Download What is atrial fibrillation?

INTERNSHIP
REPORT
Olivier Ritter
BEM Bachelor
10/09/2012
A l’attention d’Anne-Catherine Guitard
C ONTENTS
Context ................................................................................................ 2
What is Cardiac Mapping?................................................................... 2
The Product ......................................................................................... 3
The Mission ......................................................................................... 4
What is atrial fibrillation? .................................................................... 5
Clinical cases ....................................................................................... 6
Global Market Needs Analysis ............................................................. 7
Normal anatomy and physiology of the heart ............................ 7
Pathophysiology, Causal factors & Disease progression ............. 8
Clinical Presentation & Outcomes ............................................ 11
Treatments of Atrial fibrillation ................................................ 12
Epidemiology ............................................................................ 14
Economic Burden...................................................................... 17
Appendices
1
C ONTEXT
Heart disease is the number one cause of death in the United States. Cardiac arrhythmias—
an irregular heartbeat—affects 2.2 million Americans. Congestive heart failure—the inability
to pump blood properly—affects nearly 5 million Americans. Conventional treatments such
as ablation and cardiac resynchronization therapy (CRT) can improve patients’ lives; but
clinical outcomes have not reached the intended levels of success.
Catheter ablation success rates have ranged between 40-85 percent, resulting in need for
repeat procedures in 40-50 percent of the cases. For CRT patients, success is highly
dependent on selecting the right patient, placing the lead in the best location for that
patient, and optimizing the device settings.
Currently, 1/3 of all patients with CRT devices do not respond to treatment, leading to
continued progression of heart failure, increased patient morbidity, and an increasing
financial burden to the healthcare system.
W HAT IS C ARDIAC M APPING ?
Mapping the electrical activity of the heart is a critical component for the diagnosis and
treatment of heart disease. Many advanced therapies (such as ablation for the treatment of
arrhythmias) require detailed electroanatomic mapping. Currently, mapping is performed in
an electrophysiology (EP) lab, during which mapping catheters are inserted into the heart
and carefully moved to various locations around the heart to map and identify the origins of
the arrhythmia. Once the origin of the arrhythmia is identified, the specific tissue is
destroyed by ablation. Current catheter mapping technologies have several limitations
including:
 Risks and limitations associated with being an invasive and time consuming
procedure.
 Current point-to-point mapping technology does not provide simultaneous, beat-bybeat mapping. Electrical activity has to be skillfully aggregated and annotated to
make sense of the information provided by these point-to-point mapping systems.
 Does not provide the whole picture (bi-atrial or bi-ventricular) of electrical activity.
Only provides mapping information one chamber at a time.
 Does not fit into the current work flow of device based therapy (e.g. Cardiac
resynchronization therapy devices for heart failure).
Catheter ablation has evolved to become a mainstream treatment for arrhythmias, while
mapping to identify ablation treatment targets and confirm success of therapy has emerged
as its significant and critical counterpart.
For device-based therapy like Cardiac Resynchronization Therapy (CRT) for heart failure,
point-to-point, non-simultaneous catheter mapping provides very limited benefit while
adding cost and complexity to the procedure. Therefore, there is no practical mapping
solution available for use today. CardioInsight's ECVUE system has the potential to
substantially improve EP clinical practice by addressing significant unmet clinical needs
associated with current mapping technologies.
2
T HE P RODUCT
CardioInsight, a Cleveland-based medical device company, was founded in 2006 to
commercialize a breakthrough technology designed to improve the diagnosis and treatment
of electrical disorders of the heart.
The ECVUE system gathers electrical information about the heart from a proprietary, multisensor electrode "vest" placed on a patient’s body and combines it with images from a CT
scan to provide 3D maps of the electrical activity of the heart. Unlike conventional catheterbased mapping methods, the ECVUE ™ system is non-invasive and provides a view of the
entire heart’s electrical activity in a single beat, enabling electrophysiologistso better guide
treatments to localize arrhythmias, or optimize the placement and settings of CRT devices,
such as pacemakers
CardioInsight’s ECVUE mapping system is a non-invasive, single-beat electrocardiographic
mapping system with the unique ability to make the diagnosis and treatment guidance of
cardiac arrhythmias and heart failure simpler, faster, and safer.
The ECVUE system is comprised of:


Proprietary single use, disposable multi-electrode vest that gathers body surface
electrical signals, and
Advanced data analysis and visualization workstation that generates real-time, 3D
images of the electrical activity of the heart.
From the simple to use multi-electrode vest, to the intuitive, customizable data analysis and
visualization workstation, the ECVUE system offers a comprehensive tool that creates a new
paradigm in cardiac mapping that for the first time extends the use of advanced cardiac
mapping outside the existing confines of the EP lab.
ECVUE is commercially available in Europe for assisting electrophysiologists with the
diagnosis of cardiac arrhythmias.
