Impact of rate versus rhythm control on quality of life in patients with persistent atrial fibrillation

Results from a prospective randomized study

Gerian C. Grönefelda, Jürgen Lilienthalb, Karl-Heinz Kuckc and Stefan H. Hohnlosera,* for the Pharmacological Intervention in Atrial Fibrillation (PIAF) Study Investigators

a J.W. Goethe University, Department of Medicine, Division of Cardiology, Frankfurt, Germany
b Datamap GmbH, Freiburg, Germany
c St. Georg Hospital, Hamburg, Germany

* Correspondence to: Stefan H. Hohnloser, MD, FESC, FACC, J.W. Goethe University, Dept. of Medicine, Division of Cardiology, Theodor-Stern-Kai 7, 60590 Frankfurt am Main. Tel.: +49.69.6301-7404; fax: +49.69.6301-7017
E-mail address: hohnloser{at}em.uni-frankfurt.de

Received 19 January 2003; revised 10 March 2003; accepted 9 April 2003


    Abstract
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Aims Despite the high prevalence of atrial fibrillation (AF), there are only limited data on quality of life (QoL) stemming from prospective trials comparing rate versus rhythm control. This prospective study evaluated QoL in patients with symptomatic persistent AF randomized to therapy aiming at rate versus rhythm control.

Methods and results Patients with symptomatic persistent AF (7 to 360 days duration) were prospectively randomized to ventricular rate control (n=125) or to cardioversion and maintenance of sinus rhythm (n=127). QoL was assessed by the Medical Outcomes Study Short Form health survey (SF-36) at baseline and during 1 year of follow-up. Changes in QoL were compared on an intent-to-treat basis, and subsequently between patients in sinus rhythm versus AF. At baseline, all SF-36 scales were reduced compared to healthy controls. At 1 year, six of eight items had improved significantly in patients assigned to rate control, and five of eight items on rhythm control (p=ns). The physical component summary showed a comparable increase with both treatment strategies (rate control: p=0.004; rhythm control: p<0.001) whereas no significant changes were found for the mental component summary. At 1 year, 55% of patients reported a positive health transition with no inter-group differences. There were no significant differences in QoL in patients in sinus rhythm or AF at the end of the observation period.

Conclusion In patients with symptomatic persistent AF, the two treatment strategies of rate versus rhythm control are associated with similar improvements in QoL.

Key Words: Atrial fibrillation • Quality of life • Controlled clinical trials


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Atrial fibrillation (AF) is one of the major health burdens in Western countries.1The arrhythmia is associated with a variety of symptoms, such as palpitations, dizziness, reduced exercise tolerance, shortness of breath or other signs of heart failure.2,3Accordingly, the well-being of patients afflicted with this rhythm disorder is often severely compromized.4–6

In contrast to selection of specific symptoms as a study end-point, quality of life (QoL) is a multidimensional construct that was introduced to validate the general well being in a healthy population and in different disease entities.7For standardized QoL assessment, subscales for the measurement of mental, emotional, and physical well being are derived from structured psychosocial questionnaires.8During the last decade, assessment of QoL has been increasingly implemented as an end-point in clinical studies.4At present, however, published data is limited to the evaluation of specific drugs9or invasive treatment strategies in patients with AF, such as atrioventricular node ablation10,11or the maze operation.12Specifically, from recent prospective randomized trials evaluating the two major therapeutic strategies in AF, rate versus rhythm control,13–15only the PIAF study has reported preliminary data on standardized QoL.13PIAF was the first prospective randomized strategy trial in patients with symptomatic persistent AF. The present detailed analysis, thus, is the first thorough evaluation of QoL in patients treated according to rate versus rhythm control.


    2. Methods
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
The rationale, design, and results of the PIAF trial have been described in detail.13In brief, this multicentre study prospectively compared symp tomatic improvement on two treatment strategies—rhythm control versus rate control—in patients with symptomatic AF of 7 to 360 days duration. Rate control was aiming at reducing the mean ventricular rate either pharmacologically or by atrioventricular node ablation, and rhythm control was attempted by pharmacological or electrical cardioversion followed by preventive amiodarone therapy. Bothrandomization groups received adequate anticoagulation during the study period with a target INR of 2.0–3.0.

