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Can artificial intelligence save our lives?

The role of artificial intelligence (AI) in our life is advancing rapidly and is making strides in early detection of diseases. The consumer market is composed of wearable health devices that enables continuous ambulatory monitoring of vital signs during daily life (at rest or physical activity), or in a clinical environment with the advantage of minimizing interference with normal human activities1. These devices can record a wide spectrum of vital signs including: heart rate and rhythm, blood pressure, respiratory rate, blood oxygen saturation, blood glucose, skin perspiration, body temperature, in addition to motion evaluation. However, there is a lot of controversy whether these health devices are reliable and secure tools for early detection of arrhythmia in the general population2.

Atrial fibrillation (afib) is the most common arrhythmia currently affecting over 5 million individuals in the US and it’s expected to reach almost 15 million people by 2050. Afib is associated with an increased risk of stroke, heart failure, mortality and represents a growing economic burden3. Afib represents a diagnostic challenge, it is often asymptomatic and is often diagnosed when a stroke occurs. Afib represents also a long term challenge and often involves hospitalization for cardioversion, cardiac ablation, trans-esophageal echo, anti-arrhythmic treatment, and permanent pacemaker placement. However, if afib is detected, the risk of stroke can be reduced by 75% with proper medical management and treatment3.

Physicians need fast and accurate technologies to detect cardiac events and assess the efficacy of treatment. A reliable, convenient and cost-effective tool for non-invasive afib detection is desirable. Several studies assessed the efficacy and feasibility of wearable technologies in detecting arrhythmias. The Cleveland clinic conducted a clinical research where 50 healthy volunteers were enrolled. They tested 5 different wearable heart rate monitors including: (Apple Watch, Garmin Forerunner, TomTom Spark Cardio, and a chest monitor) across different types and intensities of exercises (treadmill, stationary bike and elliptical). The study found that chest strap monitor was the most accurate in tracking the heart rate across different types and intensities of exercises4.

The Apple and Stanford’s apple Heart Study enrolled more than 419,297 Apple Watch and iPhone owners. Among these users 2,161 (roughly 0.5%) received a notification of an irregular pulse. Of those who received the notifications, only about 450 participants scheduled a telemedicine consultation and returned a BioTelemetry ECG monitoring patch. When the Apple Watch notification and ECG patch were compared simultaneously, researchers found 71% positive predictive value and about 84% of the cases were experiencing Afib at the time of the alert. Additionally, in 34% of participants whose initial notification prompted an ECG patch delivery were later diagnosed with Afib. This finding shows that Apple watch detected afib in about one third of the cases which is “good” for a screening tool considering the “intermittent nature of afib and that it may not occur for a whole week” says Dr. Christopher Granger, a professor of medicine at Duke University who participated on the steering committee for the Apple Heart study5.

These studies are observational studies and are not outcome driven. They are not randomized and are not placebo controlled. There are potentials for false negatives, where the Apple watch fails to detect the afib and false positive where it detects arrhythmia that does not exist. Unfortunately, patients who are false negative don’t consult the physician about their symptoms of palpitations and shortness of breath since it provides false security. While patients with false positive are sent unnecessarily to the clinic that could lead to further unnecessarily test and anxiety for the patient.

Is the Apple Watch ready to be used as a default screening tool to monitor the heart rate and rhythm in the general population and by physicians with patients with or at high risk for Afib is still unclear and warrant further studies.  In conclusion, physicians should be cautious when using data from consumer devices to treat and diagnose patients.

 

References:

  1. Cheung, Christopher C., Krahn, Andrew D., Andrade, Jason G. The Emerging Role of Wearable Technologies in Detection of Arrhythmia. Canadian Journal of Cardiology. 2018;34(8):1083-1087. doi:10.1016/j.cjca.2018.05.003
  2. Dias D, Paulo Silva Cunha J. Wearable Health Devices-Vital Sign Monitoring, Systems and Technologies. Sensors (Basel). 2018;18(8):2414. Published 2018 Jul 25. doi:10.3390/s18082414
  3. Chugh, S., Sumeet, Havmoeller, J., Rasmus, Narayanan, F., Kumar, et al. Worldwide Epidemiology of Atrial Fibrillation: A Global Burden of Disease 2010 Study. Circulation. 2014;129(8):837-847. doi:10.1161/CIRCULATIONAHA.113.005119
  4. Wrist-Worn Heart Rate Monitors Less Accurate Than Standard Chest Strap. Medical Design Technology. http://search.proquest.com/docview/1875621494/. Published March 9, 2017.
  5. Turakhia, Mintu P., Desai, Manisha, Hedlin, Haley, et al. Rationale and design of a large-scale, app-based study to identify cardiac arrhythmias using a smartwatch: The Apple Heart Study. American Heart Journal. 2019;207:66-75. doi:10.1016/j.ahj.2018.09.002

 

 

The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.

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The Future of Wearable Technology & Detecting Atrial Fibrillation – An Update!

Last November at AHA18, I was lucky enough to catch a talk from one of the investigators, Dr. Marco Perez, working on the Apple Heart Study, where he described the goals of the project. I even wrote about it for the blog I wrote at AHA18 in Chicago, which you can find here.

To quickly recap, this unprecedented collaboration between Apple and Stanford is a progressive clinical trial that uses data from Apple Watch devices from over 400,000 participants. The main purpose of this study was to examine if atrial fibrillation (AFib) can be reliably diagnosed from irregular pulse notification data from wearable devices. In November, Dr. Perez mentioned that they wouldn’t have data until early 2019, and this past March, they released some results that are really exciting.

