Quinidine, a class IA antiarrhythmic drug (AAD), has been used for the treatment of arrhythmias since the early 1900s. Use has decreased recently because of the availability of newer AADs and concerns about side effects and safety. Quinidine can cause QT prolongation, and women have longer QT intervals and are more susceptible to torsades de pointes (TdP) than are men. We sought to evaluate the influence of gender on quinidine tolerability, safety, and efficacy. We performed retrospective analyses of patients at our institution prescribed quinidine as an AAD between 2000 and 2012. Time to quinidine discontinuation and arrhythmia recurrence were evaluated using Cox proportional hazards models. In 179 patients, 23.5% were women and median age was 65.8 years. Quinidine indication was supraventricular arrhythmias in 68.7% and ventricular arrhythmias in 27.9% of patients. At 3 years after quinidine initiation, Kaplan–Meier probability of quinidine discontinuation was 65.7% for men and 82.4% for women (p = 0.015). Women were more likely than men to discontinue quinidine for QT prolongation (14.3 vs 4.4%, p = 0.036) and TdP (4.8 vs 0%, p = 0.054). After multivariate adjustment, female gender remained independently associated with quinidine discontinuation (adjusted hazard ratio 1.97, p = 0.014). Gender had no influence on arrhythmia recurrence: 1 year after quinidine initiation, Kaplan–Meier probability of freedom from recurrent arrhythmia was 62.4% in men and 57.9% in women (p = 0.33). Quinidine is highly effective in both genders. However, women are more likely than men to experience QT prolongation and TdP on quinidine and are more likely to discontinue quinidine independent of these side effects.
Quinidine, a compound derived from the bark of the cinchona plant, is a class IA antiarrhythmic drug (AAD), which has been used for the treatment of arrhythmias since the early 20th century. It is one of the oldest cardiac medications still available today, has many favorable pharmacokinetic properties including a high oral bioavailability and rapid onset of action, and it can be safely used in patients with structural heart disease and/or renal dysfunction. Despite its historical efficacy at maintaining sinus rhythm, use of quinidine has dramatically decreased in recent years because of concerns about side effects, drug safety, proarrhythmia, increased mortality, and the availability of newer AADs, which are often viewed by physicians as being more efficacious, safer, and better tolerated. As a result, quinidine has essentially been replaced by other, newer AADs and/or catheter-based ablation. Although quinidine is used infrequently in the treatment of supraventricular arrhythmias and ventricular tachycardia, recent guidelines recommend consideration of its use in other, less-common, conditions such as Brugada syndrome (class IIa), early repolarization syndrome (class IIa), short QT-syndrome (class IIb), and idiopathic ventricular fibrillation (class IIb). Despite this, the overall volume of quinidine prescription has decreased so significantly that its manufacture is at risk of being discontinued entirely, and patients who rely on this medication often face shortages or must pay very high costs to obtain it. Limited data therefore exist on the use of quinidine for the treatment of atrial and ventricular arrhythmias unrelated to genetic channelopathies in the modern era.
Gender influences the pharmacodynamic and pharmacokinetic properties of many cardiovascular medications. In addition, compared with men, women have longer baseline QT intervals and account for a disproportionate number of cases of drug-induced torsades de pointes (TdP). As a result of its potassium channel blocking properties, quinidine can cause significant QT interval prolongation, and, at similar quinidine blood concentrations, women are more likely to develop QT prolongation than are men. Despite these observations, study of the influence of gender on the tolerability, safety, and efficacy of quinidine is lacking. At our institution, quinidine is still actively prescribed for the treatment of both supraventricular and ventricular arrhythmias, and it is often prescribed as a first-line antiarrhythmic agent. In this study, we sought to evaluate the influence of gender on the tolerability, safety, and efficacy of quinidine.
Methods
We performed a retrospective analysis of all patients who were prescribed quinidine gluconate or quinidine sulfate for treatment of a cardiac arrhythmia at Beth Israel Deaconess Medical Center between January 1, 2000, and December 31, 2012. Study data were collected and managed using REDCap electronic data capture tools. Patients were excluded if they had <7 days of follow-up after quinidine initiation and did not stop quinidine or report adverse effects within this period.
Review of the medical record was performed to assess demographic, clinical, and electrocardiographic (ECG) characteristics at the time quinidine was initially prescribed, date of and reason for quinidine discontinuation, occurrence of side effects, and date of arrhythmia recurrence. A 3-day blanking period for arrhythmia recurrence was used after quinidine initiation to allow the drug to reach therapeutic levels. All patients were not continuously monitored for long-term arrhythmia recurrence with external or implantable loop recorders, and for patients without cardiac monitors, arrhythmia recurrence was defined as recurrence of clinically recognized arrhythmia or arrhythmia detected on routine ECG monitoring. For patients with external or implantable loop recorders, implantable cardioverter-defibrillators, or pacemakers, routine interrogation notes were reviewed for evidence of arrhythmia recurrence, even if asymptomatic. Date of death was assessed through review of the medical record and/or search of the Social Security Death Index. Primary cause of death was assessed through the medical record and/or review of death certificates. Deaths within 7 days of the last administered dose of quinidine or in which the timing of the last dose of quinidine with respect to time of death was unknown were considered possibly related to quinidine and investigated further.
Categorical variables were reported as number and percentage of the total and were compared using Pearson’s chi-square test or Fisher’s exact test as appropriate. Continuous variables were reported as the median and interquartile range and compared using the Wilcoxon rank-sum test. The primary outcomes studied were discontinuation of quinidine within 3 years and arrhythmia recurrence within 1 year of drug initiation. Univariate Cox proportional hazard models were constructed to assess for associations among gender, multiple clinical and demographic factors, and drug discontinuation and arrhythmia recurrence. Multivariate analyses were performed by including variables with a univariate p value <0.1 and variables without a statistically significant association which were prespecified as potentially clinically relevant to quinidine discontinuation (quinidine dose, previous myocardial infarction [MI], and arrhythmia recurrence). The validity of the proportional hazards assumption was verified for all models. Patients were censored at the time of quinidine discontinuation or last follow-up, whichever occurred first.
All statistical analyses were independently performed by the authors using STATA version 13.1 (StataCorp, College Station, Texas). All record review and data analyses were performed under the approval of the Institutional Review Board of Beth Israel Deaconess Medical Center.
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