The Company continues to work with leading centers world-wide to further strengthen its
clinical value proposition in simplifying mapping of arrhythmias and development of
panoramic biatrial mapping for atrial fibrillation. CardioInsight is also developing the only 3D
mapping product for CRT, which is expected to have a significant impact in patient selection,
lead placement and optimization.
ECVUE is the first advanced mapping technology to non-invasively generate real-time, 3D
electrical maps of the whole heart in a single beat.
3
THE MISSION
As the company prepares for commercialization, discussions with key industry players, as
well as future fundraising activities, this business planning and valuation assessment
becomes increasingly critical.
My supervisor, Kevin Mendelsohn, vice-president of the company and in charge of finance &
corporate development, proposed that I work on a project that would culminate in the
generation of a business plan to detail and quantify the value of our mapping system for
atrial fibrillation (a certain type of arrhythmia) mapping, include detailing the unique clinical
applications of the system, quantifying the patient populations, analyzing the competition,
evaluating the pricing structure, and ultimately generating a "value" of the opportunity.
My mission was supposed to be based for one half in Bordeaux, in order for me to work with
the CHU, one of the leading centers working with the company, and the other half in the
head office in Cleveland to finalize the project.
I started this project by doing a lot of reading, as I had very little background on
electrophysiology and specifically on the subject of atrial fibrillation. I then worked on the
outline of my report (see Appendices) and once validated by my supervisor, I could begin my
research.
Throughout the whole period of the internship, Kevin and I communicated via Skype at least
once a week, and he was always very responsive when I asked for clarifications on the
project through emails.
In this report I will try to detail the various steps I took to reach the final global market needs
analysis, and will give an E X CE R P T of each section, as this project was my only mission this
summer.
4
W HAT IS ATRIAL FIBRILLATION ?
Atrial fibrillation, or AF, is the most common type of arrhythmia. An arrhythmia is a problem
with the rate or rhythm of the heartbeat. During an arrhythmia, the heart can beat too fast,
too slow, or with an irregular rhythm.
AF occurs if rapid, disorganized electrical signals cause the heart's two upper chambers (the
atria) to fibrillate. The term "fibrillate" means to contract very fast and irregularly. In AF,
blood pools in the atria. It isn't pumped completely into the heart's two lower chambers,
called the ventricles. As a result, the heart's upper and lower chambers don't work together
as they should.
The heart has a natural pacemaker, called the “sinus node,” that makes electrical signals. These signals cause
the heart to contract and pump blood.
With atrial fibrillation, random electrical activity interrupts the normal conduction rhythm and prevents the
atria from properly contracting.
People who have AF may not feel symptoms. However, even when AF isn't noticed, it can
increase the risk of stroke. In some people, AF can cause palpitations, chest pain, dizziness or
heart failure, especially if the heart rhythm is very rapid. AF may happen rarely or every now
and then, or it may become an ongoing or long-term heart problem that lasts for years.
An ECG recording of normal
heart rhythm
An ECG recording of atrial
fibrillation
5
C LINICAL CASES
Some of my first dayswere spent at the hospital to assist to some cases and see the product in
action.
The first patient I saw was a 45 years old man who was to be ablated for a Wolff–Parkinson–
White syndrome (WPW), one of several disorders of the conduction system of the heart that are
commonly referred to as pre-excitation syndromes. While the majority of individuals with WPW
remain asymptomatic throughout their entire lives, there is a risk of sudden cardiac death
associated with the syndrome. While at the hospital I was following Sandra, the CardioInsight
employee conducting ECVUE cases everyday with the physicians of the Haut-Leveque hospitalin
Pessac. We went to the patient’s room before he was sent down to the CT scan, when she
explained the technique to him and asked for his authorization, since the product is still in the
clinical testing phase. He was quite interested, asked questions about the system, and approved.
He even asked me to take a picture with the vest on for his kids!
I found the installation very easy. Two cables provide a link between the vest and the system’s
central unit. Sandra realized a segmentation of the scan images, in the operating room before
the physician arrived, and the located the area of the bundle of Kent responsible for the
arrhythmias after the software generated the 3D visualization. I was simply amazed. Then the
physician arrived and punctured soon after having seen the 3D map. 20 minutes later, she had
the ablation catheter in the area of concern, and after 5 seconds, the pre-excitation had
disappeared on the monitor. That’s when I really realized the capacity of the system to make
everything easier for both the patient and the physicians.
The second case was an aged woman with tachycardia. She was mapped using ECVUE in the
operating room, and was ablated without a break as well.
The third patient was about 45 and suffered from paroxysmal ventricular tachycardia (VT) since
the age of 25. He had an ICD, changed 2 times. They had recorded that the VT was preceded by a
short series of extrasystoles. The system was here to be used to map the electrical activity of the
heart during that very first extrasystole, in the patient’s room. Given the earliness of the
disorder, he was used to the various other techniques, and was also intrigued by this new vest
and the mapping. The physician attempted to trigger the VT by stimulation using the
programmer of the ICD. 4 or 5 morphologies of extrasystole came out, which they had to settle
for, but never the one that led to the VT.
