Volume 6, Issue 9, Pages 1335-1341 (September 2009)

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ABSTRACT

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Drugs and Brugada syndrome patients: Review of the literature, recommendations, and an up-to-date website (www.brugadadrugs.org)

Received 26 June 2009; accepted 3 July 2009. published online 10 July 2009.

Background

Worldwide, the Brugada syndrome has been recognized as an important cause of sudden cardiac death in individuals at a relatively young age. Importantly, many drugs have been reported to induce the characteristic Brugada syndrome-linked ECG abnormalities and/or (fatal) ventricular tachyarrhythmias.

Objective

The purpose of this study was to review the literature on the use of drugs in Brugada syndrome patients, to make recommendations based on the literature and on expert opinion regarding drug safety, and to ensure worldwide online and up-to-date availability of this information to all physicians who treat Brugada syndrome patients.

Methods

We performed an extensive review of the literature, formed an international expert panel to produce a consensus recommendation to each drug, and initiated a website (www.brugadadrugs.org).

Results

The literature search yielded 506 reports for consideration. Drugs were categorized into one of four categories: (1) drugs to be avoided (n = 18); (2) drugs preferably avoided (n = 23); (3) antiarrhythmic drugs (n = 4); and (4) diagnostic drugs (n = 4). Level of evidence for most associations was C (only consensus opinion of experts, case studies, or standard-of-care) as there are no randomized studies and few nonrandomized studies in Brugada syndrome patients.

Conclusion

Many drugs have been associated with adverse events in Brugada syndrome patients. We have initiated a website (www.brugadadrugs.org) to ensure worldwide availability of information on safe drug use in Brugada syndrome patients.

Keywords: Brugada syndrome, Drugs, Adverse effects, Proarrhythmia, Antiarrhythmic drug, Sudden cardiac death

Abbreviations: ACC, American College of Cardiology, AHA, American Heart Association, ECG, electrocardiogram, ESC, European Society of Cardiology

Article Outline

• Abstract

• Introduction

• Methods

• Literature review

• Recommendations

• Results

• Discussion

• Limitations

• Acknowledgment

• References

• Copyright

Introduction

Worldwide, the Brugada syndrome is recognized as an important cause of sudden cardiac death occurring in individuals at a relatively young age. Brugada syndrome is diagnosed in the presence of specific electrocardiographic (ECG) abnormalities (known as the type 1 Brugada syndrome ECG; Figure 1) seen in combination with an absence of gross structural abnormalities and several other criteria.1, 2 In addition, Brugada syndrome often shows familial aggregation.

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Figure 1. Conversion of a normal ECG to a type 1 Brugada syndrome ECG during ajmaline challenge. Note the coved-type ST segments (arrows) in the right precordial ECG leads at peak ajmaline (note that V3 is placed in the third intercostal space above V1 [V1ic3], and V5 is placed in the third intercostal space above V2 [V2ic3]).

The presence of the type 1 Brugada syndrome ECG in particular has been linked to an increased risk for ventricular tachyarrhythmias, cardiac arrest, and sudden death in patients with Brugada syndrome.3 Importantly, many drugs have been reported to induce the type 1 Brugada syndrome ECG and/or (fatal) arrhythmias in patients with Brugada syndrome (Figure 2). Therefore, patients with Brugada syndrome should be advised not to use these drugs or to use them only under controlled conditions.

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Figure 2. Nonsustained ventricular tachycardia in a patient who was given flecainide for paroxysmal atrial fibrillation. Note the coved-type ST segments (arrow). The patient was diagnosed with Brugada syndrome during an ajmaline provocation test.

Although the most appropriate treatment of Brugada syndrome is under discussion,4, 5 avoidance of potentially proarrhythmic drugs and treatment of fever (which is a well-known trigger of cardiac events in Brugada syndrome)6, 7 are generally accepted to be an important part of (prophylactic) treatment. However, some patients may (only) be appropriately treated with an implantable cardioverter-defibrillator. Some drugs may have an antiarrhythmic effect and thus may be used favorably in the acute or chronic setting.8, 9, 10 Because Brugada syndrome has a rather low prevalence (estimated at 1:2,000, varying in different regions around the world),1 these and other critical characteristics of Brugada syndrome may not be common knowledge for many physicians.11

With the aim of aiding all physicians who treat patients with Brugada syndrome, we discussed the interaction between drugs and Brugada syndrome, performed an extensive review of the literature, formed an international expert panel to produce a consensus recommendation for each drug, and initiated a website (www.brugadadrugs.org; Figure 3) to ensure worldwide online and up-to-date availability of this knowledge base.

