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 Primary Angioplasty and Stenting for Acute Myocardial Infarction.

The evolution of the management of acute myocardial infarction (MI) has been one of the crowning achievements of modern medicine. At the turn of the twentieth century, MI was an often-fatal condition. Prolonged bed rest served as the principal treatment modality. Over the past century, insights into the pathophysiology of MI revolutionized approaches to management, with the sequential use of surgical coronary artery revascularization, thrombolytic therapy, and percutaneous coronary intervention (PCI) with primary coronary angioplasty, and placement of intracoronary stents. The benefits of prompt revascularization inspired systems of care to provide rapid access to PCI. This review provides a historical context for our current approach to primary PCI for acute MI.

From fibrinolysis to the plasminogen-plasmin system and beyond: a remarkable growth of knowledge, with personal observations on the history of fibrinolysis.

Great advances have been made in our understanding of the fibrinolytic system from the initial discovery of proteolysis of fibrin by plasmin to the multifaceted and complex role of the plasminogen-plasmin (P-P) system. We now know that the P-P system is composed of several serine proteases and their inhibitors (serpins). This system is involved in many physiological functions, including embryogenesis, cell migration, and wound healing. They also play an important role in the pathogenesis of many diseases, including atherosclerosis, obesity, cancer, and even autoimmune disorders, and neuronal degeneration. Knowledge of their role in cancer enables their use as a prognostic factor. Therapeutic use of various forms of proteases derived from this system has been employed as thrombolytic agents. In addition, small molecules designed to inhibit many of the components of the P-P system are now available for clinical trial, aimed at treatment of these various disorders. The history of such remarkable development of our knowledge on fibrinolysis is reviewed in this article.

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.

Thrombolytic agents for acute ischaemic stroke treatment: the past, present and future.

Despite advances in the diagnosis and treatment of acute ischaemic stroke in the past two decades, stroke has remained the third cause of mortality and the single leading cause of disability worldwide. The immediate goal of acute ischaemic stroke therapy is to salvage the ischaemic penumbra through recanalisation of the occluded cerebral blood vessel. This is currently achieved through thrombolytics, which are pharmacological agents that can break up a clot blocking the flow of blood. To date, the only approved thrombolytic for treatment of acute ischaemic stroke is recombinant tissue plasminogen activator (alteplase, rt-PA), however, alteplase is substantially underused because of concerns regarding adverse bleeding risk. This limitation has fuelled the search for other thrombolytic agents, which display greater fibrin dependence and selectivity, but lack detrimental effects within the central nervous system. Development of alternative fibrinolytic agents that might be easier and safer to administer could lead to wider acceptance and use of thrombolytic therapy for stroke. Although other thrombolytic agents (e.g. streptokinase) have failed to show benefit over alteplase, there is still on-going research in search of alternative agents with higher target specificity and better safety profile. The potential thrombolytic agents with trials in progress include desmoteplase, tenecteplase, reteplase, plasmin and microplasmin. This review summarises current therapies with thrombolytics (e.g. alteplase and urokinase), their limitations and side effects, and also discusses ongoing clinical studies with the various potential emerging thrombolytic agents.

The history and historical treatments of deep vein thrombosis.

Deep vein thrombosis (DVT) is a common disease. However, unlike that of varicose veins, which have been depicted since antiquity in art and literature, its description was more recent in the history of medicine. The first well-documented case of DVT was reported during the Middle Ages: in 1271, Raoul developed a unilateral edema in the ankle, which then extended to the leg. The number of reported DVT cases steadily increased thereafter, particularly in pregnant and postpartum women. During the first half of the 20th century, well before the discovery of anticoagulants, many therapeutic approaches were used, and arose from the pathologic hypotheses that prevailed at their time. Despite the development of anticoagulants, and the fact that they were thought to dramatically decrease DVT mortality, numerous complementary treatments have also been developed during the last 50 years: they include vena cava clips and surgical thrombectomy, and are intended to decrease mortality or to prevent late complications. Most of these treatments have now been abandoned, or even forgotten. In this review, we recall also the discovery and the use of vitamin K antagonists and heparin, which have constituted the mainstay of treatment for decades. We also bring some perspective to historical aspects of this disease and its treatment, notably regarding elastic compression and early mobilization, but also abandoned and complementary treatments. In these times of change regarding DVT treatment, mainly marked by the arrival of new oral anticoagulants, efforts of physicians through the ages to treat this common disease provide a beautiful example of the history of knowledge.

The Thrombolysis in Myocardial Infarction (TIMI) Study Group experience.

The Thrombolysis in Myocardial Infarction (TIMI) study group, an academic research organization, was formed in 1984 with initial support from the National Heart, Lung, and Blood Institute. Its initial goal was to compare the effects of the then-new thrombolytic agent, recombinant tissue plasminogen activator, with streptokinase. The TIMI study group has remained active since then and has completed 50 multicenter clinical trials. The TIMI network now collaborates with more than 1000 separate sites in 45 countries on 5 continents. In addition to thrombolytic agents, TIMI has studied antithrombotic, antiplatelet, anti-ischemic, lipid lowering, and anti-inflammatory drugs. TIMI has also established robust biomarker and pharmacogenetics programs, and has devised a panel of risk assessment scores that are widely used. TIMI is currently conducting 7 large trials worldwide on novel agents designed to reduce the morbidity and mortality of a variety of cardiovascular disorders.