Another invasive 3D mapping system of 2 catheters, one for the endocardium and one for the
epicardium, was used the day after on this same patient, who as a result, spent half a day on the
table.
The last case was a patient who needed an ICD implantation. As mentioned in the product
section, ECVUE can also be used in CRT patients notably regarding patient selection, device lead
placement and programing optimization. But this operation was quite unique in that a new
sophisticated robotic platform, the da Vinci System, was here to be used for CRT implantation
for one of the first times in Europe.With da Vinci, small incisions are used to introduce
miniaturized wristed instruments and a high-definition 3D camera, helping doctors to take
surgery beyond the limits of the human hand. Kevin, my supervisor, suggested that I assisted to
the procedure to measure the feasibility of a joint utilization with ECVUE.
6
GLOBAL MARKETNEEDS ANALYSIS
N ORMAL ANATOMY AND PHYSIOLOGY OF THE HEAR T
Obtaining a basic working knowledge of the normal anatomy and physiology of the organ
that is affected by a need is important because it establishes a baseline against which
abnormalities are understood. This research also provided me with an understanding of
important vocabulary and context as I delved into further research. The disease is much
easier to comprehend if the anatomy of the affected organ or organ system is clearly
understood and can be visualized.
Once I learned about normal patterns of function within an affected area, I had a basis for
understanding how the disease functions.
In the case of AF, I began by determining that AF is a disease of the heart, which is part of
the cardiovascular system. As the heart is the primarily affected organ, I then focused on
investigating the basic gross anatomy of the heart and its normal function. Understanding
the heart’s size, location, and position in relation to other structures quickly establishes a
baseline context for investigating more complex concepts and interactions, such as how the
electrical system of the heart establishes a rhythm that affects the organ’s ability to
mechanically contract.
The human heart has four chambers, two superior atria and to inferior ventricles. The atria
are the loading chambers and the ventricles are the pumping chambers. The pathway of
blood through the human heart consists of a pulmonary circuit and a systemic circuit.
Deoxygenated blood, coming from peripheral organs, flows through the heart in one
direction, entering through the vena cavas (SVC& IVC) into the right atrium (RA) and is
pumped through the tricuspid valve during the passive filling of the right ventricle (RV). Then
blood is pumped out through the pulmonary valve to the pulmonary arteries into the lungs to
be oxygenated. It returns from the lungs through the pulmonary veins (PVs) to the left atrium
(LA) where it is pumped through the mitral valve during the passive filling of the left
ventricle.Then oxygenated blood leaves LV through the aortic valve to the aorta. Blood is
then distributed to the whole body.
The left ventricle is the largest and strongest chamber of the heart, as it must pump blood
around the whole body, whereas the atria pump blood into the ventricles and the right
ventricle into the lungs, and their walls are therefore much thinner.
[…]
The relative position of those anatomic structures between each other is a determining factor
of the heart’s conduction pathways. The pumping action of the heart depends on precise
electrical coordination between the atria and ventricles. As the signal travels from top to
bottom, it causes the heart to contract and pump blood.
7



The P wave is a small deflection wave that represents atrial depolarization (the
summation of all atrial cells depolarization).
The three waves of the QRS complex represent ventricular depolarization.
T waves represent ventricular repolarization (atrial repolarization is obscured by the
large QRS complex).
The electrocardiogram is recorded from10electrodes placed onthe patient's body, which can
record12 leads. The shape ofthenormal ECGof a patientis identicalto anotherofthe same age.
Theabnormalitiesmay be characteristicof agiven disease, ormaybe common todifferent
pathologies.The ECGcan diagnoserhythm disordersand theircoarse localization. Inanycase,
the ECG does not allow the precise determination of the focal origin or the reentrant circuit
responsible for the arrhythmia.
P ATHOPHYSIOLOGY , C AUSAL FACTORS & D ISEASE PROGRESSION
Once I established an understanding of anatomy and physiology of the heart in a healthy
individual, then I could examine how the disease disturbs the normal structure and function.
When investigating pathophysiology, the first step was to better understand how the
disease works from a biologic and physiologic perspective, and then how this affects the
normal function of the organ. The second step was to identify the risk factors and causal
associations (e.g., genetics, age, associated diseases, and lifestyle) that characterize the
disease. Finally, I could seek to understand the disease progression. Disease progression
examines the rate (e.g., days, weeks, or years) at which the disease leads to abnormal
function. This includes the peak age of the effect and the types of changes that occur at each
stage of the disease.
In the case of AF, I explored how the heart might be structurally altered, leading to abnormal
function, and whether or not the condition can lead to structural changes in the organ. I also
looked at the common causes of AF, the primary risk factors, and how AF progresses. I spent
quite a bit of time understanding the different types of AF and the unique characteristics of
each variation of the disease. This included looking at which type of AF is most common
among different groups of patients, whether all AF patients progress in the same way (or if
progression is more directly affected by other factors such as coexisting conditions), and
how likely patients are to progress from one type of AF to another.
