Author + information
- Received June 15, 2018
- Revision received October 11, 2018
- Accepted October 15, 2018
- Published online March 18, 2019.
- Navraj Malhi, MDa,
- Christopher C. Cheung, MDa,
- Bishoy Deif, MDb,
- Jason D. Roberts, MD, MASb,
- Lorne J. Gula, MDb,
- Martin S. Green, MDc,
- Benjamin Pang, MDc,
- Omar Sultan, MDd,
- Kaja M. Konieczny, MDe,
- Paul Angaran, MDe,
- Paul Dorian, MDe,
- Ilan Lashevsky, MDf,
- Jeff S. Healey, MDg,
- Aiman Alak, MDg,
- Rafik Tadros, MDh,
- Antoine Andorin, MDh,
- Christian Steinberg, MDi,
- Felix Ayala-Paredes, MDj,
- Christopher S. Simpson, MDk,
- Joseph Atallah, MDl and
- Andrew D. Krahn, MDa,∗ ()
- aUniversity of British Columbia, Vancouver, British Columbia, Canada
- bWestern University, London, Ontario, Canada
- cUniversity of Ottawa Heart Institute, Ottawa, Ontario, Canada
- dUniversity of Saskatchewan, Regina Qu’Appelle Health Region, Regina, Saskatchewan, Canada
- eSt. Michael’s Hospital, Toronto, Ontario, Canada
- fSchulich Heart Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
- gPopulation Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- hDepartment of Medicine, University of Montreal, Research Center, Montreal Heart Institute, Montreal, Quebec, Canada
- iLaval University, Quebec Heart and Lung Institute, Inherited Arrhythmia Clinic, Quebec City, Quebec, Canada
- jUniversité de Sherbrooke, Faculté de Médecine et des Sciences de la Santé, Montreal, Quebec, Canada
- kQueen's University, Kingston, Ontario, Canada
- lUniversity of Alberta School of Public Health, Faculty of Medicine and Dentistry, Edmonton, Alberta, Canada
- ↵∗Address for correspondence:
Dr. Andrew Krahn, Heart Rhythm Vancouver, 211-1033 Davie Street, Vancouver, British Columbia V6E 1M7, Canada.
Objectives This study sought to determine the nature of quinidine use and accessibility in a national network of inherited arrhythmia clinics.
Background Quinidine is an antiarrhythmic medication that has been shown to be beneficial in select patients with Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation. Because of the low prevalence of these conditions and restricted access to quinidine through a single regulatory process, quinidine use is rare in Canada.
Methods Subjects prescribed quinidine were identified through the Hearts in Rhythm Organization that connects the network of inherited arrhythmia clinics across Canada. Cases were retrospectively reviewed for patient characteristics, indications for quinidine use, rate of recurrent ventricular arrhythmia, and issues with quinidine accessibility.
Results In a population of 36 million, 46 patients are currently prescribed quinidine (0.0000013%, age 48.1 ± 16.1 years, 25 are male). Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation constituted a diagnosis in 13 subjects (28%), 6 (13%), and 21 (46%), respectively. Overall, 37 subjects (81%) had cardiac arrest as an index event. After initial presentation, subjects experienced 7.47 ± 12.3 implantable cardioverter-defibrillator shocks prior to quinidine use over 34.3 ± 45.9 months, versus 0.86 ± 1.69 implantable cardioverter-defibrillator shocks in 43.8 ± 41.8 months while on quinidine (risk ratio: 8.7, p < 0.001). Twenty-two patients access quinidine through routes external to Health Canada’s Special Access Program.
Conclusions Quinidine use is rare in Canada, but it is associated with a reduction in recurrent ventricular arrhythmias in patients with Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation, with minimal toxicity necessitating discontinuation. Drug interruption is associated with frequent breakthrough events. Access to quinidine is important to deliver this potentially lifesaving therapy.
Quinidine has largely fallen out of favor and has been removed from approved access by many regulatory agencies due to proarrhythmia, toxicity, and the advent of alternative agents. However, several rare sudden death syndromes appear uniquely responsive to quinidine (1–9). These include Brugada syndrome (BrS), early repolarization syndrome (ERS), and idiopathic ventricular fibrillation (IVF), in which quinidine can be lifesaving.
