the CARDIAC ELECTROPHYSIOLOGY space: a deep dive
and why we invested in CARDIOMATICS
AUGUST 2021
by Sebastian Anastassiou
When we at Nina Capital decide to invest in the most exciting companies, we do so having achieved a near-obsessive understanding of the healthcare space and healthcare need that these companies are addressing. For Cardiomatics, we took a deep dive into the cardiac electrophysiology space. We also strongly believe in sharing is caring; so here we are… sharing.
For you cliff note lovers, we have prepared a short summary. For those of you who tend to go down rabbit holes, keep reading past the event horizon.
The 1-minute bulletpoint version
- In the cardiac electrophysiology space, a need has arisen out of the widespread under diagnosis and detection of life-threatening arrhythmias, as well as the well-known limitations of the clinical diagnostic pathway built around the interpretation of the electrical activity of the heart as monitored by Holter monitors and other cardiac event recorders.
- Cardiovascular disease remains the leading cause of death globally, with approximately 1–2% of the general population thought to suffer from Atrial Fibrillation (AF), the most common cardiac arrhythmia. This prevalence is expected to increase significantly in the next 30–50 years due to an ageing population, and increasing AF risk factors, including arterial hypertension and diabetes.
- A majority of patients suffering from AF present with only episodic arrhythmias, requiring long-term monitoring of the electrical activity of the heart to confirm a diagnosis. These patients, however episodic or asymptomatic their condition, are considered at high risk of stroke. Their condition is thought to be progressive, with moving from episodic to permanent and increasingly difficult (and expensive) to treat. Appropriate diagnosis is paramount to getting the right patients to the right treatment at the right time.
- A significant problem is the burden of work related to electrocardiogram (ECG) analysis through visual control of the tracings. While high device sensitivity is required to diagnose AF, the real challenge lies in the interpretation of hundreds of hours of signals. This is a classic “needle in a haystack” problem and can be significantly time consuming.
- The past decade has seen the proliferation of fully vertically integrated devices trying to solve the challenges facing the AF diagnostic pathway. This however, has come at either the expense of accuracy or a significant tradeoff (especially, cost) to the healthcare system — a cost that is becoming unbearable to payers and unacceptable to ensure broader access to cardiac monitoring.
ENTER CARDIOMATICS, which has addressed this problem by finding a way to provide convenient, automated ECG interpretation to healthcare professionals in order to improve its accuracy and efficiency.
The event horizon — keep reading to go down the rabbit hole of why we invested in Cardiomatics
Heart rhythm problems (heart arrhythmias) occur when the electrical impulses that coordinate heartbeats don’t work properly. Tachycardia refers to a resting heart rate greater than 100 beats a minute. Bradycardia refers to a resting heart rate less than 60 beats a minute.
Atrial Fibrillation: The single most common Cardiac Arrhythmia
Atrial fibrillation (AF) (a tachycardia in the atria) is the most common cardiac arrhythmia, occurring in 1–2% of the general population. Atrial fibrillation increases with age, and presents with a wide spectrum of symptoms and severity, from episodic (Paroxysmal) to chronic (Persistent to Permanent). Its prevalence varies between continents and ethnicity, but the estimated number of patients with AF worldwide might be between 30 and 100 million. In the United States alone, the CDC estimates affects anywhere between 3 and 6 million people. This prevalence is expected to increase significantly in the next 30–50 years due to an ageing population, and increasing risk factors to develop AF, including arterial hypertension and diabetes. Both prevalence and incidence are higher in men than in women and increase with age.
AF is associated with an increased mortality, increased incidence of heart failure with an increased hospitalization rate, and a higher risk of thrombo-embolic events, including strokes. It could also signal more acute and potentially fatal conditions in the case of ventricular tachycardia or ventricular fibrillation (rhythms with dysfunctional electrical impulses originating in the ventricles). Finally, it can also be associated with a reduced exercise capacity and an altered quality of life. Its natural evolution usually progresses from short self-terminating rare episodes with little or no symptoms to longer, more frequent, more prolonged and usually clinically detectable ones, even if individual variations can also be observed.
Diagnosing Atrial Fibrillation
The AF diagnosis requires at least 30s of absolutely irregular RR intervals and no discernable, distinct P-waves on an electrocardiogram (ECG), a recording of a heart’s rhythm and electrical activity.
