July/August 2021

Matters of the Heart: What’s New in Atrial Fibrillation Treatment
By Jamie Santa Cruz
Today’s Geriatric Medicine
Vol. 14 No. 4 P. 18

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. It’s characterized by an irregular beating of the atrial chambers of the heart, causing less efficient blood flow into the ventricles. In some cases, AF occurs in brief episodes, but in other cases the irregular rhythm is persistent.

The prevalence of AF is increasing due to population aging (the disease is primarily a disease of the elderly) and rising rates of obesity. It is expected to affect as many as 12 million people by the year 2030.1 AF is of considerable concern because it increases the risk of stroke up to five-fold2 and is a significant risk factor for other serious conditions such as heart failure and dementia.3

Fortunately, five important new developments are bringing dramatic changes to AF treatment that will allow significantly more patients to achieve remission from arrhythmia.

Early Rhythm Control Is Key
There are two basic strategies for managing AF, and for decades, clinicians have disagreed on which is superior. The first and more aggressive strategy is rhythm control, which relies on either antiarrhythmic drugs or cardiac ablation to maintain sinus rhythm. The other strategy is rate control, which allows AF to persist and focuses on simply slowing down the ventricular rate.

Several studies in the early 2000s indicated that the two strategies offered approximately equal benefit,4-6 leading many clinicians to believe rhythm control was not important unless the patient was experiencing symptoms not alleviated by rate control.

Last year, however, the publication of a multinational European trial (EAST-AFNET 4) transformed the debate by demonstrating a clear advantage of early rhythm control for severe cardiovascular events and mortality.7 The study, published in the New England Journal of Medicine, included 2,789 patients at 135 centers across Europe. All participants had had been diagnosed with AF less than one year before enrollment; all also had cardiovascular conditions. Once enrolled, participants were randomized to receive either early rhythm control therapy (via either antiarrhythmic drugs or cardiac ablation) or usual care (in which patients were treated only for AF-related symptoms).

The researchers found that 316 of those who received usual care experienced a serious cardiovascular outcome—namely, stroke, death from cardiovascular causes, or hospitalization with worsening of heart failure or acute coronary syndrome (five events per 100 person-years). By contrast, only 249 of those receiving early rhythm control therapy experienced one of those outcomes (3.9 events per 100 person-years).

“This study shows that rhythm control has benefits beyond symptom relief,” says Eric Buch, MD, a cardiac electrophysiologist who practices at UCLA Health in Los Angeles and is also section editor of the Journal of the American College of Cardiology: Clinical Electrophysiology. “In patients who were recently diagnosed with atrial fibrillation, an early rhythm control strategy can improve not just symptoms but also hard outcomes like stroke and mortality.”

One reason EAST-AFNET 4 produced a different outcome than earlier trials is that previous studies enrolled patients who had already had AF for some time, whereas this study examined the impact of early rhythm control. “That is important because the longer your heart is out of rhythm, the harder it is to correct,” says John Day, MD, a cardiac electrophysiologist at St. Mark’s Hospital in Salt Lake City and coauthor of The AFib Cure: Get Off Your Medications, Take Control of Your Health, and Add Years to Your Life. “If you want to get people back into rhythm, you need to move quickly before you get irreversible changes to the heart that make it very difficult.”

Historically, geriatric patients have been passed over for rhythm control more frequently than have younger patients. In the new study, however, the average age of participants was 70, demonstrating that early rhythm control is important even for older adults. “This is a paradigm shift for the geriatric patient,” says Day, who is also a past president of the Heart Rhythm Society.

Ablation Is an Appropriate First-Line Treatment
If the major contribution of EAST-AFNET 4 was to show the advantage of early rhythm control therapy, several other studies in the past two years have shed new light on how to achieve rhythm control. Specifically, research now suggests that cardiac ablation is superior to drug therapy for reducing recurrence of arrhythmia.

The most recent trials to establish this point are the EARLY-AF and STOP-AF First trials, both of which were published in the New England Journal of Medicine.8 In the EARLY-AF trial, AF recurred in 67.8% of those on antiarrhythmic drugs compared with only 42.9% of those who received ablation. Symptomatic arrhythmia occurred in 26.2% of those receiving drugs compared with only 11% of those who received ablation.9

The CABANA trial, published in 2019 in JAMA, found similar results. The study, which is the largest international randomized controlled trial to date comparing ablation with drug therapy, found that ablation not only reduced AF recurrence by 48% compared with drug therapy alone but also was superior for relieving symptoms and improving long-term quality of life—benefits that were sustained for five years.10

“It was already established from previous studies that for drug-refractory patients, ablation was an effective method of maintaining sinus rhythm, but the procedure was offered as a second-line treatment,” Buch says. What the new studies demonstrate, he says, is that ablation is appropriate as a first-line treatment, not merely an alternative treatment when drug therapy fails.

