Clinical Management Guidelines for Friedreich Ataxia (FRDA)

Topic 4.3. The heart and cardiovascular system in Friedreich ataxia

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This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.

Topic Contents

4.3 Management strategies for arrhythmias in Friedreich ataxia
4.3.1 Atrial tachyarrhythmias
4.3.2 Ventricular arrhythmias

Disclaimer / Intended Use / Funding

Disclaimer
The Clinical Management Guidelines for Friedreich ataxia (‘Guidelines’) are protected by copyright owned by the authors who contributed to their development or said authors’ assignees.

These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.

Guidelines users must seek out the most recent information that might supersede the diagnostic and treatment recommendations contained within these Guidelines and consider local variations in clinical settings, funding and resources that may impact on the implementation of the recommendations set out in these Guidelines.

The authors of these Guidelines disclaim all liability for the accuracy or completeness of the Guidelines, and disclaim all warranties, express or implied to their incorrect use.

Intended Use
These Guidelines are made available as general information only and do not constitute medical advice. These Guidelines are intended to assist qualified healthcare professionals make informed treatment decisions about the care of individuals with Friedreich ataxia. They are not intended as a sole source of guidance in managing issues related to Friedreich ataxia. Rather, they are designed to assist clinicians by providing an evidence-based framework for decision-making.

These Guidelines are not intended to replace clinical judgment and other approaches to diagnosing and managing problems associated with Friedreich ataxia which may be appropriate in specific circumstances. Ultimately, healthcare professionals must make their own treatment decisions on a case-by-case basis, after consultation with their patients, using their clinical judgment, knowledge and expertise.
Guidelines users must not edit or modify the Guidelines in any way – including removing any branding, acknowledgement, authorship or copyright notice.

Funding
The authors of this document gratefully acknowledge the support of the Friedreich Ataxia Research Alliance (FARA). The views and opinions expressed in the Guidelines are solely those of the authors and do not necessarily reflect the official policy or position of FARA.


4.3 Management strategies for arrhythmias in Friedreich ataxia

Roger E. Peverill, Kimberly Y. Lin, Francoise Pousset, Aarti Patel and Konstantinos Savvatis

4.3.1 Atrial tachyarrhythmias

Rate controlling agents

No randomized controlled trial (RCT) has evaluated rate control of AF in FRDA, but there are no specific reasons why standard guidelines for rate control should not apply in FRDA. Recommendations for heart rate control in atrial fibrillation are provided in the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation (80).

In general, rate control is not the preferred option for long-term management in atrial arrhythmias in FRDA, as attaining and maintaining rate control, particularly during exercise in young people, can be difficult. Furthermore, young people tend to remain symptomatic when in AF even if reasonable rate control can be achieved. Nevertheless, in certain circumstances, rate control may still be a reasonable option. In such cases digoxin can be used irrespective of the left ventricular ejection fraction. A beta blocker will be the preferred option if there is a history of HF or reduced ejection fraction, but needs to be commenced slowly. If there is a reduced LVEF, verapamil and diltiazem are contraindicated because of their negative inotropic action.

Antiarrhythmic therapy

There are no RCTs which have examined the effectiveness or safety of antiarrhythmic drugs in FRDA for either reversion of atrial tachyarrhythmias or for maintenance of sinus rhythm following spontaneous, chemical or electrical cardioversion. However, the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation (80) can be used as a guide to antiarrhythmic treatment of AF in FRDA. There are important concerns raised in these guidelines about the safety of some of the antiarrhythmic medications in the setting of “organic heart disease” and it should be assumed that similar concerns apply to the abnormal heart in FRDA.

Antithrombotic therapy for prevention of thromboembolism related to atrial tachyarrhythmias

Based on data in subjects with AF and a dilated cardiomyopathy due to causes other than FRDA, a high risk of thromboembolism would be predicted for individuals with FRDA with AF and a reduced LVEF (80). Indeed, intracardiac thrombosis and systemic thromboembolism was described as a frequent finding in one post mortem study in FRDA (67). In the absence of a reduction in LVEF, where the risk of thromboembolism can be considered to be high, there are no specific reasons why the standard risk factors for thromboembolism in AF should not also apply to FRDA, and these may be a reasonable way to determine the need for anticoagulant therapy in FRDA. Anticoagulation with new oral anticoagulants, including dabigatran, rivoroxaban and apixaban, rather than a vitamin K antagonist, is recommended for individuals with FRDA and paroxysmal or permanent AF for the prevention of thromboembolism, unless there is a contraindication (81).

Ablation therapy

If the symptoms or ventricular response of atrial tachyarrhythmias are unable to be controlled with antiarrhythmic and/or ventricular rate control medications then there are electrophysiological options for management. Atrial flutter may be amenable to ablation therapy to prevent further episodes of atrial flutter. Atrial fibrillation can be treated with the percutaneous procedure of pulmonary vein isolation; however, the effectiveness of this technique in FRDA is currently unknown. There is also an option for atrioventricular (AV) node ablation or modification in combination with pacemaker insertion to prevent both a rapid ventricular response and bradycardia (80).

