Author + information
- Received October 29, 2018
- Revision received January 2, 2019
- Accepted January 31, 2019
- Published online April 15, 2019.
- Christopher C. Cheung, MDa,
- Greg Mellor, MDb,c,
- Marc W. Deyell, MD, MSc(Epi)a,
- Bode Ensam, MBBSb,c,
- Velislav Batchvarov, MDb,c,
- Michael Papadakis, MDb,c,
- Jason D. Roberts, MD, MASd,
- Richard Leather, MDe,
- Shubhayan Sanatani, MDf,
- Jeffrey S. Healey, MDg,
- Vijay S. Chauhan, MDh,
- David H. Birnie, MB, ChBi,
- Jean Champagne, MDj,
- Paul Angaran, MDk,
- George J. Klein, MDd,
- Raymond Yee, MDd,
- Christopher S. Simpson, MDl,
- Mario Talajic, MDm,
- Martin Gardner, MDn,
- John A. Yeung-Lai-Wah, MDa,
- Santabhanu Chakrabarti, MDa,
- Zachary W. Laksman, MD, MSca,
- Sanjay Sharma, MDb,c,
- Elijah R. Behr, MDb,c and
- Andrew D. Krahn, MDa,∗ ()
- aDivision of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
- bCardiology Clinical Academic Group, St. George’s University Hospitals NHS Foundation Trust, London, United Kingdom
- cInstitute of Molecular and Clinical Sciences, St. George’s University of London, London, United Kingdom
- dSection of Cardiac Electrophysiology, Division of Cardiology, Western University, London, Ontario, Canada
- eDivision of Cardiology, Royal Jubilee Hospital, Victoria, British Columbia, Canada
- fChildren’s Heart Centre, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
- gDivision of Cardiology, McMaster University, Hamilton, Ontario, Canada
- hToronto General Research Institute, University Health Network, Toronto, Ontario, Canada
- iUniversity of Ottawa Heart Institute, University of Ottawa, Ottawa, Ontario, Canada
- jInstitut Universitaire de Cardiologie et Pneumologie de Québec, Université Laval, Québec City, Québec, Canada
- kDivision of Cardiology, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
- lDivision of Cardiology, Queen’s University, Kingston, Ontario, Canada
- mInstitut de Cardiologie de Montréal, Département of Médecine, Université de Montréal, Montréal, Québec, Canada
- nDivision of Cardiology, Dalhousie University, Halifax, Nova Scotia, Canada
- ↵∗Address for correspondence:
Dr. Andrew Krahn, Heart Rhythm Vancouver, 211-1033 Davie Street, Vancouver, British Columbia V6E 1M7, Canada.
Objectives The authors studied the response rates and relative sensitivity of the most common agents used in the sodium-channel blocker (SCB) challenge.
Background A type 1 Brugada electrocardiographic pattern precipitated by an SCB challenge confers a diagnosis of Brugada syndrome.
Methods Patients undergoing an SCB challenge were prospectively enrolled across Canada and the United Kingdom. Patients with no prior cardiac arrest and family histories of sudden cardiac death or Brugada syndrome were included.
Results Four hundred twenty-five subjects underwent SCB challenge (ajmaline, n = 331 [78%]; procainamide, n = 94 [22%]), with a mean age of 39 ± 15 years (54% men). Baseline non–type 1 Brugada ST-segment elevation was present in 10%. A total of 154 patients (36%) underwent signal-averaged electrocardiography, with 41% having late potentials. Positive results were seen more often with ajmaline than procainamide infusion (26% vs. 4%, p < 0.001). On multivariate analysis, baseline non–type 1 Brugada ST-segment elevation (odds ratio [OR]: 6.92; 95% confidence interval [CI]: 3.15 to 15.2; p < 0.001) and ajmaline use (OR: 8.76; 95% CI: 2.62 to 29.2; p < 0.001) were independent predictors of positive results to SCB challenge. In the subgroup undergoing signal-averaged electrocardiography, non–type 1 Brugada ST-segment elevation (OR: 9.28; 95% CI: 2.22 to 38.8; p = 0.002), late potentials on signal-averaged electrocardiography (OR: 4.32; 95% CI: 1.50 to 12.5; p = 0.007), and ajmaline use (OR: 12.0; 95% CI: 2.45 to 59.1; p = 0.002) were strong predictors of SCB outcome.
Conclusions The outcome of SCB challenge was significantly affected by the drug used, with ajmaline more likely to provoke a type 1 Brugada electrocardiographic pattern compared with procainamide. Patients undergoing SCB challenge may have contrasting results depending on the drug used, with potential clinical, psychosocial, and socioeconomic implications.
