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Dofetilide dose reductions and discontinuations in women compared with men

      Background

      Compared with men, women have longer corrected QT (QTc) intervals, lower clearance of dofetilide, and higher rates of drug-induced torsades de pointes, but the dofetilide dosing algorithm is the same for men and women.

      Objective

      The purpose of this study was to evaluate the tolerability of the 500 μg twice daily dose of dofetilide for men and women.

      Methods

      Men and women admitted to Duke University Medical Center (January 1, 2006, to October 19, 2012) for the initiation of dofetilide 500 μg twice daily were matched 1:1 on age and estimated creatinine clearance. Electrocardiograms throughout dosing were analyzed, and rates of dofetilide discontinuations and dose reductions were compared in unadjusted and adjusted analyses.

      Results

      For 220 matched men and women, the median age was 62.5 years (interquartile range 55–69 years) and the median eCrCl was 98.1 mL/min (interquartile range 77.6–126.2 mL/min). Women were less likely than men to have hypertension and interventricular conduction delay but were otherwise similar. During dofetilide initiation, women were more likely than men to have their dofetilide dose discontinued or reduced (55% vs 32%; P < .001). In most women (82%) and men (69%), the reason for dose adjustment was significant QTc prolongation. In the adjusted analysis, female sex was associated with higher rates of dofetilide dose discontinuations or reductions (odds ratio 3.01; 95% confidence interval 1.58–5.71; P < .01).

      Conclusion

      More than half of women who initiated on 500 μg twice daily of dofetilide required medication discontinuations or dose reductions, mostly because of QTc prolongation. Additional studies are needed to evaluate the optimal dosing algorithm of dofetilide in women.

      Keywords

      Introduction

      Professional society guidelines for atrial fibrillation (AF) recommend antiarrhythmic drug therapy for patients with symptomatic recurrent paroxysmal AF and recurrent persistent AF despite rate control.
      • January C.T.
      • Wann L.S.
      • Alpert J.S.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
      Dofetilide has been shown to be effective in cardioversion of AF and maintenance of sinus rhythm in 2 randomized controlled clinical trials,
      • Pedersen O.D.
      • Bagger H.
      • Keller N.
      • Marchant B.
      • Kober L.
      • Torp-Pedersen C.
      Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function: a Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) substudy.
      • Singh S.
      • Zoble R.G.
      • Yellen L.
      • Brodsky M.A.
      • Feld G.K.
      • Berk M.
      • Billing Jr., C.B.
      Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the Symptomatic Atrial Fibrillation Investigative Research on Dofetilide (SAFIRE-D) study.
      and as a result, dofetilide is the only antiarrhythmic agent that is recommended as a first line therapy for a wide range of patients with AF—those with and those without structural heart disease (coronary artery disease or heart failure).
      • January C.T.
      • Wann L.S.
      • Alpert J.S.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
      Dofetilide is a Vaughan Williams class III antiarrhythmic medication that blocks the rapid-delayed outward rectifier potassium current (IKr) during repolarization, which can result in a dose-related prolongation of the action potential duration and corrected QT (QTc) interval on an electrocardiogram (ECG).
      • Tham T.C.
      • MacLennan B.A.
      • Burke M.T.
      • Harron D.W.
      Pharmacodynamics and pharmacokinetics of the class III antiarrhythmic agent dofetilide (UK-68,798) in humans.
      • Le Coz F.
      • Funck-Brentano C.
      • Morell T.
      • Ghadanfar M.M.
      • Jaillon P.
      Pharmacokinetic and pharmacodynamic modeling of the effects of oral and intravenous administrations of dofetilide on ventricular repolarization.
      Dofetilide is primarily excreted by the kidneys (70%–80%).
      • Mounsey J.P.
      • DiMarco J.P.
      Cardiovascular drugs: dofetilide.
      The Food and Drug Administration–approved dose selection algorithm for dofetilide is based on the estimated creatinine clearance (eCrCl; as determined using the Cockcroft-Gault equation). Lower initiation doses are selected for those with poorer renal function with the intent of minimizing the risk of QTc prolongation and torsades de pointes.
      Women have a longer baseline QTc interval than do men,
      • Rautaharju P.M.
      • Zhou S.H.
      • Wong S.
      • Calhoun H.P.
      • Berenson G.S.
      • Prineas R.
      • Davignon A.
      Sex differences in the evolution of the electrocardiographic QT interval with age.
      and female sex has been associated with at least a 2-fold higher rate of torsades de pointes with class III antiarrhythmic drugs
      • Wolbrette D.L.
      Risk of proarrhythmia with class III antiarrhythmic agents: sex-based differences and other issues.
      ; however, no differential dosing adjustment is recommended for women with the same eCrCl as men.
      The purpose of this analysis was to explore the tolerability of the 500 μg twice daily dose of dofetilide that is the recommended initiation dose for both men and women with eCrCl >60 mL/min by comparing changes in QTc interval, adverse events, and rates of dose discontinuations or reductions between men and women.

