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 first 3500 years of aspirin history from its roots - A concise summary.

Aspirin is currently the most widely used drug worldwide, and has been clearly one of the most important pharmacological achievements of the twentieth century. Historians of medicine have traced its birth in 1897, but the fascinating history of aspirin actually dates back >3500 years, when willow bark was used as a painkiller and antipyretic by Sumerians and Egyptians, and then by great physicians from ancient Greece and Rome. The modern history of aspirin precursors, salicylates, began in 1763 with Reverend Stone - who first described their antipyretic effects - and continued in the 19th century with many researchers involved in their extraction and chemical synthesis. Bayer chemist Felix Hoffmann synthesized aspirin in 1897, and 70 years later the pharmacologist John Vane elucidated its mechanism of action in inhibiting prostaglandin production. Originally used as an antipyretic and anti-inflammatory drug, aspirin then became, for its antiplatelet properties, a milestone in preventing cardiovascular and cerebrovascular diseases. The aspirin story continues today with the growing evidence of its chemopreventive effect against colorectal and other types of cancer, now awaiting the results of ongoing primary prevention trials in this setting. This concise review revisits the history of aspirin with a focus on its most remote origins.

The aspirin story - from willow to wonder drug.

The story of the discovery of aspirin stretches back more than 3500 years to when bark from the willow tree was used as a pain reliever and antipyretic. It involves an Oxfordshire clergyman, scientists at a German dye manufacturer, a Nobel Prize-winning discovery and a series of pivotal clinical trials. Aspirin is now the most commonly used drug in the world. Its role in preventing cardiovascular and cerebrovascular disease has been revolutionary and one of the biggest pharmaceutical success stories of the last century.

Living history of medicine: vascular scaffolding, from dream to reality.

Following the launch of balloon angioplasty in 1977, its deficiencies-abrupt occlusion requiring emergency bypass surgery in one in twenty attempts and recurrence in one in three cases-became soon apparent. The attempts to eliminate the element of chance from this otherwise highly attractive technique resulted in the concept of intra-vascular scaffolding. Following the inception of self-expanding mesh stents made from stainless steel and extensive bench testing and animal experiments, the first clinical data were obtained in Switzerland almost 30 years ago in 1986 with promising, albeit not undisputed results. Technical improvements including potent platelet inhibitors have made the technique a cornerstone of catheter-treatment of vascular disease. This paper gives an account of the sometimes difficult beginnings of coronary and non-coronary stenting at the University of Lausanne in Switzerland.

A critical reappraisal of aspirin for secondary prevention in patients with ischemic heart disease.

Aspirin was established more than a quarter century ago as an evidence-based therapy to reduce recurrent cardiovascular events in patients with coronary artery disease based on limited data by contemporary standards. Indeed it is unclear how regulatory agencies would define the optimal dose or duration of aspirin therapy if assessed in the current era. Subsequent clinical investigation has focused on the addition of antithrombotic agents on top of baseline aspirin therapy in the acute and chronic setting to reduce patient's risk of further ischemic events, at the cost of increased bleeding complications. The current armamentarium of potent and predictable antiplatelet and antithrombotic agents has ushered in a new era where clinicians and scientists are contemplating withdrawal of previously established agents to minimize bleeding risk while sustaining efficacy; indeed, subtraction may lead to the next advance in the treatment of acute and chronic ischemic vascular disease.

Historical Hallmarks of Anticoagulation and Antiplatelet Agents.

Thrombosis is a well known phenomenon among physicians since antiquity. A variety of peculiar agents, such as leeches and bark, were used to prevent it. Hirudin was used during the 19th century. The next eon, heparin, strepokinase, urokinase, TPA, dicumarol, warfarin, aspirin, ticlopidine, Clopidogrel, SSHA and SP54 provoked huge advances in anticoagulation. During 21st century with the use of fondaparinux, dabigatran, rivaroxaban and Ticagrelor antithrombotic prevention and therapeutic interaction entered an era of medical challenges. Although the risk after a thrombotic episode is now highly reduced, blood clots still present damaging or even lethal consequences in human organisms and further research is strongly recommended.

