Author + information
- Received July 11, 2012
- Revision received October 6, 2012
- Accepted November 13, 2012
- Published online February 19, 2013.
- Hessel F. Groenveld, MD⁎,
- Jan G.P. Tijssen, PhD†,‡,
- Harry J.G.M. Crijns, MD§,
- Maarten P. Van den Berg, MD⁎,
- Hans L. Hillege, MD∥,
- Marco Alings, MD¶,
- Dirk J. Van Veldhuisen, MD⁎,
- Isabelle C. Van Gelder, MD⁎,‡,⁎ (, )
- RACE II Investigators
- ↵⁎Reprint requests and correspondence:
Dr. Isabelle C. Van Gelder, Department of Cardiology, Thoraxcenter, University of Groningen, University Medical Center Groningen, Post Office Box 30.001, 9700 RB Groningen, the Netherlands
Objectives This study sought to investigate differences in outcome between patients treated with successful strict, failed strict, and lenient rate control.
Background The RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation) study showed no difference in outcome between lenient and strict rate control in patients with permanent atrial fibrillation (AF). However, in the strict group not all patients achieved the pre-defined heart rate target.
Methods The primary outcome was a composite of cardiovascular morbidity and mortality. For the current analysis outcome events were analyzed from end of the dose-adjustment phase until end of follow-up (median 2.9 years [interquartile range: 2.4 to 3.0 years]). Of 614 patients, 608 completed the dose-adjustment phase—301 in the strict (resting heart rate <80 beats/min, and during moderate exercise <110 beats/min) and 307 in the lenient group (resting heart rate <110 beats/min). In the strict group, 203 of 301 patients achieved the rate control target, and 98 failed.
Results Heart rate was different after the dose-adjustment phase between the successful strict (72 ± 7 beats/min), failed strict (86 ± 14 beats/min), and lenient (93 ± 8 beats/min) group (p < 0.001) and remained significantly different during follow-up. The primary outcome was reached in 27 of 203 (14.2% KM estimate) in the successful strict versus 14 of 98 (15%) in the failed strict versus 35 of 307 (12.1%) in the lenient group (p = 0.5). The components of the primary outcome and quality of life were similar in the groups.
Conclusions In patients with permanent AF, successful strict rate control does not improve outcome. Therefore, lenient rate control might be frontline therapy.
Rate control is frontline therapy in patients with permanent atrial fibrillation (AF) (1,2). Evidence is accumulating that lenient rate control is a reasonable strategy in patients with permanent AF. Post hoc analyses of the AFFIRM study (Atrial Fibrillation Follow-up Investigation of Rhythm Management) and RACE (RAte Control versus Electrical cardioversion) study showed a comparable outcome between patients with permanent AF with higher and lower heart rates (3–5). The RACE II (RAte Control Efficacy in permanent atrial fibrillation II) trial prospectively evaluated the effect of lenient versus strict rate control in patients with permanent AF (6) and showed no difference in outcome between the lenient and strict rate control groups in terms of cardiovascular morbidity, mortality, and quality of life (7,8). However, not all patients achieved the heart rate target, especially not in the strict group (7). The inability of achieving the strict rate control target might have influenced outcome, in favor of lenient rate control. The current post hoc analysis evaluates the difference in outcome between patients treated with successful strict, failed strict, and lenient rate control.
The RACE II study design
The study design and results of the RACE II study have been published previously (6,7). The study was approved by the institutional review boards of all participating centers, and all patients gave written informed consent. Patients were randomized to lenient (resting heart rate <110 beats/min) or strict rate control (resting heart rate <80 beats/min, and a heart rate <110 beats/min during moderate exercise). The primary outcome was a composite of cardiovascular morbidity and mortality as described previously (7). Patients in the strict group who failed 1 of the heart rate criteria were classified as failed strict; the remaining patients were classified as successful strict rate control. Reasons for failure of strict rate control could be drug-related adverse events, no or tolerable symptoms, or heart rate target unattainable with drugs.
