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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.
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."
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.
In the 1980's a primary focus for intense cardiovascular research
is in the treatment of patients with acute myocardial infarction.
Although the prevalence of this syndrome has been decreasing in the
United States, still over 1.5 million patients develop myocardial
infarction per year. There is about a 20% chance of a North
American male developing myocardial in farction before the age of
65. The in-hospital mortality still remains at ap proximately
10070-15070 and advances in pharmacologic and device therapy have
allowed for the intensification of research in the treatment of
patients with acute myocardial infarction. The following
manuscripts represent the collective efforts of academic in
vestigators in the United States and abroad as well as members of
the phar maceutical industry, and the Food and Drug Administration
to address the issues involved in interventions in the acute phase
of myocardial infarction. State-of-the-art papers addressing
important topics are followed by discus sion sections which have
allowed participants to express their own viewpoints leading to a
consensus opinion. The first part of this Symposium addresses the
models of experimental myocardial infarction followed by the
important issue of how one defines myocardial infarction size. The
latter is extremely important to be certain that endpoints of
therapeutic or device interventions are objective and reproducible.
A detailed description of the pharmacological interventions to
reduce myocardial infarction size as well as newer devices to
effect mechanical and electrical disorders provide an up-to-date
summary of current opinion.
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."
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.
About 2. 5 million individuals have congestive heart fai lure in
the United States with over 400,000 new cases expected annually.
Congestive heart failure also is one of the commonest causes for
hospital admissions accounting for over 5 million hospital days per
year. Despite the early recognition of this condition and active
medical research into both mechanisms and therapy, prognosis
continues to remain dismal wi th less than a 50% expected five year
survival. In the last decade we have seen many new medical and
therapeutic options for patients with congestive heart failure
which extend beyond the use of bed rest, sodium restriction,
digitalis and diuretics. These include vasodilators of a variety of
types including the angiotensin conventional enzyme (ACE)
inhibitors. Also, many new inotropes are under active investigation
both in oral and intravenous forms. In March of 1984 a survey of
over 5000 physicians was performed under the auspices of the
American Heart Association (reported in: JAOC 8:966, 1986). That
survey showed that there was no universally accepted defini tion
for congestive heart fai lure and that a wide spectrum of
diagnostic cri teria for this common condi tion existed even among
academic cardiologists. There was no clear standard as to even the
mos t bas ic treatment of conges t i ve heart fai lure. For
example, exercise restriction was recommended by 19% of physicians,
31% recommended no change in activity, and 50% either light
exercise or an exercise conditioning program.
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 .
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.
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.
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.
About 2. 5 million individuals have congestive heart fai lure in
the United States with over 400,000 new cases expected annually.
Congestive heart failure also is one of the commonest causes for
hospital admissions accounting for over 5 million hospital days per
year. Despite the early recognition of this condition and active
medical research into both mechanisms and therapy, prognosis
continues to remain dismal wi th less than a 50% expected five year
survival. In the last decade we have seen many new medical and
therapeutic options for patients with congestive heart failure
which extend beyond the use of bed rest, sodium restriction,
digitalis and diuretics. These include vasodilators of a variety of
types including the angiotensin conventional enzyme (ACE)
inhibitors. Also, many new inotropes are under active investigation
both in oral and intravenous forms. In March of 1984 a survey of
over 5000 physicians was performed under the auspices of the
American Heart Association (reported in: JAOC 8:966, 1986). That
survey showed that there was no universally accepted defini tion
for congestive heart fai lure and that a wide spectrum of
diagnostic cri teria for this common condi tion existed even among
academic cardiologists. There was no clear standard as to even the
mos t bas ic treatment of conges t i ve heart fai lure. For
example, exercise restriction was recommended by 19% of physicians,
31% recommended no change in activity, and 50% either light
exercise or an exercise conditioning program.
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 the 1980's a primary focus for intense cardiovascular research
is in the treatment of patients with acute myocardial infarction.
Although the prevalence of this syndrome has been decreasing in the
United States, still over 1.5 million patients develop myocardial
infarction per year. There is about a 20% chance of a North
American male developing myocardial in farction before the age of
65. The in-hospital mortality still remains at ap proximately
10070-15070 and advances in pharmacologic and device therapy have
allowed for the intensification of research in the treatment of
patients with acute myocardial infarction. The following
manuscripts represent the collective efforts of academic in
vestigators in the United States and abroad as well as members of
the phar maceutical industry, and the Food and Drug Administration
to address the issues involved in interventions in the acute phase
of myocardial infarction. State-of-the-art papers addressing
important topics are followed by discus sion sections which have
allowed participants to express their own viewpoints leading to a
consensus opinion. The first part of this Symposium addresses the
models of experimental myocardial infarction followed by the
important issue of how one defines myocardial infarction size. The
latter is extremely important to be certain that endpoints of
therapeutic or device interventions are objective and reproducible.
A detailed description of the pharmacological interventions to
reduce myocardial infarction size as well as newer devices to
effect mechanical and electrical disorders provide an up-to-date
summary of current opinion."
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."
Organizational Management is ideal for readers who need to
understand modern organizations. This book enables students to
understand the key issues of organizational behaviour and how to
take a critical approach when planning, leading and engaging a
workforce and its resources. The book provides fresh perspectives
on known models and critical theories on leadership, teams,
performance management, employee engagement and change. The authors
also offer the reader innovative approaches to leading-edge issues
such as trust, internet use, generational trends, the use of the
arts in organizations and leadership from a systemic perspective.
Organizational Management draws on examples from the authors'
international work across a range of business and industrial
sectors, both public and private, and is supplemented by
activities, revision questions, recommend reading and online
resources to deepen learning. Rapid technological advances,
constantly changing global environments and new kinds of workforce
cultures mean that organizations are constantly being challenged.
This book equips the reader with the ability to navigate this
turbulent environment through both established and novel forms of
organizational management. Online supporting resources for this
book include summaries, diagrams and case study scenarios to help
readers easily understand theories and contextualize experiences in
the workplace
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.
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