      Methods

       Study population

      This retrospective study included adult patients at Duke University Medical Center, initiating dofetilide for treatment of AF for the first time between January 1, 2006, and October 19, 2012, with a dose of 500 μg twice daily. Patients were identified through the Duke Enterprise Data Unified Content Explorer (DEDUCE), which is a research database of data collected through patient care at Duke University Medical Center. Manual chart abstraction was used to collect comorbid conditions, actual body weight, baseline QTc intervals, and QTc intervals after each of the first 5 doses of dofetilide, dofetilide discontinuations, dofetilide dose reductions, reasons in the chart for dofetilide dose discontinuations or reductions, adverse drug reactions, and electrophysiology procedures performed. Patients were excluded for the following reasons: previous treatment with dofetilide, reinitiation of dofetilide, or initiation of dofetilide at a dose less than 500 μg twice daily. As per hospital policy, all patients were monitored for at least the first 5 doses of dofetilide on continuous telemetry with daily electrolyte and renal function monitoring, as well as ECGs before the first dose of dofetilide and 2–3 hours after each dose. Patients were monitored by cardiologists or electrophysiologists who were certified dofetilide prescribers.
      All women initiated on dofetilide for the first time at a dose of 500 μg twice daily during the study period were included in the analysis. These women were matched 1:1—on age and eCrCl—with men who were admitted during the study period for initiation of 500 μg twice daily of dofetilide for the first time. Serum creatinine on the day of or day before the initiation of dofetilide and actual body weight on admission were used to calculate the eCrCl by using the Cockroft-Gault equation. Patients in the analysis had eCrCl > 60 mL/min, so they were dosed appropriately with the 500 μg twice daily dose.

       End points

      Measurements of baseline QTc intervals and the QTc intervals after each dose of dofetilide were performed manually using the Bazett formula by a single cardiologist (S.D.P.). The ECG reader was blinded to patient sex, whether the ECG was taken at baseline or after one of the dofetilide doses, previous and future QTc interval values for a given patient, and patient outcomes (adverse events, dose modifications, or medication discontinuation). Measurements of QTc intervals were retrospective and independent of clinical care measurements. The QT interval was measured from the onset of the QRS complex to the intersection of the line of the maximal slope of the t wave and the TP baseline. The QTc interval measurement for an ECG in sinus rhythm was determined by a single beat in the limb leads. The QTc interval measurement for an ECG in AF was based on the average of 3 QTc interval measurements, including the shortest R-R interval in any lead, the longest R-R interval in any lead, and an intermediate R-R interval in the limb leads.
      • Al-Khatib S.M.
      • LaPointe N.M.
      • Kramer J.M.
      • Califf R.M.
      What clinicians should know about the QT interval.
      Dofetilide discontinuations or dose reductions were determined through manual chart review. Dofetilide discontinuation was defined as initiation of the dofetilide 500 μg dose with subsequent discharge off dofetilide. Dofetilide dose reductions were defined as initiations of the dofetilide 500 μg twice daily dose with subsequent discharges on a dose less than 500 μg twice daily. Dofetilide discontinuations were defined as initiations of the dofetilide 500 μg twice daily dose with subsequent discharges off dofetilide. Decisions to modify the doses of dofetilide, either by medication discontinuations or by dose reductions, were made by the certified dofetilide prescriber who were clinically caring for the patients. Adverse events such as torsades de pointes, bradycardia-requiring pacemaker implantation, and in-hospital death were determined through chart abstraction. Recurrence of AF was evaluated 1 year after dofetilide initiation, and AF recurrence was defined as patient reported symptomatic recurrence of AF, ECG documented AF, or AF documented on Holter monitor.

