Advancing the management of acute intermediate-high-risk pulmonary embolism: The enduring legacy of Professor Guy Meyer.

Only few years after the first report on diagnosing acute pulmonary embolism (PE) with pulmonary angiography, studies began to investigate the effectiveness and safety of thrombolytic therapy for achieving early reperfusion. In 1992, Guy Meyer demonstrated the fast improvement of pulmonary haemodynamics after alteplase administration; this drug has remained the mainstay of thrombolysis for PE over almost 35 years. In the meantime, algorithms for PE risk stratification continued to evolve. The landmark Pulmonary Embolism International Thrombolysis (PEITHO) trial, led by Guy Meyer, demonstrated the clinical efficacy of thrombolysis for intermediate-risk PE, albeit at a relatively high risk of major, particularly intracranial bleeding. Today, systemic thrombolysis plays an only minor role in the real-world treatment of acute PE in the United States and Europe, but major trials are underway to test safer reperfusion regimens. Of those, the PEITHO-3 study, conceived by Guy Meyer and other European and North American experts, is an ongoing randomised, placebo-controlled, double-blind, multinational academic trial. The primary objective is to assess the efficacy of reduced-dose intravenous thrombolytic therapy against the background of heparin anticoagulation in patients with intermediate-high-risk PE. In parallel, trials with similar design are testing the efficacy and safety of catheter-directed local thrombolysis or mechanical thrombectomy. Increasingly, focus is being placed on long-term functional and patient-reported outcomes, including quality of life indicators, as well as on the utilization of health care resources. The pioneering work of Guy Meyer will thus continue to have a major impact on the management of PE for years to come.

Review, historical context, and clarifications of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms.

BACKGROUND AND PURPOSE: Since Food and Drug Administration approval of intravenous tissue-type plasminogen activator (tPA) for treatment of acute ischemic stroke in 1996, it has become clear that several criteria used for exclusion from therapy were not based on actual data or operationally defined for use in clinical practice. All eligibility criteria from the National Institute of Neurological Disorders and Stroke (NINDS) recombinant tPA Stroke Study were adopted within the alteplase package insert as contraindications/warnings. Many clinicians have expressed the need for clarification and better definition of these treatment criteria. METHODS: A group of investigators who also practice as stroke physicians convened a collaborative endeavor to work toward developing more clinically meaningful and consensus-driven exclusion criteria for intravenous tPA. The first of these exclusion criteria chosen was rapidly improving stroke symptoms (RISS). We reviewed and clarified the historical context and intention with the original investigators, held e-mail discussions, convened an in-person RISS Summit, and obtained the understanding of experienced stroke physicians broadly. RESULTS: Historically, the intent of this exclusion criterion within the NINDS recombinant tPA Stroke Trial was to avoid treatment of transient ischemic attacks-who would have recovered completely without treatment. There was unanimous consensus that, in the absence of other contraindications, patients who experience improvement of any degree, but have a persisting neurological deficit that is potentially disabling, should be treated with intravenous tPA. This statement is supported from the methods established for the original NINDS trial, on the basis of detailed discussions and interviews with the former NINDS trialists. It was agreed that improvement should only be monitored for the extent of time needed to prepare and administer the intravenous tPA bolus/infusion. An explicit operational definition of RISS was developed by consensus to guide future decision making in acute stroke. There was unanimous agreement that all neurological deficits present at the time of the treatment decision should be considered in the context of individual risk and benefit, as well as the patient's baseline functional status. CONCLUSIONS: A structured framework and quantitative approach toward defining RISS emerged through expert opinion and consensus. The term, RISS, should be reserved for those who improve to a mild deficit, specifically one which is perceived to be nondisabling. This is recommended to guide decision making on intravenous tPA eligibility going forward, including the design of future studies. An additional study of patients with rapid improvement to nonmild deficits is not justified because these patients should be treated.

Thrombolytics in acute ischaemic stroke: historical perspective and future opportunities.