While it appears clear at this point that ablation is more effective at reducing AF recurrence and improving quality of life, evidence about whether ablation is superior for reducing strokes and mortality remains inconclusive.11

The CABANA trial is instructive. Its investigators found a trend toward reduced risk of strokes and mortality among participants randomized to ablation compared with those randomized to drug therapy alone, but the difference was not statistically significant. However, the lack of a statistically significant finding is likely related to the fact that a significant percentage of patients who were randomized to a particular treatment group received a therapy other than what they were assigned. When investigators examined the results based on which treatment the patient actually received, they found that those who received an ablation had a statistically significant 40% lower risk of death and a 33% lower risk of the combination of death, disabling stroke, serious bleeding, or cardiac arrest.

Although not definitive, several recent large observational studies support the theory that ablation reduces risk of serious outcomes in AF.

One such observational study was actually conducted in parallel to the CABANA trial in an attempt to assess the generalizability of the CABANA results; its findings provide “big data” evidence that ablation lowers mortality, stroke, and other serious events in AF.12

Another important observational study, published in 2020, used data from the Korean National Health Insurance Service database to examine whether ablation lowered incidence of a composite outcome that included death, heart failure admission, and stroke/systemic embolism, compared with drug therapy alone. It found that ablation was indeed linked to a dramatic 53% lower risk of the composite outcome as compared with drug therapy. The association was observed in all subgroups regardless of the patients’ ages or sex and whether they had hypertension, heart failure, or AF recurrence.13

In addition to all the other benefits of ablation, another important factor to consider is the impact of ablation on dementia. In a 2020 study published in the European Heart Journal, Korean researchers found that catheter ablation for AF was linked to reduced dementia risk: After a median follow up of 52 months, the incidence of dementia was only 5.6 per 1,000 person-years in patients who had been ablated, compared with an incidence of 8.1 per 1,000 person-years in patients who received medication therapy.14

Pulsed Field Ablation Is Set to Transform Ablations
At present, the two most common methods of ablation involve either heating the tissue to be ablated (radiofrequency ablation) or freezing it (cryotherapy). Now, however, a new method appears poised to overtake the old methods. “The entire field is super excited about this therapy called pulsed field ablation [PFA],” says Dhanunjaya Lakkireddy, MD, a cardiologist specializing in electrophysiology and the executive medical director for the Kansas City Heart Rhythm Institute in Kansas City, Missouri.

The major weakness of both radiofrequency and cryotherapy ablations, according to Lakkireddy, is that neither method ablates tissue precisely. This means both methods carry risk of collateral damage, which can include injury to the phrenic nerve or the esophagus and narrowing of the pulmonary vein. Furthermore, though the cornerstone technique of cardiac ablation is to isolate the pulmonary veins, reconnection of the pulmonary veins is very common with current methods of ablation.15

PFA seems likely to solve both problems by providing a method of ablation that’s both safer and more effective. PFA relies on localized application of high-intensity electrical pulses, with each pulse lasting only nanoseconds. The pulses create high-voltage electrical fields that create tiny pores (electroporation) in the cell membrane, triggering cell death in a very precise manner.16 “Pulsed field ablation is basically similar to radiofrequency energy, but it’s a different wave form, and as a result you can create tissue destruction more precisely, minimizing collateral damage,” Lakkireddy says.

In the last few years, the first clinical trials in have demonstrated that pulsed field energy can successfully be used to achieve durable pulmonary vein isolation while avoiding the serious complications associated with other methods.17,18 Last year, a first-in-human trial used a point-by-point ablation technique to demonstrate that PFAs could safely achieve not only pulmonary vein isolation but also durable flexible lesion sets such as linear lesions.19 An additional clinical study from the same group, also published last year, demonstrated that PFAs can successfully treat not only paroxysmal AF but also persistent AF.20

“I do think it’s early, because we are still awaiting large clinical trials in humans. But observational studies suggest that PFA might be a dramatically improved way of isolating pulmonary veins compared to anything we have available now, if it pans out,” Buch says.

Alternatives to Blood Thinners
Stroke is the most-feared complication of AF, particularly since strokes that occur in AF are often more debilitating than strokes in patients without AF and are associated with higher rates of mortality. For decades, clinicians have relied on blood thinners to minimize stroke risk, but the disadvantage of blood thinners is that they cause bleeding—particularly in elderly patients (among whom AF is most prevalent).

