RAte Control Efficacy in permanent atrial fibrillation: a comparison between lenient versus strict rate control in patients with and without heart failure. Background, aims, and design of RACE II

doi:10.1016/j.ahj.2006.02.033

American Heart Journal

Volume 152, Issue 3, September 2006, Pages 420-426

https://doi.org/10.1016/j.ahj.2006.02.033 Get rights and content

Background

Recent studies demonstrated that rate control is an acceptable alternative for rhythm control in patients with persistent atrial fibrillation (AF). However, optimal heart rate during AF is still unknown.

Objective

To show that in patients with permanent AF, lenient rate control is not inferior to strict rate control in terms of cardiovascular mortality, morbidity, neurohormonal activation, New York Heart Association class for heart failure, left ventricular function, left atrial size, quality of life, and costs.

Methods

The RACE II study is a prospective multicenter trial in The Netherlands that will randomize 500 patients with permanent AF (≤12 months) to strict or lenient rate control. Strict rate control is defined as a mean resting heart rate <80 beats per minute (bpm) and heart rate during minor exercise <110 bpm. After reaching the target, a 24-hour Holter monitoring will be performed. If necessary, drug dose reduction and/or pacemaker implantation will be performed. Lenient rate control is defined as a resting heart rate <110 bpm. Patients will be seen after 1, 2, and 3 months (for titration of rate control drugs) and yearly thereafter. We anticipate a 25% 2.5-year cardiovascular morbidity and mortality in both groups.

Results

Enrollment started in January 2005 in 29 centers in The Netherlands and is expected to be concluded in June 2006. Follow-up will be at least 2 years with a maximum of 3 years.

Conclusion

This study should provide data how to treat patients with permanent AF.

Section snippets

Rate control may be adopted as first choice therapy in atrial fibrillation

Permanent atrial fibrillation (AF) is not a benign disease.¹ It may cause symptoms and is associated with thromboembolic complications. Some patients with longer-lasting AF may develop left ventricular dysfunction, even those without underlying heart disease (tachycardiomyopathy). The AFFIRM, RACE, PIAF, and STAF studies and others (HOT CAFÉ) established that morbidity and mortality was comparable between rate and rhythm control therapy.2, 3, 4, 5, 6 As a result, rate control may now be adopted

Study design and methods

The RACE II study (Figure 1) is being conducted in 29 centers in The Netherlands. The institutional review board of each institution approved the study, and all patients gave written informed consent. Recruitment began in January 2005, randomization is expected to be concluded in June 2006, and follow-up will be terminated in June 2008. At present, 375 patients have been included. The trial is funded by grants from the Netherlands Heart Foundation and the Interuniversity Cardiology Institute,

Sample size determination and statistical analysis

The primary aim is to show noninferiority of lenient rate control as compared with strict rate control in terms of the primary end point. The expected incidence of the primary end point in both groups is 25%. Noninferiority will be established if it is shown that the absolute difference in the incidence of the primary end point does not exceed 2.5% (relative difference is ≤10%). To achieve a power of at least 80% with a 95% confidence limit (1-sided test with α = 5%), 250 patients in each

Conclusions

Rate control is now first choice therapy in many patients with AF. However, the optimal heart rate during AF is unknown. The ACC/AHA/ESC guidelines recommend a heart rate between 60 and 80 bpm in rest and 90 and 120 bpm during moderate exercise. Although, these recommendations are arbitrary and are not evidence based. The results of this trial should provide information concerning two widely applicable treatment strategies in typical permanent AF patients. Clinical decision making will be

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Cited by (73)

