues (e.g., porcine or bovine intestines). Inherent drawbacks led to the development of synthetic anticoagulants, such as fondaparinux and bivalirudin. The mechanism of action of each of these four agents is illustrated in Figure 18-2 and compared in Table 18-1 .
| Medication | UFH | Enoxaparin | Fondaparinux | Bivalirudin |
|---|---|---|---|---|
| Mechanism | AT mediated factor Xa and thrombin inhibitor | AT mediated factor Xa and thrombin inhibitor | Indirect factor Xa inhibitor | Direct thrombin inhibitor, reversible |
| Route of administration | IV–SC | IV–SC | SC | IV |
| Half-life | 1–2 h | 5–7 h | 17–21 h | 25 min |
| Molecular weight | 3–30 kDa | 2–10 kDa | 1.7 kDa | 2.2 kDa |
| Metabolism | Hepatic | Hepatic | Excreted largely as unchanged drug | Plasma proteases |
| Elimination | Extra-renal | Renal | Renal | Renal |
| Onset | Immediate (IV) | Immediate (IV) 3–5 h (SC) | 2–3 h (SC) | Immediate |
| Notes | Inactive on clot-associated thrombin | Inactive on clot-associated thrombin More factor sXa selectivity | Inactive on clot-associated thrombin | Inhibits clot-associated thrombin |
| Incidence of HIT | 1%–3% | ≤0.2% | Negligible | None |
| Antidote | Protamine | Protamine (partial) | None | None |
Unfractionated Heparin
UFH was the first anticoagulant used in the treatment of MI. UFH is a heterogeneous mixture of mucopolysaccharides, with a molecular weight ranging from 2000 to 30,000 Da (mostly 15,000 to 18,000), that bind and activate antithrombin, greatly increasing the inhibitory effects of antithrombin on thrombin. Activated antithrombin inhibits several coagulation factors, including factor Xa, resulting in an anticoagulant effect. Because its actions are via binding to antithrombin, UFH is classified as an indirect thrombin inhibitor (see Figure 18-2 ). Because UFH is poorly absorbed when injected via the subcutaneous (SC) route, intravenous (IV) administration is the preferred route of administration.
A major drawback of UFH is the significant variability of its therapeutic response. The heterogeneous composition and variable elimination of UFH through the endoplasmic reticulum results in marked interpatient therapeutic response variability and necessitates close monitoring of anticoagulant intensity with activated clotting time (ACT) or with activated partial thromboplastin time (aPTT). UFH can also cause an immunologically mediated thrombocytopenia, also known as heparin-induced thrombocytopenia (HIT), which is rare (2% to 3% of patients), but potentially life-threatening. Other drawbacks of UFH include an increase in platelet activation and aggregation, a dependency on antithrombin for inhibition of thrombin activity, a sensitivity to platelet factor 4, and an inability to inhibit clot-bound thrombin.
Even with standardized weight-based dosing nomograms, less than one-third of initial aPTT measurements are within the therapeutic range. The anticoagulant effect of UFH dissipates rapidly, within a few hours after interruption. During the first 24 hours after heparin cessation, there is a risk of reactivation of the coagulation process, and therefore, a transiently increased risk of recurrent ischemic events despite adjunctive aspirin treatment. A desire to overcome the disadvantages of UFH has stimulated interest in the development of alternative anticoagulants.
Historically, high doses of UFH were used in fibrinolysis or PCI to overcome thrombotic complications; however, studies showed that these higher doses were associated with a higher rate of bleeding without an effect on the ischemic endpoints, and that efficacy was preserved at the lower doses. The initial doses of UFH used in PCI (up to 175 UI/kg) were gradually lowered to 140, 100, 85, 70, 60, and 50 UI/kg in the latest trials when glycoprotein IIb/IIIa receptor inhibitors (GPIs) were used. A similar pattern was shown with the target ACT for the optimal ranging of UFH efficacy, suggesting that the therapeutic window for UFH is relatively narrow.