Design of the current analysis
For the current analysis outcome events in the strict rate control group were analyzed from end of the dose-adjustment phase (i.e., the moment the heart rate targets were either achieved or deemed impossible or unnecessary [due to absence of complaints] to achieve) until end of follow-up. In the lenient rate control group the endpoints were analyzed from 9 days after randomization, the mean duration of the dose-adjustment phase in the lenient group, until end of follow-up. Patients with a primary outcome event occurring during the dose-adjustment phase in the strict group and before 9 days after randomization in the lenient group were not included in the present analysis.
Quality of life
Quality of life was assessed with the Medical Outcome Study Short Form-36, University of Toronto AF Severity Scale, and Multidimensional Fatigue Inventory-20 as has been described previously (8–12).
Baseline descriptive statistics are presented as mean ± SD or median (range) for continuous variables and counts with percentages for categorical variables. Differences between groups, in terms of patient characteristics, were evaluated by one-way analysis of variance, Kruskal-Wallis test, or chi-square test, depending on normality and type of data. Differences in quality of life between the groups were assessed with a general linear model and a general linear model repeated measures. In all analyses a value of p < 0.05 was considered statistically significant. Kaplan-Meier analysis was performed to assess differences in outcome between the 3 groups. Noninferiority was tested by comparing the upper boundary of the 90% confidence interval (CI) for the primary outcome (7).
Rate control achievement during the dose adjustment phase
In the current analysis 608 patients were included. Two hundred and three patients had successful strict, 98 had failed strict, and 307 patients had lenient rate control (Fig. 1). In 25 patients strict rate control failed due to drug-related adverse events, 52 patients had no or tolerable symptoms, and in 21 patients the strict heart rate criteria were unattainable to achieve with drugs.
Heart rates were higher in the failed strict and lenient group as compared with the successful strict group (Table 1). Median follow-up was 2.9 (interquartile range: 2.4 to 3.0) years. Clinical characteristics were almost comparable between the groups (Table 2).
After the dose-adjustment phase, more patients in the lenient group either used no rate control drugs or a beta blocker alone. Fewer patients in the lenient group used a combination of drugs and used significantly lower dosages of beta blockers and verapamil (Table 1).
Primary outcome after dose-adjustment phase
A total of 76 patients (27 of 203 in the successful strict and 14 of 98 in the failed strict group, and 35 of 307 in the lenient group) reached the primary outcome (Fig. 2,Table 3). The cumulative difference between successful strict and failed strict was −0.8 (90% CI: −6.6 to 8.2, p for noninferiority = 0.02). The cumulative difference between successful strict and lenient rate control was 0.2 (90% CI: −7.4 to 3.2, p for noninferiority <0.001). There was no significant difference between the 3 groups, considering the composites of the primary outcome, nor was there any difference in all-cause mortality (Table 3). There was also no difference in primary outcome when analyzing patients with an ejection fraction <40% (data not shown, p = 0.6).
Additional visits, heart rate, left ventricular function, and drug use during the study
At 1- and 2-year follow-up, more patients in the successful strict (17.7% and 12.3%, respectively) and failed strict (14.3% and 8.2%, respectively) as compared with the lenient (4.6% and 4.2%, respectively) group had at least 1 additional visit (p < 0.001 and p = 0.007 for 1 and 2 years of follow-up, respectively). There was no difference in additional visits between the successful strict and failed strict groups.
Heart rates during the study and left ventricular ejection fraction during the study are shown in Table 4. During follow-up no significant changes in drug or combination of drugs occurred in any of the groups, nor were there significant changes in the dosages of the rate control drugs (data not shown).
Symptoms and quality of life
At the end of study fewer patients in the failed strict group had any symptom of AF (Table 5). Neither at study entry nor at study end were there any significant differences in The Medical Outcome Study Short Form-36, Multidimensional Fatigue Inventory-20, and AF-severity scale between the groups (Fig. 3). There was no effect of the different rate control strategies over time.
This analysis of the RACE II study shows no difference in cardiovascular outcome between successful strict, failed strict, and lenient rate control in patients with permanent AF. In addition, quality of life was comparable between the groups at the end of follow-up.
