The Thrombin Hypothesis in ACS: A Disappointing Disconnect between Bench Data and Bedside Clinical Trials

Studies have demonstrated the efficacy and safety of unfractionated heparin and low-molecular-weight heparin in the management of patients with acute coronary syndrome. However, a common limitation of unfractionated heparin and low-molecular-weight heparin is that neither can neutralize clot-bound thrombin. To overcome this limitation of the broad heparin-based anticoagulants, novel anticoagulants targeted for both the free and clot-bound forms of thrombin (direct thrombin inhibitors), or other individual components of the coagulation cascade (eg, direct and indirect factor Xa inhibitors), were developed. These targeted anticoagulation agents showed promising results in preclinical testing and have been evaluated in large-scale clinical acute coronary syndrome trials. This review discusses the disconnect between the excellent preclinical findings obtained with these novel, targeted agents and the efficacy and safety data observed in patients with acute coronary syndrome, compared with the broader-range heparin-based anticoagulants.     

Novel Oral Anticoagulants After Acute Coronary Syndromes

Purpose

A number of novel oral anticoagulants, including direct thrombin inhibitors and direct factor Xa inhibitors, have been developed. This review discusses these agents and their respective clinical trials in patients with acute coronary syndromes.

Methods

This review discusses the results of phase 2 and 3 clinical trials with novel oral anticoagulants.

Results

Phase 2 clinical trials demonstrated that novel oral anticoagulants increase the risk of bleeding in a dose-related fashion, particularly when used in addition to dual antiplatelet therapy. What was less clear is their impact on recurrent ischemic events. In phase 3 trials, rivaroxaban was found to have a benefit on ischemic events and perhaps a greater benefit at the lower dose. The phase 3 trial with apixaban was stopped early due to increased bleeding without a meaningful reduction in ischemic events.

Conclusions

Novel oral anticoagulants represent a promising, potentially beneficial treatment for patients with a recent acute coronary syndrome but come with a risk of bleeding. The benefits and risks of these agents will need to be carefully weighed and may depend on both patient risk and concomitant therapy. Additional research is needed to determine how to best integrate these medications into the care of patients with acute coronary syndromes.     

Stroke prevention in patients with atrial fibrillation—anticoagulation strategy 2012

Vitamin K antagonists have been recommended as the only available oral anticoagulants for stroke prevention in patients with atrial fibrillation for many years. Despite their proved effectiveness, there are several limitations and drawbacks of this therapy. Recently three major clinical trials of novel oral anticoagulants clinical trials have been published. Dabigatran, a direct thrombin inhibitor, as well as rivaroxaban and apixaban, direct Xa factor inhibitors, were found to have at least noninferior efficacy and safety in comparison to vitamin K antagonists for stroke prevention in patients with non-valvular fibrillation. These novel oral anticoagulants may constitute a valuable alternative to vitamin K antagonists.     

Practical issues, limitations, and periprocedural management of the NOAC’s

The recent introduction of new oral anticoagulants or novel target specific oral anticoagulants (TSOA’s) is likely to have a major impact in the years ahead. Many large clinical trials have been published in the past few years showing these agents are generally safe and effective in several clinical settings including acute venous thromboembolic disease, prophylaxis in the postoperative setting, prevention of thromboembolism in patients with atrial fibrillation, and in the management of acute coronary syndromes. Reported rates of overall and intracranial bleeding are lower compared to oral vitamin K antagonists. Other major advantages of oral direct thrombin inhibitors (dabigatran) and Xa inhibitors (rivaroxaban and apixaban) include rapid onset and offset of action and predictable pharmacodynamics with relatively wide therapeutic window allowing for unmonitored drug use. The relatively short half-life, rapid onset of action, and predictable pharmacokinetics should simplify periprocedural use of these agents. In this review we focus on some practical issues related to TSOA’s including some limitations, potential complications, considerations to be made for certain patient populations, periprocedural management and issues pertaining to transition to and from these novel agents.     