Low–Molecular-Weight Heparins
LMWHs are a class of heparin-derived compounds with molecular weights ranging from 2000 to 10,000 Da ( Table 18-2 ). By virtue of enhanced binding of LMWH-antithrombin to factor Xa, LMWHs have a balanced anti-Xa and anti-IIa activity, with the relative activity against factor Xa versus IIa depending on the molecular weight of the molecule; the heavier the LMWH is, the greater relative anti-IIa activity it has (see Figure 18-2 ). Enoxaparin is the most studied and widely used LMWH for the treatment of ACS. LMWHs are approximately one-third of the molecular weight of UFH, conferring greater bioavailability that enables administration via the SC route. Other advantages of enoxaparin include a stable and reliable anticoagulant effect without any need for monitoring, provided that weight-based dosing is used and renal failure is absent.
| Generic Name (Trade Name or Synonym) | Mean Molecular Weight (Da) | Anti-Xa: Anti-IIa Ratio | FDA Indication for ACS |
|---|---|---|---|
| Enoxaparin (Lovenox, Clexane) | 4200 | 3.8 | Yes |
| Nadroparin (Fraxiparine, Sleparina) | 4500 | 3.6 | Yes |
| Reviparin (Clivaparine) | 4000 | 3.5 | No |
| Dalteparin (Fragmin) | 6000 | 2.7 | Yes |
| Parnaparin (Fluxum, Minidalton) | 4500–5000 | 2.4 | No |
| Ardeparin (Normiflo) | 6000 | 1.9 | No |
| Tinzaparin (Innohep, Logiparin) | 4500 | 1.9 | No |
| Certoparin (Alphaparin, Sandoparin, Embolex) | 4200–6200 | N/A |
∗ In descending order of relative anti-Xa:anti-IIa activity.
Once bound to antithrombin, enoxaparin provides a greater specificity for factor Xa compared with UFH, producing an enhanced blockade of the coagulation cascade upstream of thrombin generation. The ratio of inhibition of factor Xa/IIa varies between agents, and is 3 to 1 for enoxparin. HIT is 20 times less common with enoxaparin than with UFH, but it can still occur. On top of these anticoagulant actions, enoxaparin may have some anti-inflammatory properties and does not activate platelets.
The main drawback of enoxaparin is its renal elimination, which in the presence of renal dysfunction, can result in accumulation over time with repeated injections (>3 injections). Similarly to UFH, enoxaparin was used at high doses in the first phase II trials, such as TIMI 11A (Thrombolysis In Myocardial Infarction), which demonstrated that doses higher than 1.0 mg/kg should not be used because of excess bleeding.
Fondaparinux
Fondaparinux is a synthetic pentasaccharide that was developed to have a chemical structure similar to the antithrombin-binding active site domain of heparin (see Figure 18-2 ). This highly selective drug induces conformational changes, leading to a potent inhibition of factor Xa, and thus, reducing thrombin generation. Unlike UFH and LMWH, fondaparinux has no inhibitory effect on thrombin (factor IIa) itself. Fondaparinux inhibits factor Xa by binding reversibly, with a high affinity to antithrombin. Like LMWH, but in a more selective manner, it targets this upstream step in the coagulation cascade of thrombin generation ( Figure 18-3 ).
Advantages of fondaparinux include 100% bioavailability after SC injection and a long half-life of 15 to 17 hours, which allows for once daily administration. Fondaparinux is eliminated mainly by the kidneys and is contraindicated if creatine clearance is less than 30 mL/min. It has a predictable anticoagulant effect with no requirement for monitoring, and no cross reactivity with antibodies associated with HIT. Fondaparinux is insensitive to inactivation by platelet-released heparin neutralization proteins. Therefore, monitoring the platelet count is unnecessary, as is monitoring of anti-Xa activity. Phase II trials evaluated different doses of intravenous fondaparinux (2.5 and 5.0 mg) compared with UFH, and the lower dose of 2.5 mg was selected because of its good safety profile.
Bivalirudin
Bivalirudin and hirudin are synthetic drugs that are direct thrombin (IIa) inhibitors. Several direct thrombin inhibitors have been tested over time, but only bivalirudin reached clinical use in PCI and ACS settings. Unlike UFH and LMWH, bivalirudin inactivates both fluid-phase thrombin and clot-bound thrombin, with less activation of platelets. Because it does not bind to plasma proteins, the anticoagulant effect of bivalirudin is more predictable. Bivalirudin is eliminated by the kidney. The effect of bivalirudin can be followed with routine coagulation tests (aPTT and ACT).
Initial phase II studies tested different regimens of the drug, starting with low bolus doses of 0.5 and 0.75 mg/kg, which were considered insufficient for PCI, and the first large trial used higher doses (bolus dose of 1.0 mg/kg followed by a 4-hour infusion of 2.5 mg/kg per hour and a 14- to 20-hour infusion of 0.2 mg/kg per hour) compared with high doses of UFH (175 UI/kg) for PCI. Subsequently, both the bolus and the infusion doses were lowered (0.75-mg/kg bolus plus 1.75 mg/kg per hour for the duration of PCI) with uncertainty about the optimal duration of infusion after PCI.