One of the comments on the RACE II study is that only 67% of the patients randomized to the strict group achieved the heart rate targets, as compared with 98% in the lenient group. The data of the present analysis confirm our prior findings that lenient rate control is not inferior to strict rate control, not even when the lenient strategy is compared with patients who were successfully treated with a strict rate control strategy (1,2,7,13,14). Instead, the present analysis shows that attempts to achieve strict rate control targets are unsuccessful in one-third of the patients and not necessary. The latter might not hold for every patient. If patients remain symptomatic or a tachycardiomyopathy develops, lower heart rate targets might be indicated.
In accordance with the AFFIRM study, we also showed that a strict rate control strategy is time consuming, necessitating more outpatient visits and more combinations and higher dosages of rate-control drugs (3,7,15). These differences emphasize the difference in strategy. Although the dissimilarity in heart rates between the groups was not as marked as might have been anticipated, strategies to obtain those heart rates were completely different.
Why was successful strict rate control not associated with an improved outcome? First, the incidence of heart failure, being a major concern of a lenient rate control, was not lower during successful strict rate control. Apparently, a heart rate <110 beats/min was low enough to prevent heart failure, being in line with post hoc analyses of large heart failure trials showing that beta blockers do not improve outcome in patients with heart failure and AF (16–18). Second, patients with AF might need higher heart rates due to loss of the atrial kick and the irregular ventricular response (19).
There were no differences in quality of life between the 3 rate control groups. Apparently, not only heart rate alone but also the use of more and higher dosages of rate control drugs and the underlying disease influence quality of life.
The difference in heart rate between the groups was not as marked as would have been expected from the design of the study. However, the strategies to achieve those heart rates were completely different. Outcome might have been different when all patients in the lenient group would have had a heart rate >100 beats/min (13). The RACE II study was not designed to assess differences between successful strict, failed strict, and lenient rate control; therefore the current study is underpowered for this analysis. Follow-up was limited to 3 years.
There is no difference in outcome between successful and failed strict rate control. Strict rate control seems to have no favorable effect in this group of permanent AF patients, not even when the heart rate targets are achieved. Therefore, lenient rate control might be used as frontline therapy in patients with permanent AF.
The RACE II study was supported by the Netherlands Heart Foundation (2003B118), Interuniversity Cardiology Institute, the Netherlands, Working Group on Cardiovascular Research, the Netherlands, and unrestricted educational grants from AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Medtronic, and Sanofi Aventis France (paid to the Interuniversity Cardiology Institute of the Netherlands). Dr. Crijns has received consulting fees from Boehringer Ingelheim, Sanofi-Aventis, and AstraZeneca; grant support from St. Jude Medical, Boston Scientific, Boehringer Ingelheim, Sanofi-Aventis, Medapharma, and Merck; and honoraria from Medtronic, Sanofi-Aventis, Medapharma, Merck, Boehringer Ingelheim, and Biosense Webster. Dr. Alings has received consulting fees from Boehringer Ingelheim and Sanofi-Aventis; has served on advisory boards for Bayer AG, Boehringer-Ingelheim, MSD, and Sanofi-Aventis; and has received travel support from Boston Scientific, Bristol-Myers Squibb, and St. Jude Medical. Dr. Van Veldhuisen has received board membership fees from Amgen, BG Medicine, Pfizer, Sorbent, and Vifor; consulting fees from Medtronic, Biotronik, and Biosite-Inverness; lecture fees from Merck, Menarini, and Medtronic; and travel reimbursement from Pfizer. Dr. Van Gelder has received consulting fees from Sanofi-Aventis, Boehringer Ingelheim, and Cardiome; grant support from Medtronic, Biotronik, and St. Jude Medical; and lecture fees from Sanofi-Aventis, Boehringer Ingelheim, and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- atrial fibrillation
- confidence interval
- Received July 11, 2012.
- Revision received October 6, 2012.
- Accepted November 13, 2012.
- American College of Cardiology Foundation
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