The Future of Treatment of Atrial Fibrillation

Educational Objectives

Refine risk stratification for patient-tailored atrial fibrillation therapy and lower rates of complications.

Summary

Interviewer: S. Ben Freedman, MBBS, FACC

Take-home Messages:

• Atrial fibrillation is an old problem with some new solutions, such as an app that gives iPhones the ability to produce a single-lead ECG.
• Oral anticoagulants are being used more broadly and evaluated in settings such as cardioversion and AF ablation.
• Refining risk stratification may lead to better patient-tailored AF therapy and lower rates of complications.

Do you have AF? Some individuals now can answer that question with their iPhones. Given the increasing incidence of AF, community screening programs might be helpful in detecting undiagnosed AF, but such widespread screening with ECGs has not been considered cost effective — until now. An iPhone application records a high-quality, single-lead ECG, perhaps making mass ECG screening feasible.

Investigators assessed the accuracy of the iPhone ECG as a diagnostic screening tool by comparing it with a contemporaneous 12-lead ECG interpreted by a cardiologist.¹ An ECG was easily recorded in patients in only 1 minute. Recording began with finger placement of right and left hands on two electrodes at the back of the iPhone case.

There were 109 patients in the original learning set and 204 patients in a subsequent validation set. Compared to standard ECG assessment, the high sensitivity, specificity, and accuracy of the algorithm, combined with the widespread distribution of smartphones, might make this approach ideal for community screening. The investigators are currently using this device, with only manual reading by a cardiologist, in an ongoing study in community pharmacies with pharmacists trained in the use of the iPhone ECG.

New Drugs, New Uses

The app approach to detecting AF is one of what Irina Savelieva, MD, describes as a number of fascinating advances that are now or soon may be improving the management of atrial fibrillation. She said new anticoagulants are like buses in London: you wait and you wait and you wait — and then they all arrive at once and you’re not sure which one to take.

At this point, she said, rather than concentrating on which of the oral anticoagulants is better, the goal should be to move away from using warfarin and instead utilize these newer agents in appropriate patients, “because, as a class, these drugs outperformed warfarin in terms of their efficacy” and safety.

In just one example, Gregory Y.H. Lip, MD, and colleagues have reported that in the setting of everyday clinical practice, there were similar rates of stroke/systemic embolism and major bleeding with dabigatran compared to warfarin, but mortality, intracranial bleed, pulmonary embolism, and myocardial infarction were lower with dabigatran.²

Many physicians have begun switching to the novel, non-vitamin K oral anticoagulants (NOACs), such as rivaroxaban, in AF patients undergoing cardioversion. Good news: that was not a bad idea.

X-Vert (which may be going for a record in trial titles: eXplore the efficacy and safety of once-daily oral riVaroxaban for the prevention of caRdiovascular events in patients with non-valvular aTrial fibrillation scheduled for cardioversion) is the first prospective, randomized trial to examine the safety and efficacy of rivaroxaban compared to vitamin A antagonist (VKA) therapy in patients undergoing elective cardioversion for the treatment of AF.³ The pharmacologic characteristics of rivaroxaban might be particularly useful in this setting; it has a rapid onset of action — within 2 to 4 hours — that could expedite cardioversion.

The study included 1,504 patients scheduled for either electrical (almost 98%) or pharmacologic cardioversion. Using established guidelines, patients were assigned to either early or delayed cardioversion. Compared to treatment with a VKA, rivaroxaban was associated with an overall 50% reduction in the risk of cardiovascular (CV) events and a 24% lower risk of major bleeding, the primary safety outcome. (While not powered for statistical significance, it was thought this large of a trial still would give clinically meaningful information.)

According to first author Riccardo Cappato, MD, University of Milan, Italy, “You should be aware that many physicians are already switching to novel oral anticoagulants despite the absence of any information about their use. So we thought that bringing this methodologically sound information would provide more consistent evidence for those who are doing this anyway, and a little bit more evidence for those who may be reluctant to use the novel oral agents.”

Dr. Savelieva notes other studies are underway evaluating edoxaban and epixaban in this same setting with results likely in 2015 or 2016. However, like the US, Europe is already using these anticoagulants for cardioversion, with one survey of 45 centers showing that VKA is still preferred for elective cardioversion in nearly half the centers (46.9%), while one of the newer anticoagulants is preferred in 21.9%; 32.3% had no preference.⁴

(Editor’s note: Along with John Camm, MD, Dr. Savelieva recently published a review examining practical considerations related to the use of NOACS in patients with AF.⁵)

Recently, Dr. Savelieva published a review of pharmacologic cardioversion of AF with vernakalant.⁶ Despite a rough regulatory road in the US, the drug has been approved in Europe and is included in the guidelines there. Vernakalant’s advantage is a rapid effect, with the median time to conversion between 8 and 14 minutes, and with the majority of patients (75% to 82%) converting after the first dose.