Other Parenteral Anticoagulants
Other parenteral anticoagulation therapies have been developed and tested in clinical trials. Otamixaban is a synthetic intravenous direct factor Xa inhibitor, with rapid onset and/or offset, linear kinetics, and no significant renal elimination. However, compared with UFH and eptifibatide, the drug failed to show a benefit in the large phase III Treatment of Acute Coronary Syndromes with Otamixaban (TAO) trial (n = 13,229 patients) of ACS and planned early PCI.
REG-1, first of its class, was composed of two components, the first being a specific and synthetic factor IX inhibitor, pegnivacogin, and the second an injectable and specific antidote to the active drug, anivamersen. Although such a combination seems ideal for emergency situations, allergic reactions to the drug led to a cessation of development of this molecule. The factor XI antisense oligonucleotide (ISIS 416858) that specifically reduces factor XI levels compared favorably against enoxaparin in the prevention of thrombosis after knee arthroplasty.
Monitoring of Available Anticoagulant Therapy
Biological monitoring of the anticoagulant effect of the various available drugs is not mandatory for all agents. For UFH, the therapeutic window is narrow; thus, it requires frequent monitoring of its anticoagulant activity. Two different biomarkers are commonly used to monitor the activity of UFH. One is aPTT, which can be obtained at less than 1 hour, has an optimal target of 50 to 75 seconds, and corresponds to 1.5 to 2.5 times the upper limit of normal. Above these values, the risk of bleeding complications increases, without further antithrombotic benefits; below these values, the antithrombotic effect is insufficient. The second biomarker available is ACT, which can be used for monitoring of UFH during PCI, but has not been linked to an improved prognosis.
Enoxaparin can reliably be monitored by assessing the anti-Xa activity level in a standard chromogenic laboratory assay. Although data showed that with a standard protocol adjusted for weight and renal function (more than 90% of patients are in the therapeutic window), insufficient levels of anti-Xa during PCI of patients with ACS have been linked to an increased risk of death and ischemic events in the periprocedural period. There is no easy bedside approach to monitoring of enoxaparin. ACT is not discriminant enough for monitoring LMWH therapy. Tests (e.g., the Hemonox bedside test) were developed and validated in a cohort of patients, but these tests have not been adopted into routine use in practice because the enoxaparin level is within the therapeutic window in 95% of patients.
Fondaparinux has no significant influence on the usual variables that monitor anticoagulant activity, such as aPTT, ACT, prothrombin, and thrombin times, and requires an adapted anti-Xa assay that uses an appropriate standard curve.
Bivalirudin plasma concentration correlates well with coagulation tests (aPTT and ACT), which can be used to monitor the anticoagulant activity of bivalirudin in the same manner as UFH. In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, it was mandated to check the ACT after the initial bivalirudin bolus, with an additional bolus in case of a low ACT. However, the pharmacokinetics and pharmacodynamics of bivalirudin are such that low ACTs were only found in 2% to 3% of the patients, and therefore, there is no need to routinely monitor the degree of anticoagulation for short-term use as an adjunct to PCI.
In summary, the only anticoagulant that routinely requires monitoring is UFH. However, meta-analyses have shown that the available bedside test for ACT has a poor correlation with ischemic or bleeding complications.
Reversal of Anticoagulant Therapy
Because bleeding remains an important complication of anticoagulation therapy, availability of an antidote is important to the physician. Protamine sulfate can be used in an equimolar concentration to inhibit UFH, and to a lesser degree, it inhibits the anticoagulant effect of enoxaparin. Protamine has no effect on fondaparinux or bivalirudin. Because of the short half-life of bivalirudin, waiting until the end of its effect after drug cessation is reasonable. In the case of fondaparinux, there is currently no available specific antidote. Recombinant factor VIIa has been recommended, but it is associated with an increased risk of thrombotic complications.
Initial Anticoagulant Therapy
ST-Elevation Myocardial Infarction Treated with Primary Percutaneous Intervention
Although extensively studied, anticoagulation during primary PCI remains controversial (see also Chapter 17 ). Patients undergoing primary PCI should receive a combination of dual antiplatelet therapy (see Chapter 19 ) with the combination of a parenteral anticoagulant. Fondaparinux carries a possible hazard related to catheter thrombosis, is not recommended as an anticoagulant in this setting, and is not discussed in this section. Three options are used to support primary PCI: UFH, bivalirudin, or enoxaparin, all administered intravenously. Professional society guidelines for anticoagulant therapy in STEMI treated with primary PCI are summarized in Table 18-3 .