       Statistical methods

      Men were identified for the analysis by matching them 1:1 to women on age and eCrCl. Patients were first matched on age with the goal of obtaining an exact match whenever possible. Patients were then matched on eCrCl, and women and men were a match if their eCrCl were within 10% of each other. If there were no matches based on eCrCl for patients of the same age, a match was then pursued for women and men with ages with a maximum of 5-year difference while maintaining the 10% difference in eCrCl; if there was still no match, the unmatched women (n = 2) were excluded from the analysis. If more than 1 match was identified, the matched pair with the closest eCrCl was used.
      Baseline characteristics were compared between men and women. Categorical variables were summarized as counts and percentages and were compared using the Pearson χ2 test. Continuous variables were summarized as medians and interquartile ranges and were compared using the Kruskal-Wallis test. The unadjusted number and prevalence of dofetilide discontinuations or dose reductions by sex during in-hospital initiation were reported. Logistic regression modeling assessed the adjusted association between sex and dofetilide dose modifications (discontinuations or dose reductions). The covariates in the model included age, race, sex, actual body weight, hypertension, diabetes, heart failure, coronary artery disease, obstructive sleep apnea, chronic obstructive pulmonary disease, eCrCl, and baseline QTc interval.
      All analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC). The study was approved by the Duke University's Institutional Review Board.

      Results

       Baseline characteristics

      There were 110 female patients and 110 male patients matched and included in the analysis with the median age of 62.5 years (interquartile range 55–69 years) and the median eCrCl of 98.1 mL/min (interquartile range 77.6–126.2 mL/min). The median age and eCrCl were similar for male and female patients (Table 1). The actual body weight in men was significantly higher than that in women (median 95.5 kg vs 84.1 kg; P < .001). β-Blockers or diltiazem were present at dofetilide initiation in 86 women (78%) and 89 men (81%), and one of these medications was prescribed at discharge after dofetilide load in 83 women (75%) and 88 men (80%). The baseline median QTc interval was similar for women (435 ms; interquartile range 417–456 ms) and men (430 ms; interquartile range 405–458 ms) (P = .41). The prevalence of comorbid conditions was similar in women and men, although hypertension was less common in women (n = 59 [54%] vs n = 75 [68%]; P = .027) (Table 1).
      Table 1Patient characteristics
      Men and women were matched on age and eCrCl.
      CharacteristicWomen (n = 110)Men (n = 110)P
      Demographics
       Age (y)62 (55–69)63 (55–69).92
       Weight (kg)84.1 (72.7–101.4)95.5 (86.0–110.0)<.001
       Black race7 (6)8 (7).79
      Medical history
       Heart failure17 (15)17 (15)1.00
       Hypertension59 (54)75 (68).027
       Coronary artery disease19 (17)29 (26).10
       Diabetes20 (18)15 (14).36
       Chronic obstructive pulmonary disease5 (5)4 (4).73
       Obstructive sleep apnea23 (21)23 (21)1.00
       eCrCl (mL/min)
      eCrCl is defined by Cockroft-Gault.
      99.0 (74.9–123.0)98.1 (78.3–127.1).57
      Baseline medications
       β-Blockers or diltiazem86 (78)89 (81).62
      Baseline electrocardiographic findings
       Atrial fibrillation at initiation45 (41)52 (47).34
       QRS duration (ms)90 (80–100)100 (90–110)<.001
       QRS duration > 120 ms10 (9)18 (16).032
       QTc interval (ms)435 (417–456)430 (405–458).41
      Values are presented as median (interquartile range) or n (%).
      eCrCl = estimated creatinine clearance; QTc = corrected QT.
      Men and women were matched on age and eCrCl.
      eCrCl is defined by Cockroft-Gault.