Vernakalant retains its efficacy in subgroups of patients with associated CV disease such as hypertension and ischemic heart disease, but Dr. Savelieva’s review noted that its benefit may be lower and risk of adverse effects higher in patients with HF. In the postmarket reports, cardioversion rates with vernakalant are 65% to 70%.

For patients undergoing AF ablation, a recent meta-analysis suggested that dabigatran has similar efficacy and safety compared with warfarin when used for periprocedural anticoagulation during AF ablation.⁷

Sometimes a good drug with problematic effects can be used creatively by combining agents with multiple anti-AF mechanisms at reduced individual drug doses that might produce synergistic efficacy with good tolerability. Such a fixed-dose combination was evaluated in the HARMONY trial, where a reduction in AF burden was achieved using moderate-dose ranolazine plus reduced-dose dronedarone, with good tolerance and safety. The study was conducted in patients with paroxysmal AF and implanted pacemakers, where AF burden could be continuously assessed.

Assessing Risk

One final example: recently, investigators assessed the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with AF enrolled in the ARISTOTLE trial (18,201 patients randomized to apixaban or warfarin).⁸ The authors found that levels of NT-proBNP are often elevated in AF and are independently associated with an increased risk for stroke and mortality. During the 1.8 years of follow-up, the annual rates of stroke or systemic embolism ranged from 0.74% in the bottom NT-proBNP quartile to 2.2% in the top quartile (adjusted hazard ratio [HR]: 2.33; p < 0.0001). Adding NT-proBNP levels to CHA₂DS₂-VASC score improved the c-statistics from 0.62 to 0.65 (p = 0.0009) for stroke or systemic embolism and from 0.59 to 0.69 for cardiac death (p < 0.0001).

Said Dr. Savelieva, “We are facing many changes in our practices in how we manage the AF patient.” She foresees a paradigm shift, with the NOACs eventually replacing VKA in the majority of AF patients. She said refining risk stratification may lead to better patient-tailored therapy and lower rates of complications, whereas active screening will identify more patients who can benefit from early treatment.

Readings

1. Lau JK, Lowres N, Neubeck L, et al. iPhone ECG application for community screening to detect silent atrial fibrillation: a novel technology to prevent stroke. Int J Cardiol 2013;165:193-4.

2. Larsen T, Rasmussen L, Skjøth F, et al. 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. http://content.onlinejacc.org/article.aspx?articleID=1677747

3. Cappato R, Ezekowitz MD, Klein AL, et al. Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation. Eur Heart J 2014;35:3346-55.

4. Lip GY, Bongiorni MG, Dobreanu D, et al. Novel oral anticoagulants for stroke prevention in atrial fibrillation: results of the European Heart Rhythm Association survey. Europace 2013;15:1526-32.

5. Savelieva I, Camm AJ. Practical considerations for using novel oral anticoagulants in patients with atrial fibrillation. Clin Cardiol 2014;37:32-47.

6. Savelieva I, Graydon R, Camm AJ. Pharmacological cardioversion of atrial fibrillation with vernakalant: evidence in support of the ESC Guidelines. Europace 2014;16:162-73.

7. Hohnloser SH, Camm AJ. Safety and efficacy of dabigatran etexilate during catheter ablation of atrial fibrillation: a meta-analysis of the literature. Europace 2013;15:1407-11.

8. Hijazi Z, Wallentin L, Siegbahn A, et al. N-Terminal Pro–B-Type Natriuretic Peptide for Risk Assessment in Patients With Atrial Fibrillation: Insights From the ARISTOTLE Trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation). J Am Coll Cardiol 2013;61:2274-84. http://content.onlinejacc.org/article.aspx?articleID=1677773

Disclosures

Irina Savelieva, MD
Bristol-Myers Squibb Co (C,B,A); Pfizer Inc (C,B,A); DAIICHI SANKYO CO Ltd (C,B,A); Boehringer Ingelheim GmbH (C,B,A); Bayer AG (C,B,A); Sanofi (C,B,A); Menarini/Gilead (C,B,A)

Interviewer: S. Ben Freedman, MBBS, FACC
Merck & Co Inc (C); Novartis AG (C); Sanofi (C); Bayer AG (C,G); Servier (C); Bristol-Myers Squibb Co / Pfizer Inc (C); Boehringer Ingelheim GmbH (G)

The planning committee reported nothing to disclose.

A = Advisory panel B = Speakers’ bureau C = Consultant fees/honoraria D = Data and Safety Monitoring Board E = Equity interests/stock options F = Fellowship support G = Grant support L = Licensing Agreement O = Other relationship R = Royalties S = Salary W = Expert witness

Acknowledgements

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