8
P ATHOPHYSIOLOGY
During AF, ventricular and atrial activities become irregular and unsynchronized and rapid
irregular discharges come from various areas in the atria. There are several “triggersites”,
which create a pattern of rapid and apparently chaotic electrical activity that is characteristic
of AF. The majority of these focal sources (approximately 94 percent) are located in areas
inside the muscular sleeve of the four pulmonary veins, at their connection to the left atrium.
Other less common areas include the superior vena cava, right and left trial free walls, and
the coronary sinus. Though not fullyunderstood, inflammation and injury to the cardiac atrial
cell structure related to causal factors may predispose to abnormal electricaldischarges that
can initiate and maintain AF. However, any kind of myocardial disease may induce impair
ment of atrial cellular physiology, at the origin of AF.As a result of these irregular discharges,
the “electrical” atrial rate (not the contraction rate) isbetween 300 and 600 times per
minute. Thisresult in improper filling and ejection of blood, as well asa decreased efficiency of
the heart’s pumping process.
Since all electrical activity from the atria can typically only get to the ventricle via the AV
node, the AV node is able to filter many of the irregular electrical discharges associated
with AF, preventing the rapid rate of the atrial beat from being conducted into the ventricles.
However, not all of the signals are blocked and AF is often accompanied by irregular
ventricular beating, at 50 to 200 per minute.
[…]
On the electrocardiogram, AF is described by the absence of consistent P waves; instead
there are rapid oscillations or fibrillatory waves that vary in size, shape and timing and are
generally associated with an irregular ventricular response when atrioventricular (AV)
conduction is intact.
The patient may experience AF as palpitations, chest pain, and dizziness. In many cases,
however, it may occur asymptomatically.
C AUSES
AND
A SSOCIATED C ONDITIONS
AF is often an electrical manifestation of underlying cardiac disease. Nonetheless,
approximately 30% to 45% of cases of paroxysmal AF and 20% to 25% of cases of persistent
AF occur in younger patients with “lone AF”, defined as AF without overt structural heart
disease. AF can present as an isolated or familial arrhythmia, although a responsible
underlying disease may appear over time. Although AF may occur without underlying heart
disease in the elderly, the changes in cardiac structure and function that accompany aging,
such as an increase in myocardial stiffness, may be associated with AF, just as heart disease
in older patients may be coincidental and unrelated to AF.
Concomitant medical conditions have an additive effect on the perpetuation of AF by
promoting a substrate that maintains AF.
9
Conditions associated with AF are also markers for global cardiovascular risk and/or cardiac
damage rather than simply causative factors.







Ageing
Hypertension
Symptomatic heart failure
Tachycardiomyopathy
Valvular heart diseases
Cardiomyopathies
Atrial septal defect







Other congenital heart defects
Coronary artery disease
Overt thyroid dysfunction
Obesity
Diabetes mellitus
Sleep apnea
Chronic renal disease
Many dietary and lifestyle factors have also been associated with AF. These include excessive
alcohol or caffeine consumption and emotional or physical stress.
D ISEASE
PROGRESSION &
C LASSIFICATION
The clinical course of AF is frequently progressive, often beginning with increased ectopy
(premature atrial contractions), progressing to brief runs of AF that are typically transientand
self-terminating. Over a period of time ranging from months to years,episodes of AF tend to
increase in duration, sometimes becoming persistent.
Clinically, it is reasonable to distinguish five types of AF based on the presentation and
duration of the arrhythmia: first diagnosed, paroxysmal, persistent, long-standing persistent
and permanent AF.
Terminology
First-diagnosed
Clinical features
Pattern
Symptomatic
May or
Asymptomatic
(first
detected) reoccur
Onset unknown (first detected)
Paroxysmal
Spontaneous
termination Recurrent
<7 days and most often <48h
Persistent
Not
self-terminating Recurrent
Lasting >7 days or prior cardioversion
Long-standing persistent
Not
self-terminating Recurrent
Lasting >1 year when it is decided to
adopt a rhythm control strategy.
Permanent
Not
terminated Established
Terminated
but
relapsed
No cardioversion attempt
may
not
This classification is useful for clinical management of AF patients, especially when AF-related
symptoms are also considered. Many therapeutic decisions require careful consideration of
additional individual factors and co-morbidities.
10
The “natural time course” of atrial fibrillation, a flowchart that I created to describe the clinical progression of
the disease and the associated therapies.
C LINICAL P RESENTATION & O UTCOMES
While researching clinical presentation I focused on the impact of the disease on the patient.
I emphasized the symptoms (what the patient says s/he experiences) and the signs (what the
astute healthcare provider identifies or observes during the patient examination) of the
disease. Gaining an understanding of clinical presentation was important because it is often
the target for improved care and the development of new therapies that address identified
needs. When evaluating clinical presentation, it seemed important to describe what patients
complain about when they see a clinician and how they feel. Patients with the same disease
may present differently based on a number of factors, such as age, gender, ethnicity, and
coexisting conditions. Since every individual is different, each is likely to experience
symptoms slightly differently. Ultimately, clinical presentation manifested itself in the
signs/symptoms that result from the primary effect of the disease or from the long-term
consequences of having and managing the disease over time.