       Dofetilide dose changes or discontinuations

      Forty-one women (37%) initiated on dofetilide 500 μg twice daily and had their dofetilide dose reduced during in-hospital initiation. Fewer men (n = 27 [25%]) of similar age and eCrCl had dose reductions in comparison to women (P = .042) (Figure 1). A greater number of women initiated on 500 μg twice daily of dofetilide had the medication discontinued during hospitalization in comparison to men (17% vs 7%; P = .024). Overall, women were more likely than men to have discontinuations or dose reductions (55% vs 32%; P < .001), and the most common dose reduction was down to 250 μg twice daily (Figure 2).
      Figure thumbnail gr1
      Figure 1Dofetilide discontinuations or dose reductions by sex. The P values represent the statistical difference between the prevalence in women and the prevalence in men.
      Figure thumbnail gr2
      Figure 2Dofetilide dose at discharge by sex. The bars represent the proportion of women and men who were discharged on the respective dofetilide doses. The doses are all twice daily doses.
      Most discontinuations or dose reductions were due to QTc prolongation in women (n = 49 [82%]) and men (n = 24 [69%]) (Table 2 and Supplemental Appendix 1). Bradycardia (5 women [8%] and 8 men [23%]) was the second most common reason for dose modification, and 4 women and 7 men who developed bradycardia were on β-blockers or calcium channel blockers at baseline (Table 2). There were 2 women (2%) and 1 man (1%) who developed profound sinus bradycardia on dofetilide requiring pacemaker implantation during the dofetilide initiation hospitalization in order to safely continue dofetilide.
      Table 2Events resulting in discontinuations or dose reductions
      Based on documentation identified in the medical records.
      VariableWomen (n = 60)Men (n = 35)
      QTc prolongation49 (82)24 (69)
      Angioedema0 (0)0 (0)
      Atrioventricular block1 (2)0 (0)
      Sinus bradycardia5 (8)8 (23)
      Cardiac arrest0 (0)0 (0)
      Headache1 (2)1 (3)
      Torsades de pointes0 (0)0 (0)
      Nonsustained ventricular tachycardia4 (7)2 (6)
      Values are presented as n (%).
      Based on documentation identified in the medical records.
      After adjustment, female sex was associated with dofetilide discontinuations or dose reductions (odds ratio [OR] 3.01; 95% confidence interval [CI] 1.58–5.71) (Table 3). There was also an association between female sex and dofetilide discontinuations (OR 2.92; 95% CI 1.13–7.54) and a trend toward an association between female sex and dose reductions (OR 1.93; 95% CI 1.00–3.74) (Table 3).
      Table 3Adjusted association between female sex vs male sex and outcomes
      OutcomeAdjusted odds ratio95% confidence intervalP
      Dofetilide discontinuations2.921.13–7.54.03
      Dofetilide dose reductions1.931.00–3.74.05
      Dofetilide discontinuations or dose reductions3.011.58–5.71<.01
      There were no cases of torsades de pointes or in-hospital death among women or men.

       AF 1-year follow-up data

      There were 91 female (83%) and 102 male (93%) patients discharged on dofetilide, while 84 women (76%) and 88 men (80%) had follow-up data at 1 year (6 women lost to follow-up and 1 died; 13 men lost to follow-up and 1 had cardiac transplant). Rates of any AF recurrence at 1 year were higher for male (n = 56 of 88 [64%]) than for female (n = 41 of 84 [49%]) patients (P < .001). Rates of AF recurrence were similar for men discharged on 500 μg twice daily (n = 67) vs 250 μg twice daily (n = 10) (64% vs 70%, respectively), as well as for women discharged on 500 μg twice daily (n = 46) vs 250 μg twice daily (n = 31) (50% vs 48%, respectively).