| Anticoagulant | AHA | ESC | ||
|---|---|---|---|---|
| COR | LOE | COR | LOE | |
| UFH | ||||
| With GP IIb/IIIa inhibitor planned: 50–70 U/kg | I | C | I | C |
| Without GP IIb/IIIa inhibitor planned: 70–100 U/kg | I | C | I | C |
| Bivalirudin | ||||
| 0.75 mg/kg IV bolus, then 1.75 mg/kg/h infusion with or without previous treatment by UFH. An additional bolus of 0.3 mg/kg can be given if needed. Reduce infusion to 1 mg/kg/h with estimated CrCl <30 mL/min. | I | B | IIa | A |
| Preferred over UFH with GP IIb/IIIa inhibitor in patients at high risk of bleeding | IIa | B | ||
| Enoxaparin | ||||
| 0.5 mg/kg IV bolus with or without GP IIb/IIIa inhibitor | IIa | B | ||
| Fondaparinux | ||||
| Not recommended as sole anticoagulant for primary PCI | III | B | III | B |
Unfractionated Heparin During Primary Percutaneous Coronary Intervention
An intravenous UFH bolus adapted to the concomitant use of a GPI and titrated to an appropriate ACT time is a familiar and well-tested strategy for initial anticoagulant therapy at the time of primary PCI for STEMI. UFH has a class I recommendation in both the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) and European Society of Cardiology (ESC) guidelines, but it also has a level of evidence C because of the absence of placebo-controlled trials evaluating UFH in primary PCI. Dosing should follow standard recommendations for PCI (initial bolus 70 to 100 U/kg when no GPI is planned or 50 to 60 U/kg when the use of GPI is expected).
Enoxaparin versus Unfractionated Heparin for Primary Percutaneous Coronary Intervention
Enoxaparin is generally not used in the United States as adjunctive therapy for primary PCI. Nevertheless, intravenous enoxaparin (0.5 mg/kg followed by prophylactic 40 mg SC) has been suggested by several nonrandomized studies and an international open-label randomized trial (ATOLL [Acute Myocardial Infarction Treated with Primary Angioplasty and Intravenous Enoxaparin or Unfractionated Heparin to Lower Ischaemic and Bleeding Events at Short- and Long-term Follow-up]) to possibly be more predictable and reliable than UFH in primary PCI. The primary composite endpoint of 30-day death, complication of MI, procedural failure, and major bleeding was not significantly reduced (relative risk reduction 17%; p = .063). Prespecified exploratory analyses showed reductions in the main secondary endpoint of death, recurrent MI, or ACS or urgent revascularization, and in other secondary composite endpoints such as death, or resuscitated cardiac arrest, death, or complication of MI. Importantly, bleeding was not increased with enoxaparin versus UFH. In the exploratory per-protocol analysis of the ATOLL trial, which was pertinent to more than 87% of the study population, IV enoxaparin was superior to UFH in reducing the primary endpoint (relative risk [RR], 0.76; 95% confidence interval [CI], 0.62 to 0.94; P = .012), ischemic endpoints, mortality (RR, 0.36; 95% CI, 0.18 to 0.74; P = .003), and major bleeding (RR, 0.46; 95% CI, 0.21 to 1.01; P = .050), which contributed to the improvement of the net clinical benefit (RR, 0.46; 95% CI, 0.3 to 0.74; P = .0002) in patients who underwent primary PCI.
In a systematic review and meta-analysis of enoxaparin versus UFH in PCI, which regrouped nonrandomized studies, post hoc analysis of randomized trials, and the ATOLL randomized trial, 10,243 patients underwent primary PCI for STEMI with either enoxaparin or UFH ( Figure 18-4 ). In this meta-analysis, enoxaparin was associated with a significant 48% RR reduction of mortality with an enoxaparin relative reduction (RR, 0.52; 95% CI, 0.42 to 0.64; P < .001), a reduction of death or MI (RR, 0.61; 95% CI, 0.47 to 0.79; P < .001), a reduction of complications of MI (RR, 0.70; 95% CI, 0.62 to 0.80; P < .001), and also a reduction in the incidence of major bleeding (RR, 0.72; 95% CI, 0.56 to 0.93; P = .01). Such results were corroborated by others. In another meta-analysis, the combination of LMWH with a GPI was considered the first choice for efficacy and the third choice for safety behind bivalirudin and UFH ( Table 18-4 ). Authors also mentioned that the bleeding risk could be reduced by using a high-rate radial approach, as was used in ATOLL and in routine practice in most European countries (see also Chapter 17 ). This combination was considered by the authors of the meta-analysis to be the best approach, balancing efficacy with preserved safety ( Figure 18-e1 ).