As part of the study protocol, QoL was prospectively assessed as a secondary study end-point. The Medical Outcomes Study short form health survey (SF-36)16questionnaire was completed before randomization (baseline), after 3 weeks, and at the 3 and 12 month visit. QoL was evaluated by patient self administrated questionnaires assisted by a trained interviewer independent from the primary symptom assessment of this trial. The SF-36 consists of 36 questions yielding an eight-scale profile describing health-related QoL and one measurement of self reported health transition. From the eight scales, two summary measures are aggregated as physical and mental component summary, respectively.8In these component summary scores, the general population norm is built into the scoring algorithm. All scores above or below 50 can be interpreted as above or below the general population norm.8

The primary QoL evaluation of the present data is based on the intention-to-treat analysis. Two further analyses were prospectively designed to compare differences in QoL between patients in sinus rhythm versus patients in AF at the end of the observation period and between patients with and without symptomatic improvement according to the primary studyend-point.13

2.1. Statistical analysis
Continuous demographic values, SF-36 scales and component summary measures are given as mean values and standard deviation. Student's t-test was used for within-group comparisons of continuous variables, while an analysis of covariance model was applied for between-group comparisons (with the baseline value as covariable). Health transition was evaluated using the Wilcoxon Signed Rank Test for within-group comparisons and a logistic regression model for between-group comparisons. In addition, a repeated measures model was applied to test for treatment effects over time.17P-values (two-sided) derived from statistical tests were used in an exploratory sense. All calculations were done by using SAS, Version 8.2 (SAS Institute Inc., Cary, NC, USA).


    3. Results
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
3.1. Patient characteristics
Two hundred fifty two patients were included in the study. Of these, 125 were randomized to rate, and 127 to rhythm control. The majority of patients had a well preserved left ventricular function, and there were no significant differences between the randomized groups regarding demographic or clinical characteristics at baseline (Table 1). Only four patients from rate control crossed over to rhythm control and only six from rhythm control to rate control during the study period.


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Table 1 Patient populationa

 
3.2. Quality of Life at baseline
One hundred ninety seven patients completed the baseline SF-36 questionnaire, 102 patients (82%) in assigned to rate control and 97 patients (76%) assigned to rhythm control. There were no differences with regard to baseline data between patients who completed the SF-36 and those who failed to report on QoL due to language difficulties or non-compliance. At baseline, the scores of the eight subscales of the SF-36 showed no significant differences between the two randomized groups (Fig. 1A). Values, however, were significantly lower than those reported from healthy individuals.8Concerning their health transition during the preceding 12 months prior to enrolment in PIAF, only 10% of patients reported an improvement, 22% reported no change, and 58% from both groups reported worsening of their general health perception at baseline (Fig. 2).



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Fig. 1 Bar graph representing absolute values for the eight subscales of the SF-36 from both treatment groups on intent-to treat analysis. P-values shown are for between-group comparison. Panel A: Values before randomization (baseline). Panel B: Values at 1-year follow-up. Asterisk on bottom of column show significant increase in the respective item after 1 year of treatment (*p<0.05 for within-group changes).

 


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Fig. 2 Percentage of patients reporting an improved, identical, or worsening health transition during the preceding year. The two upper bars illustrate data from the two treatment groups at baseline. From both groups, only 10% of patients reported some improvement, whereas almost 60% of patients reported worsened health status. The bottom bars represent data obtained at the end of the 1-year treatment period. More than 50% of patients from both groups reported an improvement whereas about 30% reported no change.

 
3.3. Quality of life: changes over time
Complete SF-36 data until the 12-month follow-up were available in 165 patients (rate control: 84 patients (67%); rhythm control: 81 patients (64%). There were no significant differences in QoL changes between the two treatment groups at any time during the observation period. At 1 year, six of eight items had improved significantly in patients assigned to rate control, and five of eight items on rhythm control (Fig. 1B). The physical component scale showed a significant improvement in both groups during the first three months and remained unchanged thereafter (Fig. 3A, Table 2). The mental component scale showed an improvement which did not reach statistical significance (Table 2). The assessment of health transition at the final follow-up visit improved significantly with 55% of patients reporting somewhat or much improved health perception over the 12 months treatment period (Fig. 2). In both treatment groups, the largest benefit was achieved within the first 3 weeks of treatment initiation with continued improvement until the three month assessment. Thereafter, values remained stable until the end of the observation period (Fig. 3A).