The discovery of thrombolytic agents goes back to the 1930s, when it was shown that substances derived from bacteria (streptokinase, staphylokinase), tissue (fibrinokinase), urine (urokinase) or bat saliva could activate the fibrinolytic system. The potential to treat arterial thrombosis with plasmin was recognized, but it was not until 1958 that its first use in acute ischaemic stroke (AIS) was described. However, since computer tomography (CT) was not available until the mid 1970s, optimal selection of patients was not possible. Early studies with streptokinase in AIS showed an increased risk of intracranial haemorrhage and lack of efficacy, which was associated with low fibrin specificity. The search for new agents with a better risk-benefit profile continued until 1979 when tissue plasminogen activator (t-PA) was discovered. In 1983 it became possible to produce recombinant t-PA (rt-PA) by expression of a cloned gene which enabled clinical trials to be started, mainly for coronary thrombolysis. In 1995, the National Institute of Neurological Disorders and Stroke study showed that rt-PA was an effective treatment for AIS, nowadays for use up to 4.5 h after onset. However, rt-PA still often fails in achieving rapid reperfusion, has relatively low recanalization rates and is associated with an increased bleeding risk. Several attempts have been made to develop thrombolytics with a better risk-benefit profile than rt-PA, but no real impact on clinical practice was observed. In 1994, it was shown that tenecteplase (rt-PA-TNK) had a higher fibrin specificity than rt-PA, but its clinical use in AIS was described only in 2005. The recently reported results of a small phase 2B trial showed significantly better reperfusion and clinical outcome with rt-PA-TNK compared to rt-PA; patients were selected by CT perfusion and angiography, and treated within 6 h after stroke onset. Currently, a phase 3 trial of rt-PA-TNK versus rt-PA is being planned in patients at an onset up to 4.5 h. The most fibrin-specific recombinant plasminogen activator desmoteplase originates from 1991, and its clinical development in AIS started in 2005. Desmoteplase is in phase 3 development for the treatment of AIS between 3 and 9 h after onset in AIS patients presenting with occlusion or high-grade stenosis.

Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor.

Apixaban (BMS-562247; 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide), a direct inhibitor of activated factor X (FXa), is in development for the prevention and treatment of various thromboembolic diseases. With an inhibitory constant of 0.08 nM for human FXa, apixaban has greater than 30,000-fold selectivity for FXa over other human coagulation proteases. It produces a rapid onset of inhibition of FXa with association rate constant of 20 µM⁻¹/s approximately and inhibits free as well as prothrombinase- and clot-bound FXa activity in vitro. Apixaban also inhibits FXa from rabbits, rats and dogs, an activity which parallels its antithrombotic potency in these species. Although apixaban has no direct effects on platelet aggregation, it indirectly inhibits this process by reducing thrombin generation. Pre-clinical studies of apixaban in animal models have demonstrated dose-dependent antithrombotic efficacy at doses that preserved hemostasis. Apixaban improves pre-clinical antithrombotic activity, without excessive increases in bleeding times, when added on top of aspirin or aspirin plus clopidogrel at their clinically relevant doses. Apixaban has good bioavailability, low clearance and a small volume of distribution in animals and humans, and a low potential for drug-drug interactions. Elimination pathways for apixaban include renal excretion, metabolism and biliary/intestinal excretion. Although a sulfate conjugate of Ο-demethyl apixaban (O-demethyl apixaban sulfate) has been identified as the major circulating metabolite of apixaban in humans, it is inactive against human FXa. Together, these non-clinical findings have established the favorable pharmacological profile of apixaban, and support the potential use of apixaban in the clinic for the prevention and treatment of various thromboembolic diseases.

The tissue-type plasminogen activator story.

Milestones in the development of tissue-type plasminogen activator (t-PA) as a fibrin-specific thrombolytic agent include: purification of human t-PA from the culture fluid of the Bowes melanoma cell line, elucidation of the molecular basis of fibrin-specific plasminogen activation, first experimental animal models of thrombosis, first patient (renal allograft) treated with melanoma t-PA, pilot studies in patients with acute myocardial infarction, cloning and expression of recombinant t-PA providing sufficient amounts for large scale clinical use, and demonstration of its therapeutic benefit in large multicenter clinical trials.

Current evidence and clinical implications of aspirin resistance.