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Figure 3. Screenshot of the website www.brugadadrugs.org.

Methods

Literature review

PubMed (Text: Brugada; MeSH terms: Chemicals and Drugs Category; only reports in English were considered) and expert knowledge was used to investigate drugs that have been associated with the type 1 Brugada syndrome ECG, with arrhythmias or with antiarrhythmic properties in Brugada syndrome patients. Although there is large variation in the extent to which different drugs have been associated with Brugada syndrome, we aimed to investigate the first reported drug–Brugada syndrome association for each drug but favored larger, combined clinical–experimental or otherwise important studies (e.g., those that report arrhythmias). Thus, we refer to many, but not to all, reports that describe an association between a certain drug and Brugada syndrome. Furthermore, we sought drugs with cardiac ion channel blocking effects that hypothetically have the potential to have deleterious effects in Brugada syndrome patients but that have not yet been reported to have deleterious effects. Finally, for most drugs having a clinical association with Brugada syndrome, we were able to retrieve confirmatory experimental studies showing the effects of the drug on cardiac electrophysiology.

Recommendations

As there are no randomized clinical trials in Brugada syndrome, the level of evidence (American College of Cardiology/American Heart Association/European Society of Cardiology [ACC/AHA/ESC] format) for most associations is C (only consensus opinion of experts, case studies, or standard of care) and for some associations is B (nonrandomized studies). To ascertain the validity of the recommendations given, we formed an international expert panel (the BrugadaDrugs.org Advisory Board) to summarize the clinical and experimental evidence and expert opinion. The classification of recommendation is expressed in a modified ACC/AHA/ESC format as follows:

•Class I: There is evidence and/or general agreement that a given treatment is potentially proarrhythmic (or potentially antiarrhythmic) in Brugada syndrome patients.

•Class IIa: There is conflicting evidence and/or divergence of opinion about the drug, but the weight of evidence/opinion is in favor of a potentially proarrhythmic (or potentially antiarrhythmic) effect in Brugada syndrome patients.

•Class IIb: There is conflicting evidence and/or divergence of opinion about the drug, and the potential proarrhythmic (or potentially antiarrhythmic) effect in Brugada syndrome patients is less well established by evidence/opinion.

•Class III: There is very little evidence and/or agreement that a drug is potentially proarrhythmic (or potentially antiarrhythmic) in Brugada syndrome patients.

Subsequently, we have listed the drugs into four groups:

•Drugs to be avoided by Brugada syndrome patients

•Drugs preferably avoided by Brugada syndrome patients

•Potential antiarrhythmic drugs in Brugada syndrome patients

•Diagnostic drugs in Brugada syndrome

Within these groups, we differentiated between different drug classes (e.g., antiarrhythmic drugs and psychotropic drugs).

Results

The PubMed search yielded 563 reports, including 506 written in English. The BrugadaDrugs.org Advisory Board selected approximately 15% of these reports as adding considerably to our knowledge and understanding of drug effects in Brugada syndrome. The drugs and accompanying recommendations are listed in Table 1, Table 2, Table 3, Table 4.

Table 1.

Drugs to be avoided by Brugada syndrome patients


Drug category	Drug (generic)	Recommendation
Antiarrhythmic drugs	Ajmaline26, 27, 28, 29	ClassI
	Flecainide30, 31, 32, 33, 34	ClassI
	Pilsicainide35, 36, 37, 38	ClassI
	Procainamide17, 26, 39, 40	ClassI
	Propafenone41, 42, 43, 44, 45	ClassIIa
Psychotropic drugs	Amitriptyline46, 47, 48, 49	ClassIIa
	Clomipramine50, 51	ClassIIa
	Desipramine52, 53, 54, 55	ClassIIa
	Lithium52, 56	ClassIIa
	Loxapine47, 57	ClassIIa
	Nortriptyline55, 58, 59	ClassIIa
	Trifluoperazine47, 60	ClassIIa
Anesthetic drugs	Bupivacaine61, 62, 63, 64	ClassIIa
	Propofol62, 65, 66, 67	ClassIIb
Other substances	Acetylcholine17, 68, 69	ClassIIa
	Alcohol (toxicity)47, 70, 71	ClassIIb
	Cocaine72, 73, 74, 75	ClassIIa
	Ergonovine68, 76	ClassIIb

Recommendation: Class I: convincing evidence/opinion; Class IIa: evidence/opinion less clear; Class IIb: conflicting evidence/opinion.