Highlights from the findings include:

  • Around 0.5% of participants received irregular pulse notifications, which was particularly important since people were concerned that these devices would potentially over-notify people.
  • The pulse detection algorithm of the Apple Watch has a 71% positive predictive value – this was compared to simultaneous electrocardiography patch recordings.
  • The majority of the time (84%) when participants received irregular pulse notifications, they were found to be in AFib at the time of the notification.
  • 1/3 of the participants who received irregular pulse notifications and were then followed up by using an ECG patch over a week later were found to have AFib. This isn’t entirely surprising since AFib is an intermittent condition, so it’s not uncommon for it to go undetected in subsequent monitoring.
  • 57% of people who received irregular pulse notifications sought medical attention afterwards.
  • A clinical trial could be conducted in this large-scale virtual manner

The last point is particularly important because this is the first study of its kind. It was almost completely virtual, at least from the standpoint that the researchers analyzing the data never once had any contact with the participants. Additionally, the scope of the number of people who were analyzed is impressive – 400,000 participants is quite the sample size, especially for someone like me who studies heart disease in mice!

Because AFib is an extremely common condition, affecting between 2-6 million people in the United States, that often goes undiagnosed, understanding that wearable technology can aid patients in detecting their condition is huge. Also, with the increase in technology in our health care sphere (specifically in cardiology), something that was expertly discussed by Dr. John Chen earlier this year on his blog is that this is just the beginning in understanding how wearable technology can help us treat disease. We now have another tool in our kit, and this one looks promising.

In Stanford’s press release, Dr. Perez said, “The performance and accuracy we observed in this study provides important information as we seek to understand the potential impact of wearable technology on the health system. Further research will help people make more informed health decisions.”

Interestingly, Johnson & Johnson and Apple recently announced their plans to build off these preliminary results by partnering together in a new project called HEARTLINE. This study will focus on an older population (~ 65 years) of around 150,000 participants who, due to their age, are at a higher risk of AFib. It’s a really exciting time to be in the cardiology field since this is just the beginning of this type of research, which is full of therapeutic potential.

It’s also really thrilling to be able to follow-up with this study, especially since it all started with my father-in-law, who has AFib, being nervous about using wearable technology to detect his condition. I’m excited to share this data with him as well since maybe he’ll feel a little more comfortable using it now.

Examples of the notifications that participants in the Apple Heart Study receive. Courtesy of Apple

Examples of the notifications that participants in the Apple Heart Study receive. Courtesy of Apple

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AHA18: Notes From a Structural Heart Disease Specialist

How can one experience science and scenic beauty together? You know the answer to this, if you attended this year’s annual Scientific Sessions of the American Heart Association (AHA) in the beautiful city of Chicago. AHA18 showcased the latest advancements and studies in the field of cardiovascular medicine and stroke.

 

AHA Coming Back To The Center Stage

I attended AHA Scientific Sessions for the first time when I was an intern. Science from different sub-specialties of cardiovascular and stroke was truly inspiring and triggered curiosity. However, over the years as I specialized in general cardiology, then interventional cardiology and structural heart disease (SHD), it became increasingly difficult to attend all major scientific meetings every year.  Meetings focused on sub-cardiovascular specialties had taken priority in my schedule in last few years. However, this has changed in 2018. As a SHD specialist I realized the need and importance of a multidisciplinary approach, and science that cuts across various specialties. With widespread adoption of heart team and brain team models, we have realized the importance and benefits of collaboration between physician and surgeons across different specialties.  AHA provides a perfect platform to present and promote such multidisciplinary science.

 

How Far We Came in the TAVR World

Two separate studies using national administrative databases reported significant reduction in the complications rates associated with transcatheter aortic valve replacement (TAVR).

In the first study, Dr. Sameer Arora and his colleagues at University of North Carolina School of Medicine, Chapel Hill, evaluated the complication rates following both TAVR and surgical aortic valve replacement (SAVR) using the Nationwide Inpatient Sample1.  They included more than 90,000 patients and reported reduction in all cause mortality (4% to 1%), vascular complications (8% to 5%), acute kidney injury (12% to 10%), need for blood transfusions (31% to 10%), and cardiogenic shock (3% to 1%) in patients who underwent TAVR between 2012 and 2015 [P < 0.001 for all].

However, there was an increase in the need for a permanent pacemaker implantation (2% to 12% %; P < 0.001). They also noted trends towards improvement in outcomes with SAVR during same period. Improvement in device profile and valve design, operator experience, and inclusion of patients with lower baseline risk could explain these outcomes with TAVR.

In the second study, Dr. Rajat Kalra, MBChB and colleagues at University of Minnesota, Minneapolis, analyzed rates of new-onset atrial fibrillation and its association with clinical outcomes among patients who underwent TAVR (N=48,715) and SAVR (N=122,765), also using the Nationwide Inpatient Sample from 2012 to 20152. The study reported rates of new-onset atrial fibrillation as 50.4% and 50.1% for TAVR and SAVR respectively. They also noted higher in-hospital mortality, and post procedure stroke, among patients who had new-onset AFib post TAVR or SAVR.

Results from both of these studies are in coherence with findings from clinical trials and our experience with TAVR. However, due to lack of randomization, long term follow up, potential confounders and potential of inappropriate coding, caution should be exercise in extrapolating results of these studies or comparing TAVR with SAVR based on such data.

 

Flyer from Future

In addition to various studies and presentations from all across the nation and the international scientific community, AHA18 had dedicated sessions for Structural Heart Disease, 3D imaging, and Artificial Intelligence, giving us a glimpse of the near future for SHD. Cardiac imaging is critical to plan and perform any transcatheter based structural heart disease procedure, and 3D printing has potential to revolutionize the treatment planning of patients with SHD as highlighted by Dr. Frank Rybicki (University of Ottawa) during his presentation at AHA18. A potential role of 3D bioprinting for preoperative planning for TAVR and SAVR and the future of this technology was further emphasized in another interesting talk “Personalized Care: Print your own valve,” by Dr. Kamal Khabbaz (Beth Israel Deaconess Medical Center, Harvard Medical School, MA).