Adjunctive pharmacologic therapy in percutaneous coronary intervention: part II anticoagulant therapy

Pharmacological adjuvant therapies to protect against procedure-related thrombotic complication are indispensable during percutaneous coronary intervention. In addition to antiplatelet therapy, use of anticoagulants to prevent acute thrombotic complication during percutaneous coronary intervention is essential. Besides unfractionated heparin (UFH), new anticoagulants have been developed and compared with UFH. Low-molecular weight heparins, direct thrombin inhibitors (e.g. bivalirudin), and recently developed agents such as fondaparinux (a factor Xa inhibitor) provide new alternatives to conventional UFH.     

Argatroban

Antithrombotic and antiplatelet therapies are the cornerstones of management of cardiovascular disorders today. Due to the safety and efficacy limitations of the classic antithrombotic, unfractionated heparin, considerable effort has been directed at developing novel anticoagulants. Direct thrombin inhibitors as a class of drugs offer inhibition of clot-bound as well as fluid-phase thrombin and a more predictable anticoagulant response. Specifically, argatroban, a synthetic small molecule direct thrombin inhibitor, selectively inhibits the catalytic site of thrombin in a reversible manner. Overall, argatroban's short half-life, ease of monitoring with an activated partial thromboplastin time, and safety in renal failure patients make this drug the preferable mode therapy for prevention of thrombosis in heparin-induced thrombocytopenia. The role of adjunctive argatroban therapy in acute coronary syndromes and during percutaneous coronary intervention is currently being studied.     

New anticoagulant treatments to protect against stroke in atrial fibrillation

Warfarin has long been the 'gold standard' of oral anticoagulation for stroke prevention in atrial fibrillation (AF). Recently, the oral direct thrombin inhibitors and direct factor Xa inhibitors have emerged as attractive alternatives to warfarin and have already changed the landscape of stroke prevention in AF. The new anticoagulants have important advantages over warfarin. Despite their impressive performance in clinical trials, their long-term efficacy and safety still require evaluation in 'real-world' clinical practice. In this review, the emerging role of the new oral anticoagulants for stroke prevention in patients with AF is discussed.     

New anticoagulants

Anticoagulants are pivotal agents for prevention and treatment of thromboembolic disorders. Limitations of existing anticoagulants, vitamin K antagonist and heparins, have led to the development of newer anticoagulant therapies. These anticoagulants have been designed to target specific coagulation enzymes or steps in the coagulation pathway. New anticoagulants that are under evaluation in clinical trials include: (1) inhibitors of the factor VIIa/tissue factor pathway; (2) factor Xa inhibitors, both indirect and direct; (3) activated protein C and soluble thrombomodulin; and (4) direct thrombin inhibitors. Although most of these are parenteral agents, several of the direct inhibitors of factor Xa and thrombin are orally active. Clinical development of these therapies often starts with studies in the prevention of venous thrombosis before evaluation for other indications, such as prevention of cardioembolism in patients with atrial fibrillation or prosthetic heart valves. At present, the greatest clinical need is for an oral anticoagulant to replace warfarin for long-term prevention and treatment of patients with venous and arterial thrombosis. Ximelagatran, an oral direct thrombin inhibitor, is the first of a series of promising new agents that might fulfill this need. Large phase 3 trials evaluating ximelagatran for the secondary prevention of venous thromboembolism and prevention of cardioembolic events in patients with atrial fibrillation have been completed.     

Drug and dietary interactions of warfarin and novel oral anticoagulants: an update

Clinicians and patients around the world have been intrigued by the concept of developing an oral anticoagulant with a broad therapeutic window and few drug and dietary interactions that can be administered at fixed doses with no or minimal monitoring. The recently approved oral direct thrombin inhibitor dabigatran, along with the emerging oral anti-factor Xa inhibitors, rivaroxaban, apixaban, and edoxaban, have been developed to address many of the shortcomings of warfarin therapy. As warfarin is associated with extensive food and drug interactions, there is also a need to consider such interactions with the new oral anticoagulants. While to date few drug and dietary interactions have been reported with the new oral anticoagulants, it is still early in their development and clinical use cycle. Pharmacokinetic and pharmacodynamic profiles will have to be closely accounted for when determining the likelihood of a potential drug interaction prior to therapy initiation. As the list of drugs and supplements that interact with warfarin is continuously expanding, and the knowledge on drug interactions with the novel oral anticoagulants is still in its infancy, clinicians need to be vigilant when initiating any of these agents or when any changes in the patient’s medication profile occur and perform a close screening for potential drug and dietary interactions. The objective of this paper is to give an update on drug and dietary interactions with warfarin and the novel oral anticoagulants, dabigatran, rivaroxaban, apixaban, and edoxaban.     