Quinidine is an antiarrhythmic medication that blocks multiple ion channels. Its specificity is poorly categorized despite years of use, but it has apparent and empiric benefit in a variety of arrhythmias. Quinidine blocks sodium influx through inhibition of fast inward sodium current, and potassium efflux through inhibition of delayed rectifier current and transient outward potassium current (Ito). Ito is proposed to play a role in the genesis of ventricular arrhythmias in BrS, ERS, and IVF (1). Quinidine’s benefit in these conditions may relate to its Ito blocking effect (1). Recent publications have supported the efficacy of quinidine in reducing implantable cardioverter-defibrillator (ICD) shock burden in patients with this unique family of sudden death syndromes (2–9). Expert consensus guidelines now recommend consideration of oral quinidine therapy for secondary prevention of ventricular arrhythmias in patients with BrS, ERS, and IVF who have an ICD (10).
Despite its potentially lifesaving effects in patients with BrS, ERS, and IVF, access to quinidine is limited globally, including in Canada (11–14). Currently, quinidine may be available for medical emergencies through Health Canada’s Special Access Program. In part because of this limited accessibility, quinidine use is rare in Canada and is used almost exclusively for secondary prevention of ventricular arrhythmias. The scope of quinidine use in a single-provider health care system allows estimation of the scope of use nationally, because care for Canadian patients requiring it is almost entirely provided by sites or regional partner sites of the Hearts in Rhythm Organization (HiRO) (15). In this study, we determined the scope and efficacy of quinidine use in Canada for the prevention of ventricular arrhythmias and explored the national issue of quinidine accessibility.
All patients over the age of 8 taking quinidine for prevention or treatment of ventricular arrhythmia were included in our study. Patients were identified using the HiRO network, including the CASPER (Cardiac Arrest Survivors with Preserved Ejection Fraction Registry).
CASPER is a national registry including patient data from 17 Canadian centers. Since January 1, 2004, the registry has prospectively enrolled survivors of unexplained cardiac arrest and their first-degree family members, as well as first-degree relatives of victims of sudden unexpected death with negative autopsy. Details of the protocol and eligibility criteria have been described previously (15). The study has enrolled 558 patients with unexplained cardiac arrest (16,17). Patients with cardiac arrest attributed to ERS, latent BrS, and IVF are typically captured in CASPER. Patients with BrS managed with quinidine were managed by sites that also managed CASPER patients.
Quinidine use capture and data collection involved the following steps (Online Figure 1):
1. CASPER was used to identify patients currently taking quinidine across all CASPER and HiRO partner sites.
2. To capture data on patients not enrolled in CASPER, the senior author (AK) recruited participation from adult and pediatric sites in the HiRO network.
3. Members of the Canadian Heart Rhythm Society were contacted through their quarterly newsletter, promoting the study and inviting participation.
4. Investigators from interested sites with at least 1 patient meeting inclusion criteria were sent a protocol, ethics approval from the host institution (University of British Columbia), and a data collection sheet.
5. Participating centers selected an independent reviewer for retrospective chart review of identified patients. Electronic and/or paper health records were also reviewed for patients in CASPER to ensure data accuracy and completeness.
6. Two reminder e-mails for data submission were sent to all participating centers.
7. All authors submitted the requested data.
8. Health Canada was contacted, requesting scope of patients approved for access to dispense quinidine.
This process identified 46 patients from 12 adult centers. To verify that our estimation of patients taking quinidine in Canada was accurate, Health Canada’s Special Access Program was contacted, requesting information to summarize the scope of patients approved for access to dispense quinidine.
This project was conducted in compliance with the protocol and principles laid down in the Declaration of Helsinki and good clinical practice, as defined by the International Conference on Harmonization where applicable, along with all other local regulatory requirements. The protocol was approved by the University of British Columbia Institutional Review Board/Independent Ethics Committee.
Data regarding patient demographics, diagnosis, antiarrhythmic drug (AAD) use, and ICD shocks were collected from retrospective review of identified patient health records. We analyzed 12-lead electrocardiograms (ECG), echocardiograms, and electrophysiology study results to assess for cardiac parameters that included heart rate, QT interval, PR interval, QRS duration, Brugada pattern or early repolarization pattern at baseline, ejection fraction, and ventricular tachycardia (VT) ablation details. Standard definitions for ECG parameters were used (10,18). Diagnostic test results were abstracted from health records without formal adjudication blinding.