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Fig. 3 Mean values and 95% confidence intervals of the physical component summary score across time presented on an intent-to-treat analysis (A) and for patients actually in sinus rhythm versus patients in persistent AF at study end (B). (0=Baseline, 3=Week 3, 12=Week 12, 48=Week 48).

 

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Table 2 Changes in QoL summary scores during time

 
3.4. Analysis of quality of life changes according to the presence of sinus rhythm or AF at 12 months
According to 24-h Holter recording, maintenance of sinus rhythm persisted in 56% of patients assigned to rhythm control until the 12-month follow-up. Twelve patients assigned to rate control (10%) spontaneously converted to sinus rhythm. Accordingly, changes in QoL from baseline to the 1-year follow-up were compared between patients in sinus rhythm versus patients in AF. There were no significant differences between those two patient cohorts with regard to baseline variables (Table 3). The physical component scale significantly improved from 40±10 to 44±9 in patients who were in sinus rhythm at the final assessment (p<0.05) and from 39±10 to 43±11 in patients in AF (p<0.001). There was no significant difference with regard to the relative improvement between the two subgroups (p=0.81) (Fig. 3B). The mental component scale did not significantly change during the study in any of the groups. With only 12 patients in sinus rhythm primarily assigned to rate control, a statistical subgroup analysis between the two primary randomization groups was not performed for sinus rhythm patients. Improvement in QoL in AF patients from both primary study groups, however, did not reveal any difference between patients primarily assigned to rate versus rhythm control therapy (p=0.93).


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Table 3 Comparison between patients in sinus rhythm versus atrial fibrillation at study enda

 
3.5. Analysis of quality of life changes according to symptomatic response to therapy
According to the primary study end-point, 146 of 252 (58%) patients showed an improvement in specificAF-associated symptoms.13The physical component summary significantly increased in these responders (41±10 to 45±10; p<0.001) but not in non-responders (38±10 to 39±11; p=ns) (p<0.02 for group comparison). Similarly, the mental summary scale also improved in the responder group from 47±11 to 51±10 (p<0.01) reflecting normalization of this QoL domain whereas no change was found in non-responders (46±10 to 45±11, p=ns). Stratifying the responders according to the primary treatment strategy did not show any difference between the relative improvements in both groups (p=0.83 for differences in the physical component changes and p=0.371 for differences in the mental component changes between rate control and rhythm control).


    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
The present evaluation of QoL derived from a prospective randomized trial comparing rate versus rhythm control in patients with persistent AF demonstrates a lack of significant difference with regard to QoL between both therapeutic strategies. Of note, a significant improvement in the SF-36 subscales reflecting physical health components was observed in both treatment groups over time.

4.1. Methodology of quality of life assessment
Translating the various domains and components of well-being into a quantitative value reflecting the health related QoL is a complex process.7Individual health perception is influenced by a persons general state of health which might be dominated by comorbidity rather than by AF. In addition, QoL depends on a persons life experience, beliefs, and expectations as well as social or cultural differences. This may be one of the reasons for the still limited use of such instruments in clinical studies. With regard to AF, different generic and disease specific instruments have been applied.4,18In the present study, the SF-36 questionnaire was selected for QoL assessment due to the availability of previous data from patients with different cardiovascular diseases including AF.19In addition, the SF-36 has been validated in non-English languages20and established summary scoring normalized to healthy controls8allows for comparison to other disease entities and persons without cardiovascular disease. Despite some data suggesting that QoL may be influenced by covariables like gender or age,21the SF-36 was evaluated according to the manual without correction for such variables.

Therefore, it should be kept in mind that QoL assessment is an instrument with limited sensitivity towards subtle changes.22Also, according to our data, the time course of health transition indicates an improvement of QoL which is demonstrable during the first weeks of treatment initiation with continued further improvement until the 3-month follow-up. Whereas symptomatic response in up to 60% of patients was achieved as early as 3 weeks after initiation of treatment,13health transition refers to the individual perception of changes during the preceding 12 months. Accordingly, it may take some time until significant changes measured by an exercise test or symptom scores are reflected by QoL assessment.