Atherothrombosis, characterized by atherosclerotic plaque rupture and subsequent occlusive or subocclusive thrombus formation is the primary cause of acute ischemic syndromes involving all vascular beds and accounts for more than one-third of all deaths in the developed world. Platelet activation and aggregation constitute the most critical component in the pathophysiology of atherothrombotic disease. Aspirin is currently the most commonly used antiplatelet agent and one of the most frequently prescribed drugs, with as many as 30 million Americans on chronic aspirin regimens. Multiple well-designed prospective randomized clinical trials have demonstrated aspirin's efficacy in both primary and secondary prevention of a wide variety of entities that the atherothrombotic disease spectrum encompasses, such as cerebrovascular, coronary artery, and peripheral vascular disease. Despite its proven benefit, however, a growing body of evidence suggests that up to 70% of aspirin-takers may still be at risk for atherothrombotic complications due to resistance. Patients with laboratory-confirmed aspirin resistance seem to have an almost fourfold increase in their risk for acute thrombotic episodes, which underlines the magnitude of the problem for the vascular specialist. In this article, we review the physiology of platelet activation and the role of aspirin as an antiplatelet agent; the various laboratory assays used in assessing aspirin effectiveness; and current data on aspirin resistance and its clinical implications in patients with cardiovascular disease. We also review the studies that explore this phenomenon in patients with peripheral arterial disease and discuss the optimal management options in aspirin-resistant individuals. Suggestions are advanced for the direction of future trials evaluating aspirin resistance in patients with vascular disease.

Fifty years of research on antithrombotic therapy: Achievements and disappointments.

The achievements with antithrombotic therapy over the past 50 years have been monumental and the disappointments relatively few. In this review, we will discuss, chronologically, the major developments of the two recognized classes of antithrombotics - anticoagulants and antiplatelet agents.

The discovery of aspirin's antithrombotic effects.

Aspirin has long been established as a useful analgesic and antipyretic. Even in ancient times, salicylate-containing plants such as the willow were commonly used to relieve pain and fever. In the 20th century, scientists discovered many details of aspirin's anti-inflammatory and analgesic properties, including its molecular mechanism of action. In addition, the latter half of the century brought reports that daily, low doses of aspirin could prevent myocardial infarction and stroke. This finding was first reported by Lawrence Craven, a suburban general practitioner in Glendale, California. Unfortunately, Craven's work went largely unnoticed, and decades passed before his observations were verified by clinical trial. We present Craven's story, which demonstrates the value of a single physician's commitment to lifelong learning. In addition, we summarize the work of the physicians and scientists who discovered the molecular mechanisms by which aspirin exerts its antiplatelet effects. Collectively, these discoveries exemplify the complementary roles of basic science and clinical observation in advancing medicine.

Pulmonary Embolism in 2017: How We Got Here and Where Are We Going?

In the 1970s, both the Urokinase Pulmonary Embolism and Urokinase-Streptokinase Pulmonary Embolism trials began the quest to develop thrombolytic therapy for the treatment of acute massive and submassive pulmonary embolism (PE). The goals of these studies were the immediate reduction in clot burden, restoration of hemodynamic stability, and improved survival. Major bleeding became the major barrier for clinicians to employ these therapies. From 1980s to the present time, a number of studies using recombinant tissue-type plasminogen activator for achieving these same above outcomes were completed but major bleeding continued to remain an adoption barrier. Finally, the concept of bringing the thrombolytic agent into the clot has entered the quest for the Holy Grail in the treatment of PE. This article will review all the major trials using peripheral thrombolysis and provide insight into the need for a team approach to pulmonary care (Pulmonary Embolism Response Team), standardization of pulmonary classification, and the need for trials designed for both short- and long-term outcomes using thrombolysis for selected PE populations.

The History of Antithrombotic Therapy: The Discovery of Heparin, the Vitamin K Antagonists, and the Utility of Aspirin.

The administration of intravenous heparin to postoperative patients by Barritt and Jordan reduced the incidence of fatal and nonfatal pulmonary embolism and established heparin as the standard for parenteral anticoagulation. The coumarin family of vitamin K antagonists quickly became the standard for long-term oral anticoagulation. Aspirin became a widely used antithrombotic agent after the discovery that chronic oral administration reduced the incidence of secondary strokes and myocardial infarction. This article gives a brief history of antithrombotic therapy, including the discovery of heparin, the vitamin k antagonists, and the utility of aspirin.