All 12 lead ECG were interpreted by the respective site-specific investigator, all of whom were cardiologists. ECG of interest were the most recent prior to quinidine initiation, and the earliest were ≥48 h post-quinidine initiation. Echocardiograms and electrophysiology studies included were those soonest after index event, defined as the event that led to initial electrophysiology investigation and typically ICD implantation.
Because the study was designed to include only patients currently on quinidine, participating investigators were asked to identify patients in whom quinidine had been discontinued. For these patients, investigators were asked to comment on the reason for quinidine discontinuation, which included clinical failure, adverse events, and issues with access. Participating sites were also asked to describe any difficulty with accessing quinidine and to describe alternative routes of quinidine delivery to patients.
All results are expressed as mean ± SD or median after data was evaluated with the Kolmogorov-Smirnov test for normalcy of distribution. Continuous variables were compared by use of a 2-tailed Student’s t-test for continuous variables and Fisher exact test for categorical variables with normal distribution, whereas the Mann-Whitney U test was used for continuous variables with non-normal distribution. ICD shock outcomes before and subsequent to quinidine initiation were examined with intention-to-treat event analysis, as well as “on-treatment” event analysis performed after patients who had quinidine interruption or noncompliance were excluded. GraphPad Prism version 7, (San Diego, California) was used for Kaplan-Meier survival analysis. Differences in time-to-first event distribution were evaluated by the log-rank test. All other statistical analysis was performed using IBM SPSS version 22.0, (Armonk, New York). We considered p values <0.05 significant. The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Forty-six patients from 12 centers met inclusion criteria for the study (Table 1). The study population was predominantly middle-aged Caucasians, with preserved left ventricular function, who did not have a family history of sudden unexpected death. Eighty-seven percent of the population had a “J-wave” syndrome diagnosis, summarized in Online Figure 2. All but 2 patients studied underwent ICD implantation. On average, quinidine was initiated 3.9 years after initial diagnosis was made. The most common AAD used before quinidine was amiodarone, followed by beta-blockers and sotalol (Online Figure 3). AAD were discontinued due to recurrent ICD shock in the majority of patients. Quinidine sulfate was the formulation used in most patients. Thirteen patients had side effects attributed to quinidine, and 8 of these toxicities necessitated quinidine dose reduction (Table 1).
Compared with the pre-quinidine period, quinidine use significantly reduced the number of subsequent ICD shocks. Total ICD shocks per patient was 7.47 ± 12.3 before quinidine initiation and 0.86 ± 1.69 while on quinidine (p < 0.001) (Figure 1). The ICD shocks per year were 0.023 before quinidine initiation and 0.002 after initiation of quinidine (p < 0.001). The incidence of VT storm, defined as 3 or more sustained VT episodes in 24 h, was also significantly lower after quinidine initiation.
Thirty-six patients received an ICD shock. After excluding patients who had ICD shocks during quinidine interruption or nonadherence (n = 7) (Online Table 1), on-treatment event-rate analysis demonstrated greater ICD shock–free survival in patients after quinidine initiation (Figure 2). Intention to treat event-rate analysis is detailed in Online Figure 4. Clinical characteristics of the 12 patients (11 alive, 1 deceased) who experienced breakthrough ventricular arrhythmia resulting in appropriate ICD shocks while taking quinidine are displayed in Table 2. Ten of these 12 patients were prescribed quinidine for prevention of recurrent ventricular arrhythmia with a diagnosis other than BrS or ERS (Online Table 2). None of these ventricular arrhythmias were interpreted as proarrhythmia by the site investigator (no evidence of torsade de pointes on ECG or ICD interrogation).
Six patients developed recurrent ventricular arrhythmias during transient interruption of quinidine (Table 3). This led to appropriate ICD shocks in 5 patients, with resolution after resumption of quinidine in all but 1 patient, who was lost to follow-up. Of the sites that responded to the survey and had experience with at least 1 patient treated with quinidine, none identified patients that had to discontinue quinidine due to clinical failure or side effects. One patient on quinidine died at home and was presumed to have an arrhythmic cause of death without ICD interrogation (Online Table 2).