Oral Anticoagulant Use Around the Time of Atrial Fibrillation Ablation: A Review of the Current Evidence of Individual Oral Anticoagulant Use for Periprocedural Atrial Fibrillation Ablation Thromboembolic Prophylaxis

Atrial fibrillation is the most common arrhythmia and ablation is becoming more prevalent as a treatment option. Appropriate treatment of atrial fibrillation mandates thromboembolic prophylaxis, and atrial fibrillation ablation periprocedural management of oral anticoagulation is paramount because of the unique susceptibility for thromboembolism that exists for a patient undergoing ablation. Uninterrupted warfarin therapy is the current standard approach for periprocedural atrial fibrillation anticoagulation. Novel oral anticoagulants, including direct thrombin and factor Xa inhibitors, are being used more frequently for thromboembolic prophylaxis in atrial fibrillation patients, but the best strategy for using novel oral anticoagulants in periprocedural anticoagulation is unknown. Optimal periprocedural anticoagulation management strategies with oral anticoagulants, limitations of using novel oral anticoagulants, and future directions in this field are discussed.     

Intracoronary macrothrombus formation during percutaneous coronary intervention despite optimal activated clotting time using bivalirudin--a case report

The occurrence of intracoronary thrombus during percutaneous coronary intervention (PCI) is a well-known complication. It has been estimated that it complicates approximately 6% of all coronary procedures. Patients at highest risk for this complication include those with acute ischemic syndromes or with angiographically apparent thrombus. Since the development of PCI, intravenous unfractionated heparin (UFH) has remained the primary antithrombotic therapy for the prevention of periprocedural ischemic complications. The availability of a rapid "point of care' test for dose individualization (the activated clotting time [ACT]) has facilitated this process. Other forms of antithrombotic therapies such as direct thrombin inhibitors or low-molecular-weight heparin have been proposed as more effective anticoagulants during PCI. Bivalirudin is a direct thrombin inhibitor proven to decrease post-PCI ischemic complication rate compared with UFH and have a lower vascular complication rate compared with glycoprotein IIb/IIIa receptor antagonists. We herein report a case of acute macrothrombus formation during PCI despite adequate ACT achieved with bivalirudin.     

Anticoagulants in coronary artery disease

Anticoagulant therapy for acute coronary syndromes is becoming more complex as newer agents are added to unfractionated heparin and warfarin. The anticoagulants used in current clinical practice are low molecular weight heparins, direct thrombin inhibitors, and heparinoids. Properties of and recent clinical trial data regarding these newer anticoagulants are reviewed in reference to current American College of Cardiology/American Heart Association guidelines.     

A Review of the Role of Anticoagulation in the Treatment of Peripheral Arterial Disease

Peripheral arterial disease (PAD) is a major medical/surgical problem associated with high risk for coronary heart disease (CHD). Anticoagulation plays a significant role in the management of the PAD patient. However, evidence-based medicine supports only select anticoagulants, mainly antiplatelet agents. The available anticoagulant classes, their individual medications, and the mechanisms of action are described. Dextran 40, platelet glycoprotein (GP) IIb/IIIa receptor antagonists, direct thrombin (factor IIa, FIIa) inhibitors, and factor Xa (FXa) inhibitors do not, at this juncture, appear to have a significant role to play in the PAD patient. Aspirin has been used in PAD patients for a few decades, as has warfarin, but the role of warfarin is very limited. An attempt has been made to place each medication and its function in context all the way to the present with oral direct thrombin (FIIa) and FXa inhibitors described. These inhibitors may ultimately play an, as yet, undefined role in PAD. Specific use of anticoagulants in PAD patients is described and aspirin still stands out as a fundamental therapy. The thienopyridines, especially clopidogrel, have their established place and there is some evidence for benefit from the use of clopidogrel in dual therapy with aspirin. Dipyridamole, especially with aspirin as dual therapy, and cilostazol also have their evidence-based niches. The main role played by warfarin is for the patient with a vein graft in the arterial circulation. Heparin retains significant procedural importance. For now, Class I, Level of Evidence A center around aspirin for the PAD patient with clopidogrel, an alternative agent.     

