Sex-related differences in outcome of cardiovascular diseases have long been recognized.^1,2 However, only a small number of studies have focused on sex-related differences in arrhythmias.³ The prevalence of atrial fibrillation is lower in women compared with men. But because the incidence of atrial fibrillation increases with age and there are more women older than 75 years of age, the number of patients with atrial fibrillation is comparable for both sexes.³ Women with atrial fibrillation have a greater risk of bleeding and thromboembolic problems resulting from treatment with anticoagulant drugs.^4,5 In addition, with the use of QT-prolonging agents, female patients are more apt to progress to proarrhythmia.⁶

Similar results between rate control and rhythm control have been shown in large trials with regard to cardiovascular morbidity, mortality, and quality of life (QOL).^7-10 None of these trials, however, have focused on potential sex differences. In a substudy of the Rate Control Versus Electrical Cardioversion (RACE) study, we assessed cardiovascular morbidity, mortality, and QOL, as well as the difference between rate control and rhythm control treatment in patients of both sexes with persistent atrial fibrillation.¹¹

Patients and methods
The 192 women and 330 men in the RACE study all had recurrent persistent atrial fibrillation. Participants were randomly assigned to receive either rate control or rhythm control treatment.⁸ Those assigned to the rate control treatment group received digitalis, a non-dihydropyridine calcium channel blocker, or a beta blocker, individually or in combination, to achieve a heart rate of < 100 beats per minute at rest. Those in the rhythm control group received serial electrical cardioversions and serial antiarrhythmic drugs, including sotalol (Betapace, Sorine), class IC drugs, and eventually amiodarone hydrochloride (Cordarone, Pacerone). Sufficient anticoagulant therapy to achieve an international normalized ratio of 2.5 to 3.5 was given to all patients undergoing electrical cardioversion. Fenprocoumon or acenocoumarol was given to all participants. Participants were permitted to receive 80 to 100 mg of aspirin daily if they had no stroke risk factors or when long-term sinus rhythm was achieved. The composite of cardiovascular mortality, heart failure, thromboembolic complications, bleeding, severe adverse effects of antiarrhythmic drugs, and pacemaker implantations was the primary end point.⁸ The Medical Outcomes Study Short-Form Health Survey (SF-36) was given to participants to evaluate QOL factors.¹²

Results
Women were older than men (71 ± 8 vs 67 ± 9 years, respectively; P< .001) and more often had diabetes and hypertension. Men, however, had previous myocardial infarction (MI) and coronary artery disease more often. Compared with men, systolic blood pressure was higher in women. Women also experienced more atrial fibrillation-related symptoms, such as palpitations and fatigue. Quality of life was lower in women compared with men and healthy control women. Men and women had similar atrial diameters, but the left ventricular end-systolic and end-diastolic diameters were significantly smaller in women, resulting in a higher fractional shortening. There were no important sex differences regarding drug therapy.

The rhythm control treatment group consisted of 51% of the total male participants and 49% of the total female participants. The mean follow-up period was 2.3 ± 0.6 years. Sinus rhythm was restored in 39% and 35% of the men and women, respectively (P= 0.6. About two thirds of all patients were given continuous oral anticoagulation, mainly in the rate control arms. There were no significant sex-related differences with reference to New York Heart Association (NYHA) functional class or heart rate during follow-up. Throughout the follow-up period, however, the higher systolic blood pressure observed in women continued.

Similar proportions of men and women (19% vs 21%, respectively, P= 0.6) experienced the composite end point. The components of the primary end point were distributed equally in both groups, although bleeding occurred slightly more frequently in men than in women (5.5% vs 3%, respectively). Women, however, experienced severe adverse effects from antiarrhythmic drugs more often: 1 woman had torsades de pointes; 1 woman had recurrent atrial flutter with a rapid, hemodynamically significant atrioventricular conduction; and 7 women had sick sinus syndrome. Complications in pace­maker implantations also occurred more often in women.

For women, the treatment approach significantly affected the incidence of the primary end point: 33% of women in the rhythm control group experienced the primary end point compared with 11% in the rate control group. This unequal distribution of end points was mainly the result of the occurrence of adverse effects from antiarrhythmic medications, thromboembolic complications, and heart failure. For women, an independent association was shown between the occurrence of the primary end point over time and treatment with rhythm control (adjusted hazard ratio = 3.1; 95% confidence interval, 1.5-6.3; P= .002) in multivariate Cox proportional hazard regression analysis. No relation existed between treatment and event-free survival in men. The sex-related differences in QOL shown at baseline persisted during follow-up. Treatment strategy did not influence QOL in women.