Table 2.

Drugs preferably avoided by Brugada syndrome patients


Drug category	Drug (generic)	Recommendation
Antiarrhythmic drugs	Amiodarone77, 78, 79	ClassIIb
	Cibenzoline80, 81, 82	ClassIIb
	Disopyramide14, 17, 83, 84, 85	ClassIIb
	Lidocaine17, 86 ⁎	ClassIIb
	Propranolol17, 18, 70, 87, 88	ClassIIb
	Verapamil17, 89, 90	ClassIIb
Psychotropic drugs	Carbamazepine91, 92	ClassIIb
	Cyamemazine47, 93	ClassIIb
	Doxepin48, 94	ClassIIb
	Fluoxetine47, 51	ClassIIb
	Imipramine95	ClassIIb
	Maprotiline46, 96	ClassIIb
	Perphenazine46, 97	ClassIIb
	Phenytoin98, 99	ClassIIb
	Thioridazine100	ClassIIb
Antianginal drugs	Diltiazem1, 101, 102, 103	ClassIII
	Nicorandil1, 104	ClassIII
	Nifedipine1, 105	ClassIII
	Nitroglycerine1, 106, 107	ClassIII
	Sorbidnitrate1, 89, 108	ClassIII
Other substances	Dimenhydrinate109, 110, 111	ClassIIb
	Edrophonium17, 18	ClassIIb
	Indapamide112	ClassIIb

Recommendation: Class I: convincing evidence/opinion; Class IIa: evidence/opinion less clear; Class IIb: conflicting evidence/opinion; Class III: very little evidence.

⁎

Lidocaine use for local anesthesia seems to be safe if the amount administered is low and if it is combined with adrenaline, which results in a local effect only.

Table 3.

Potential antiarrhythmic drugs in Brugada syndrome patients


Drug category	Drug (generic)	Recommendation
Antiarrhythmic drugs	Isoproterenol/isoprenaline15, 17, 113, 114 ⁎	ClassI
	Orciprenaline115	ClassIIa
	Quinidine8, 9, 10, 15, 116, 117 †	ClassI
Other substances	Cilostazol118, 119, 120	ClassIIb

Recommendation: Class I: convincing evidence/opinion; Class IIa: evidence/opinion less clear; Class IIb: conflicting evidence/opinion.

⁎

In adults, an isoproterenol regimen of 0.003 ± 0.003 μg/kg/min has been used by Ohgo et al15 and 0.01–0.02 μg/kg/min has been used by Kasanuki et al.18

†

Aim for quinidine plasma levels of 1–3 μg/mL or 3.5–11 μmol/L.

Table 4.

Diagnostic drugs in Brugada syndrome


Drug category	Drug (generic)	Use
Antiarrhythmic drugs	Ajmaline26, 27, 28, 29	Maximal dose 1 mg/kg
Antiarrhythmic drugs	Flecainide30, 31, 32, 33, 34 ⁎	Maximal dose 2 mg/kg
	Pilsicainid35, 36, 37, 38	Maximal dose 1 mg/kg
	Procainamide17, 26, 39, 40 †	Maximal dose 10 mg/kg

⁎

Wolpert et al28 reported that flecainide has 32% lower sensitivity than ajmaline in uncovering a type 1 Brugada ECG.

†

In the first consensus report (Wilde et al2), the sensitivity of procainamide was considered relatively low.

Discussion

In this study, we reviewed the literature on drug use in Brugada syndrome patients and made recommendations about their safety that were based on the literature and expert opinion. We also initiated a website (www.brugadadrugs.org) where these drugs and the recommendations can be accessed by all physicians who treat patients with Brugada syndrome and by other individuals with a possible interest (e.g., patients). On this website, we provide more detailed information on the drugs used in Brugada syndrome than is reviewed in this article. In addition, the website is updated frequently (drugs added or removed, recommendations changed) according to the latest evidence.