Brugada syndrome (BrS) is diagnosed in patients with a spontaneous type 1 Brugada electrocardiographic pattern, defined as coved-type ST-segment elevation (STE) with ≥2 mm in ≥1 lead among the right precordial leads in standard and high lead positions (i.e., V1 and V2 positioned in the fourth, third, or second intercostal spaces) (1). In patients with nondiagnostic baseline electrocardiographic findings, a drug provocation challenge using a sodium-channel blocker (SCB) may be used to provoke a type 1 Brugada pattern (1). In previous guidelines, a provoked type 1 Brugada pattern unmasked through SCB challenge (i.e., drug-induced type 1) was considered diagnostic for BrS, and thus patients should receive appropriate risk stratification and management similar to patients with a spontaneous type 1 Brugada pattern (1). However, a recent consensus statement has placed less emphasis on a drug-induced type 1 Brugada pattern, advocating the use of the proposed Shanghai score (2).
Although a spontaneous Brugada electrocardiographic pattern confers the greatest risk for sudden cardiac death (SCD), a provoked Brugada pattern (i.e., fever, drug provocation) is sufficient for diagnosis and may confer an increased risk for SCD as well (1). Furthermore, a diagnosis of BrS may lead to significant changes in clinical care and/or sequelae (including implantable cardioverter-defibrillator placement) and may also have psychosocial and socioeconomic impacts on those diagnosed (3). Multiple Class I antiarrhythmic drugs are used internationally for the purpose of SCB challenge (i.e., ajmaline, flecainide, pilsicainide, and procainamide), but the relative potencies of these drug for provoking a type 1 Brugada electrocardiographic pattern are unclear. Previous small studies have compared intravenous flecainide and ajmaline, demonstrating greater response to ajmaline (4,5). Further comparison of agents is hampered by a lack of availability of all agents in any single country, and commonly only a single intravenous form is available in most countries. A differential response to SCB challenge may affect diagnostic rates and in turn affect the subsequent management for patients with suspected BrS and their families. Our objective was to compare the relative yield of ajmaline and procainamide, the most commonly used agents in Europe and North America, respectively, in provoking a type 1 Brugada electrocardiographic pattern.
Patients were identified from several prospective registries. First, the CASPER (Cardiac Arrest Survivors With Preserved Ejection Fraction) registry enrolls patients and families with histories of sudden unexplained death or cardiac arrest from across Canada (6,7). Second, local inherited arrhythmia registries from Vancouver, British Columbia, and London, Ontario, routinely enroll families referred for suspected inherited arrhythmias or BrS. In this combined Canadian cohort, the SCB challenge (using procainamide) was conducted in keeping with the CASPER diagnostic algorithm or at the discretion of the local investigator on the basis of the index of suspicion from the context of event, family history, and related diagnoses (6). The second cohort was a prospective institutional registry at St. George’s, University of London, composed of patients undergoing SCB challenge (with ajmaline) as part of a comprehensive evaluation for a family history of sudden arrhythmic death syndrome (SADS; sudden unexplained death with normal postmortem findings) as previously described (8). All subjects underwent transthoracic echocardiography to exclude structural heart disease. To account for differences between cohorts, patients were matched for a positive family history of SCD, SADS, or BrS but no personal history of cardiac arrest. All patients were required to have undergone 12-lead electrocardiography (ECG), high precordial lead ECG (HLECG), and SCB challenge to be enrolled in this study. Patients with a spontaneous type 1 Brugada electrocardiographic pattern at baseline were excluded. The research ethics board at each institution approved the protocol.
Data collection consisted of demographics and clinical history and cardiac investigations, including 12-lead ECG, HLECG (leads V1 and V2 in the second and third intercostal spaces), signal-averaged ECG (SAECG), and SCB challenge (7). Results of baseline ECG and HLECG were classified as normal or non–type 1 Brugada STE if either type 2 or type 3 Brugada electrocardiographic pattern was present. Standard definitions of Brugada electrocardiographic types 1 to 3 were used (9). The results of SCB challenge were considered positive with the precipitation of a type 1 Brugada electrocardiographic pattern in ≥1 lead in either standard or high lead positions (Figure 1) (1). The results of SAECG were considered abnormal if 1 or more positive parameters were present (i.e., filtered QRS duration >114 ms, low-amplitude signal duration >38 ms, terminal QRS root mean square voltage <20 μV).