Current diagnostic pathways and their limitations
In almost all cases, the AF diagnostic pathway today begins either with an opportunistic find of AF in the asymptomatic patient (rare) or with a General Practitioner (GP) observing symptoms including breathlessness, chest pain, syncope/dizziness and palpitations also reduced exercise tolerance, malaise and polyuria.
The diagnosis starts with a careful clinical history. The GP performs manual pulse palpation to assess for the presence of an irregular pulse. In this setting, absence of an irregular pulse makes a diagnosis of AF unlikely, but its presence does not reliably indicate AF. The GP might then perform a resting electrocardiogram (ECG), where sensors (electrodes) attached to the skin are used to detect the electrical signals produced by your heart each time it beats. The test has a duration of 5–10 minutes. If there is anything unusual in the recording, the patient is usually referred to a specialist (cardiologist) and further tests are performed.
Although detecting an AF episode during a brief ECG examination can be possible for Persistent or Permanent AF, it’s a challenge for Paroxysmal AF since the patient could be experiencing brief episodes distanced over numerous days or even weeks — sometimes just a few times over the course of a month.
If AF is not confirmed (initial resting ECG is negative) but clinical suspicion remains because an irregular pulse has been detected, the next step is referral to a Cardiologist for prescription of an appropriate long-term event cardiac monitoring device (see below: Existing solutions) followed by recording interpretation. Specialized training (which the GP does not have) is required for correct interpretation.
If an AF diagnosis is confirmed by the Cardiologist, the patient receives a referral for specialized management which may include education and information (stroke awareness), anticoagulation treatment, cardioversion, or controlling heart rate and treatment. Persistent AF has the lowest responses to the available treatment options; PAF can generally be treated successfully; for example, the efficiency of ablation techniques varies greatly depending on type of AF, being highest in Paroxysmal and lowest in long-term Persistent AF.
Note: the clinical pathway changes from country to country and in the United States, even between different types of practices.
Existing monitoring solutions
Until recent years, physicians had three cardiac monitoring options or “multi-lead” devices. All of these monitors are assemblies of wires, electrodes, and external recorders, some of which require the patient to unhook and then reconnect the device when showering or exercising.
- 24–48 Hour Traditional Holter monitor — A technology that first became available in 1962, a modern Holter typically has 2–5 leads (wires) that are connected to electrodes, which are attached to the patient’s chest in strategic locations so as to maximize the precision and clarity of the reading. The leads are attached on the other end to a recorder, which saves the recording onto flash memory. After 24–48 hours, the recording is analyzed by a technician and physician, with the aid of software that eliminates the majority of the dataset made up of “normal” heart rhythms.
- Cardiac Event Monitors — Event Monitors (EM) have at least two leads connected to a recording device similar to a Holter. EMs differ from a Holter in their duration and purpose — they can be worn by patients for up to 30 days, and only offer episodic, rather than continuous, monitoring. If the device senses an arrhythmia, or the patient signals the occurrence of symptoms (by pressing the appropriate button), the rhythm data from the episode is saved and transmitted to a scanning facility. A technician, or the patient’s doctor, is immediately able to analyze the episode in close to real time.
- Mobile Cardiac Telemetry — MCT takes all the capabilities of Holters and Event Monitors, and combines them. An MCT device records continuously for up to 30 days and there’s always a technician at a scanning facility watching the patient’s heart rhythm in real time. MCT is mostly overkill for patients without potentially life-threatening symptoms, and the constant monitoring is expensive, leading to reimbursement difficulties.
A 24-hour ambulatory ECG monitor is preferred in patients with suspected asymptomatic episodes or symptomatic episodes less than 24 hours apart; an event recorder ECG is used in those with symptomatic episodes more than 24 hours apart.
ECG Analysis Today
A significant problem is the burden of work related to ECG analysis performed with visual control of the tracings. While high device sensitivity is required to diagnose AF, the real challenge lies in the interpretation of hundreds of hours of signals. Holter examinations are currently analysed using software written in the 1980s.
ECG analysis requires physicians to have a high level of expertise and experience. For patients with Paroxysmal AF (PAF), the Cardiologist may be looking at a recording of over one hundred thousands heartbeats in order to find one episode of AF. This is a classic “needle in a haystack” problem and can be significantly time consuming: not surprisingly, for the traditional clinical pathway, the typical turnaround time is two weeks.