       Subgroup analysis

      Of the 10 women with QRS duration ≥120 ms, 7 had dofetilide discontinuations or dose reductions, while 7 of the 18 men with QRS duration ≥120 ms had dofetilide discontinuations or dose reductions. Among patients with QRS duration <120 ms, 53% of women ( n = 53 of 100) and 32% of men (n = 28 of 92) had dofetilide discontinuations or dose reductions (P < .001).
      At baseline, 14 women (13%) and 29 men (26%) had QTc interval >440 ms with a narrow QRS complex or QTc interval >500 ms with QRS duration ≥120 ms. Nearly all (n = 13 [93%]) of these women had dofetilide discontinuations (n = 6 [43%]) or dose reductions (n = 7 [50%]), while fewer than half (n = 13 [45%]) of these men had dofetilide discontinuations (n = 3 [10%]) or dose reductions (n = 10 [34%]). Among 96 women (87%) and 81 men (74%) with QTc interval ≤440 ms with a narrow QRS complex or QTc interval ≤500 ms with QRS duration ≥120 ms, women still tended to have more dofetilide discontinuations (n = 13 [14%]) or dose reductions (n = 34 [35%]) as compared with dofetilide discontinuations (n = 5 [6%]) or dose reductions (n = 17 [21%]) in men.