All Canadian sites used a standard SCB challenge protocol (7). Procainamide was infused through a peripheral intravenous line with continuous electrocardiographic monitoring at a dose of 15 mg/kg (maximum 1,000 mg) at 50 mg/min. In contrast to previous studies in which a dose of 10 mg/kg was administered at 100 mg/min, the infusion protocol was adapted to comply with the product monograph in Canada, and by doing so, a higher total dose was administered at a slower rate, thereby enhancing sensitivity (7). Standard 12-lead ECG and HLECG were performed at baseline and were repeated at 10-min intervals during the infusion and at 30-min intervals for 1 h following completion of the infusion (Central Illustration).
The United Kingdom site administered ajmaline intravenously at 1 mg/kg (maximum 100 mg) over 5 min with continuous electrocardiographic recordings from baseline until the electrocardiogram normalized, with simultaneous 15-lead electrocardiographic recordings including high precordial leads as previously described (10). For both protocols, the infusion was terminated if a type 1 Brugada electrocardiographic pattern was provoked, the QRS duration increased by ≥130% from baseline, premature ventricular complexes or ventricular arrhythmias developed, or any significant side effects were noted.
Statistical analysis was performed using StataIC version 15.0 (StataCorp, College Station, Texas). Comparisons were performed using chi-square and univariate logistic regression analyses. Variables demonstrating significant association on univariate analysis (p < 0.05) were included in a multivariate logistic regression. Patients who underwent SAECG were included in a secondary subgroup analysis. The dependent outcome for all univariate and multivariate analyses was the response to SCB challenge.
Baseline clinical characteristics of full cohort
Four hundred twenty-five patients (mean age 39 ± 15 years, 54% men) were enrolled and underwent all pre-requisite investigations. Clinical characteristics including age, sex, ethnicity, history of syncope, indications for testing, and baseline electrocardiographic findings are presented in Table 1. There were 42 patients (10%) with baseline non–type 1 Brugada STE in standard (5%) or high (9%) precordial leads. The procainamide and ajmaline groups were of similar age (38.3 ± 15.6 years vs. 39.4 ± 14.8 years; p = 0.562), with the procainamide group having a higher proportion of non-Caucasian patients (52% vs. 6%; p < 0.001) and patients with baseline non–type 1 Brugada STE (16% vs. 8%; p = 0.031).
A total of 154 patients (36%) underwent SAECG as part of their assessment (Table 1). SAECG patients were similar with respect to baseline clinical characteristics (Online Table 1). Late potentials (≥1 abnormal parameter) were present in 63 patients in the combined cohort (41%). Thirty-seven patients (24%) had ≥2 abnormal parameters. Abnormal findings on SAECG were more frequent in the procainamide group than the ajmaline group (53% vs. 34%; p = 0.028).
Four hundred twenty-five patients underwent the SCB challenge with either ajmaline (n = 331 [78%]) or procainamide (n = 94 [22%]). In the combined cohort, 89 patients (21%) had positive results on SCB challenge, with ajmaline patients more likely to have positive results compared with procainamide patients (26% vs. 4%; p < 0.001). In the SAECG subgroup (n = 154), 21 patients (14%) had positive results on SCB challenge, with ajmaline patients again more likely to have positive results (19% vs. 5%; p = 0.027).
Predictors of positive SCB challenge results
Univariate and multivariate analyses were performed to identify predictors of positive results on SCB challenge (Table 2). In the combined cohort, increasing age, ethnicity, non–type 1 Brugada STE at baseline, and ajmaline use were associated with positive results on SCB challenge on univariate analysis. On multivariate analysis, non–type 1 Brugada STE (odds ratio: 6.92; 95% confidence interval: 3.15 to 15.2; p < 0.001) and ajmaline use (odds ratio: 8.76; 95% confidence interval: 2.62 to 29.2; p < 0.001) were independently associated with positive results on SCB challenge (Figure 2, Central Illustration). Patients with positive SCB results provoked by ajmaline or procainamide were similar with respect to baseline clinical characteristics, but ajmaline-positive patients were less likely to have non–type 1 Brugada STE at baseline compared with procainamide-positive patients (standard leads, p = 0.002; any leads, p = 0.034) (Online Table 2).
In the SAECG subgroup (n = 154), non–type 1 Brugada STE, late potentials on SAECG, and ajmaline use were associated with positive results on SCB challenge on univariate analysis (Table 3). These variables remained associated with positive challenge results on multivariate analysis, with ajmaline use demonstrating the strongest association (odds ratio: 12.0; 95% confidence interval: 2.45 to 59.1; p = 0.002).