As we will describe later, fully vertically integrated devices have shown the ability to reduce this to 5 days, albeit at a significant cost to the healthcare system — a cost that is becoming unbearable to payers in the United States and unacceptable to ensure broader access to cardiac monitoring.
Who suffers most from the current state?
Paroxysmal AF (PAF) is suspected to be more prevalent than Persistent AF among patients with stroke. In a large study in acute stroke and transient ischemic attack patients, nearly two thirds of cases of AF were Paroxysmal. Despite its brief, asymptomatic episodes, PAF carries the same risk of stroke as persistent AF. Thus, occult PAF is thought to be the most likely candidate to explain at least a large portion of cases of stroke that remain of cause unknown (cryptogenic).
It is believed that the natural history of AF is progressive, initially being nonsustained and induced by trigger activity and manifesting as PAF. However, these bouts of AF induce electric alteration within the atrial myocardium (electrical remodeling). Eventually, the alteration of the atrial myocardial substrate contributes to maintain AF (Persistent AF) by means of complex self-sustained electrical activity. In other words, many patients start with PAF that if left untreated may become the more difficult to treat Persistent AF.
In summary, early detection of AF in its Paroxysmal stages offers better success ratios of treatment options, yet a significant percentage of patients with Paroxysmal AF remains undiagnosed. Although a large scale screening program of long term ECG monitoring (like Holter devices) would be the ideal solution to detect these patients, there are several unsolved obstacles tied to interpreting long term ECG recordings.
The Case for Screening
Asymptomatic or clinically silent AF is common and patients may not report any symptom commonly attributable to an arrhythmia, or may experience both symptomatic and asymptomatic episodes of AF, of variable duration, with a ratio up to more than 10 asymptomatic per 1 symptomatic episode in some patient groups. The precise prevalence of patients with asymptomatic or clinically silent AF is by definition unknown, but it has been estimated that among patients with diagnosed AF, one-third does not report symptoms.
An earlier detection of AF could allow an earlier adequate management to avoid later complications. Approximately 10% of ischemic strokes are associated with AF first diagnosed at the time of stroke. Detecting asymptomatic AF would provide an opportunity to prevent these strokes by instituting appropriate anticoagulation. In the past five to ten years, new initiatives such as the “AF-SCREEN” international collaboration were formed to promote discussion and research about AF screening as a strategy to reduce stroke and death and to provide advocacy for implementation of country-specific AF screening programs. The fundamental idea is that screen-detected AF found at a single timepoint or by intermittent ECG recordings over 2 weeks is not a benign condition and, with additional stroke factors, carries sufficient risk of stroke to justify consideration of anticoagulation. To be effective, settings for screening could include various venues in both the community and the clinic, so long as they are linked to a pathway for appropriate diagnosis and management. To date, there is a strong case for AF screening however large randomized outcomes studies are missing that would strengthen the evidence base.
In particular, studies supporting a health economics argument for AF screening do not yet exist (at the time of analysis). The economic assessment of AF screening depends on a range of factors, including: (1) rate of undiagnosed AF in the target population, (2) difference in AF detection between the screening intervention and routine practice without screening (3) stroke and mortality risk of the target population, (4) expected reduction in stroke and mortality and increase in bleeding risk from oral anticoagulant (OAC) therpay, (5) cost of the screening methodology, and (6) country-specific “willingness-to-pay” thresholds to avoid stroke.
Limited studies in Japan, Sweden, and The Netherlands as an example, confirm that annual ECG screening and pulse palpation with confirmatory ECG are cost-effective in a Japanese population. In The Netherlands in particular, a study of lifetime costs and effects of a single handheld ECG screening of patients >65 years of age during the annual influenza vaccination found that screening would decrease overall costs by €764 (USD$939) and increase quality-adjusted life years by 0.27 per patient.
In the United States, a simulation of direct medical costs in the United States concluded that costs were greater in those patients with undiagnosed AF than for similar people without AF, justifying strategies to identify and treat undiagnosed AF. To date, however, the American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines make no recommendation on the topic of screening but do state that early detection and treatment of asymptomatic AF before the first complications occur is a recognized priority for the prevention of stroke.
It is reasonable to expect that new country-wide initiatives may exist in the future, wherein asymptomatic populations will be “screened out” instead of symptomatic patients being “screened in” as is today.
Cardiomatics is well-positioned to truly understand and address the needs of the cardiac electrophysiology space, to democratize access to cardiac health.
