Bøger af J. Morganroth

With the beginning of the 1980's it was becoming increasingly evident that the lack of approval of new cardiovascular agents for use by clinicians in the United States for the treatment of cardiovascular disorders was becoming a problem. Patients requiring medical therapy for hypertension, angina pectoris, arrhythmias, congestive heart failure, and vasospastic disorders of the coronary arteries could receive in the United States only a small number of the drugs available to physicians in the rest of the world. In fact, as the 1980's began, there was only one available beta blocking agent released by The Food and Drug Administration; and even as of this writing, no oral calcium antagonist agent. This lag, in part, has been due to the confusion of proper and expeditious methods to define safety and efficacy of such agents so that the United States regulatory agency (Food and Drug Administration) could approve the use of such agents by clinicians. The vast number of new beta blocker and calcium antagonist agents being developed, as well as the long-term use abroad of many new drugs, has raised important questions as to how relative safety and efficacy of such agents can be determined to facilitate availability in the United States.

Thus, there are now several chronic canine myocardial infarction­ ventricular tachyarrhythmia models which are available for the evaluation of new antiarrhythmic drugs (Table I). The available models fulfill many, but not all of the requirements for an ideal chronic arrhythmia model (Table 11). The sustained arrhythmias initiated in these models using programmed pacing presumably have the same localized reentrant mechanism that characterizes chronic human myocardial infarction and chronic coronary 26 artery disease. However, these models are not suitable for determining whether a new drug will abolish spontaneous ly-occurring PVCs. In addition, these models are of unproven value in the study of acute spontaneously­ occurring sudden death; although recently initiated, provocative work may shed further light on this subject. Most importantly, the available models do seem well-suited to the evaluation of new drugs intended for use in chronic coronary artery disease patients at risk for sustained reentrant ventricular tachycardia or VF. Notably, the results of preliminary electropharmacologic studies in these canine models parallel closely those findings reported in human patients with sustained life-threatening ventricu­ lar tachyarrhythmias (Table Ill). Therefore, increased use of these chronic models for new antiarrhythmic drug testing is strongly recommended. TABLE II Ideal vs Available Chronic Canine - Arrhythmia Models Ideal Available 1. (a) Arrhythmia mechanism comparable to Yes patients with chronic CAD: Reentry (b) Pathophysiology similar (e. g. , atherogenic CAD) No 2. Susceptible to: (a) spontaneous PVCs No l No (b) spontaneous VT/VF (c) inducible VT/VF Yes 3.

The Symposium on New Drugs provides for an annual forum for academic investigators, research and development personnel from the pharmaceutical and related health care industries, and members of the Food and Drug Administration to discuss important clinical research issues. The Tenth Annual Symposium on New Drugs addressed the problem of whether it was still appropriate to approve antihypertensive agents soley on the endpoint of lowering cuff blood pressure. The initial discussions at this symposium related to the approaches and methods to studying antihypertensive agents. Dr. William Frishman provided a detailed list of the new approaches to the treatment of hypertension and pointed out the many new concepts that are currently active in the development of many new antihypertensive agents. Dr. William White detailed the growing importance of ambulatory blood pressure monitoring to define hypertension and to determine the change in blood pressure due to pharmacologically active agents. Dr. Jay Cohn pointed out the flaws in using cuff blood pressure and detailed the potential virtues of using vascular compliance to identify patients requiring treatment for hypertension. Dr. Thomas Pickering also discussed the potential value of evaluating changes in left ventricular hypertrophy a finding which identifies high risk patients who need to be included in clinical trials. Dr. Michael Weber detailed the issues and suggested refinements in the approaches to clinical trial designs for antihypertensive agents and Dr. Raymond Lipicky discussed the definition of dose-duration and the role of non-Mem and Peak/Through measurements in defining an antihypertensive drug effect.