4.3.2 Ventricular arrhythmias

Antiarrhythmic therapy

There are no RCTs addressing the effectiveness or safety of antiarrhythmic drugs in FRDA for the treatment of ventricular arrhythmias. Furthermore, as there are few reports of symptomatic VT, syncope due to VT or resuscitated sudden death in FRDA, antiarrhythmic therapy to prevent recurrent ventricular arrhythmias will rarely be indicated. With the exception of beta blockers, no currently available antiarrhythmic drugs have been shown in RCTs to be effective in the primary management of people with life-threatening ventricular arrhythmias or in the prevention of sudden cardiac death (SCD) (82). On the other hand, beta blockers are effective in suppressing ventricular ectopic beats and arrhythmias as well as in reducing SCD in a spectrum of cardiac disorders in people with and without HF (82). As a general rule, antiarrhythmic agents may be effective as adjunctive therapy in the management of arrhythmia-prone individuals under special circumstances. Because of potential adverse side effects of the available antiarrhythmic drugs, these agents must be used with considerable caution.

If individuals with FRDA develop ventricular arrhythmias, then beta blockers should be considered first-line therapy for secondary prevention, but if not effective at full therapeutic doses, then amiodarone or sotalol can be tried, with careful monitoring for adverse effects during administration. Amiodarone is the only option if beta blockers are contraindicated. Both sotalol and amiodarone have also been shown to reduce the frequency of internal cardioverter-defibrillator (ICD) shock therapy. Sotalol should be used with caution in individuals with HF, severely reduced LVEF or renal dysfunction.

ICD for primary and secondary prevention of ventricular arrhythmias

There are no RCT data regarding ICD implantation for either primary or secondary prevention of ventricular arrhythmias in FRDA. Multiple clinical trials in other cardiac conditions have demonstrated a survival benefit of ICD use compared to antiarrhythmic therapy for secondary prevention of resuscitated SCD, sustained VT or sustained VF. It is recommended that the ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities be used to guide ICD placement for the secondary prevention of SCD or sustained VT/VF in FRDA (83). Importantly, these guidelines do not support ICD placement if the predicted lifespan from other causes is less than a year.

Primary prevention of SCD refers to the use of ICDs in individuals who are at risk for, but have not yet had an episode of sustained VT, VF, or resuscitated cardiac arrest. Clinical trials have evaluated the risks and benefits of ICD implantation in prevention of sudden death and have shown improved survival with ICD in multiple patient populations, including those with HF due to non-ischemic dilated cardiomyopathy (83). However, making a recommendation to use an ICD for primary prevention in FRDA is not possible at this time due to absence of evidence for ventricular arrhythmias as a common cause of death.

One series of five subjects with FRDA who received ICD implantation has been reported (ages from 14-26 years) (84). However, none of this cohort had syncope, near syncope, symptomatic VT or a dilated cardiomyopathy with reduced LVEF (i.e. there were no standard indications for an ICD).

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Please note: Recommendations are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group. Best Practice Statements are commonly accepted practices, as such formal rating of the quality of evidence by the GRADE process is not indicated. In addition if recommendations from the 2014 guidelines were deemed still relevant, although unable to undergo the scrutiny from a GRADE framework, they were also included as best practice statements.
Anticoagulation for atrial fibrillation

QUESTION: Should anticoagulation versus no anticoagulation be used for individuals with permanent, persistent or paroxysmal atrial fibrillation with Friedreich ataxia?

STRENGTH OF RECOMMENDATION:
LEVEL OF EVIDENCE: ⨁◯◯◯

RECOMMENDATION: We conditionally recommend anticoagulation over no anticoagulation in individuals with Friedreich ataxia with permanent, persistent or paroxysmal atrial fibrillation.

JUSTIFICATION: There is no evidence to suggest treatment should be different for individuals with Friedreich ataxia versus individuals without Friedreich ataxia, where anticoagulation therapy would be appropriate for individuals with permanent, persistent or paroxysmal atrial fibrillation unless there is a contraindication. Shared decision-making should consider younger age of this cohort in the context of increased risk of falls, stroke, females with concomitant heavy menstrual bleeding and desire to maintain autonomy in decisions related to health.

SUBGROUP CONSIDERATION: The recommendation is for individuals with Friedreich ataxia with permanent, persistent or paroxysmal atrial fibrillation. Stroke happens across the age spectrum in Friedreich ataxia. The recommendation does need to encourage clinicians to think across all ages; however, be mindful of specific groups as specified in the justification above.

Evidence to Recommendation Table PDF
Rhythm control for atrial fibrillation

QUESTION: Should rhythm control versus rate control be used for atrial fibrillation/flutter with Friedreich ataxia?