My experience during 2018 session has reinforced my believe that AHA has the potential to be ‘The Platform’ to present and promote SHD science.

 

References:

  1. Arora S. Trends in inpatient complications after transcatheter and surgical aortic valve replacement in the TAVR era. Presented at: AHA 2018. November 11, 2018. Chicago, IL.
  2. Kalra R. New-onset atrial fibrillation after aortic valve replacement: evaluation of a national cohort. Presented at: AHA 2018. November 12, 2018. Chicago, IL.

 

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Management of Stroke Patients: A One Man Show or A Tag-Team?

Atrial fibrillation (AF) increases risk of stroke up to 5 folds, resulting in considerable physical, cognitive impairment and high mortality1. Thus, AF related strokes are very expensive to treat compared to non-AF strokes2. Oral anticoagulation is a well-established therapy in the majority of stroke cases3. Warfarin reduces the risk of stroke by 64% and mortality by 30% compared to placebo3.

Recent data from the pinnacle registry presented by ‘Roopinder Sandhu, Edmonton, AB, Canada’ at the Scientific Sessions 2018, highlighted three key challenges in anti-coagulants management in stroke patients4. Data from a national outpatient registry reported over 700,000 patients had a diagnosis of atrial fibrillation5. Although oral anticoagulation use increased over time, around 40% of patients who are eligible for anti-coagulation never got started on therapy5. The second gap is sub-therapeutic dosing. Recent data from the orbit registry evaluated over 5700 patients who were recently started on a new drug and reported that one in eight patients were either underdosed or overdosed6. Further, there was a higher rate of adverse events in patients who had dosing that was sub therapeutic. The third gap is non-adherence. Data from administrative claims based on a large U.S. commercial insurance database, calculated adherence based on the fill date and the days of supply on the pharmacy claims over a median of 1.1 years7. Less than half of patients who were started on a drug therapy reached the threshold of proportion days covered of 80% or higher. This proportion was less for patients who were on Warfarin.

Given the public health consequences of untreated AF, it is necessary to evaluate different strategies to deliver stroke prevention therapy. Data from 30 randomized clinical trials evaluating the impact of pharmacists, versus standard care, showed superior results in the pharmacist care group in reducing systolic blood pressure (by 8 mm HG), diastolic blood pressure (by 4 mm HG) and total cholesterol (by 17 milligrams DL) and LDL (by 13 mg DL)10. This was done through educational intervention and identification of drug related problems followed by early feedback to the treating physician.

Roopinder added a few possible explanations to what could be driving such impact in the Canadian setting. Typically, a general practitioner would be dealing with patients with a higher evidence of chronic diseases. Further, patient demands often exceed the available physician capacity.

While these results collectively suggest that pharmacist led strategies may be a promising way forward because of their accessibility, drug expertise and their ability to build a trusted relationship. A few key things should be considered. First, that anticoagulation remains to be a complicated problem when it comes to individual patients, with many factors playing a role in the decision process including; medical history (as prior bleeding) and patient preferences. Second, while these interventions seem beneficial in the short-term it may lead to the same shortcomings in the long-term with the increase in demand on the pharmacists as the main provider.

Finally, a key question remains, would a collaborative approach between physicians and pharmacists yield better outcomes through reducing the burden on both providers and simultaneously increasing the time allocated to stroke patients on a case-by-case basis?

 

REFERENCES

  1. Developed with the special contribution of the European Heart Rhythm Association (EHRA), Endorsed by the European Association for Cardio-Thoracic Surgery (EACTS), Authors/Task Force Members, Camm, A. J., Kirchhof, P., Lip, G. Y., … & Al-Attar, N. (2010). Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). European heart journal31(19), 2369-2429.
  2. Stewart, S., Murphy, N., Walker, A., McGuire, A., & McMurray, J. J. V. (2004). Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart90(3), 286-292.
  3. Ruff, C. T., Giugliano, R. P., Braunwald, E., Hoffman, E. B., Deenadayalu, N., Ezekowitz, M. D., … & Yamashita, T. (2014). Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. The Lancet383(9921), 955-962.
  4. Sandhu, R. K., Guirguis, L. M., Bungard, T. J., Youngson, E., Dolovich, L., Brehaut, J. C., … & McAlister, F. A. (2018). Evaluating the potential for pharmacists to prescribe oral anticoagulants for atrial fibrillation. Canadian Pharmacists Journal/Revue des Pharmaciens du Canada151(1), 51-61.
  5. Marzec, L. N., Wang, J., Shah, N. D., Chan, P. S., Ting, H. H., Gosch, K. L., … & Maddox, T. M. (2017). Influence of direct oral anticoagulants on rates of oral anticoagulation for atrial fibrillation. Journal of the American College of Cardiology69(20), 2475-2484.
  6. Steinberg, B. A., Peterson, E. D., Kim, S., Thomas, L., Gersh, B. J., Fonarow, G. C., … & Piccini, J. P. (2015). Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Circulation131(5), 488-494.
  7. Yao, X., Abraham, N. S., Alexander, G. C., Crown, W., Montori, V. M., Sangaralingham, L. R., … & Noseworthy, P. A. (2016). Effect of adherence to oral anticoagulants on risk of stroke and major bleeding among patients with atrial fibrillation. Journal of the American Heart Association5(2), e003074.
  8. Santschi, V., Chiolero, A., Burnand, B., Colosimo, A. L., & Paradis, G. (2011). Impact of pharmacist care in the management of cardiovascular disease risk factors: a systematic review and meta-analysis of randomized trials. Archives of internal medicine171(16), 1441-1453.