4.2. Available data on QoL in AF
Most AF studies addressing QoL report significantly impaired values compared to healthy controls.6,18,23For instance, in patients with various supraventriculararrhythmias, lowest SF-36 scales were reported for AF patients, and despite some improvement following therapy, QoL remained reduced after atrioventricular nodal ablation.23The International Study of Quality of Life in AF was a multicentre trial comparing a series of six QoL instruments in 152 relatively young patients with paroxysmal AF.6QoL was found to be markedly impaired and was similar on most scales to the health impairment observed in previous studies evaluating patients with heart failure or after myocardial infarction.6

Until recently, QoL data associated with the two major treatment modalities in AF, rate versus rhythm control, were extremely sparse. For instance, in a small study 36 selected patients with persistent AF and an indication for VVI-pacemaker implantation were randomized to atrioventricular nodal ablation (rhythm control) or pharmacological rate control.24Similar symptomatic benefit was found for both groups and was accompanied by an improvement in QoL.24The present study represents the largest series of patients who were randomly assigned to rate or rhythm control in persistent AF13and who were prospectively evaluated by the SF-36. Our results indicate that for patients with symptomatic persistent AF, both therapeutic strategies result in significant improvements of important SF-36 subscales.

The explanation for QoL improvement observed in uncontrolled studies on radiofrequency ablation or pacemaker implantation may be at least partially due to a selection bias since only highly symptomatic patients are generally considered for such invasive treatment options. Moreover, all of these studies had no control group for comparative purposes. In contrast, the AFFIRM trial allowed inclusion of patients with no or only mild symptoms, and approximately one-third of patients were enrolled after a first episode of paroxysmal atrialfibrillation.14PIAF was intended to provide QoL data in symptomatic patients with persistent AF which were suitable for both treatment strategies. In this population, 58% of patients showed a symptomatic improvement which was accompanied by improvement in QoL.

4.3. Results from the subanalyses
In PIAF, the primary study end-point which consisted of changes in specific AF-associated symptoms13and the SF-36 questionnaires were assessed independently. Whereas non-responders according to symptom scoring showed no improvement in QoL, responders showed a significant increase in both, the physical and mental summary scores of the SF-36. For ethical reasons PIAF was designed without control group receiving no treatment at all. Therefore, a mere placebo effect may have led to improvement in symptoms in both groups masking a small difference between the two treatment strategies. Furthermore, it has been shown that assessment of symptoms and QoL in patients with AF are often only poorly correlated.5,25The independent confirmation of the primary study end-point by the results of QoL assessment in PIAF, however, supports the conclusions that the reported changes are actually due to treatment effects.

The comparison of patients in sinus rhythm versus AF at 1 year did not reveal any difference in QoL confirming the result from the intent-to-treat analysis. Even after 1 year of specific treatment, a reduction in some aspects of QoL persisted, and patients in sinus rhythm and those in AF at study end did not differ in those aspects. This outcome is of interest, since it disputes the argument that sinus rhythm may yield a better symptomatic outcome if it could only be achieved in a higher percentage of patients. Interpretation of this data, however, is limited by the lack of randomization power. Of note, we found no differences with regard to any baseline characteristics between those two groups. Unmeasured variables, however, may have influenced this analysis without the possibility for correction.


    5. Conclusions
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
QoL is impaired in patients with persistent AF. Responders to both treatment strategies, rate and rhythm control, demonstrated a significant improvement in QoL. At 1 year, maintenance of sinus rhythm was not associated with a significantly better QoL compared to rate control only. Overall, QoL remains reduced in some SF-36 subscales compared to healthy individuals which might be attributed to comorbidity.