Impact of heart rate on adverse events in patients with non-valvular atrial fibrillation: Subanalysis of the J-RHYTHM Registry
2022, IJC Heart and Vasculature
Citation Excerpt :
Thus, the impact of HR on adverse events in patients with NVAF remains controversial [4,17,18]. In the present study, first of all, we evaluated the impact of baseline HR on adverse events, since baseline HR was often analyzed in previous studies [17–19]. However, our results demonstrated that the baseline HR quartiles did not show a significant trend for any event across study groups (Table 2).
Although heart rate (HR) is reportedly associated with major cardiovascular outcomes in the general population, its impact on adverse events in patients with non-valvular atrial fibrillation (NVAF) remains controversial. Thus, we performed post hoc analyses of data from the J-RHYTHM Registry to clarify this in patients with NVAF.
Of 7406 outpatients with NVAF from 158 institutions, 6886 (age, 69.8 ± 9.9 years; men, 70.8%), in whom both baseline HR and HR-end (at the time closest to an event or at the last visit of follow-up) were measured during the two-year follow-up period or until the occurrence of an event, constituted the study group. The baseline HR and HR-end values were 72.5 ± 13.3 bpm and 73.3 ± 13.3 bpm, respectively. Thromboembolism, major hemorrhage, all-cause death, and cardiovascular death occurred in 117 (1.7%), 130 (1.9%), 157 (2.3%), and 58 (0.8%) patients, respectively. Baseline HR was not associated with any adverse event, whereas HR-end (per 1-bpm increase) was significantly associated with an increased incidence of all adverse events. Furthermore, the highest quartile of HR-end (≥80 bpm) was independently associated with the incidence of major hemorrhage (adjusted odds ratio [OR], 2.90; 95% confidence interval [CI], 1.69–4.96; P < 0.001), all-cause death (OR, 3.42; 95% CI, 1.99–5.88; P < 0.001), and cardiovascular death (OR, 5.07; 95% CI, 1.49–17.22; P = 0.009) compared with the second quartile (64–71 bpm), even after adjusting for known confounding factors, HR-controlling drug use, and systolic blood pressure-end.
In patients with NVAF, HR-end was significantly associated with adverse events independent of systolic blood pressure-end, whereas baseline HR was not.
Target heart rate in heart failure with reduced ejection fraction and atrial fibrillation: Goldilocks zone
2022, American Heart Journal Plus: Cardiology Research and Practice
The rates of atrial fibrillation (AF) and heart failure with reduced ejection fraction (HFrEF) continue to grow with many patients suffering from their combined impact on quality of life and prognosis.
A lower heart rate (HR) in HFrEF is associated with reduced morbidity and mortality due to beta-blocker and ivabradine therapy. Postulated mechanisms include reduced neurohumoral activation, increased diastolic filling time and myocardial energy conservation. In contrast, the landmark randomised controlled non-inferiority RACE II trial demonstrated that a lenient rate control strategy (target HR <110 beats per minute [bpm]) was more attainable and safer than a strict rate control strategy (resting HR <80 bpm) in permanent AF. Physiologically, a higher HR is needed to compensate for the lost ‘atrial kick’ that contributes to the cardiac output by coordinated atrial contractions in normal sinus rhythm.
This leaves the not insignificant number of patients with HFrEF and AF in a conundrum over optimal HR control. Retrospective analyses of AF and HR control in landmark HFrEF trials (e.g. CHARM, PARADIGM and ATMOSPHERE) point towards better outcomes with a less stringent target HR. However, this association disappears after adjustment for known prognostic markers in HFrEF, including left ventricular ejection fraction, New York Heart Association class and NT-proBNP levels. There is a clear need for dedicated randomised controlled trials, investigating rate control strategies in this increasingly large subgroup of patients.
Regardless of rate control strategy, effective anti-coagulation and guideline-directed medical therapy must not be forgotten in the treatment of patients with HFrEF and AF.
Rate control in atrial fibrillation
2016, The Lancet
Control of the heart rate (rate control) is central to atrial fibrillation management, even for patients who ultimately require control of the rhythm. We review heart rate control in patients with atrial fibrillation, including the rationale for the intervention, patient selection, and the treatments available. The choice of rate control depends on the symptoms and clinical characteristics of the patient, but for all patients with atrial fibrillation, rate control is part of the management. Choice of drugs is patient-dependent. β blockers, alone or in combination with digoxin, or non-dihydropyridine calcium-channel blockers (not in heart failure) effectively lower the heart rate. Digoxin is least effective, but a reasonable choice for physically inactive patients aged 80 years or older, in whom other treatments are ineffective or are contraindicated, and as an additional drug to other rate-controlling drugs, especially in heart failure when instituted cautiously. Atrioventricular node ablation with pacemaker insertion for rate control should be used as an approach of last resort but is also an option early in the management of patients with atrial fibrillation treated with cardiac resynchronisation therapy. However, catheter ablation of atrial fibrillation should be considered before atrioventricular node ablation. Although rate control is a top priority and one of the first management issues for all patients with atrial fibrillation, many issues remain.