 

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The Future of Wearable Technology & Detecting Atrial Fibrillation at AHA18

Like many of us, I have several family members who experience atrial fibrillation (AFib) regularly, as between 2-6 million people in the United States have this disorder. My father-in-law in particular has experienced difficultly with AFib recently and because he knows I study the heart, he often asks me about different treatment options and advice for handling his disease. Of course since I’m a basic research scientist, I always remind him that I’m not that kind of doctor and gently recommend he talk about it with his medical doctor and receive second opinions. However, when I got the chance to attend the AHA’s Scientific Sessions 2018 for the first time as an AHA Early Career Blogger, I knew I wanted to attend some sessions about AFib so I might have a little more to say for the next time I see my family. As a basic researcher, I don’t often get the often opportunity to hear from physicians about the day-to-day AFib issues they encounter with their patients.

Naturally, I jumped at the chance to attend the “Hey Doc, My Wristband Says I Have AF What Do I Do?” session yesterday afternoon. I was initially drawn to this particular event because my husband and I actually bought my father-in-law a wearable device last year for Christmas when he expressed interest in counting his steps and also keeping an eye on his heart rate, based on a comment from his doctor. Surprisingly though, the gift backfired since my father-in-law’s anxiety about his heart rate skyrocketed after he started wearing the device, because anytime it gave him an “abnormal” heart rate alert, he would get nervous and eventually ended up just staring at the device all day. So we all agreed it would be best if he just stopped wearing it. During this time, I kept wondering how accurate these devices actually are, and if my father-in-law actually was experiencing AFib that regularly, or maybe these were just false positives? Luckily, medical researchers primed to study this question were already on it, because the Apple Heart Study was initiated last November.

This collaboration between Apple and Stanford, spearheaded by Dr. Marco Perez, is a progressive clinical trial that uses data from Apple Watch devices from over 400,000 participants. The main purpose of this unprecedented study is to examine if AFib can be reliably diagnosed from irregular pulse notification data from wearable devices. In this session, Dr. Perez outlined how easy it is for participants for to sign up for the study and how a single reminder email from Apple actually doubled the amount of study participants almost over night, highlighting the power of these types of collaborations. One of the most interesting aspects of this study is how it is all done remotely. Interested participants just have to download the application, where they consent to study and then the algorithm monitors them. If an individual receives an irregular heart rate alert, they are recommended to a local doctor who can then prescribe them a patch monitor, which is mailed to the participants. After the monitor period, the participants simply mail the patch monitor back to Stanford where the scientists analyze the data. If AFib or other cardiac disorders are identified from this data, the participants are then referred to a doctor to get treatment. The clinical trial scientists never even meet the participants.

Dr. Perez mentioned that they are hopeful to have all of the data analyzed by the end of January as they are still collecting data everyday. Some of the most pressing questions this study hopes to answer is how accurate are these irregular heart rate alerts in diagnosing AFib? False positive rates are particularly of interest since many in the community think these devices could be causing alert when none is needed. Also an important thing to consider is how does the user’s behavior change after the alert? I know my father-in-law’s anxiety increased after getting these alerts, but I’m sure some people might find these devices as a comfort, particularly if this study reveals them to be accurate. Since many physicians here at the AHA 2018 Sessions have expressed that their patients are coming into their office with irregular alert data from their wearable devices, I’m sure doctors and users alike are excitedly awaiting the results of this powerful study – I know I am. The most important take home from this study truly has to be the actual size and manner in which it has been conducted. The results of this study have the potential to impact the future of clinical trials in general, since a trial of this magnitude run completely virtually has never been done before.

Picture source: https://www.apple.com/newsroom/2017/11/apple-heart-study-launches-to-identify-irregular-heart-rhythms/

 

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WATCHMAN: An Alternative to Warfarin for the High Risk Patient

“Wisdom consists of the anticipation of consequences”
Norman Cousins

I recently saw Mr. John Doe for atrial fibrillation (AF). Well into his eighties, he enjoys a good quality of life. This elderly gentleman is mostly unaware of his paroxysms of AF. However, he had also suffered a stroke in the past, and as such was managed with warfarin. He was lucky. Recently, he experienced a gastrointestinal hemorrhage, requiring temporary reversal of his anticoagulant in addition to receiving a few pints of blood. There were no apparent clinical triggers for this event. Mr. Doe is not a fictional person but is a typical example of what is a common clinical dilemma: how best to protect against stroke in a patient who is at high risk, yet becomes intolerant to warfarin.

Previously, these patients were commonly switched to aspirin alone as a poor alternative to anticoagulation. Most clinicians would feel apprehensive of taking a gamble switching to novel oral anticoagulants which do not have available reversal agents (at the time this blog was written).

So, what then?

Enter the “Watchman.”

The majority of thromboembolic strokes in patients with AF originate in the left atrial appendage (LAA). The function of this structure is to assist with atrial transport, however during AF, atrial blood flow becomes impaired and stasis can occur in the LAA leading to thrombus formation at this location. Fragmentation and embolization of thrombi can lead to stroke, which is commonly disabling. The presence of comorbid factors such as diabetes, heart failure among other clinical variables can further increase this risk [1].