In the case of AF, I sought to understand the most common symptoms for patients with the
disease, how they feel with AF, and the signs most commonly observed by physicians in
patients with the disease. I also considered whether all AF patients are affected by the same
symptoms and what factors have the greatest impact on symptoms presented (e.g., age,
coexisting conditions). For example, young patients are much more likely to report
symptoms of palpitations with AF than older ones. This may directly impact the goal of
therapy for different age groups.
11
Importantly, clinical outcomes are different from symptoms. Outcomes generally refer to
hard data points associated with a disease that can be measured. The two most important
types of clinical outcomes to consider are morbidity and mortality. Morbidity refers to the
severity of the disease and its associated complications. Measures of morbidity may be
evaluated using quality of life questionnaires, or they can be assessed by more specific
endpoints such as distance walked in six minutes, hospital admissions, or a clinical event that
does not cause immediate death (e.g., stroke, heart attack). Mortality refers to the death
rate associated with a disease. Clinical outcomes are particularly important as they often
serve as endpoints for clinical trials since they can be assessed more easily and objectively
than symptoms and have a direct impact on cost.
In the AF case, key clinical outcomes to address were the morbidities associated with AF,
their likelihood of occurrence, and what factors have the greatest impact on morbidities
(e.g., age).
AF has a heterogeneous clinical presentation, occurring in the presence or absence of
detectable heart disease. An episode of AF may be self-limited or require medical
intervention for termination.
The adverse effects of AF are the result of haemodynamic changes related to the rapid
and/or irregular heart rhythm, and thromboembolic complications related to a
prothrombotic state associated with the arrhythmia. Onset of AF can result in a reduction in
cardiac output of up to 10–20% regardless of ventricular rate. The presence of fast
ventricular rates can push an already compromised ventricle into heart failure.
[…]
While patients can be asymptomatic, many experience a wide variety of symptoms as a
consequence of the hemodynamic dysfunction. The lost of the synchronous atrial activity,
the irregular ventricular response, the rapid heart rate, and the impaired coronary blood flow
all contribute to the mechanism. Palpitations, fatigue, and dizziness can be quiet common,
while symptoms related to congestive heart failure including dyspnea and angina can
develop in more severe cases.
[…]
AF is associated with increased rates of death, stroke and otherthrombo-embolic events,
heart failure and hospitalizations,degraded quality of life, reduced exercise capacity, and left
ventricular(LV) dysfunction
T REATMENTS OF A TRIAL FIBRILLATION
The goal of any treatment is to improve outcomes in those patients with a disease or
disorder. Treatment analysis involved detailed research to understand what established and
emerging therapies exist, how and when they are used, how and why they work, their
effectiveness, and their economics. This analysis also provided me with an understanding of
the clinical and patient-related requirements that any new treatment must meet to be
equivalent or superior to existing alternatives. It further establishes a baseline of knowledge
against which the uniqueness and other merits of ECVUE can be evaluated.
12
There are two ways to approach the treatment of AF using drugs: rate control and rhythm
control, which are often associated given the similarity of the medication used in both
strategies.
R AT E CO N T R O L
Rate control lowers the heart rate closer to normal, usually 60 to 100 bpm, without trying to
convert to a regular rhythm. It is about minimizing the effect of AF on the ventricular rate by
the prescription of medication increasing the degree of block at the level of the AV and
decreasing the number of impulses that conduct into the ventricles.
Catheter ablation of the AV junction (AV node/Bundle of His) combined with pacemaker
implantation can be carried out if the ventricular rate cannot be managed by medication, but
the introduction of a foreign body may have its own complications.
R H Y T HM CO N T RO L
In the case of rhythm control, it is about terminating AF and maintaining SR in a process
called cardioversion. This approach is most important in the acute setting of AF, notably
when first-diagnosed, using medication. In case of persistent or long-standing AF,
cardioversion is often electrical, and involves the restoration of normal heart rhythm through
the application of a DC electrical shock. In those cases, the treatments are only palliatives, in
the sense that the objective is to terminate the fibrillation and restore SR without
fundamentally modifying the substrate. On the other hand, catheter ablation or the Maze
procedure, carried out most often on the LA, is meant to modify the substrate of AF, by
removing the trigger zones (such as PVs) or the abnormal conduction channels (fibrotic
tissue) generated by the arrhythmia over time.
[…]
As far as mortality is concerned, the AFFIRM trial showed that there is lower mortality using
rate control with anticoagulation treatment versus rhythm control treatment and the
difference increases up to 5 years (end of study).
A N T I CO AG U L AT I O N
In every case, the prevention of complications is imperative and dictates the therapeutic
techniques that will be performed. Anticoagulation is designed to prevent the thromboembolic risk associated with AF. Beyond anticoagulants, alternatives are proposed, such as
the Left Atrial Appendage (LAA) Closure, to prevent blood clot formation in patients with AF,
given that 90% of them form in the LAA.