Thrombolytics and myocardial infarction.

Coronary artery disease is the single leading cause of death in the United States. Occlusion of the coronary artery was identified to be the cause of myocardial infarction almost a century ago. Following a series of investigations, streptokinase was discovered and demonstrated to be beneficial for the treatment of patients with acute myocardial infarction in terms of reducing short- and long-term mortality. Newer agents including tissue plasminogen activators such as alteplase, reteplase, tenecteplase were developed subsequently. In the present era, thrombolytic therapy and primary percutaneous coronary intervention has revolutionized the way patients with acute myocardial infarction are managed resulting in significant reduction in cardiovascular death. This article provides an overview of the various thrombolytic agents utilized in the management of patients with acute myocardial infarction.

Hybrid procedures for acute limb ischemia.

The most efficient treatment for acute arterial embolism is operative embolectomy using Fogarty's balloon catheter, especially if a single large artery is involved. Unfortunately, although the early surgical success of arterial thromboembolectomy often seems acceptable, the early clinical outcome still remains unsatisfactory. This may be related to the incomplete restoration of perfusion (i.e., residual thrombus in distal vessels not reached by the balloon catheter thromboembolectomy), propagation of residual thrombi or presence of underlying steno-occlusive lesions. In such a situation a meticulous intraoperative assessment of the adequacy of clot removal is decisive. Residual thrombus, chronic atherosclerotic disease and even vessel injuries secondary to balloon catheter passage can be corrected by endovascular techniques (hybrid procedures). The combination of surgical and endovascular options may overcome the limitations that characterize the traditional approach, and it is likely that in the future many treatments will be a mix of techniques that can be performed by vascular surgeons in the operating room or in a dedicated endovascular suite. This review article summarizes the hybrid treatment options for acute arterial occlusion caused by either embolism or local thrombosis.

Sonothrombolysis: an emerging modality for the management of stroke.

OBJECTIVE: Ischemic stroke and intracranial hemorrhage remain a persistent scourge in Western civilization. Therefore, novel therapeutic modalities are desperately needed to expand the current limitations of treatment. Sonothrombolysis possesses the potential to fill this void because it has experienced a dramatic evolution from the time of early conceptualization in the 1960s. This process began in the realm of peripheral and cardiovascular disease and has since progressed to encompass intracranial pathologies. Our purpose is to provide a comprehensive review of the historical progression and existing state of knowledge, including underlying mechanisms as well as evidence for clinical application of ultrasound thrombolysis. METHODS: Using MEDLINE, in addition to cross-referencing existing publications, a meticulous appraisal of the literature was conducted. Additionally, personal communications were used as appropriate. RESULTS: This appraisal revealed several different technologies close to broad clinical use. However, fundamental questions remain, especially in regard to transcranial high-intensity focused ultrasound. Currently, the evidence supporting low intensity ultrasound's potential in isolation, without tissue plasminogen, remains uncertain; however, possibilities exist in the form of microbubbles to allow for focal augmentation with minimal systemic consequences. Alternatively, the literature clearly demonstrates, the efficacy of high-intensity focused ultrasound for independent thrombolysis. CONCLUSION: Sonothrombolysis exists as a promising modality for the noninvasive or minimally invasive management of stroke, both ischemic and hemorrhagic. Further research facilitating clinical application is warranted.

Systems of care for ST-segment elevation myocardial infarction: impact of different models on clinical outcomes.

ST-segment elevation myocardial infarction (STEMI) is one of the greatest medical emergencies, for which organization of care has a determinant impact on patient outcomes. The purpose of this paper is to review systems of care for STEMI patients. Although primary percutaneous coronary intervention (PCI) is the preferred option for patients with STEMI, offering easy and emergent access to this procedure often remains difficult because of geographic and diverse structural difficulties. intravenous fibrinolysis, especially when administered early after symptom onset and as part of a pharmacoinvasive strategy (i.e., followed by rapid coronary angiography with PCI when necessary), offers a reasonable therapeutic option in selected cases and has yielded satisfactory clinical results. Network organization is central for optimizing patient care at the acute stage of myocardial infarction. This review describes different clinical experiences with network implementation both in Europe and in North America. In all instances, early recognition of STEMI and, particularly in the pre-hospital setting, shortening time delays is central for the achievement of optimal clinical results. Overall, the encouraging results described in the models presented here, as diverse as they might be, should be an encouragement to promote and implement regional protocols according to the specific local constraints and to monitor their effectiveness by recording simple quality indicators in ongoing registries.

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.

A history of pulmonary embolism and deep venous thrombosis.

Although enormous progress has been made in understanding the physiology of pulmonary embolism, developing new diagnostic modalities and strategies, and constant refinement in the use of heparin therapy and thrombolytic therapy, venous thromboembolism remains a common and lethal process. As the history of this disease illustrates, advances continue to be made and it is anticipated that with newer diagnostic studies and anticoagulants under development, diagnosis and treatment of pulmonary embolism will continue to improve.