In a cohort of 425 subjects with family histories of sudden death, SADS, or BrS who underwent SCB challenge for the diagnosis of BrS, there was a marked difference in the likelihood of a positive result with the use of ajmaline compared with procainamide. After adjustment for other predictors, including male sex, ethnicity, familial clustering, baseline STE, and late potentials on SAECG, ajmaline provocation was the strongest predictor of positive results on SCB challenge. These results suggest that ajmaline is significantly more potent than procainamide for precipitating a type 1 electrocardiographic pattern and raise concern about diagnostic accuracy. This is further compounded by the lack of a clear gold standard for the diagnosis of BrS, limiting interpretation of sensitivity or specificity for either drug. It is not possible to decide whether ajmaline has more false-positive results or if procainamide has more false-negative results. To our knowledge, this is the largest study comparing 2 SCBs for the diagnosis of BrS, using a matched cohort across 2 countries.
A more “sensitive” test may be seen as favorable, as more subjects at potential risk from sudden death will be identified, who had preventive measures may be instituted. Indeed, sudden death victims with familial BrS may not show a spontaneous type 1 electrocardiographic pattern prior to death, and cardiac arrest survivors with BrS may not show a spontaneous pattern without provocation (7). However, a higher “sensitivity” test may also lead to overdiagnosis, particularly when patients do not have baseline STE (11). A diagnosis of BrS leads to significant clinical and psychological sequelae, which can often be complicated by imperfect risk stratification and a lack of effective medical therapies (apart from quinidine in select high-risk patients) (12). As such, in the absence of symptoms, patients with a drug-induced electrocardiographic pattern will not have sufficiently elevated risk for SCD to warrant specific therapy, and “specificity” may be preferred to “sensitivity” (11). Importantly, these findings do not identify the correct drug of choice in the assessment of BrS, only that there is a significant difference between procainamide and ajmaline. Determining the drug of choice will likely depend on circumstance and a correlation of outcomes such as major arrhythmic events.
Ajmaline is a potent inhibitor of the cardiac sodium channel and may be associated with precipitation of a type 1 pattern in the context of conditions other than BrS. In a study of patients with atrioventricular nodal re-entrant tachycardia, 27% of patients and 4.5% of healthy control subjects had a type 1 electrocardiographic pattern when treated with ajmaline (13). Genetic testing revealed mutations or rare variants in up to 77%, although a large proportion of variants were subsequently classified as benign or nondamaging (13). The investigators hypothesized that loss-of-function sodium-channel mutations may simultaneously lead to BrS and atrioventricular nodal re-entrant tachycardia through a preferential block of 1 of the atrioventricular nodal pathways, although this remains unproven (11). Peters et al. (14) also identified positive ajmaline test results in 16% of patients with diagnoses of arrhythmogenic right ventricular cardiomyopathy. In a large study of family members with documented SCN5A mutations, ajmaline provocation was positive in 5.6% of genotype-negative subjects (i.e., false positives) (15). In a recent study of 637 patients evaluated for unexplained cardiac arrest or SCD, 8% of families had positive ajmaline responses that were identified to be a confounder in the context of an alternative genetic diagnosis or noncosegregation of the ajmaline response and arrhythmia (16). Conversely, we have shown that 28% of systematically evaluated families of autopsy-negative SCD (SADS) victims yield a positive ajmaline response (17). In another study of SCB agents administered to 672 relatives with clear familial BrS, Therasse et al. (18) reported 54% as ajmaline positive compared with 37% with flecainide, suggesting a tendency toward overdiagnosis with ajmaline and underdiagnosis with flecainide.
Current guidelines state that BrS is diagnosed in the presence of a type 1 ECG pattern either spontaneously or after positive SCB provocation regardless of symptomatic status (1). In the recent J-Wave Syndromes Expert Consensus Conference Report, the investigators recommended removing the label of BrS among patients whose only type 1 Brugada pattern was drug induced, unless there is a symptom or family history that accompanies the finding, largely in response to concerns about a poor “specificity” of ajmaline (2). In the proposed “Shanghai score,” a drug-induced type 1 electrocardiographic pattern is assigned fewer points than a spontaneous or fever-induced Brugada pattern (2). The results of our study suggest further complexity in the interpretation of a drug-induced ECG pattern, with the drug choice significantly affecting “sensitivity.” Arguably clinical context should primarily inform the use of any test, and the context of a SADS death in an immediate relative is important for the a priori likelihood of BrS being present.