Health Canada identified 30 patients who were dispensed quinidine through the Special Access Program in 2016. All but 1 site described issues with quinidine accessibility, either resulting in significant delays due to quinidine shortages or necessitating patients to go through alternative means to receive quinidine. Inquiry indicated that 7 sites accessed quinidine outside of Health Canada’s Special Access Program to ensure quinidine delivery for their patients. These alternative methods of access included local compounding pharmacies that import quinidine (from Germany) in powder form and formulate the drug in capsule form on site (n = 8); a large online pharmacy that similarly uses imported quinidine, in powder form, from Germany and then compounds it into capsule form (n = 12); and importing the medication from foreign countries (n = 2). These alternative methods are detailed in Online Table 3.
This national study demonstrated that quinidine in Canada is most commonly used for secondary prevention of ventricular arrhythmia in patients with BrS, ERS, and IVF. This is supported by the 2013 expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes (10), based on modest-sized case series suggesting benefit (2–9).
A national estimate of prevalence of 1.5 cases per million adult population is possible with the current study design, because patients receiving quinidine typically do so through an established network of specialty clinics. The HiRO network provides process support for sites applying to Health Canada’s Special Access Program for quinidine access.
The most compelling finding in our study was the lower ICD shock burden and increased ICD shock–free survival on quinidine. Our results are similar to those of Anguera et al. (3), who reported on 29 ICD patients with BrS given quinidine for secondary prevention of ventricular arrhythmia. The median number of shocks per patient decreased from 6 to 0 over a follow-up period of 10 months. Ten of the 29 patients had ICD shocks after quinidine initiation, 4 of which were associated with dose reduction (3).
Haïssaguere et al. (5) also reported on quinidine use in 9 patients with a diagnosis of IVF and early repolarization pattern on ECG with more than 3 episodes of ventricular fibrillation in a retrospective report. Patients who developed recurrent ventricular arrhythmia were prescribed AAD by their individual physicians. Quinidine was successful in preventing ventricular arrhythmia in all 9 patients during a follow-up period of 33 ± 35 months. Amiodarone (1 of 7), mexiletine (0 of 4), verapamil (0 of 4), and beta-blockers (2 of 16) were much less effective in maintaining arrhythmia-free survival over their respective follow-up periods (5).
This combined experience provides compelling noncomparative evidence that quinidine is the most effective AAD for prevention of ventricular arrhythmia in this family of arrhythmia syndromes. Furthermore, we found 5 patients who experienced ventricular arrhythmia after brief interruptions in quinidine use. Anguera et al. (3) also found that 4 of their 10 patients on quinidine that experienced recurrent ventricular arrhythmia had quinidine dose reduction and 2 had temporary discontinuation. Similarly, Shen et al. (2) describe 10 male patients with BrS taking quinidine for secondary prevention of ventricular arrhythmia, with a single breakthrough event in a patient taking quinidine discontinuously due to anxiety. Once the patient was counselled on adherence and took quinidine consistently, he experienced no further ventricular arrhythmia or ICD shocks (2).
Despite the growing evidence of quinidine “dependence” in this patient population, access to quinidine continues to be challenging in many jurisdictions. Viskin et al. (11) conducted an international survey regarding the availability of quinidine. This report found that 10% and 39% of all physicians who treated BrS and IVF, respectively, reported caring for 1 or more patients who developed arrhythmic events associated with challenges with quinidine access. They reported 2 patients that died in association with inaccessibility to quinidine (11).
Reasons for quinidine inaccessibility have been well described by Viskin et al. (11–14). Briefly, 1 of the main manufacturers of quinidine sulfate, AstraZeneca, discontinued its production in 2006 due to the decreasing use of quinidine for management of common arrhythmias (11). Issues with distribution may contribute more to quinidine inaccessibility than lack of production (11,13). In the survey by Viskin et al. (11), quinidine was unavailable in 99 countries and is only available through a regulatory process in 13 countries.