La evolución de la terapia antiplaquetaria / The evolution of antiplatelet therapy

Las plaquetas juegan un rol importante en la fisiopatología de la trombosis coronaria. Los antagonistas de los receptores de ADP actúan en la superficie de las plaquetas inhibiendo la activación y agregación plaquetaria en pacientes que tienen una ruptura espontanea o cuando se realiza una intervención coronaria percutanea atenuando el inicio de una trombosis aguda. La adicion del clopidogrel al acido acetil salicilico fue un cambio revolucionario en el tratamiento del Sindrome Coronario Agudo. Sin embargo, a pesar de los resultados obtenidos con esta asociación, el clopidogrel ha mostrado tener ciertas limitaciones incluyendo una variabilidad en el efecto inhibitorio antiplaquetario, que han sido asociados con eventos adversos de tipo trombotico. Por esta razón se han realizado nuevos estudios de antagonistas de los receptores P2Y12 siendo los mas importantes los realizados con el Prasugrel y Ticagrelor, que demostraron mayor inhibición plaquetaria que el clopidogrel. Sin embargo esta potente acción inhibitoria viene asociado con un incremento en las complicaciones hemorrágicas, siendo necesario una adecuada estratificación de riesgo trombotico /y o hemorrágico en cada paciente. El éxito en la terapia bloqueadora de los receptores P2Y12 han reducido el uso de los Inhibidores de Glicoproteina IIB/IIIA, usandose en forma complementaria en pacientes con alto riesgo trombotico o en pacientes cuya angiografía evidencia trombos residuales.

Historical lessons in translational medicine: cyclooxygenase inhibition and P2Y12 antagonism.

The development of drugs that inhibit platelets has been driven by a combination of clinical insights, fundamental science, and sheer luck. The process has evolved as the days of stumbling on therapeutic gems, such as aspirin, have long passed and have been replaced by an arduous process in which a drug is designed to target a specific protein implicated in a well-characterized pathophysiological process, or so we would like to believe. The development of antiplatelet therapy illustrates the importance of understanding the mechanisms of disease and the pharmacology of the compounds we develop, coupled with careful clinical experimentation and observation and, yes, still, a fair bit of luck.

Clinical use of aspirin in ischemic heart disease: past, present and future.

Aspirin is an antiplatelet drug, inhibiting the cyclooxygenase activity of platelet prostaglandin H synthase-1 and almost complete suppressing platelet capacity to generate the prothrombotic and proatherogenic thromboxane A2. Antiplatelet therapy with aspirin reduces the risk of serious vascular events by about a quarter in patients who are at high risk because they already have occlusive vascular disease. However, the inhibition of thromboxane-dependent platelet function by aspirin is effective for the prevention of thrombosis, but is also associated with excess bleeding, although the absolute increase in major gastrointestinal or other major extracranial bleeds is an order of magnitude smaller. For secondary prevention of vascular events, the benefits of aspirin therapy substantially exceed the risks. Therefore, aspirin is a cornerstone of antithrombotic therapy in acute coronary syndromes, in chronic ischemic heart disease and in percutaneous coronary intervention. On the other hand, the role of aspirin in primary prevention remains uncertain and it is still debated, because the absolute risk of vascular complications is the major determinant of the absolute benefit of antiplatelet prophylaxis and the reduction in vascular events needs to be weighed against any increase in major bleeds. Future data from ongoing studies will help us to identify people at high vascular risk who take advantage from aspirin therapy for primary prevention or will indicate if specific category of high risk patients, like patients with diabetes, could be better protected from an increase in the frequency of aspirin administration.

Historical observations on the discovery of platelets, platelet function testing and the first antiplatelet agent.