Discussion
The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM), RACE, Pharmacological Intervention in Atrial Fibrillation (PIAF), and Strategies of Treatment of Atrial Fibrillation (STAF) studies have shown that rate control and rhythm control are similar with regard to cardiovascular death and morbidity.^7-10 The current study, however, indicates that this result cannot directly be applied to women with recurrent persistent atrial fibrillation.^11,13 Although men and women had similar morbidity and mortality rates, more women receiving rhythm control treatment experienced end points than women receiving rate control treatment, mainly as a result of more cardiovascular mortality, serious adverse effects from antiarrhythmic medications, heart failure, and thromboembolic complications. The end point occurred in 33% of women in the rhythm control group vs 11% of women in the rate control group. There were no differences in the oc­currence of the primary end point between men in the rate control vs rhythm control groups.

The relatively large number of thromboembolic complications and hospitalizations for heart failure in women in the rhythm control arm may have been caused by hypertension and the constantly present higher systolic blood pressure, although we statistically adjusted for those effects. Furthermore, it is known that diastolic heart failure is more common in women.¹⁴ This may also have been the case in our study, especially because of the high prevalence of hypertension in women. Unfortunately, diastolic dysfunction was not measured in the RACE study.

The observed dissimilarity in patient characteristics between men and women was consistent with the findings of other studies.^5,15 Women were older and had more symptoms, poorer QOL, and an increased prevalence of hypertension and diabetes. In contrast, men had a higher prevalence of coronary artery disease, including previous MI. Although we observed no significant differences in the occurrence of cardiovascular morbidity and mortality, we noticed important differences in the distribution of bleeding and severe adverse effects of antiarrhythmic drugs between men and women. Women may have had a lower rate of bleeding because they may not have taken their anticoagulant medication or they may have been less apt to have it prescribed for them.⁵ Women experienced most of the severe adverse effects from antiarrhythmic medications, which were not due to tachyarrhythmias but rather to the uncovering of sick sinus syndrome triggering symptomatic bradycardia.

Compared with men and healthy control women, QOL was significantly reduced in women. The treatment strategy did not influence QOL in women. Therefore, women with persistent atrial fibrillation do not benefit from a rhythm control strategy. Because QOL is not improved and significantly more cardiovascular morbidity and mortality occurs with this strategy, a pharmacologic rhythm control approach is not beneficial for women. Rate control may therefore be adopted as first-choice therapy. In cases of severe symptoms, however, a nonpharmacologic rhythm control approach should be considered.

Conclusion
We evaluated cardiovascular morbidity, mortality, and QOL among men and women with persistent atrial fibrillation and compared the effects of rate control treatment with sinus rhythm restoration and maintenance in a substudy of the RACE study. Rhythm control treatment was associated with greater cardiovascular morbidity and mortality in women, mainly because of more heart failure, thromboembolic complications, and severe adverse effects of antiarrhythmic drugs. Because treatment did not influence QOL, rate control may be considered as first-choice therapy in women. Future studies are needed to assess the outcome of nonpharmacologic rhythm control approaches, in particular, curative catheter ablation procedures, for women.

References
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8. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med. 2002;347(23):1834-1840.

9. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibril-lation—Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet. 2000;356(9244):1789-1794.

10. Carlsson J, Miketic S, Windeler J, et al. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol. 2003;41(10):1690-1696.

11. Rienstra M, van Veldhuisen DJ, Hagens VE, et al. Gender-related differences in rhythm control treatment in persistent atrial fibrillation: data of the Rate Control Versus Electrical Cardioversion (RACE) study. J Am Coll Cardiol. 2005;46(7):1298-1306.

12. Hagens VE, Ranchor AV, van Sonderen EF, et al. Effect of rate or rhythm control on quality of life in persistent atrial fibrillation: results from the Rate Control Versus Electrical Cardioversion (RACE) study. J Am Coll Cardiol. 2004;43(2):241-247.

13. Kerr CR, Humphries K. Gender-related differences in atrial fibrillation. J Am Coll Cardiol. 2005;46(5):1307-1308.

14 Aronow WS, Ahn C, Kronzon I. Normal left ventricular ejection fraction in older persons with congestive heart failure. Chest. 1998;113(4):867-869.

15. Kannel WB, Wolf PA, Benjamin EJ, et al. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol. 1998;82(8A): 2N-9N.

A more detailed discussion of this topic may be found in Rienstra M, Van Veldhuisen DJ, Hagens VE, et al for the RACE Investigators. Gender-related differences in rhythm control treatment in persistent atrial fibrillation: data of the Rate Control Versus Electrical Cardioversion (RACE) study. J Am Coll Cardiol. 2005;46(7): 1298-1306.