Rate Control Efficacy in Permanent Atrial Fibrillation: A Comparison Between Lenient Versus Strict Rate Control II - RACE II

Aug 15, 2011
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
The Netherlands Heart Foundation, and grants from AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Medtronic, Roche, and Sanofi Aventis.
Date Presented:
01/01/2010
Date Updated:
08/15/2011
Original Posted Date:
08/15/2011
References

Description:

Although rate control has been shown to be associated with similar outcomes, as compared with rhythm control in patients with atrial fibrillation (AF), the optimal level of heart rate (HR) control/lowering is unclear. Current guidelines recommend strict rate control, although data to support this approach are lacking. Accordingly, the RACE II trial sought to investigate whether lenient rate control would be noninferior to strict rhythm control in patients with permanent AF.

Hypothesis:

Lenient rate control would be noninferior to strict rate control in patients with permanent AF.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patients Enrolled: 614
NYHA Class: I (65.1%), II (30.1%), III (4.7%)
Mean Follow Up: 3 years
Mean Patient Age: 68 years
Female: 34
Mean Ejection Fraction: 52%

Patient Populations:

  • Permanent AF for up to 12 months
  • Age ≤80 years
  • Mean resting HR >80 bpm
  • Current use of anticoagulation (or aspirin alone, if deemed at low risk for thromboembolism)

Exclusions:

  • Paroxysmal AF
  • Known contraindications for either strict or lenient rate control (e.g., previous adverse effects on negative chronotropic drugs)
  •  Unstable heart failure defined as New York Heart Association class IV heart failure or heart failure necessitating hospital admission <3 months before inclusion
  • Cardiac surgery <3 months
  • Any stroke
  • Current or foreseen pacemaker, ICD, and/or cardiac resynchronization therapy
  • Signs of sick sinus syndrome or AV conduction disturbances (i.e., symptomatic bradycardia or asystole >3 seconds or escape rate <40 bpm in awake symptom-free patients
  • Untreated hyperthyroidism or <3 months of euthyroidism
  • Inability to walk or bike

Primary Endpoints:

  • CV death, hospitalization for heart failure and stroke, systemic embolism, major bleeding, arrhythmic events, and implantation of PPM or ICD

Secondary Endpoints:

  • CV death
  • Hospitalization for congestive heart failure and stroke
  • Systemic embolism
  • Major bleeding
  • Arrhythmic events
  • Implantation of PPM or ICD
  • All-cause mortality
  • Symptoms
  • Functional status

Drug/Procedures Used:

Patients were randomized to either a lenient rate control strategy (target resting HR <110 bpm), or strict control strategy (target resting HR <80 bpm, and <110 bpm with moderate exercise). HR control was achieved with the use of beta-blockers (45%), non-dihydropyridine calcium-channel blockers (6%) or digoxin (7.2%), or a combination of these. A small number of patients also received sotalol (5.0) and amiodarone (1.3%).

Concomitant Medications:

Angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (49.8%), statin (28.8%), vitamin K antagonist (98.7%), aspirin (1.6%)

Principal Findings:

A total of 614 patients were randomized, 311 to lenient control, and 303 to strict control. Baseline characteristics were fairly similar between the two arms. The resting baseline HR was 96 bpm. The median duration of AF was 18 months, while the median duration of permanent AF was 3 months. About 20% had coexisting valvular heart disease. About 56.7% of these patients had symptomatic AF, and 1.8% had lone AF. The majority of patients had a CHADS2 score of 0 or 1 (60.7%), whereas 13.4% had a CHADS2 score >2.

The mean HR at the end of the dose-adjustment phase was 93 ± 9 bpm in the lenient control group, as compared with 76 ± 12 bpm in the strict control group (p < 0.001). Only nine patients in both groups were in normal sinus rhythm at the end of follow-up. Target HR was achieved in 97.7% of the patients in the lenient control arm, as compared with 67.0% in the strict control arm (p < 0.001). Only 1.9% of patients in the lenient control arm and 75.2% of patients in the strict control arm had resting HR <80 bpm. About 72.6% of patients in the strict control arm achieved an exercise HR of <110 bpm. About half of the patients in the strict control arm could not achieve target HR due to drug-related adverse events or was noted to be impossible to achieve with drugs.

The 3-year estimated cumulative incidence of the primary endpoint (cardiovascular [CV] death, hospitalization for heart failure and stroke, systemic embolism, major bleeding, arrhythmic events, and implantation of permanent pacemaker [PPM] or implantable cardioverter defibrillator [ICD]) was similar between the lenient and strict control arms (12.9% vs. 14.9%, hazard ratio 0.84, 90% confidence interval 0.58-1.21, p for noninferiority = 0.001). This was true for patients irrespective of CHADS2 score. Secondary outcomes, including CV death (2.9% vs. 3.9%), congestive heart failure (3.8% vs. 4.1%), bleeding (5.3% vs. 4.5%), syncope (1% vs. 1%), and PPM implantation (0.8% vs. 1.4%) were similar between the two arms. The incidence of stroke was significantly lower in the lenient control arm, as compared with the strict control arm (1.6% vs. 3.9%, p < 0.05).

In the subgroup of patients with available echocardiographic data, there were no significant differences in measures of LA or LV remodeling between the two arms at the end of follow-up: change in LA diameter 0.8 vs. -0.8, LA volume 5.0 vs. 1.7, and LVEDD -0.3 vs. 1.4 (p > 0.05 for all). Of the various predictors tested, female gender was noted to be associated with adverse LA and LV remodeling.

Interpretation:

The results of this trial indicate that a lenient rate control strategy, with a target resting HR <110 bpm is easier to achieve with beta-blockers, calcium-channel blockers, and/or digoxin, as compared with a strict control strategy, with a target resting HR <80 bpm, and an exercise HR <110 bpm. The former strategy is also noninferior for CV outcomes, and is associated with a reduction in the incidence of strokes.

Target HR was achieved in only 67% of the patients in the strict control arm. Hence, it is possible that if other means of achieving a lower HR were pursued, there may have been a difference in the strict control strategy. Furthermore, the majority of patients in this study were low risk (CHADS2 score 0-1). Although the investigators did not note a difference in patients with a higher CHADS2 score, few patients were available for this analysis. This also will need to be explored in further analyses. The impact of female gender on LA and LV remodeling noted in this study also deserves further study.

References:

Smit MD, Crijns HJ, Tijssen JG, et al., on behalf of the RACE II Investigators. Effect of Lenient Versus Strict Rate Control on Cardiac Remodeling in Patients With Atrial Fibrillation: Data of the RACE II (RAte Control Efficacy in permanent atrial fibrillation II) Study. J Am Coll Cardiol 2011;58:942-949.

Van Gelder CI, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;Mar 15:[Epub ahead of print].

Presented by Dr. Isabelle C. Van Gelder at the ACC.10/i2 Summit, Atlanta, GA, March 2010.

Keywords: Dihydropyridines, Stroke, Follow-Up Studies, Digoxin, Syncope, Heart Rate, Calcium, Thromboembolism, Research Personnel, Heart Failure, Heart Valve Diseases, Confidence Intervals, Sotalol, Embolism, Defibrillators, Implantable


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