The last several years has witnessed the development and refinement of procedures referred to as left atrial appendage occlusion. Although there are several of the devices available worldwide, I will refer to the WATCHMAN system which is approved for use in the United States. In brief, the WATCHMAN device resembles a small umbrella (Figure 1). The FDA approved the device for the purpose of preventing embolic stroke with non-valvular AF. The available data that lead to its approval implies a non-inferiority to warfarin [2,3]

the WATCHMAN device resembles a small umbrella

Figure 1. (accessed from www.bostonscientific.com; www.modernhealthcare.com)

The method of device introduction is via a femorally placed venous sheath delivered transseptally (from right to left atrium). The destination of the device is the ostium of the LAA (Figure 2). The ultimate goal of the procedure is to totally exclude the LAA from the chamber, thus preventing flow into and from the LAA, in effect precluding thrombus formation. The procedure is performed with the guidance of transesophageal echocardiography, and typically under general anesthesia. The duration of the implant typically does not exceed an hour. Patients are continued on warfarin during the initial perioperative phase.

the destination of the device is the ostium of the LAA

Figure 2. (Accessed from www.bostonscientific.com; openaccessjournals.com)

Generally, after a forty-five-day period, transesophageal echocardiography is repeated to confirm the absence of peri-device leaks and verify device endothelialization. If the results are favorable, patients can often stop warfarin and switch to antiplatelet therapy. Presently, the available evidence compares WATCHMAN to warfarin, and comparisons to other anticoagulants is lacking.

It appears that enthusiasm for the WATCHMAN appears to be growing. For patients who require long-term warfarin use, but are at risk for hemorrhagic complications, this device appears to be a very good option. Cumulative experience will invariably lead to further improvements in design and greater safety [4,5].
 
References

  1. Lip GY, Lane DA. Stroke prevention in atrial fibrillation: a systematic review. JAMA. 2015;313:1950-62
  2. Holmes DR Jr, Kar S, Price MJ, Whisenant B, Sievert H, Doshi SK, Huber K, Reddy VY Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial.J Am Coll Cardiol. 2014;64:1-12
  3. https://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=2 81&bc=ACAAAAAAAgAAAA%3d%3d&
  4. Reddy VY1, Doshi SK2, Kar S3, Gibson DN4, Price MJ4, Huber K5, Horton RP6, Buchbinder M7, Neuzil P8, Gordon NT9, Holmes DR Jr10; PREVAIL and PROTECT AF Investigators. 5-Year Outcomes After Left Atrial Appendage Closure: From the PREVAIL and PROTECT AF Trials.J Am Coll Cardiol. 2017;70:2964-2975
  5. Obeyesekere MN.Watchman Device: Left Atrial Appendage Closure For Stroke Prophylaxis In Atrial Fibrillation.J Atr Fibrillation. 2014; 7: 1099

Christian Perzanowski Headshot

Christian Perzanowski is an electrophysiologist in Tampa, FL. His main interests are in ablation techniques for atrial fibrillation and device therapy for congestive heart failure. He reports no conflicts of interests.

Apollo Beach, FL (05/17, CP)

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Deciphering the CABANA trial and what if anything do the results mean to the management of atrial fibrillation?

“The truth is rarely pure and never simple.”
Oscar Wilde

“Facts do not cease to exist because they are ignored.”
Aldous Huxley

As is apparent from my previous blogs, I am very passionate about atrial fibrillation (AF). Undoubtedly, the most common arrhythmia nationally, and likely worldwide, can cause disabling symptoms, lead to a stroke and exacerbate heart failure. In my experience, patients with AF can be categorized as either asymptomatic, or highly affected. Essentially the former are unaware of their diagnosis, and are often found to have AF by serendipity. Life is in fact very easy for them, as well as their clinicians: anticoagulate, rate control and move on.

Now, for those who are symptomatic, there exist management challenges. AF is classified as paroxysmal, which is an intermittent or periodic form of arrhythmia; persistent, which is a sustained form and generally felt to be a progressed state of AF; or permanent, where no interventions are done. There is a paucity of available antiarrhythmic agents to treat and suppress AF. Antiarrhythmic drugs have earned a reputation of not being very effective while causing significant systemic adverse effects. Clinicians who care for symptomatic AF patients have certainly observed them to often experience shortness of breath, chest discomfort, loss of stamina, sensation of tachycardia and in some cases heart failure. Not uncommonly, these symptoms lead to anxiety as well as a compromised quality of life. In short, these patients must be treated.

Over the last decade, the techniques employed to treat AF by catheter-based means have improved in efficacy, even for more advanced forms of persistent AF. Although far from ideal, a number of studies have demonstrated ablation methods (e.g. radiofrequency, referred to colloquially as “heat” or cryoablation, “freezing”) to be superior to attempts at drug suppression. This is no surprise, as ablation addresses the problem directly (e.g. preventing AF from initiating) by calculated tissue destruction. While repeat studies are sometimes needed, the improvement in quality of life and improvement in heart failure class (such as observed with CASTLE-AF, AATAC) are known benefits1,2.

CABANA (Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial) sought to determine whether AF ablation versus antiarrhythmic drug therapy could prevent a composite endpoint of total mortality, disabling stroke, serious bleeding, or cardiac arrest1. This was a large randomized study with over 2,000 patients. The results, which were presented at the annual Heart Rhythm Society last month, yielded a rather disappointing result: ablation was not superior to drugs for preventing the above composite endpoint2. That’s a rather dubious final score.

In spite of acknowledging what Wilde and Huxley might say, I would like to reconcile several of CABANA’s limitations:

– Personally, I have a grievance with the use of a “composite score” in the above scenario; stroke and “serious bleeding” are in no way equivalent; mechanistically, how would the investigators theorize that ablation could prevent a cardiac arrest?
– Death, while inevitable is indeed a categorical variable, one is either alive or not. Given that the causes of death are innumerable, it does not seem appropriate to consider that ablation could prevent all causes of death. Rather than try to postulate that ablation, or a potpourri of antiarrhythmics could stave of death, a more appropriate measure would be to ascertain prevention of death from heart failure.
– Approximately 25% of patients assigned to drug therapy crossed to ablation. Notably, some sources cited difficulty in enrollment as patients and referring physicians likely felt that ablation would be more beneficial.
– The ablation techniques used, as were the drugs prescribed, were left to the discretion of the treating physicians. Hence, the methods employed were not uniform, and paroxysmal AF cases were pooled with more advanced forms of persistent AF.
– How about continued drug therapy after ablation? The POWDER-AF investigators were able to show less AF burden with continued antiarrhythmic support following AF ablation. This should be expanded upon with larger studies.