In the group in which SAECG was performed, late potentials were also independently associated with positive results on SCB challenge. This is in keeping with recent evidence suggestive of conduction abnormalities and myocardial fibrosis in BrS (19). Furthermore, a direct correlation between abnormalities on SAECG and positive results on SCB challenge has been suggested (20). Cumulatively, the presence of late potentials and baseline STE may be useful in counseling patients regarding undergoing SCB testing, but their absence does not eliminate the need for SCB provocation when clinical suspicion remains.
There were differences in the clinical characteristics of the ajmaline and procainamide groups, reflecting demographic differences in the practices of the 2 recruiting groups. Although we matched patients for family history of BrS or SCD, there remained significant differences in the clinical characteristics between the 2 groups, with the possibility of residual confounding despite our multivariate analysis. Notably, there were significant differences in baseline ethnicities between the ajmaline and procainamide cohort, which were included in our multivariate analysis. Without direct comparison of the effect of each drug in the same patient and clinical follow-up to identify differences in clinical events between the groups, it is not possible to recommend 1 drug over the other. Similarly, in the absence of a gold standard, it is impossible to determine whether the type 1 Brugada pattern reflects a drug-induced and/or dose-dependent effect of the SCB and whether ajmaline has more false-positive results or if procainamide has more false-negative results. Future studies should perform head-to-head comparisons and include long-term follow-up to fully understand the clinical implications of an ajmaline versus procainamide-provoked type 1 Brugada pattern. Unfortunately, this was not possible, because of the lack of universal access to SCBs in Canada and the United Kingdom. In our cohort, genetic testing was performed on the basis of clinician access and discretion in a small proportion of patients after the SCB challenge. Given the low rate of pathogenic mutations and retrospective interpretation (SCB challenge generally before genetic testing), we did not evaluate genetic results or incorporate this into our multivariate analysis. With a relatively heterogenous population of family members with no prior cardiac arrest, we also did not report outcomes, because of the low rate of clinical events in follow-up (insufficient numbers for comparison).
The outcome of the SCB provocation test for BrS was significantly affected by the agent used, with ajmaline substantially more likely to provoke a type 1 Brugada electrocardiographic pattern than procainamide. These results have significant implications for the “sensitivity” and “specificity” of the test in patients suspected of BrS, albeit in the absence of a gold standard. Ajmaline provocation is a more potent test than procainamide provocation, raising concerns about overdiagnosis and underdiagnosis of BrS, respectively. Large cohort head-to-head comparisons are needed to identify the optimal testing strategy in suspected BrS.
COMPETENCY IN MEDICAL KNOWLEDGE: Multiple Class I antiarrhythmic drugs are used internationally in the SCB challenge (i.e., ajmaline, flecainide, pilsicainide, and procainamide), but the relative potencies of each drug in provoking a type 1 Brugada electrocardiographic pattern are unclear. Although a spontaneous type 1 Brugada electrocardiographic pattern confers the greatest risk for SCD, a provoked type 1 Brugada pattern is sufficient for diagnosis and may confer an increased risk for SCD as well. A diagnosis of BrS may lead to significant changes in clinical care and/or sequelae, including implanTable cardioverter-defibrillator placement.
TRANSLATIONAL OUTLOOK 1: After adjustment for factors associated with positive SCB challenge, the outcome of the SCB challenge was significantly affected by the drug used.
TRANSLATIONAL OUTLOOK 2: Ajmaline was much more likely to provoke a type 1 Brugada pattern, compared with procainamide. It is not possible to determine if ajmaline has more false-positive results or if procainamide has more false-negative results.
TRANSLATIONAL OUTLOOK 3: Varying sensitivities and specificities depending on the agent used in the SCB challenge may have potential clinical, psychosocial, and socioeconomic implications.
The authors thank the Heart and Stroke Foundation of Canada, the UK Charity Cardiac Risk in the Young, and McColl’s RG for their generous funding and continued support. The authors thank Dr. Kathy Li for her statistical support in preparing this paper.
This study was supported by the Heart and Stroke Foundation of Canada (G-13-0002775 and G-14-0005732), Cardiac Risk in the Young, and the Robert Lancaster Memorial fund sponsored by McColl’s RG. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Abbreviations and Acronyms
- Brugada syndrome
- high precordial lead electrocardiography
- sudden arrhythmic death syndrome
- signal-averaged electrocardiography
- sodium-channel blocker
- sudden cardiac death
- ST-segment elevation
- Received October 29, 2018.
- Revision received January 2, 2019.
- Accepted January 31, 2019.
- 2019 American College of Cardiology Foundation
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