PACES/HRS expert consensus statement on the recognition and management of arrhythmias in adult congenital heart disease: Developed in partnership between the Pediatric and Congenital Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS). Endorsed by the governing bodies of PACES, HRS, the American College of Cardiology (ACC), the American Heart Association (AHA), the European Heart Rhythm Association (EHRA), the Canadian Heart Rhythm Society (CHRS), and the International Society for Adult Congenital Heart Disease (ISACHD)
2014, Heart Rhythm
Citation Excerpt :
Clinical trials in adults with and without heart failure have included targets such as a maximum heart rate of 80 bpm at rest and <110 bpm on exertion.126,127,132 However, more lenient objectives in patients without CHD, including a mean resting heart rate >80 bpm, have been associated with similar outcomes.133,134 As such, some management guidelines have revised the recommended resting ventricular rate target to 100 bpm.135
PACES/HRS Expert Consensus Statement on the Recognition and Management of Arrhythmias in Adult Congenital Heart Disease
2014, Canadian Journal of Cardiology
Digoxin in patients with permanent atrial fibrillation: Data from the RACE II study
2014, Heart Rhythm
Citation Excerpt :
Patients were stratified by the use of digoxin after the dose-adjustment phase. The study design, patient characteristics, and results of the RACE II trial have been published previously.11,14,17–20 In short, the RACE II trial was a randomized multicenter study comparing long-term effects of lenient vs strict rate control on morbidity and mortality in 614 patients with permanent AF in the Netherlands.
The Atrial Fibrillation Follow-up Investigation of Rhythm Management trial showed that digoxin was associated with increased mortality in patients with atrial fibrillation.
To assess the association of digoxin with cardiovascular (CV) morbidity and mortality in patients with permanent atrial fibrillation enrolled in the Dutch Rate Control Efficacy in Permanent AF: A Comparison Between Lenient Versus Strict Rate Control II trial as well as to assess the role of digoxin to achieve heart rate targets.
The primary outcome was a composite of CV morbidity and mortality. Secondary outcomes included CV hospitalization and all-cause mortality or heart failure (HF) hospitalization. Of the 614 patients, 608 (99%) completed the dose-adjustment phase. Outcome events were analyzed from the end of the dose-adjustment phase until the end of follow-up. The median follow-up period was 2.9 years (interquartile range 2.7–3.0 years).
In total, 284 patients (46.7%) used digoxin after the dose-adjustment phase (median dosage 0.250 mg; interquartile range 0.0625–0.750 mg). These patients were more often women, previously admitted for HF, had an increased left ventricular end-systolic diameter, and more often randomized to strict rate control. By using Cox proportional hazards regression analysis, the use of digoxin was not associated with an increased risk for the primary and secondary outcomes. For the primary outcome, the 3-year estimated cumulative incidence was 12.9% vs 13.4% in the digoxin group vs the no-digoxin group (unadjusted hazard ratio [HR] 0.97; 95% confidence interval [CI] 0.62–1.52). Incidence was 19.4% vs 19.5% for CV hospitalization (unadjusted HR 1.00; 95% CI 0.69–1.45) and 6.6% vs 9.9% for all-cause mortality or HF hospitalization (unadjusted HR 0.62; 95% CI 0.34–1.13) in the digoxin group vs the no-digoxin group.
The use of digoxin was not associated with increased morbidity and mortality.

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: The study is supported by NHS (Netherlands Heart Foundation, 2003B118), ICIN (Interuniversity Cardiology Institute, The Netherlands), WCN (Working Group Cardiology, The Netherlands); AstraZeneca, Biotronik, Guidant, Medtronic, Roche, and Vitatron (all The Netherlands); and Sanofi-Aventis France.

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Trial DesignRAte Control Efficacy in permanent atrial fibrillation: a comparison between lenient versus strict rate control in patients with and without heart failure. Background, aims, and design of RACE II

Background

Objective

Methods

Results

Conclusion

Section snippets

Rate control may be adopted as first choice therapy in atrial fibrillation

Study design and methods

Sample size determination and statistical analysis

Conclusions

Lancet

J Am Coll Cardiol

Chest

J Am Coll Cardiol

Am J Cardiol

Int J Cardiol

J Am Coll Cardiol

Am J Cardiol

Trial Design
RAte Control Efficacy in permanent atrial fibrillation: a comparison between lenient versus strict rate control in patients with and without heart failure. Background, aims, and design of RACE II