From my perspective, I do not believe that CABANA results will affect my practice. Many of us will be curious to see publications regarding future subanalysis. In my opinion, patients who are very symptomatic with AF and have not responded to antiarrhythmics should be treated with AF ablation, and especially those who have developed cardiomyopathy or worsened heart failure as a result of AF6.

References

  1. http://circ.ahajournals.org/content/early/2016/03/30/CIRCULATIONAHA.115.019406
  2. https://www.nejm.org/doi/full/10.1056/NEJMoa1707855
  3. https://clinicaltrials.gov/ct2/show/NCT00911508
  4. https://www.nhlbi.nih.gov/news/2018/atrial-fibrillation-catheter-ablation-or-drug-therapy-results-are
  5. Duytschaever M, Demolder A, Phlips T, Sarkozy A, El Haddad M, Taghji P, Knecht S, Tavernier R, Vandekerckhove Y, De Potter T. Pulmonary vein isolation With vs. without continued antiarrhythmic Drug treatment in subjects with Recurrent Atrial Fibrillation (POWDER AF): results from a multicentre randomized trial. Eur Heart J. 2018;39:1429-1437
  6. https://www.hrsonline.org/Policy-Payment/Clinical-Guidelines-Documents/2017-HRS-EHRA-E CAS-APHRS-SOLAECE-Expert-Consensus-Statement-on-Catheter-and-Surgical-Ablation-of-Atrial-Fibrillation

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Christian Perzanowski is an electrophysiologist in Tampa, FL. His main interests are in ablation techniques for atrial fibrillation and device therapy for congestive heart failure. He reports no conflicts of interests.

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Tampa, FL (8/17 CP)

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Shared Decision Making In Cardiac Care

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Shared decision making (SDM) is an approach both patients and clinicians can use to improve patient education and discussion in decision making. Decision aids are tools that promote SDM by improving patient-clinician communication about all treatment options and how the risks and benefits fit with their personal values and preferences. Today, we’ll chat about SDM in the context of cardiac care, with examples from atrial fibrillation and heart failure, as well as the entire CAD spectrum.

A Chronological Look at SDM
In 2012, Karen Sepucha reflected on shared decision-making and patient decision aids in an editorial for Circulation: Cardiovascular Quality and Outcomes. Two studies published in the same issue evaluated the impact of decision aids in urgent management of acute coronary syndrome (The Chest Pain Choice Decision Aid) and vascular access choice for coronary angiogram procedures. These studies reflect scenarios that are not traditionally thought to be amenable to SDM, but the results show that SDM in the emergency department and regarding technical treatment decisions, such as femoral versus radial access, had a positive impact on patient knowledge and decisional conflict. Sepucha’s concluding statement still rings true today: “Despite considerable evidence from many studies of decision aids, few of these tools are used routinely in practice.”

There are several challenges to using decision tools in practice. Decision aids should be brief and easily incorporated into the workflow of clinical practice, as well as easily accessible in the public domain. In 2015, CMS implemented a policy around healthcare for atrial fibrillation patients requiring all non-implanting physicians to use evidence-based decision tools and SDM practices. A 2017 article by Megan Coylewright and David Holmes in Circulation caution against this CMS mandate for SDM for patients with atrial fibrillation. The authors cite reasons reminiscent of Sepucha’s conclusions in 2012. Coylewright and Holmes point out that there is limited guidance on navigating SDM for patients with atrial fibrillation at risk for stroke. Specifically, while research consistently shows that “decision aids improve patient outcomes including knowledge, engagement, and satisfaction”, SDM has yet to become an integral part of clinical practice for a variety of reasons, both on the patient side and the clinician side. For example, barriers to use of SDM by physicians include insufficient training in the skillsets necessary to implement SDM, such as “inadequate assessment of patient preferences,” in addition to logistic challenges to implementation, whether at the institutional level, the lack of publicly available decision aids, or the time availability during patient-clinician interactions to thoroughly discuss patient preferences.

Atrial Fibrillation
Atrial fibrillation presents a particularly challenging case for optimizing treatment, due to low prescription, low adherence due to side effects and frequent testing, as well as increased risk of negative reactions due to polypharmacy. Thomson et al. found that atrial fibrillation patients at risk of stroke may deicide to forgo treatment with anticoagulants to avoid the medications’ adverse effects, with the knowledge that their stroke risk later on increased. However, professional guidelines on treatment of atrial fibrillation promote SDM and use of evidence-based decision tools while recognizing that inviting patients to participate in care decisions can be challenging to physicians.

A recent systematic review, “Availability of Patient Decision Aids for Stroke Prevention in Atrial Fibrillation” by O’Neill and colleagues summarize the current state of decision aids for patients with atrial fibrillation at risk for stroke and their treating physicians. The current landscape of pharmacologic therapy for stroke reduction includes multiple DOACs, implantable LAA closure devices, aspirin, and warfarin – each treatment with benefits and trade-offs that must be considered “in the context of individual values and preferences and willingness to adhere to therapy”. Many of the decision aids in the studies reviewed by O’Neill et al. did not display all therapeutic choices, were delivered to patients primarily by nonphysicians, and were not publicly available.