Patients with Brugada syndrome should be advised not to take the drugs from the “avoid” and “preferably avoid” lists or to use these drugs only after extensive consideration and/or under controlled conditions. We advise patients to give a list of these drugs to all of their health care providers (including their general practitioner, dentist and pharmacist). In many patients with Brugada syndrome, avoidance of these drugs (and treatment of fever)6, 7 probably is appropriate and safe treatment. Some Brugada syndrome patients seem to perform well on quinidine.8, 9, 10 Recently, a prospective registry has started investigating the use of empiric quinidine therapy for treatment of asymptomatic Brugada syndrome patients (ClinicalTrials.gov identifier NCT00789165).12 Furthermore, the QUIDAM study (HydroQuinidine to Decrease Arrhythmic events in Brugada syndrome patients, ClinicalTrials.gov identifier NCT00927732), a French national double-blinded randomized study, is currently investigating the role of quinidine therapy in improving the outcome of high-risk Brugada syndrome patients. Reports have postulated an antiarrhythmic effect of other drugs (amrinone,13 bepridil,14, 15 clarithromycin,13 denopamine,15 dimethyl lithospermate B,16 mexiletine,17, 18 milrinone,13 phentolamine,17 prazosin,17 sotalol,19, 20 tedisamil13, 21 and 4-aminopyridine13) in Brugada syndrome. We consider the evidence on use of these drugs as antiarrhythmic treatment in Brugada syndrome patients currently to be too low.

In Brugada syndrome patients, an important issue regarding ventricular tachyarrhythmias is that they can present as an epileptic seizure and that the cerebral hypoperfusion may create a clinical picture easily confused with a postictal phase. Therefore, in patients with seizures, both epilepsy and arrhythmia syndromes such as Brugada syndrome7 (or, e.g., long QT syndrome)22 are part of the differential diagnosis. Many antiepileptic drugs, such as carbamazepine and phenytoin, act through cerebral ion channel blockade but also will result in cardiac ion channel blockade.23, 24, 25 The latter may have a deleterious (and possibly fatal) effect in patients with an arrhythmia syndrome such as Brugada syndrome. Therefore, it is important to exclude arrhythmia syndromes such as Brugada syndrome in patients suspected of epilepsy before a possible harmful treatment is started.

We hope that the website will helpful to physicians who are in need of this information, and we welcome your suggestions and/or documentation on the safe or unsafe use of drugs in Brugada syndrome patients. We hope that use of the information provided on our website will prevent Brugada syndrome patients from suffering a cardiac arrest or sudden cardiac death initiated by drugs that should be avoided.

Limitations

The principal limitation of the association between certain drugs, Brugada syndrome, and arrhythmias is the limited number of case reports and experimental studies suggesting an effect in Brugada syndrome. Furthermore, Brugada syndrome patients may show conflicting results and large variability in their response to certain drugs. This response may also vary in different conditions (e.g., with or without fever, drug in therapeutic range, overdose, or in combination with other drugs). Therefore, clinical decision making should be based on more than the presence or absence of a (single) association in another patient. In additionally, it remains important for health care providers to recognize the active substances in medicines containing a combination of drugs and to be aware of the drug category (e.g., many tricyclic antidepressants are potentially proarrhythmic in Brugada syndrome patients).

Acknowledgments

We gratefully acknowledge CardioNetworks (a nonprofit organization based in The Netherlands that was founded in 2007 with the aim of providing unbiased and up-to-date medical knowledge to the global community) and particularly its chair Jonas S.S.G. de Jong, MD, for hosting the website. The inspiration for the website comes from www.qtdrugs.org, which contains lists of drugs associated with the long QT syndrome.

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⁎ Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

† 1st Department of Medicine-Cardiology, University Hospital Mannheim, Mannheim, Germany

‡ Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

¶ L'Institut du Thorax, Service de Cardiologie du CHU de Nantes and INSERM UMR 915, Université de Nantes, Nantes, France

§ Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee

∥ Molecular Cardiology, Fondazione Salvatore Maugeri, Department of Cardiology, University of Pavia, Pavia, Italy

⁎⁎ Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

†† Arrhythmia Section, Cardiovascular Institute, Hospital Clínic, University of Barcelona, Barcelona, Spain

Address reprint requests and correspondence: Dr. Pieter G. Postema or Dr. Arthur A. M. Wilde, Department of Cardiology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands

This study was supported by The Netherlands Heart Foundation Grant 2005T024 to Dr. Postema; Fondation Leducq Trans-Atlantic Network of Excellence, Preventing Sudden Death Grant 05-CVD-01 to Dr. Wilde; CHU de Nantes, France, and Société Française de Cardiologie Grant P.H.R.C. 2004 R20/07 to Dr. Probst; and National Institutes of Health Grant HL65962 to Dr. Roden.

PII: S1547-5271(09)00739-5

doi:10.1016/j.hrthm.2009.07.002

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