    References
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

  1. Kannel WB, Wolf PA, Benjamin EJ et al. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol. 1998;82:2N–9N.[CrossRef][Medline]
  2. Lip GY, Tean KN, Dunn FG. Treatment of atrial fibrillation in a district general hospital. Br Heart J. 1994;71:92–95.[Abstract]
  3. Levy S, Maarek M, Coumel P et al. Characterization of different subsets of atrial fibrillation in general practice in France: the ALFA study. The College of French Cardiologists. Circulation. 1999;99:3028–3035.[Abstract/Free Full Text]
  4. Jung W, Luderitz B. Quality of life in patients with atrial fibrillation. J Cardiovasc Electrophysiol. 1998;9:S177–S186.[Medline]
  5. Savelieva I, Paquette M, Dorian P et al. Quality of life in patients with silent atrial fibrillation. Heart. 2001;85:216–217.[Free Full Text]
  6. Dorian P, Jung W, Newman D et al. The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy. J Am Coll Cardiol. 2000;36:1303–1319.[CrossRef][Medline]
  7. Testa MA, Simonson DC. Assessment of quality-of-life outcomes. N Engl J Med. 1996;334:835–840.[Free Full Text]
  8. Ware JE, Kosinski M, Keller SK. SF-36 Physical and Mental Health Summary Scales: A User's Manual. Boston, MA: The Health Institute, New England Medical Center, 1994..
  9. Bhandari AK, Anderson JL, Gilbert EM et al. Correlation of symptoms with occurrence of paroxysmal supraventricular tachycardia or atrial fibrillation: a transtelephonic monitoring study. The Flecainide Supraventricular Tachycardia Study Group. Am Heart J. 1992;124:381–386.[Medline]
  10. Brignole M, Gianfranchi L, Menozzi C et al. Influence of atrioventricular junction radiofrequency ablation in patients with chronic atrial fibrillation and flutter on quality of life and cardiac performance. Am J Cardiol. 1994;74:242–246.[Medline]
  11. Fitzpatrick AP, Kourouyan HD, Siu A et al. Quality of life and outcomes after radiofrequency His-bundle catheter ablation and permanent pacemaker implantation: impact of treatment in paroxysmal and established atrial fibrillation. Am Heart J. 1996;131:499–507.[Medline]
  12. Lonnerholm S, Blomstrom P, Nilsson L et al. Effects of the maze operation on health-related quality of life in patients with atrial fibrillation. Circulation. 2000;101:2607–2611.[Abstract/Free Full Text]
  13. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation — Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet. 2000;356:1789–1794.[CrossRef][Medline]
  14. Wyse DG, Waldo AL, DiMarco JP et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347:1825–1833.[Abstract/Free Full Text]
  15. 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;347:1834–1840.[Abstract/Free Full Text]
  16. Ware JE, Snow KK, Kosinski M. SF-36 Health Survey Manual and Interpretation Guide. Boston, MA: The Health Health Insitute, New England Medical Center, 1993..
  17. Bender R, Lange S. Adjusting for multiple testing — when and how? J Clin Epidemiol. 2001;54:343–349.[CrossRef][Medline]
  18. Wood MA, Brown-Mahoney C, Kay GN et al. Clinical outcomes after ablation and pacing therapy for atrial fibrillation: a meta-analysis. Circulation. 2000;101:1138–1144.[Abstract/Free Full Text]
  19. Shiely JC, Bayliss MS, Keller SD. SF-36 Health survey annotated bibliography: the first edition (1988–1995). Boston, MA: The Health Institute, New England Medical Center, 1996..
  20. Wagner AK, Gandek B, Aaronson NK et al. Cross-cultural comparisons of the content of SF-36 translations across 10 countries: results from the IQOLA Project. International Quality of Life Assessment. J Clin Epidemiol. 1998;51:925–932.[CrossRef][Medline]
  21. Paquette M, Roy D, Talajic M et al. Role of gender and personality on quality-of-life impairment in intermittent atrial fibrillation. Am J Cardiol. 2000;86:764–768.[CrossRef][Medline]
  22. Smith HJ, Taylor R, Mitchell A. A comparison of four quality of life instruments in cardiac patients: SF-36, QLI, QLMI, and SEIQoL. Heart. 2000;84:390–394.[Abstract/Free Full Text]
  23. Bubien RS, Knotts-Dolson SM, Plumb VJ et al. Effect of radiofrequency catheter ablation on health-related quality of life and activities of daily living in patients with recurrent arrhythmias. Circulation. 1996;94:1585–1591.[Abstract/Free Full Text]
  24. Levy T, Walker S, Mason M et al. Importance of rate control or rate regulation for improving exercise capacity and quality of life in patients with permanent atrial fibrillation and normal left ventricular function: a randomised controlled study. Heart. 2001;85:171–178.[Abstract/Free Full Text]
  25. Ganiats TG, Browner DK, Dittrich HC. Comparison of Quality of Well-Being scale and NYHA functional status classification in patients with atrial fibrillation. New York Heart Association. Am Heart J. 1998;135:819–824.[Medline]