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.

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.

Tissue-type plasminogen activator: a historical perspective and personal account.

Over the past two decades tissue-type plasminogen activator (t-PA), the main physiological plasminogen activator, has been developed as a fibrin-specific thrombolytic agent for the treatment of various thromboembolic diseases. Milestones in this development include: first purification of human t-PA from uterine tissue, elucidation of the interactions regulating physiological fibrinolysis, thus providing a molecular basis for the concept of fibrin-specific plasminogen activation, first animal models of thrombosis and pilot studies in patients supporting the therapeutic potential of t-PA, 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, mainly in patients with acute myocardial infarction (AMI), but also in patients with massive pulmonary embolism, ischemic stroke, deep vein thrombosis and peripheral arterial occlusion. Genetically modified variants of t-PA have been developed for bolus administration in patients with AMI.