In summary, there are many animal models that are useful in selecting new antiarrhythmic drugs. The selection of which model is most idea depends upon precisely what question is being asked. The large number of experimental models used to evaluate antiarrhythmic compounds points out the inability of anyone model to define the probability of antiarrhythmic efficacy in man. It has therefore become standard practice to utilize a batter of animal models for the evaluation of new antiarrhythmic agents. Each model has its own advantages and disadvantages and it is necessary to understand each model fully in oder to evaluate experimental findings and apply them to clinical settings. We believe that the availability of the chronic myocardial infarction ventricular tachyarrhythmia model provides 1) an excellent opportunity to more precisely understand arrhythmia mechanisms, 2) to develop new techniques such as signal averaging for evaluating late low level potentials identifying hearts at high risk of sudden death 3) to identify new antifibrillatory drugs versus drugs that are effective primarily against PVC's and ventricular tachycardia 4) to identify new surgical techniques to eliminate VT/VF, and 5) to evaluate new pacing modalities including implantable cardioverters. Although all animal models are wrong, many are very useful in furthering our knowledge directed at decreasing the distressingly high mortality from heart disease. NORMAL HtART TACHYCMDIA HtART , .. '" \ I I I I I I I I I .

In Harch of 1980, we organized the first symposium on how to evaluate new antiarrhythmic agents in which the participants included members of the Cardio-Renal Division of the Food and Drug Administration, academic investigators from the United States and Abroad and directors and imple­ mentors of pharmacological research representing the pharmaceutical industry. By bringing together all three elements, it was hoped that better communication and under­ standing would ensue to more rapidly bring new cardiac agents to the American public. This goal was important since a rather limited number of antiarrhythmic agents were and are currently available to treat patients with such disorders in the United States. These agents are needed not only for the treatment of patients with sustained ventricular tachyarrhythmias which produce life-threatening hemodynamic consequences but also and in fact more potentially important as a prophylactic measure in the high risk patient subject to sudden cardiac death. This book represents the proceedings of the third of these Symposiums whose purpose was to evaluate the clinical research methodology and models used in the evaluation of ne" antiarrhythmic agents for not only acute therapeutic inter­ vention but also for the prophylaxis of sudden cardiac death. In addition, new devices have evolved over the past few years that can detect and treat life-threatening cardiac arrhythmias and the evaluation of efficacy and safety of these devices is detailed.

Although some investigators have questioned the importance and even the existence of silent myocardial ischemia, documentation presented at this two day symposium leaves little doubt about its existence and importance. It has been estimated that about 3 million of the estimated 4 million angina sufferers in the United states have frequent episodes of silent myocardial ischemia. Although it is not possible to define how many Americans die due to silent ischemia, it has been suggested that the mortality rate may exceed hundreds of thousands of victims annually. Unfortunately, there still remains a lack of definitive information as to why some ischemic events are painless. Some suggest the concept that the location and size of the myocardium at jeopardy relates to pain, that the pain threshold varies from patient to patient or that there are neurological deficits in the myocardium of some patients with silent ischemia. Abnormalities in myocardial perfusion and function can occur without pain. An interesting observation presented by several investigators has been that when a coronary artery is occluded in man, no ischemic pain is perceived for the first 30 seconds. Only after a 30 second period or so of occlusion does angina occur. An even more confusing observation is that some 30 second periods of occlusion of the same vessel in the same patient results in angina while the next occlusion can be a totally silent event.

The Symposium on New Drugs provides a forum for academic investigators, research and development personnel from the pharmaceutical industry and members of the Food and Drug Administration to discuss important clinical research issues. The Ninth Annual symposium on New Drugs addressed the problem of determining the risk versus benefit for use of three important classes of cardiovascular agents: thrombolytic, antiarrhythmic, and hypolipidemic agents. The use of thrombolytic agents has become one of the major advances in clinical intensive cardiologic care in the 1980s. While the lysis of clot(s) obstructing a major coronary artery should reverse or prevent the damage of acute myocardial ischemia and infarction, one must carefully consider the potential risks of such agents in regards to their potential benefits. The time when a thrombolytic agent should be administered to maximize benefit as well as how one defines a dose response relationship using intravenous critical care medicines were discussed as important clinical trial issues. The benefit versus risk data on currently available thrombolytic agents was reviewed and the potential roles for adjunctive agents addressed. Overall strategies regarding post- x thrombolytic care and relationships to sudden cardiac death were also detailed. The panel discussion sections provided a comprehensive view of the current thinking of the various participating groups in this symposium. Sudden cardiac death remains the number one cause of mortality in western industrialized societies.

Preceeding of the Symposium on New Drugs and Devices, held in Philadelphia, October 30-31, 1986.