In Canada, a request for quinidine must be made through Health Canada’s Special Access Program, in keeping with standard procedures for nonapproved drugs or devices. The approval and transportation time can take weeks, which can result in delays detrimental to patient well-being. In attempts to partially overcome this difficulty, we found that a substantial proportion of Canadian physicians go through routes alternative to Health Canada’s Special Access Program to ensure timely quinidine delivery for their patients. These methods include using local and online compounding pharmacies, as well as importing quinidine from foreign countries. Despite these alternative physician-initiated solutions, delays in quinidine delivery have resulted in potentially life-threatening ventricular arrhythmias for Canadian patients. It is fundamental to increase access to quinidine globally, with manufacturers providing product to market, though solutions are not simple and, in part, are country-specific with respect to regulatory processes.
Study limitations and future directions
Due to the narrow indication for quinidine use, we believe that health care practitioners outside of the network of specialty clinics that were included in this study are highly unlikely to be prescribing quinidine for their patients. Nonetheless, we cannot be absolutely certain that all patients taking quinidine were included in our study, although attempts at verification through Health Canada support this conclusion. Furthermore, access limitation specifics were not measured, which encompass manufacturing, shipping, regulatory approval times, and requesting site factors.
By the nature of the study design, only patients currently taking quinidine were studied. This is a cohort study without a control group. Thus, confounding variables cannot be accounted for, and a causal relationship between the use of quinidine and outcomes cannot be established. Many patients were initiated on quinidine after occurrence of breakthrough ICD shocks or VT storm, thus an element of “regression to the mean” following these events may have contributed to overestimating the reduction in ventricular arrhythmia associated with quinidine. Furthermore, patients who had failed quinidine may not have been completely captured, though we attempted to ascertain whether this was the case from site recollection, which did not suggest this was a prevalent concern. For these reasons, these data should not be interpreted as comparative between quinidine and other AAD, but rather the data suggest that quinidine is effective when other AAD have failed in this population and that clinicians should strongly consider use of quinidine. The latter is supported by guidelines and the current data (2–4,10,18).
A randomized controlled trial comparing quinidine as first-line therapy to other AAD in patients with BrS, ERS, and IVF could be an important next step to overcome the limitations of a retrospective study and demonstrate the true utility of quinidine in preventing ventricular arrhythmia in this patient population. Perhaps the results of such a study could expand the role of quinidine in consensus guidelines, which would provide further stimulus to increase global quinidine production and accessibility. This may be hard to justify in the context of widely accepted albeit noncomparative evidence that is supported by guideline recommendations to use quinidine in this population.
National use of quinidine is uncommon, but quinidine plays a potentially lifesaving role by reducing ICD shocks and VT storm in this select population with responsive syndromes. Access to quinidine needs to be ensured to protect these patients from adverse outcomes including electrical storm and sudden death.
COMPETENCY IN MEDICAL KNOWLEDGE: Quinidine is effective in patients with J-wave syndromes in reducing ICD shocks, with an apparent quinidine responsive/dependence rate of 1.5 patients per million population.
TRANSLATIONAL OUTLOOK: Global access to quinidine needs to be improved to ensure delivery of this lifesaving medication to the 1.5 patients per million in whom the drug is clearly lifesaving.
The authors are indebted to the tireless work of the study coordinators and to our patients who gladly participate to advance our understanding of cardiac arrest and inherited arrhythmias.
The study was supported by the Heart and Stroke Foundation of Canada (G-13-0002775 and G-14-0005732), and the Canadian Institute of Health Research (MOP-142218 and SRG-15-P09-001), and the Canadian Arrhythmia Network (CANet SRG-15- P09-001). Dr. Krahn receives support from the Heart and Stroke Foundation of Canada, the Sauder Family and Heart and Stroke Foundation Chair in Cardiology, the Paul Brunes Chair in Heart Rhythm Disorders, and the Paul Albrechtson Foundation. All other 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
- antiarrhythmic drug
- Brugada syndrome
- early repolarization syndrome
- Hearts in Rhythm Organization
- implantable cardioverter-defibrillator
- transient outward potassium current
- idiopathic ventricular fibrillation
- ventricular tachycardia
- Received June 15, 2018.
- Revision received October 11, 2018.
- Accepted October 15, 2018.
- 2019 American College of Cardiology Foundation
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