An understanding of the historical paths that have lead to our current state of knowledge in the field of platelet studies can be both illuminating and inspiring. Considering that the existence and function of platelets were initially described just barely over 100 years ago it is exciting to recognize how far our knowledge has advanced in such a relatively short period of time. Within 20 years of Giulio Bizzozero's definitive description of blood platelets investigators began to develop tests that could quantitate the relationship between platelets, hemostasis and bleeding, and these tests have continued to be refined ever since. At the same time, and well before the role of platelets and antiplatelet agents in cardiovascular disease was appreciated, several clinicians started using aspirin for the prevention of heart attacks. All three of these paths of research - platelet biology, platelet function testing and antiplatelet therapies - all converge on what is arguably one of the most important questions in clinical medicine today: how to best prevent arterial thrombosis. For the current and future pioneers of platelet research an understanding of how we got to where we are today will hopefully allow for a clearer and inspired vision of where we will go next.

Facts versus theories: an everlasting struggle. The Johann Jakob Wepfer Award 2010.

Rather than a complete overview of the contribution of Utrecht to stroke research, I have selected a few subjects and attempt to put these in historical context. Johann Jakob Wepfer (1620-1695) was unique in that he approached 'apoplexy' through post-mortem observations, in the tradition of Padua. However, the interpretation of his findings in haemorrhagic and especially non-haemorrhagic stroke was still heavily influenced by the authority of Galen's writings. Wepfer's category of 'serous apoplexy' assumed that extravasation of blood serum might lead to compression of brain substance and blockage of 'nerve pores' through which mental 'spirit' was supposed to flow. This notion of 'cerebral congestion' or 'cerebral hyperaemia' lived on, at least to the middle of the 20th century! The pitfalls of theorizing are also evident from recent history (the facile assumption that cerebral ischaemia occurs in the same way as leg ischaemia). By implication, similar errors may well be hidden in present ideas about stroke. Probable or possible examples are the idées reçues that 30 mg of aspirin is less efficacious in the secondary prevention of stroke than 100 mg, that vasospasm is the cause of delayed ischaemia after aneurysmal subarachnoid haemorrhage and that perimesencephalic haemorrhage is not caused by rupture of an artery. Physicians still speculate more often than they care to admit.

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.

The evolution of platelet-directed pharmacotherapy.

The evolution of platelet directed pharmacotherapy in the prevention and treatment of patients with thrombotic disorders is based soundly on a rapidly expanding knowledge of platelet biology. Traditionally viewed, throughout most of its relatively brief history in medicine, as an anucleate, passive contributor to hemostasis, a more contemporary perspective acknowledges platelets as complex, multidimensional cells that participate actively in coagulation, vascular repair, angiogenesis and thrombosis within the micro and the macro-circulatory systems. Herein, we consider platelet-directed pharmacotherapy from these fundamental, biology-based exemplars--megakaryocytes, signal transduction and the platelet--coagulation protease interface. We also highlight the emerging biopharmacology platform of oligonucleotide platelet adhesion antagonists and their complementary antidotes.

The preventive and therapeutic impact of antiplatelet agents: past and present.

Already more than two thousands years ago the Greek physician Hippocrates (V-IV century B.C.) used the extracts of the willow bark to fight fever. At the end of the eighteen hundreds the German chemist Felix Hoffmann obtained acetylsalicylic acid in stable and pure form, and from then on Aspirin (where A is the abbreviation of acetyl and Spir stands for Spirsaure, the German name of salicylic acid) has had enormous diffusion. In 1953 Lawrence Craven reported that he had successfully prescribed aspirin to hundreds of adult male patients for the non-specific prophylaxis of coronary thrombosis. Aspirin is now one of the most well-known drugs in the world, and in the last decades a large body of scientific evidence has appeared with regard to the preventive and therapeutic effects of aspirin and those of other antiplatelet agents. In fact, antiplatelet agents constitute a cornerstone in current pharmacological treatment and prophylaxis. Among the most interesting recent and beneficial areas of impact of aspirin and of other antiplatelet drugs, there are those of stroke and of coronary artery disease, and today targeted pharmacological and non-pharmacological interventions should be carefully combined to deal, preventively and therapeutically, with the cardiovascular epidemic.