      Discussion

      The recommended initiation dose of dofetilide for women and men with eCrCl >60 mL/min by Cockroft-Gault is 500 μg twice daily. Despite following this dosing recommendation, more than 50% of women who were initiated on the 500 μg twice daily dose of dofetilide had medication discontinuations or dose reductions during in-hospital monitored initiation. Prolongation of the QTc interval was the most common reason for dose modification and occurred in more than two-thirds of women and men. Female sex was associated with medication discontinuations or dose reductions in unadjusted and adjusted analyses when compared with men of matched age and eCrCl.
      Data from the dofetilide clinical trials demonstrated that dose reductions of dofetilide for QTc prolongation occurred in 5% and 7% of Danish Investigation of Arrhythmia and Mortality ON Dofetilide (DIAMOND) CHF and DIAMOND MI patients, respectively. Data from 2 cardioversion trials found that 3% of patients had their dofetilide dose reduced because of QTc prolongation. The rates of dofetilide discontinuations across all 4 trials were 2%–3%.
      • Huxley R.R.
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      Absolute and attributable risks of atrial fibrillation in relation to optimal and borderline risk factors: the Atherosclerosis Risk in Communities (ARIC) Study.
      The rates of discontinuations and dose reductions were meaningfully higher in our analysis, with 32% of male patients and 55% of female patients unable to complete the initiation with 500 μg of dofetilide twice daily. Compared with those in clinical trials, dose reduction rates in women were 5- to 12-fold higher in this analysis, while dofetilide discontinuation rates in women in this analysis were 6- to 9-fold higher than those in clinical trials. However, this analysis evaluated only patients with eCrCl >60 mL/min who were initiated on the 500 μg twice daily dose. The data in this analysis were in line with reports from other clinical practices in which the rates of discontinuations during dofetilide initiation were also meaningfully higher than those in the trials, ranging from 7% to 12%, while the rates of dofetilide dose reductions ranged from 17% to 29%.
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      Rates of QTc prolongation may be even higher in patients who chemically cardiovert with the initiation of dofetilide.
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      Prolongation of the QTc interval was the reason that dofetilide was discontinued or dose reduced in more than 2 of 3 men and women patients in this analysis. It is known that women have longer baseline QTc intervals than do men, which may make them more prone to drug-induced QT prolongation. This difference in QTc interval arises after puberty when men experience shortening of their QTc intervals while women do not.
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      A proposed mechanism for this is the effect of sex hormones on cardiac repolarization. In animal studies, testosterone was protective against action potential prolongation, including with infusion of QTc-prolonging cardiovascular medications.
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      Animal models have also found a higher prevalence of early afterdepolarizations in adult female patients exposed to dofetilide.
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      A difference in baseline QTc intervals between women and men was not seen in this study, which may have been due to selection bias, as patients were not eligible for dofetilide initiation if their QTc interval was prolonged. Early afterdepolarizations can cause polymorphic ventricular tachycardia, so the findings of longer QTc intervals in women could contribute to the association between female sex and torsades de pointes with class III antiarrhythmic medications.
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      Risk of proarrhythmia with class III antiarrhythmic agents: sex-based differences and other issues.
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      Our analysis did not identify any cases of in-hospital torsades de pointes. Sinus bradycardia was the second most common reason for discontinuations or dose reductions. It is difficult to determine from the chart review what portion of these events were related to better identification of bradycardia due to continuous telemetry monitoring vs bradycardia associated with the dofetilide itself. Dofetilide has previously been shown to decrease heart rate and prolong sinus node recovery time.
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      • DiMarco J.P.
      Cardiovascular drugs: dofetilide.
      Despite the potential sex differences in QTc interval, female sex was underrepresented in the landmark dofetilide clinical trials, as women comprised 28% of all enrolled patients in both the DIAMOND CHF and DIAMOND MI trials as well as 16% of patients in the Symptomatic Atrial Fibrillation Investigative Research on Dofetilide trial.
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      • Billing Jr., C.B.
      Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the Symptomatic Atrial Fibrillation Investigative Research on Dofetilide (SAFIRE-D) study.
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      • Carlsen J.
      • Videbaek J.
      • Marchant B.
      • Camm A.J.
      Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group
      Dofetilide in patients with congestive heart failure and left ventricular dysfunction.
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      Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial.
      Fewer than 25% of DIAMOND patients with AF at baseline were women.
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      • Torp-Pedersen C.
      Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function: a Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) substudy.
      Several of the pharmacokinetic and pharmacodynamic analyses of dofetilide were done only in men.
      • Tham T.C.
      • MacLennan B.A.
      • Burke M.T.
      • Harron D.W.
      Pharmacodynamics and pharmacokinetics of the class III antiarrhythmic agent dofetilide (UK-68,798) in humans.
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      • Funck-Brentano C.
      • Morell T.
      • Ghadanfar M.M.
      • Jaillon P.
      Pharmacokinetic and pharmacodynamic modeling of the effects of oral and intravenous administrations of dofetilide on ventricular repolarization.
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      • Oliver S.D.
      The pharmacokinetics and pharmacodynamics of oral dofetilide after twice daily and three times daily dosing.
      Pharmacokinetic and pharmacodynamic data show that women have clearance rates of dofetilide that are 12%–18% lower than those in men, resulting in plasma concentrations of dofetilide that are 14%–22% higher in women than in men.
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      • Lopez F.L.
      • Folsom A.R.
      • Agarwal S.K.
      • Loehr L.R.
      • Soliman E.Z.
      • Maclehose R.
      • Konety S.
      • Alonso A.
      Absolute and attributable risks of atrial fibrillation in relation to optimal and borderline risk factors: the Atherosclerosis Risk in Communities (ARIC) Study.
      Two small studies, consisting of 107 patients with AF (41% women) and 22 healthy patients (50% women), evaluated potential differences in QTc prolongation between the sexes in response to dofetilide, and neither study found a statistical difference in QTc prolongation.
      • Guanzon A.V.
      • Crouch M.A.
      Phase IV trial evaluating the effectiveness and safety of dofetilide.
      • Vicente J.
      • Johannesen L.
      • Mason J.W.
      • Pueyo E.
      • Stockbridge N.
      • Strauss D.G.
      Sex differences in drug-induced changes in ventricular repolarization.
      However, the 22-patient study involved giving single doses of dofetilide to healthy control patients.
      • Vicente J.
      • Johannesen L.
      • Mason J.W.
      • Pueyo E.
      • Stockbridge N.
      • Strauss D.G.
      Sex differences in drug-induced changes in ventricular repolarization.
      The larger study that included 44 women did not restrict the patient population to the 500 μg twice daily dose, and the patient population did not include matching or adjustment.
      • Guanzon A.V.
      • Crouch M.A.
      Phase IV trial evaluating the effectiveness and safety of dofetilide.
      A third study of 114 male patients identified a 19% rate of dofetilide discontinuations during hospitalization for initiation of dofetilide, and 88 of the 114 patients were on the 500 μg twice daily dose.
      • Anand V.
      • Vakil K.
      • Tholakanahalli V.
      • Li J.
      • McFalls E.
      • Adabag S.
      Discontinuation of dofetilide from QT prolongation and ventricular tachycardia in the real world.
      We had nearly twice as many patients as the largest of these 3 previous studies, and our analysis was the only study limited to patients initiating on 500 μg twice daily dofetilide. Our study also included matched women and men. These factors likely contributed to our ability to demonstrate higher unadjusted rates of dofetilide discontinuations (P = 0.024), dose reductions (P = 0.042), and discontinuations or dose reductions (P < .001) in women in the present analysis. Similarly, even after adjustment for baseline characteristics, female sex was associated with higher rates of dofetilide discontinuations (OR 2.92), dose reductions (OR 1.93), and discontinuations or dose reductions (OR 3.01). Reasons for these findings are likely multifactorial and related to disproportionate effects of actual body weight vs ideal body weight on eCrCl by sex- and gender-specific differences, with women being more prone to QTc prolongation. The concept that women are more prone to QTc prolongation is supported by the 1:1 matching for age and eCrCl in this analysis, as well as the fact that twice as many men (n = 29 [26%]) as women (n = 14 [13%]) had baseline QTc interval >440 ms with a narrow QRS complex or QTc interval >500 ms with QRS duration ≥120 ms, but women still had greater QTc prolongation.