Newer anticoagulants in cardiovascular disease: a systematic review of the literature

Vitamin K antagonists (VKAs) such as warfarin have traditionally been the major therapeutic option for anticoagulation in clinical practice. VKAs are effective and extensively recommended for the prevention of venous and arterial thromboembolism in cardiovascular disease. Despite its effectiveness, warfarin is limited by factors such as a narrow therapeutic index, drug-drug interactions, food interactions, slow onset and offset of action, hemorrhage, and routine anticoagulation monitoring to maintain therapeutic international normalized ratio. During the last 2 decades, the approval of anticoagulants, such as low-molecular-weight heparins, indirect factor Xa inhibitors (eg, fondaparinux), and direct thrombin inhibitors (eg, argatroban, lepirudin, and desirudin), have expanded the number of available antithrombotic compounds with additional targets within the anticoagulation pathway. Although these medications offer several potential therapeutic advantages, they all require parenteral or subcutaneous administration and are substantially more expensive than VKAs. Thus, VKAs, despite several limitations, have remained the major option for most patients requiring chronic anticoagulation. These limitations have prompted interest in the development of newer oral anticoagulants. Novel anticoagulants targeting inhibition of factor Xa and thrombin (factor IIa) have now been incorporated into clinical practice based on the results of large randomized clinical trials, with the recent U.S. Food and Drug Administration approval of dabigatran for stroke prevention in atrial fibrillation and rivaroxaban for deep vein thrombosis and stroke prevention in atrial fibrillation, with multiple other agents in various stages of development for these and other indications. This review discusses the pharmacological properties, clinical results, and therapeutic applications of novel and new anticoagulants, thereby providing an outline for the future of anticoagulation in cardiovascular disease.     

New anticoagulants and their potential impact on the treatment of thromboembolic disease

Traditional anticoagulants have drawbacks that make them complex to manage, limit their usefulness, and increase the possibility of adverse events. New anticoagulants are being developed that directly target a single coagulation factor. The agents have improved pharmacokinetics and pharmacodynamics and may not need coagulation monitoring. In addition, many are available orally. Agents that target factor Xa or factor IIa are the most advanced in development and of greatest interest. Fondaparinux and idraparinux are parenteral, specific, indirect, factor Xa inhibitors that have a mechanism of action similar to that of heparin. Idraparinux has a prolonged half-life and is dosed once weekly. Razaxaban is a small-molecule, oral, direct FXa inhibitor with demonstrated efficacy in orthopedic surgery for primary prevention of venous thromboembolism. Other oral Xa inhibitors are entering clinical trials. Ximelagatran is an oral factor IIa or thrombin inhibitor with documented efficacy for primary prevention of venous thromboembolism in orthopedic surgery, for the acute and chronic treatment of deep venous thrombosis and stroke prevention in atrial fibrillation. Other oral IIa inhibitors are entering clinical trials. Many of these agents will have a profound effect on the treatment of venous thromboembolism potentially resulting in reduced costs, improved patient satisfaction with treatment, and greater use of selected indications.     