13
A B L AT I O N
Catheter ablation techniques are constantly evolving. Initial catheter ablations attempted to
recreate the lesion set used in the open-chest Cox maze procedure by creating linear ablation
lines that interrupted the AF wavelets. However, doctors had difficulty duplicating the Cox
maze lesion set during a closed-chest catheter ablation. The procedure had high complication
rates and required long fluoroscopy times.
[…]
Research in Bordeaux, France, by Michel Haïssaguerre, MD, and colleagues, suggested that
electrophysiologists didn't need to duplicate the Cox maze lesion set. Dr. Haïssaguerre's
group found that over 90% of AF is triggered in or near the pulmonary veins. As a result of
these findings, a new type of catheter ablation technique, called Segmental Pulmonary Vein
Isolation or Ostial Pulmonary Vein Isolation, was created. Dr. Haïssaguerre and his colleagues
used radiofrequency energy to ablate the pulmonary vein ostium, the opening to the
pulmonary veins. When "isolated", pulmonary veins can no longer be a trigger point for atrial
fibrillation. Dr.Haïssaguerre and his colleagues were able to terminate atrial fibrillation in,
and stop prescribing antiarrhythmic drugs for, 62% (28) of patients in the study.
E L EC T R I C A L C AR DI O V E RSI O N
Electrical cardioversion is a process by which the heart is shocked to convert it from an
irregular rhythm back into a normal sinus rhythm.
For patients in persistent AF, electrical cardioversion may be done early in the process to stop
the AF and put the heart back into normal sinus rhythm. For other AF patients, electrical
cardioversion may not be tried until later, when medication has stopped working.
E PIDEMIOLOGY
While conducting research on epidemiology, I included data for the disease as a whole, as
well as the most relevant patient subsegments. I tried to find information about disease
dynamics, such as growth rate, to illustrate how the disease will impact society in the future.
Epidemic, a term generally used to describe a rapidly spreading infectious disease within a
population, has recently been used to describe the rising prevalence of atrial fibrillation (AF).
The prevalence, defined as the proportion of a population affected by the disease at a point
in time (and probably the incidence, defined as the rate at which new cases occur in a
population during a specified time period) of AF is rising for reasons that are not completely
known. The rising incidence of the etiological factors of AF, such as the aging population and
a higher prevalence of cardiovascular diseases, only partly explains this phenomenon.
14
P REVALENCE
Estimates of the overall adult prevalence of AF in the United States range from 1 to 6%.
Because the prevalence of AF rises sharply with age, these estimates must be interpreted in
the context of the age distribution in the samples studied. Most studies indicate that the
overall prevalence of AF exceeds 5% in individuals aged 70 and above.
[…]
The medical community has been helped by the foresight of investigators who designed and
executed several longterm population-based studies, that have provided valuable
information about the epidemiology of AF. Even with significant differences in the
methodology and populations studied, the remarkably similar results point to the rather
homogeneous prevalence of AF in the Western world.
T RENDS
IN
P REVALENCE & I MPLICATION S
Several studies indicate that the prevalence of AF has been increasing in the past several
decades. Estimates from the National Ambulatory Medical Care Survey indicate that office
visits for AF increased from 1.3 to 3.1 million between 1980 and 1992. Hospital discharges for
AF in individuals over age 65 increased from 30.6 to 59.5 per 10,000 between 1982 and 1993.
The increasing prevalence has been confirmed by more recent data published in the National
Heart, Lung, and Blood Institute’s Chartbook. Between 1980 and 1999, AF hospitalizations
increased 80%for patients aged 45 to 65 and doubled for patients 65 years of age and older.
The aging of the population alone is expected to raise the number of individuals with AF from
just over 2 million in 1995 to more than 3 million by 2020 and 5.6 million by 2050. However,
increases in the prevalence of AF may also be driven by factors other than aging.
15
However, population studies may underestimate the prevalence of AF for two reasons: AF
may not be present at the follow-up time, and a significant population may have
asymptomatic episodes. According to the U.S. Census Bureau Population Projections
Program, the number of Americans aged 65 years or older will increase substantially to more
than 20% of the population (82 million) by the year 2050. This aging of the population is
projected to result in a 2.5-fold rise in AF prevalence.
The economic consequences of this arrhythmia are highlighted by the fact that AF is the most
common arrhythmia among patients hospitalized in the United States with a primary
diagnosis of an arrhythmia.
With the expected rise in the elderly population and the prevalence of AF, preventive
measures to reduce its incidence will have profound societal benefits. Although proven
preventive measures are lacking, control of risk factors such as hypertension and MI appear
prudent.
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E CONOMIC B URDEN
The focus of economic research was to understand the distribution of costs. I looked at the
aggregate, system-level cost of AF on an annual basis, the annual condition costs of AF, the
evaluation and treatment-related annual cost, the annual cost of hospitalization, and the
annual cost of lost productivity from absenteeism due to AF.
