I need someone to rewrite a whole report, so that there is no plagiarism (copy/paste) involved.

I need someone to rewrite a whole report, so that there is no plagiarism (copy/paste) involved.

 

Due date: 8pm (Paris Time)

(
Olivier Ritter
BEM Bachelor

10

/09/2012
) (
A l’attention d
’
Anne-Catherine

Guitard
) (
INTERNSHIP REPORT
)

Contents

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

Context

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.

What is Cardiac Mapping?

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-by-beat 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.

The Product

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, multi-sensor 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 catheter-based 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.

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 excerpt of each section, as this project was my only mission this summer.

What 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
)

Clinical 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.

GLOBAL MARKETNEEDS ANALYSIS

Normal anatomy and physiology of the heart

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.

· 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.

Pathophysiology

, Causal factors & Disease 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.

Pathophysiology

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.

Causes and Associated Conditions

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.

Conditions associated with AF are also markers for global cardiovascular risk and/or cardiac damage rather than simply causative factors.

·
10

· Ageing

· Hypertension

· Symptomatic heart failure

· Tachycardiomyopathy

· Valvular heart diseases

· Cardiomyopathies

· Atrial septal defect

· Other congenital heart defects

· Coronary artery disease

· Overt thyroid dysfunction

· Obesity

· Dicourseworkhero.co.uktes 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.

Disease progression& Classification

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

Clinical features

Pattern

First-diagnosed

Symptomatic
Asymptomatic (first detected)
Onset unknown (first detected)

May or may not reoccur

Paroxysmal

Spontaneous termination
<7 days and most often <48h Recurrent Persistent Not self-terminating Lasting >7 days or prior cardioversion

Recurrent

Long-standing persistent

Not self-terminating
Lasting >1 year when it is decided to adopt a rhythm control strategy.

Recurrent

Permanent

Not terminated
Terminated but relapsed
No cardioversion attempt

Established

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.

The “natural time course” of atrial fibrillation, a flowchart that I created to describe the clinical progression of the disease and the associated therapies.

Clinical Presentation & Outcomes

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.

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

Treatments of Atrial 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.

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.

Rate control

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.

Rhythm control

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).

Anticoagulation

In every case, the prevention of complications is imperative and dictates the therapeutic techniques that will be performed. Anticoagulation is designed to prevent the thrombo-embolic 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.

Ablation

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.

Electrical Cardioversion

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.

Epidemiology

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.

Prevalence

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.

Trends in Prevalence & Implications

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.

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.

Economic Burden

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.

Economic Considerations

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.

Atrial Fibrillation Condition Costs

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 age-matched 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 follow-up 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.

Mortality

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.

Quality of Life

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.

Productivity

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.

Evaluation and Treatment Costs

Acute Management

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.

Chronic Management

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.

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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.

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.

Future Directions

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.

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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.

Discussion
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.