Over the last two decades of research, the left atrial appendage, a pouch attached to the left upper chamber of the heart, has been identified as a major source of clots and thus strokes. Eliminating or closing off this structure has been found to decrease the risk of stroke and eliminate the need for blood thinners. Two major trials, PROTECT and PREVAIL, both demonstrated improved the safety and similar efficacy of left atrial appendage closure compared with warfarin in AF patients.21,22

As a result, devices that enable left atrial appendage closure are gaining popularity as an alternative to blood thinners. One of these, the Watchman device, was approved by the FDA in 2015, and a newer version, the Watchman FLX, received FDA approval in 2020 after demonstrating superiority to the original device.23 Several other devices are also in various stages of clinical research, including the Amulet device and the LARIAT device. “This is a rapidly evolving area of AF science that can completely change the way we address stroke risk in AF patients” says Lakkireddy, who directs the annual International Symposium on Left Atrial Appendage.

Lifestyle Is Key for Prevention and Treatment
It’s long been known that lifestyle-associated factors influence the incidence of AF, but evidence is now accumulating that lifestyle changes can also significantly affect AF once a patient has been diagnosed.

“Historically, you would get diagnosed with AFib, they would put you on a blood thinner, they would put you on drugs to slow down the heart, and tell you, ‘Just live with it.’ Live with AFib, live with the side effects of the drugs,” Day says. Now, however, that’s changing. “Lifestyle is critical, and there is a growing awareness of it,” Day says.

According to Buch, the evidence for a role of lifestyle factors in AF treatment has been building for years, but the case was forcefully summarized in a 2018 review published in Current Cardiology Reports.24 That review, from researchers in Australia, demonstrated that factors such as obesity, hypertension, sleep apnea, exercise, alcohol intake, and diet are mechanistic drivers of AF and thus appropriate targets for therapy. “It is changing the way we approach AFib,” Buch says. “A lot of centers have established these lifestyle modification clinics in conjunction with their other AF treatments and are seeing convincing results.”

Although various lifestyle-associated factors can reduce AF burden and decrease likelihood of AF recurrence, an example of a factor with a particularly beneficial impact is weight loss, Day says. The rising incidence of obesity globally is contributing to an increase in prevalence of AF because of the way obesity is linked to remodeling of the left atria.25 However, clinical studies demonstrate that weight loss is associated with beneficial structural remodeling, including decreases in left atrial volumes and left ventricular hypertrophy.26 In turn, long-term weight loss is associated with a markedly higher likelihood of achieving freedom from arrhythmia.

One long-term follow-up study of individuals with obesity and AF found that participants who lost weight equal to or greater than 10% of their total body weight had an 86.2% likelihood of arrhythmia-free survival after four years—a six-fold greater likelihood of arrhythmia-free survival than for those who lost less than 10% of body weight.26 Intriguingly, 45.5% of those who lost 10% or more of their body weight went into complete remission without antiarrhythmic drugs or ablation.

Even when lifestyle alone does not put AF into remission, it still improves the effectiveness of drug treatment, Day says. In particular, it reduces the risk that a patient will develop new AF circuits after having been successfully treated once. “If patients don’t make lifestyle changes, then it’s very possible that at a future date, their AFib may come back,” he explains. “It’s like going to the dentist: They can drill and fill your cavities, but if you’re drinking a six-pack of sugary Mountain Dew and eating a box of donuts every day … and not brushing or flossing, you’re going to get new cavities. It’s the same with AFib.”

Takeaways for Clinicians
The first key takeaway is that irregular heart rhythm matters. While the evidence of previous decades suggested that rate control was as good as rhythm control, new research indicates that returning sinus rhythm to normal does in fact have major benefits. “Normal rhythm is much better than atrial fibrillation, for several reasons,” Lakkireddy says. “It perfuses the brain and body better, so people can potentially minimize the risk of premature dementia.” In addition, people with normal heart rhythm tend to remain more physically active than those with AF, meaning that they debilitate physically at a slower rate. Finally, “being in normal rhythm reduces the risk of systemic thromboembolic events and strokes, [and it] minimizes the risk of heart failure.”

The second key takeaway is that early intervention—especially through cardiac ablation and/or lifestyle change—can be transformative. If patients persist in AF, Buch says, the atrium enlarges and becomes more fibrotic and scarred, reducing the effectiveness of any intervention, whether drug or ablation therapy. The key, then, is rapid treatment. “It’s become more and more clear now that the earlier we try to achieve and maintain sinus rhythm, the more successful we’ll be.”

— Jamie Santa Cruz is a health and medical writer in the greater Denver area.

References
1. Colilla S, Crow A, Petkun W, Singer DE, Simon T, Liu X. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. Am J Cardiol. 2013;112(8):1142-1147.

2. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22(8):983-988.

3. Alonso A, de Larriva APA. Atrial fibrillation, cognitive decline and dementia. Eur Cardiol. 2016;11(1):49-53.

4. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347(23):1825-1833.

5. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med. 2002;347(23):1834-1840.

6. Saxonhouse SJ, Curtis AB. Risks and benefits of rate control versus maintenance of sinus rhythm. Am J Cardiol. 2003;91(6A):27D-32D.

7. Kirchhof P, Camm AJ, Goette A, et al. Early rhythm-control therapy in patients with atrial fibrillation. N Engl J Med. 2020;383(14):1305-1316.

8. Wazni OM, Dandamudi G, Sood N, et al. Cryoballoon ablation as initial therapy for atrial fibrillation. N Engl J Med. 2021;384(4):316-324.

9. Andrade JG, Wells GA, Deyell MW, et al. Cryoablation or drug therapy for initial treatment of atrial fibrillation. N Engl J Med. 2021;384(4):305-315.

10. Packer DL, Mark DB, Robb RA, et al. Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA Randomized Clinical Trial. JAMA. 2019;321(13):1261-1274.

11. Ryad R, Saad-Omer SM, Khan F, Limbana T, Jahan N. Does catheter ablation lower the long-term risk of stroke and mortality in patients with atrial fibrillation? A concise review of the current state of knowledge. Cureus. 2020;12(8):e9701.

12. Noseworthy PA, Gersh BJ, Kent DM, et al. Atrial fibrillation ablation in practice: assessing CABANA generalizability. Eur Heart J. 2019;40(16):1257-1264.

13. Yang PS, Sung JH, Jang E, et al. Catheter ablation improves mortality and other outcomes in real-world patients with atrial fibrillation. J Am Heart Assoc. 2020;9(11):e015740.

14. Kim D, Yang PS, Sung JH, et al. Less dementia after catheter ablation for atrial fibrillation: a nationwide cohort study. Eur Heart J. 2020;41(47):4483-4493.

15. Hussein A, Das M, Riva S, et al. Use of ablation index-guided ablation results in high rates of durable pulmonary vein isolation and freedom from arrhythmia in persistent atrial fibrillation patients: the PRAISE Study Results. Circ Arrhythm Electrophysiol. 2018;11(9):e006576.

16. Caluori G, Odehnalova E, Jadczyk T, et al. AC pulsed field ablation is feasible and safe in atrial and ventricular settings: a proof-of-concept chronic animal study. Front Bioeng Biotechnol. 2020;8:552357.

17. Reddy VY, Koruth J, Jais P, et al. Ablation of atrial fibrillation with pulsed electric fields: an ultra-rapid, tissue-selective modality for cardiac ablation. JACC Clin Electrophysiol. 2018;4(8):987-995.

18. Reddy VY, Neuzil P, Koruth JS, et al. Pulsed field ablation for pulmonary vein isolation in atrial fibrillation. J Am Coll Cardiol. 2019;74(3):315-326.

19. Reddy VY, Anter E, Rackauskas G, et al. Lattice-tip focal ablation catheter that toggles between radiofrequency and pulsed field energy to treat atrial fibrillation: a first-in-human trial. Circ Arrhythm Electrophysiol. 2020;13(6):e008718.

20. Reddy VY, Anic A, Koruth J, et al. Pulsed field ablation in patients with persistent atrial fibrillation. J Am Coll Cardiol. 2020;76(9):1068-1080.

21. Reddy VY, Sievert H, Halperin J, et al. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA. 2014;312(19):1988-1998.

22. Holmes DR Jr, Kar S, Price MJ, et al. 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):1-12.

23. Neale T. PINNACLE FLX: new-generation Watchman has high closure rates, good safety. TCTMD website. https://www.tctmd.com/news/pinnacle-flx-new-generation-watchman-has-high-closure-rates-good-safety. Published May 15, 2020. Accessed March 24, 2021.

24. Nalliah CJ, Sanders P, Kalman JM. The impact of diet and lifestyle on atrial fibrillation. Curr Cardiol Rep. 2018;20(12):137.

25. Lavie CJ, Pandey A, Lau DH, Alpert MA, Sanders P. Obesity and atrial fibrillation prevalence, pathogenesis, and prognosis: effects of weight loss and exercise. J Am Coll Cardiol. 2017;70(16):2022-2035.

26. Pathak RK, Middeldorp ME, Meredith M, et al. Long-term effect of goal-directed weight management in an atrial fibrillation cohort: a long-term follow-up study (LEGACY). J Am Coll Cardiol. 2015;65(20):2159-2169.