E CONOMIC C ONSIDERATIONS
Given its large and growing prevalence, AF has substantial economic impact. Proper
economic analysis of AF requires explicit definitions of perspective, costs, and outcomes.
Perspective is the vantage point from which costs and outcomes are assessed. For example,
costs can be quantified from the perspective of the patient. In this case, potential costs
include AF symptoms, discomfort from therapy, and time lost from work. In contrast,
potential costs from the perspective of a payor, such as a health insurance company, include
covered services for hospitalization or other treatments and administrative costs in
processing claims. Ultimately, a societal perspective, in which all costs and outcomes are
assessed regardless of who pays the costs or experiences the outcomes, provides the most
complete insight into the economic impact of AF.
In cost accounting, costs should be clearly distinguished from the charges assessed by
physicians, hospitals, and other health care providers and should reflect the actual financial
resources required to provide care. Costs can be divided into direct and indirect costs.
Direct costs are those incurred directly from medical care and include inpatient costs
(hospital fees, physician fees, procedure and therapy costs) and follow-up costs (physician
visits, outpatient testing, medications, home health care providers, long-term care, and
future hospitalizations).
Indirect costs quantify the remaining nonmedical impact of AF, such as missed days of work
and lost productivity. If possible, costs are usually presented in terms of dollar (or other
currency) expenditure. When assessment of monetary costs is difficult, such as for mortality
or decreased quality of life, proxy values such as lost years of work or lost productivity are
used.
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A TRIAL F IBRILLATION C ONDITION C OSTS
Atrial fibrillation increases the risk of a variety of adverse outcomes, most notably stroke. It
also has an impact on mortality, impairs quality of life, decreases productivity, and increases
hospitalization rates. All of these adverse outcomes have substantial costs.`
STROKE
Stroke is the most debilitating complication of AF. With its associated hypercoagulable state,
structural abnormalities in the fibrillating atria, and relative blood stasis, AF fulfills Virchow’s
triad for the development of thrombi and their subsequent embolization to the cerebral
vasculature. As a result, stroke is five times more likely to occur in AF patients than in agematched controls.
Indirect care costs (time and opportunity costs of nonpaid caregivers for cerebrovascular
accident [CVA] patients) exceeded £1.7 billion ($3.12 billion). For an individual patient, the
mean estimated lifetime cost of a stroke, including inpatient care, rehabilitation, and followup care for lasting deficits, is $140,000.
[…]
Acute care costs, such as hospitalization, diagnostic testing, initial therapy, and
rehabilitation, are substantial. The average estimated cost for the first 30 days of stroke care
is $13,000/patient for mild strokes and $20,000/patient for severe strokes. In addition,
inpatient costs can account for 70% of the overall cost of the first year after stroke. Wolf and
colleagues illustrated costs of acute care in the first year after stroke using 1991 Medicare
data. Among men aged 65 to 74, Medicare spent $21,231 per patient, 95% of which was
spent on acute care needs.
M O R T A LI T Y
Multiple national and international cohorts describe an independent association between AF
and mortality. The mechanism by which AF confers this independent mortality risk is poorly
understood. Nonetheless, the Framingham Heart Study illustrated an age-adjusted 1.5 to 1.9
hazard ratio for mortality among patients with AF compared with those without AF.
It showed an increased likelihood of mortality or major cardiovascular events (congestive
heart failure, MI, resuscitated cardiac arrest, or stroke) among those patients who developed
AF compared to those who did not. Mortality costs are difficult to compute and are generally
unavailable. Regardless, the burden of AF, its associated mortality, and its effect on lost
earnings and productivity imply substantial societal costs.
Q U A LI T Y O F L I F E
Atrial fibrillation adversely affects patients’ quality of life. Patients with AF and poor rate
control have palpitations, fatigue, shortness of breath, or lightheadedness, especially if they
have underlying cardiac or pulmonary disease. However, even asymptomatic AF patients
experience lower perceived health and life satisfaction compared to patients without AF,
possibly because of the burden of the diagnosis and its attendant needs for medical care and
therapies. This reduction in quality of life has a direct impact on costs. Although
quantification of quality of life in monetary terms is difficult, symptoms and poor functional
status can lead to lost productivity, both professionally and personally.
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P R O D U CT I V I T Y
Atrial fibrillation results in significant indirect nonmedical costs, such as lost work and
productivity. For example, a French survey of AF patients found that costs caused by missed
work accounted for 6% of total AF costs. In addition to the workers affected by this condition,
employers face increased costs, not only from decreased productivity, but also from
increased insurance premiums to cover affected employees. A U.S. study of 16 employers,
conducted from 1999 to 2002, found large cost differences between employees with AF and
those without. Annually, excess direct medical costs for AF patients were $12,349 per patient,
and excess indirect medical costs were $2,524 per patient, as compared to patients without
AF. Although they account for a relatively small portion of overall AF costs, these indirect
medical costs play a meaningful role in the overall economic impact of the condition.