Depression and CAD
SDM and decision tools pair nicely with assessment of depression in heart disease patients. In a recent paper, “Identifying and Managing Depression in Patients with CAD,” Aimee Salzer Pragle and Susan Salashor discuss the epidemiology and risk factors, clinical presentation, assessment tools, and treatment options for depression in patients with heart disease. In a 2011 review, Christopher Celano and Jeff Huffman estimated that 20-40% of patients with CAD may suffer from depression, and despite the availability of screening tools brief enough for clinical practice (such as the Patient Health Questionnaire-9 or -2), depression often goes unrecognized in cardiac care. Depression in patients with CAD is associated with progression of heart disease, poor quality of life and physical functioning, repeat cardiac events, and 2-2.5 fold increased risk of mortality [link]. Risk factors for depression in patients with CAD include “younger age, female sex, a history of depression, social isolation, previous cardiac events, and diabetes” and depression can increase risk of suicide, homicide, and substance abuse (which can exacerbate cardiac symptoms and promote further degeneration).

Innovative Frameworks – A Segue to Implementing SDM?
From the clinician side, disease-specific evaluation frameworks inclusive of all relevant aspects of a patient’s health provide another avenue towards optimizing patient-clinician communication. For example, in a recent paper, Gorodeski et al. present a multi-domain framework for managing heart failure and the associated questionnaires and tools that go with each task.

Gorodeski image
These tools include the Mini Nutritional Assessment Short Form (MNA-SF), the Mini-Cog and PHQ-2 (Patient Health Questionnaire) for mental and emotional state, gait speed, timed Up and Go test, FRAIL questionnaire, and ADL/IADL discussion for assessing physical function, as well as inquiries to social support at home, adaptable and safe environment plans, access to nutrition and transportation, as well as abilities and support in medication management (Table 1, Gorodeski et al).

 Does your department or institution use shared decision making or decision aids in practice?

 What barriers to implementation do you see in incorporating these tools into everyday patient interactions?

SDM and Decision Aids Resources
The Ottawa Hospital Research Institute hosts an up-to-date A to Z inventory of patient decision aids, and includes tools for angina, atrial fibrillation, CABG and other cardiac procedures, blood pressure medications, peripheral artery disease surgery, type 2 diabetes, depression, kidney disease and dialysis, and many others. Many of the tools geared towards cardiac care were in the form of informative articles for patients to read, or interactive tutorial-style pages for patients. None that I found were visual or brief enough to be used in clinical practice. Additionally, purely text-based “decision aids” are not useful for low-literacy populations, and online-only resources are not easily accessible for patients who are less tech-savvy. However, the Heart to Heart tool developed by the University of North Carolina General Internal Medicine department provides a user-friendly interface, even for the less technologically-savvy patients, that guides the user through several slides on how to join the discussion of their own treatment with their doctor. Similarly, the AHA Rise above Heart Failure initiative has two resources heart failure patients and physicians might find particularly useful: a guide to overcoming barriers to shared-decision making and a list of questions to ask the doctor. If you are a physician, reviewing these materials provides you with the guidance of what questions and topics to address during the clinic visit.

Quick links to select decision aids related to heart disease:

 

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Bailey DeBarmore is a cardiovascular epidemiology PhD student at the University of North Carolina at Chapel Hill. Her research focuses on diabetes, stroke, and heart failure. She tweets @BaileyDeBarmore and blogs at baileydebarmore.com. Find her on LinkedIn and Facebook.

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An Antidote To Factor Xa Inhibitors – Andexanet Alfa

“Success consists of going from failure to failure without loss of enthusiasm.” Winston Churchill

Treatment options for systemic anticoagulation (AC) have grown substantially during the last several years. One of the most common indications for AC is to reduce the risk of embolic stroke secondary to atrial fibrillation (AF). Although there are multiple reasons to anticoagulate, my column today references stroke prevention for AF. The major concern to both patients and clinicians is the risk of significant bleeding or hemorrhage. The ideal anticoagulant would effectively prevent stroke, hopefully at a low risk for bleeding and interact minimally with other agents. If required, the “perfect” agent could be easily reversed. That last caveat to perfection has proven elusive until recently.

In clinical practice, many patients will refuse AC based upon perceptions of death by uncontrollable bleeding. Notwithstanding the sensational television commercials paid for by legal firms waging lawsuits against pharmaceutical manufacturers, the thought of “bleeding out” understandably makes a reluctant patient even more apprehensive to initiate or continue AC. Nowadays, it is quite common to encounter patients who have studied the different drug options. In my experience, a common motive for rejection of AC is the absence of an antidote. Perhaps this can be better expressed in the words of one my patients… “I don’t want to bleed internally and die because they can’t stop the bleeding …”

Historically, warfarin (e.g. Coumadin) a Vitamin-K antagonist was the most commonly used agent. Widely available, the principal agent used to reverse warfarin effect is Vitamin-K itself. In 2010, the Federal Drug Administration approved Dabigatran, a direct thrombin inhibitor, as an option for stroke prevention for non-valvular AF. This agent became a popular alternative to warfarin. Strengthening its popularity, the ability to reverse and nullify its clinical effects became a reality. In the past few years, idarucizumab was developed as an antidote to dabigatran.

Further research lead to the development of Factor Xa inhibitors: rivaroxaban (Xarelto), Apibixan (Eliquis), and Edoxaban (Savaysa). Factor Xa is an important step in the coagulation cascade. In fact, it is at the convergence of both intrinsic and extrinsic pathways prior to the production of thrombin1,2. Although these AC drugs share desirable clinical characteristics such as convenient dosing, the lack of any significant drug-drug interactions, this class of drugs was saddled with the potential shortcoming of being available clinically without a means to reliably counter the effects.

