Anticoagulation in Percutaneous Coronary Intervention

Introduction

The last two decades have witnessed the introduction of a number of new pharmacologic agents aimed at improving patient outcomes after percutaneous coronary intervention (PCI). Optimizing ischemic prevention while minimizing bleeding complications remains the cornerstone of contemporary pharmacologic practice. Notably, this period has seen improvements in PCI with the use of radial artery access, more potent antiplatelet P2Y ₁₂ receptor inhibitors, and the availability of bleeding risk calculators (i.e., Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines? [CRUSADE]); these advances, together with improvements in drug-eluting stent technology, have helped minimize the bleeding and ischemic risks during PCI.

Heparin, enoxaparin, and bivalirudin are the most widespread anticoagulant agents used in current PCI practice, and these form the basis of recommendations from major society guidelines. This chapter will discuss the current biologic basis of atherothrombosis and its key effector, thrombin; the pharmacology of the anticoagulant agents in current use; and the targets for future therapy. Also reviewed will be the landmark trials that support anticoagulant use in ST-elevation myocardial infarction (STEMI), non–ST-elevation myocardial infarction (NSTEMI), and elective PCI.

The Biology of Atherothrombosis

The coagulation cascade reflects the complex interplay among the coagulation proteins, platelets, and cellular phospholipid membranes of not only vascular endothelial cells but of a wide range of inflammatory cells that include monocytes and vascular smooth muscle cells. The subsequent discussion will focus on the coagulation factors that serve as targets, although modern antithrombotic regimens, additional effects on platelet-mediated thrombosis, and vascular tissue function should not be ignored.

The Central Role of Thrombin

Disruption of endothelial integrity and expression of prothrombotic molecules such as tissue factor (TF) lead to the activation of the soluble coagulation proteins ( Fig. 11.1 ). This amplifying cascade converges on the generation of activated factor X (FXa) and the prothrombinase complex, which leads to the conversion of thrombin from its parent molecule, prothrombin. Thrombin generation leads to multiple effects that influence the formation of thrombosis. Specifically, thrombin catalyzes the conversion of fibrin from fibrinogen; this enables clot formation and also activates factors V, VIII, and X; thus it promotes its own generation. In addition, via its direct effects on protease-activated receptors (PARs) 1 and 4, thrombin promotes platelet activation that leads to the expression of CD40 ligand, P-selectin, and the glycoprotein (GP) IIb/IIIa receptor as well as to the secretion of vasoactive agents that include adenosine diphosphate (ADP), serotonin, and thromboxane A ₂ (TxA ₂ ). Direct effects of thrombin on endothelial cells and smooth muscle cells result in the expression of adhesion molecules that enables platelet and leukocyte attachment, and its effect on endothelial membrane permeability contributes to the transmigration of the cellular- and cytokine-mediated inflammatory response within the vascular wall. Thrombin promotes vasodilation in the intact endothelium, and it contributes to vasoconstriction where the endothelium is damaged or denuded. Thrombin also appears to promote fibroblast cytokine production and is mitogenic ( Fig. 11.2 ).

However, thrombin has a short circulating half-life, and in the context of a normal endothelial barrier, the effects of thrombin are tightly controlled by a negative-feedback mechanism. Antithrombin is a single-chain plasma glycoprotein produced by the liver. As an inhibitor of coagulation, this molecule has the ability to bind to thrombin and FXa and activated factor IX (FIXa) in equimolar concentrations. Antithrombin’s action is increased over a thousand-fold by the binding of pentasaccharide-chain containing heparins. The pentasaccharide sequence enables the binding of heparins to antithrombin and augments the binding affinity for thrombin and the other clotting factors. Antithrombin is also activated by the glycosaminoglycan heparin sulfate found on the surface of endothelial cells. However, other pathways for the inhibition of thrombin exist and include the binding of thrombin to thrombomodulin and to protein C together with protein S. This inactivates the upstream coagulation proteins, factors Va and VIIIa, and promotes the release of tissue plasminogen activator (TPA).