E VALUATION
AND
T REATMENT C OSTS
A CUT E M AN A G E M EN T
Patients with new-onset AF, or an exacerbation of previously diagnosed AF, often require
extensive evaluation and treatment. Management approaches for AF vary dependent on
patients’ hemodynamic stability, symptoms and comorbidities, and the duration of the AF
episode. A new diagnosis of AF, either in isolation or in association with another medical
condition such as congestive heart failure, initiates an investigation into its cause. These
investigations, which can include laboratory testing, monitoring, cardiac imaging, and
hospitalization, play a significant role in the economic impact of AF. One study analyzed costs
between AF patients who were hospitalized and those discharged from an emergency
department. Admitted patients incurred mean costs of $2,012 in their care compared to
$1,878 among discharged patients. A French survey of AF patients found that consultations
and investigations for AF patients drove 9% and 8%, respectively, of their overall costs of AF
care.
C H R O N I C M AN A G E ME N T
After the initial evaluation and treatment of an acute AF episode, focus turns to arrhythmia
control and anticoagulation. Arrhythmia control involves antiarrhythmic or atrioventricular
(AV) nodal blocking medications. Rhythm control of AF with antiarrhythmic medications can
reduce symptoms, improve functional capacity, and lower both stroke and mortality risk.
These benefits must be weighed against the potentially dangerous side effects associated
with antiarrhythmic medications. An alternative method of AF management is rate control
strategies with AV nodal blocking agents.
[…]
Two studies demonstrated cost savings in the rate control arm, even after sensitivity
analyses. In the 2000 RACE study, mean costs of rate control were 7,386 ($7,017), while
mean costs of rhythm control were 8,284 ($7,870).In the AFFIRM trial, the incremental cost
of rhythm control over rate control was nearly $1,500 per patient per year. Several
interventional procedures are an alternative to medication-based antiarrhythmic strategies
for AF management. Catheter-based AV node modification or ablation can be used to treat
highly symptomatic patients or patients who cannot tolerate rate-controlling agents. The
procedure can improve symptoms, functional capacity, and LV function.
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In a 1997 report, costs of AV node modification were $19,389, and costs of the AV node
ablation were $28,485. Over time, with technical advances, these costs will likely decline, as
evidenced by 2003 costs of $17,173 for AV nodal ablation.
F UTURE D IRECTIONS
Although the current burden of AF, both in the United States and abroad, is already large,
forecasts predict major increases over the coming decades. As the population ages and
survival from other cardiac conditions that predispose to AF increases, the prevalence of AF
will likely rise. Projections for the number of adults in the United States with AF in 2050 range
between 5.6 and 15.9 million, as compared to 2.2 million in 2006. Approximately 50% of this
projected population will be over the age of 85 years. As the numbers of AF patients increase,
AF care costs will also increase. In the 2004 U.K. survey of AF patients, costs rose from 0.62%
(£244 million, or $418 million) of the National Health Service (NHS) budget in 1995 to 0.97%
(£459 million, or $788 million) of the 2000 NHS budget.
[…]
Future developments in AF care, such as new anticoagulants and procedures, could have a
significant impact on costs. For example, direct antithrombin agents or new antiplatelet
combinations may show efficacy in AF-related stroke prevention. Since these new therapies
do not require the intensive monitoring required by warfarin, substantial cost savings could
be realized. Similarly, innovations or improvements in interventional procedures such as
ECVUE, both in efficacy and safety, could also affect costs. Atrial fibrillation presents
significant challenges to both individual practitioners and policymakers. With its substantial
costs in diagnosis, treatment, and outcomes, it will become increasingly important to
determine the best strategies in caring for these patients.
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D ISCUSSION
When I was first proposed the project, I just could not turn it down. I immediately saw the
revolutionary aspect of ECVUE and was thrilled to work on it at such early stages. I must say
that I got quite a good grasp of what a biomedical start-up can be, how it performs and what
challenges it must overcome on a daily basis.
At first, the amount of information was quite overwhelming, given that I had no background
in the field, and the fact that most of the information I needed was to be extracted from
studies in English written by physicians, for physicians. But after a while I became familiar
with the vocabulary and concepts, and could focus on delivering a high-quality report.The
theoretical knowledge in Marketing and Business Planning that I gathered during two years
has proved to be very useful, mostly regarding methodology of research.
As mentioned previously, my mission was supposed to be based for one half in Bordeaux, in
order for me to work with the CHU in the first place, and the other half in the head office in
Cleveland to finalize the project. Unfortunately, my supervisor took last minute vacation for
2 weeks in August. This resulted in an internship almost completely from home, by
correspondence. While it enabled me to learn how to work independently, using only
technology to communicate with the firm, I missed the relational side of the experience.
Besides, the procedures I was given the opportunity to attend were fascinating. I have
always been interested by technology and innovations, especially in the medical field, and I
realize that seeing this kind of operations was a unique chance.
Overall, this internship at CardioInsight this year has been very rewarding on many levels,
and I am pleased to say that my contract was extended for at least another month, outside
the internship framework.
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