       Study limitations

      Even though women and men were well matched and appropriate statistical adjustment was performed, residual measured and unmeasured confounders could have affected the analysis. This was a single-center experience with limited racial diversity, as only 7% of the population was black, so our data may not generalize to racial minorities. The Bazett formula was used for QTc interval calculation, and there are limitations on the accuracy of this formula, especially in the setting of tachycardia; however, the same methodology was used for patients of both sexes. Although there were no episodes of torsades de pointes, this study focused on safety during the in-hospital initiation period of dofetilide in a study population that was smaller than that of the dofetilide clinical trials. Follow-up data are needed to determine the long-term safety of the 500 μg twice daily dose in women who tolerate the initiation and are discharged on the 500 μg twice daily dose. There was no standardized approach to monitor for AF recurrence. The 1-year follow-up data are not sufficient to prove effectiveness of the 250 μg twice daily dose for women, and additional effectiveness data of the maintenance of rhythm control after dose reduction are needed. This study was limited to dofetilide initiation through late 2012, because around that time many providers at our institution began to systematically avoid the 500 μg twice daily dose in women even in patients with eCrCl >60 mL/min. This analysis focused on the 500 μg twice daily dose, and no comments can be made about differences in the tolerability of loading women and men meeting the dosing recommendations for the 250 or 125 μg twice daily doses.

      Conclusion

      More than half of women with normal renal function who initiated on dofetilide 500 μg twice daily required dofetilide discontinuations or dose reductions during the in-hospital initiation period as compared with about one-third of age- and CrCl-matched men. Female sex was associated with 3-fold higher odds of dofetilide discontinuations or dose reductions relative to male sex. Further studies are needed to better understand the optimal dofetilide dose for women, including evaluating short-term tolerance of the medication load as well as long-term persistence and clinical outcomes.

      Appendix. Supplementary data

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      Linked Article

      • Sex, drugs, and funky rhythms
        Heart RhythmVol. 15Issue 4
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          “It has only been possible to collect a few figures for normal women, but so many of these fall outside the range for normal men…” wrote Bazett (p 356) in his 1920 analysis of cardiac electrical activity.1 Despite the passage of nearly 100 years since the first recognition of sex-based differences in cardiac electrical activity, there have not been comprehensive investigations into the differences in responses of men and women to pharmacological intervention. This is despite the generally accepted fact that female sex is associated with a longer baseline heart rate–corrected QT (QTc) interval and is an independent risk factor for the development of torsades de pointes (TdP) in acquired (drug-induced) long QT syndrome (LQTS) and associated TdP arrhythmias.
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