Andexanet Alfa has been undergoing clinical studies evaluating its role a reversal agent to the class of Factor Xa class inhibitors. Simplistically, this antidote functions as a decoy receptor3. Given the favorable data, the FDA very recently approved its use4. The presence of such an antidote has potentially broad implications: giving patients and practitioners a certain level of comfort to prescribe a novel anticoagulant knowing there exists treatment means to stop hemorrhage related to AC therapy. How much Andexanet’s presence will be able to convince an apprehensive patient to start AC remains to be seen.

References

  1. Ansell J. Factor Xa or thrombin: is factor Xa a better target? J Thromb Haemost. 2007;5 Suppl 1:60-4
  2. Perzborn E, Roehrig S, Straub A, Kubitza D, Misselwitz F. The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat Rev Drug Discov. 2011;10:61-75
  3. Connolly SJ1, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, Bronson MD, Lu G1, Conley PB1, Verhamme P1, Schmidt J, Middeldorp S1, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J1, Goodman S, Leeds J, Wiens BL, Siegal DM, Zotova E, Meeks B, Nakamya J, Lim WT, Crowther M; ANNEXA-4 Investigators. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors.N Engl J Med. 2016;375:1131-41 4.https://www.thepharmaletter.com/article/fda-approves-andexxa-first-antidote-for-the-reversal-o f-factor-xa-inhibitors

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Christian Perzanowski is an electrophysiologist in Tampa, FL. His main interests are in ablation techniques for atrial fibrillation and device therapy for congestive heart failure. He reports no conflicts of interests.

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Crabtree, NC (1/18 CP)

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Options To Rat Poison – Other Mousetraps?

“The policy of being too cautious is the greatest risk of all.” Jawaharlal Nehru

Of all the potential complications associated with atrial fibrillation (AF), stroke is the most feared. Attempting to predict a stroke has proven to be a daunting task. The mechanism by which AF leads to a stroke is undoubtedly due to the formation of a thrombus within the left atrium, in particular the left atrial appendage (LAA). The latter structure serves to enhance the atrial contribution to ventricular diastolic filling. When AF sets in, effective atrial contractions are greatly minimized, and blood can become stagnant within the LAA and form a thrombus. Should parts of the thrombus embolize, a stroke can result. Such cerebrovascular events can be devastating.

My thoughts today will focus not on the symptoms caused by AF, and their treatments but to summarize medical options in stroke prevention. The mainstay of stroke prevention with this arrhythmia is the use of an anticoagulant. For many years, warfarin was the only anticoagulant available. Although this agent can be a forgiving drug if a dose is missed, it can also be the most fickle. Not uncommonly, patients often perceive this agent to be “rat poison.” Historically, this was its previous use. The drug’s notoriety can be appreciated by the numerous interactions with certain foods (particularly ingredients which have a high content of vitamin K which inhibit its actions), or with other medications such as antibiotics. Additionally, excessive anticoagulation may result with ceratin cardiac medications such as the widely used antiarrhythmic amiodarone. Unfortunately, when the anticoagulant level, colloquially known as the INR, increases above the desired clinical range, bleeding may occur1. Frequent, at least monthly office monitoring is recommended. As such, the quality of life may be impacted for many patients.

In my practice, I have encountered numerous patients that were very determined to avoid warfarin despite facing a risk of stroke. The anticoagulation landscape changed with the introduction of the “novel oral anticoagulants” (NOACs) which exert their effects at different levels of the coagulation cascade. The development of the direct thrombin inhibitor dabigatran (marketed as Pradaxa) was a welcome option to warfarin. However, true to the nature of the class of drugs with which it belongs to, bleeding complications still occur. Since its approval approximately seven years ago, dabigatran is no longer the only NOAC2. The last several years saw the emergence of the factor Xa inhibitors rivaroxaban (Xarelto), apibixan (Eliquis) and most recently edoxoban (Savaysa)3-5.

With that being said, the clinical studies used to obtain FDA approval for use in the United States concluded that collectively these agents have relatively low rates of bleeding. However, the post-marketing experience may be very different than what is observed in the safe confines of a clinical trial. It is vital that there exists medically equivalent options to prevent an AF-related stroke. In general, The NOACs have the clinical advantage of not commonly interacting with other medications, and typically do not require any change in dietary habits or such constraints. Frequent monitoring is not universally required, and other than adjusting for renal function, dosing is often straightforward. With the exception of dabigatran, the other NOACs do not have any readily available reversal agent to counter an acute bleeding event or hemorrhage. This is potentially a serious limitation, and a clinically relevant factor which must be discussed with patients when counseling them on anticoagulation. The ideal “drug” would be completely effective at preventing an atrial thrombus from occurring, and yet lead to no bleeding6. Neither of those objectives are tangible options yet. At the end of the day, both the clinician and patient need to decide which medicine is most likely to be protective and be an acceptable risk.
 
References

  1. Seet RC, Rabinstein AA, Christianson TJ, Petty GW, Brown RD. Bleeding complications associated with warfarin treatment in ischemic stroke patients with atrial fibrillation: a population-based cohort study. J Stroke Cerebrovasc Dis. 2013;22:561-9
  2. Larsen TB, Rasmussen LH, Skjøth F, Due KM, Callréus T, Rosenzweig M, Lip GY. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol. 2013;61:2264-73
  3. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-91
  4. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-92
  5. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093-104
  6. Deshpande CG1, Kogut S, Laforge R, Willey C. Impact of medication adherence on risk of ischemic stroke, major bleeding, and deep vein thrombosis in atrial fibrillation patients using novel oral anticoagulants. Curr Med Res Opin. 2018 Jan 16:1-17. doi: 10.1080/03007995.2018.1428543. [Epub ahead of print]

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Christian Perzanowski is an electrophysiologist in Tampa, FL. His main interests are in ablation techniques for atrial fibrillation and device therapy for congestive heart failure.

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Apollo Beach, FL 01/18 CP.