Pharmacology,benefits, unaddressed questions,and pragmatic issues of the newer oral anticoagulants for stroke prophylaxis in non-valvular atrial fibrillation and proposal of a management algorithm

This systematic review aims to provide an update on pharmacology, efficacy and safety of the newer oral direct thrombin and factor Xa inhibitors, which have emerged for the first time in ~ 60 years as cogent alternatives to warfarin for stroke prophylaxis in non-valvular atrial fibrillation. We also discuss on four of the most common clinical scenarios with several unsolved questions and areas of uncertainty that may play a role in physicians' reluctance to prescribe the newer oral anticoagulants such as 1) patients with renal failure; 2) the elderly; 3) patients presenting with atrial fibrillation and acute coronary syndromes and/or undergoing coronary stenting; and 4) patients planning to receive AF ablation with the use of pulmonary vein isolation. New aspects presented in current guidelines are covered and we also propose an evidence-based anticoagulation management algorithm.     

Advances in adjunctive pharmacological therapy for percutaneous coronary interventions

All percutaneous interventions disrupt atherosclerotic plaque and denude the endothelium. These processes stimulate both platelet aggregation and the coagulation cascade. Therefore, pharmacological treatment during percutaneous intervention is based on the use of antithrombotic agents. In addition to aspirin, whose benefit has been clearly demonstrated in all forms of ischemic heart disease, clopidogrel, given before and after cardiac catheterization, also reduces the rate of thrombosis after stent placement. Moreover, the introduction of glycoprotein IIb/IIIa inhibitors has improved the results of percutaneous revascularization, especially in high-risk patients. On the other hand, anticoagulants are essential for preventing the acute thrombotic complications that result from the invasive nature of the procedure. Low-molecular-weight heparins, direct thrombin inhibitors (e.g., hirudin and its derivatives), and recently developed pentasaccharides, which inhibit factor X, provide new alternatives to classical unfractionated heparin. These novel compounds lead to fewer hemorrhagic complications than unfractionated heparin and do not require such extensive monitoring. Finally, new antiproliferative agents, such as oral rapamycin, have been introduced to reduce the rate of coronary restenosis during follow-up.     

Clinician Update: Direct Thrombin Inhibitors in Acute Coronary Syndromes

Antithrombotic therapy has become the cornerstone of the treatment for atherosclerotic cardiovascular disease. Unfractionated heparin (UFH) has been the thrombin inhibitor of choice for decades. UFH, however, has its deficiencies. To overcome these problems several direct thrombin inhibitors (DTIs) have been developed. These agents are capable of inactivating clot-bound thrombin more efficiently, and provide more predictable and safer anticoagulation in patients with of acute coronary syndromes (ACS). The initial studies of hirudin and bivalirudin in the clinical settings of acute myocardial infarction (AMI), unstable angina (UA) and percutaneous coronary interventions (PCI) conducted in the early 1990s proved to be disappointing. As the knowledge of more appropriate use of these drugs progressed, there is a renewed interest in DTIs. Herein we will review the clinical studies assessing hirudin, bivalirudin and argatroban in the settings of AMI, UA and PCI.     

Universal,class-specific and drug-specific reversal agents for the new oral anticoagulants

Although there is controversy about the absolute need for a reversal agent for the new direct oral anticoagulants (DOACs), the absence of such an agent is a barrier to more widespread use of these agents. For the management of major life-threatening bleeding with the DOACs, most authorities recommend the use of four factor prothrombin complex concentrates, although the evidence to support their use in terms of improving outcomes is meager. At the present time, there are three antidotes in development and poised to enter the market. Idarucizumab is a drug-specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran. Andexanet alfa is a class-specific antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor, enoxaparin. Ciraparantag is a universal antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor, enoxaparin.     

Treatment of heparin-induced thrombocytopenia: a critical review

Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin therapy that has a high rate of morbidity (thrombosis and amputation) and mortality. In the past, a number of different anticoagulants have been used to treat HIT in an attempt to prevent these complications. More recently, direct thrombin inhibitors have become popular. This systematic review summarizes the risk for thrombosis in HIT patients when heparin therapy is stopped; evidence of the efficacy of thrombin inhibitors in patients with HIT with and without thrombosis; evidence supporting the use of thrombin inhibitors in patients with a history of HIT who require a coronary intervention procedure; and the risk for bleeding when antithrombotic agents are used.