Hence, thrombin plays a central effector role in the vascular response to balloon- and stent-induced vascular injury and remains an important therapeutic target for the prevention of ischemic complications during PCI. A schematic of the structure of the thrombin molecule is presented in Fig. 11.3 . Separate substrate recognition sites are involved in the binding of heparin, fibrinogen, and thrombomodulin, and the catalytic site is responsible for the serine protease activity that is blocked by the direct thrombin inhibitors.

Adverse Events Following Percutaneous Coronary Intervention

Improvements in interventional techniques and refinements in antithrombotic therapies have led to a substantial decline in the incidence of ischemic complications following PCI. Hence further iterations in antithrombotic strategies can be considered a double-edged sword, with improved prevention of ischemic complications potentially leading to an increase in bleeding complications associated with increased mortality, stroke, nonfatal myocardial infarction (MI), and stent thrombosis. The contemporary definition of PCI-related MI includes a troponin elevation more than five times the 99th percentile in patients with normal values before PCI or a rise greater than 20% if the baseline values are elevated and are stable or falling ( Table 11.1 ). Accompanying the troponin elevation must be at least one of the following three factors: (1) new symptoms or electrocardiographic (ECG) changes, (2) angiographic findings consistent with a procedural complication, or (3) imaging findings consistent with new ischemia. This definition has limitations, however, because the levels of post-PCI troponin elevation whereby long-term prognosis is affected has not been well established. The troponin values in this definition are arbitrarily chosen and lack clinical utility to predict outcome.

More recently, definitions of clinically meaningful postprocedural MI have been proposed that are more in line with levels of myocardial injury used to define post-coronary artery bypass graft (CABG) MI. These so-called clinically relevant values in patients with normal baseline biomarkers include a post-PCI creatinine kinase myocardial band (CK-MB) elevation 10 or more times the upper limit of normal (ULN) and a lower threshold five or more times the ULN in the presence of new Q-waves or left bundle branch block (LBBB). For patients with elevated CK-MB prior to PCI that is either stable or falling , an increment 10 or more times the ULN from the most recent level is considered diagnostic. The definition for those whose CK-MB level is not stable or falling includes a further rise above the most recently measured value of 10 or more times the ULN plus new ST elevation or depression plus signs consistent with a clinically relevant MI, such as new or worsening heart failure or hypotension.

Historical definitions of PCI-related MI have included CK elevation (two times the ULN) but underestimated the incidence of periprocedural MI by 40% to 50%. In an analysis of patients enrolled in the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 study, CK-MB elevation greater than or equal to three times the ULN was associated with a 3.5-fold excess risk of mortality at 12 months and accounted for 13.2% of all mortality seen by 12 months ( Fig. 11.4 ).

In one study, an isolated post-PCI troponin elevation, compared with no elevation, in patients with normal preprocedural values carried a small but increased risk of 30-day mortality (0.3% vs. 0.1%); however, this was not an independent predictor of long-term mortality. Pre-PCI troponin elevation—as well as age, diabetes, and a history of congestive heart failure and stroke—were all independent predictors of long-term mortality.

Non–CABG-related bleeding within 30 days of PCI is strongly associated with increased mortality, stroke, nonfatal MI, and stent thrombosis ( Table 11.2 ). Factors that contribute to these outcomes include reduced myocardial oxygen delivery as a result of hypotension and anemia, cessation of anti-thrombotic and anti-ischemic agents, increased myocardial oxygen demand from the systemic inflammatory response syndrome, and the adverse effects of the storage lesion in the transfusion of red blood cells. The bleeding rates after PCI in patients with acute coronary syndromes (ACSs) have been estimated to be as high as 10%, and various risk calculators have been developed. However, the definition of bleeding in the major PCI trials has varied over the last 20 years, which makes comparisons among trials more difficult. Many trials use their own definitions of bleeding, along with the commonly used thrombolysis in myocardial infarction (TIMI) and global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries (GUSTO) definitions, both originally developed to monitor bleeding complications in fibrinolytic trials. This lack of uniformity has made it more difficult to judge the effectiveness of anticoagulant therapies among trials. More recently, however, an Academic Consortium definition of bleeding has been created in an attempt to standardize trial data and better evaluate the safety and efficacy of antithrombotic therapies ( Table 11.3 ).

Pharmacology of Anticoagulant Agents Used in Current ERA Percutaneous Coronary Intervention