STRENGTH OF RECOMMENDATION:
LEVEL OF EVIDENCE: ⨁◯◯◯

RECOMMENDATION: We conditionally recommend attempts to maintain a normal cardiac rhythm over rate control in individuals with Friedreich ataxia and atrial tachyarrhythmias, and also recommend consideration of ablation for those who remain severely symptomatic due to a persistent atrial tachyarrhythmia or frequent paroxysms of an atrial tachyarrhythmia.

JUSTIFICATION: Highly symptomatic individuals who are younger in particular require careful consideration regarding intervention. Some consideration should be given for moderate risks of pharmacological intervention versus higher risks with ablation, including prolonged anesthesia.

SUBGROUP CONSIDERATION: This recommendation is for individuals with Friedreich ataxia with atrial fibrillation/flutter, with particular considerations as described in the justification above.

Evidence to Recommendation Table PDF
Please note: Recommendations are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group. Best Practice Statements are commonly accepted practices, as such formal rating of the quality of evidence by the GRADE process is not indicated. In addition if recommendations from the 2014 guidelines were deemed still relevant, although unable to undergo the scrutiny from a GRADE framework, they were also included as best practice statements.
For treatment of symptomatic arrhythmias in Friedreich ataxia, antiarrhythmic medications (other than betablockers) which are negatively inotropic or are recognized to have a high risk for proarrhythmic effects cannot be assumed to be safe and should rarely, if ever, be used.

Lay summary of clinical recommendations for arrhythmias in Friedreich ataxia

Why these recommendations?

Individuals with Friedreich ataxia can experience arrhythmias (irregular heart rate), with symptoms including palpitations, dizziness, shortness of breath and chest discomfort.

These recommendations are about the use of medication or procedures to treat individuals with Friedreich ataxia who have permanent or episodic atrial fibrillation (an irregular and often rapid heart rate).

We suggest using anticoagulation medication for people with Friedreich ataxia with atrial fibrillation because the overall benefits (e.g., preventing a stroke) are likely to be greater than the risks (bleeding is the most common risk).

For individuals with Friedreich ataxia who have persistent or episodic atrial fibrillation, we also suggest that medication and possibly procedures (i.e. cardioversion) can be used to obtain a normal heart rhythm, as well as medication to maintain a normal heart rhythm. This is because maintaining a normal heart rhythm may lead to an improvement in symptoms. Even if there is no immediate improvement in symptoms, the treatment might help to look after heart function in the medium term. On the other hand, the risks of the use of cardioversion and medication for this purpose are small.

For those individuals who continue to have severe symptoms due to atrial fibrillation even after using medication, we suggest considering a procedure that can help break up the electrical signals that cause irregular heartbeats (called an ablation).

What does this mean for you as a person living with Friedreich ataxia or caring for someone living with Friedreich ataxia?
It may be important for you to speak with your healthcare professional about the investigation of palpitations you may be having. Making a diagnosis of atrial fibrillation has important management implications. If atrial fibrillation is confirmed, then it is important to discuss the management options with a cardiologist.

Who are these recommendations specifically for?
These recommendations are for individuals with Friedreich ataxia who have permanent or episodic atrial fibrillation.

Kimberly Y. Lin, MD
Associate Professor, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

Aarti Patel, MD
Associate Professor of Medicine, University of South Florida, Tampa, Florida, USA
Email: apatel15@usf.edu

Roger E. Peverill, MBBS, PhD
Cardiologist, MonashHeart, Monash Health, Clayton, Victoria, Australia
Email: roger.peverill@monash.edu

Francoise Pousset, MD
Sorbonne Université, Cardiology Department, AP-HP, Pitié-Salpêtrière University Hospital, Paris, France
Email: f.pousset@aphp.fr

Konstantinos Savvatis, MD, PhD
Consultant Cardiologist, St. Bartholomew’s Hospital, Barts Health NHS Trust, London, UK
Email: k.savvatis@ucl.ac.uk

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These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.

This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.

It is our expectation that going forward individual topics can be updated in real-time in response to new evidence versus a re-evaluation and update of all topics simultaneously.

For the rating of the strength of the recommendation, in addition to evidence from studies in FRDA, evidence from like conditions, clinical experience and expert consensus are taken into account when published evidence is not available.

The level of evidence is based on published evidence from studies in FRDA. If there is no published evidence in FRDA, evidence from other like conditions or clinical expertise may have been used to make the recommendation – this is graded as ‘very low’ or in some cases ‘low’ level evidence. See the table below for an explanation of the symbols used to grade recommendations.

Strength of recommendation Symbol Level of evidence Symbol
Strong for intervention ↑↑ High ⨁⨁⨁⨁
Conditional for intervention Moderate ⨁⨁⨁◯
Neither intervention nor comparison Low ⨁⨁◯◯
Conditional against intervention Very low ⨁◯◯◯
Strong against intervention ↓↓
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