The origin of thrombolytic therapy.

The origin of thrombolytic therapy is briefly reviewed. It began 40 years ago with the demonstration that the injection into patients of a partially purified activator of the native plasminogen-plasmin enzyme system was capable of dissolving clotted blood and fibrinous loculations in the chest. However, the application of this form of therapy for the dissolution of intravascular thrombi had to await a series of further developments, including extensive purification of the thrombolytic agents, evidence that plasminogen activators would be more appropriate than plasmin for thrombolysis and proof, first in animals and then in humans, that thrombi could be dissolved by the systemic administration of plasminogen activators. The first study of thrombolytic therapy in acute myocardial infarction was reported in 1958. However, despite many studies conducted during the next 20 years, with encouraging reductions in mortality, thrombolytic therapy for acute myocardial infarction became established only when angiography provided visual evidence of the presence of a thrombus obstructing an infarct-related artery and of the achievement of prompt lysis with the administration of thrombolytic agents.

Thrombosis and anticoagulation.

Most of the major advances in thrombosis research have occurred in the last 50 years, reflecting progress in biomedical sciences and clinical trials methodology. Improved understanding of the mechanisms of thrombogenesis has led to the discovery of a plethora of new antithrombotic agents that target many of the key steps in blood coagulation and platelet activation. Although most of these compounds are still under development, low-molecular-weight heparins (LMWH), glycoprotein (GP) IIb/IIIa receptor antagonists, and inhibitors of the adenosine diphosphate (ADP) receptor on platelets have already established their niche in the clinic. The vessel wall has emerged as a major player, both in protecting against and in promoting thrombosis, and as we approach the new millennium, compounds are being developed that have the potential to prevent and treat thrombosis by modulating vessel wall function.

Historical overview of antithrombotic and thrombolytic therapy.

Early attempts to treat thromboembolic disorders focused on the prevention of thrombus formation, along with the prevention of extension and/or embolization of an existing thrombus. Antithrombotic therapy for these conditions included intravenous and oral anticoagulants and later antiplatelet agents, all of which remain in use today. Subsequent research sought a thrombolytic agent that could lyse a clot directly. Intravenously administered streptokinase and urokinase were found to act on the inactive proenzyme plasminogen to produce the active enzyme plasmin that could safely and effectively lyse fresh fibrin clots. These agents have proved effective for the treatment of myocardial infarction and pulmonary embolism, as well as peripheral arterial and venous thromboembolic conditions. Recent efforts have been directed toward a search for clot-specific agents that would avoid the systemic lytic state associated with the use of urokinase and streptokinase. Three clot-specific plasminogen activators are currently being evaluated: recombinant tissue-specific plasminogen activator, anisoylated streptokinase plasminogen activator complex, and pro-urokinase.

Participation versus education: the GISSI story and beyond.

Approximately 20 years ago, the Italian cardiology community realized the scientific importance and the potential impact on clinical practice of the new concept of evidence-based medicine and launched (without funds) a national megatrial, the Gruppo Italiano por lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) study. In the following 20 years, 4 GISSI trials have been carried out, and a fifth is underway. The conceptual process that followed this experience shaped the role of the medico-scientific society that sponsored these trials as an active player in research, with the public health as the common target. This process of getting together was founded on the basic principle that active participation can be much more effective and rewarding than education (a passive process). Accordingly, further studies were undertaken dealing with clinical epidemiology, observational outcome research introduced complementarily to develop lines of clinical investigation along 2 mainstreams: ischemic heart disease and heart failure. The original decision to directly sponsor countrywide research projects in critical and relevant areas of care had broader implications not only for the role of scientific societies, but more generally for the nurture of independent research, which is today widely recognized to be at risk. The articulation among experimental, observational, and evaluative protocols in which all caring physicians are allowed to be producers and authors and not simply users of knowledge can favor a cultural continuity that minimizes the risk of parallelisms and gaps between research and care.