RACE II

Published

Van Gelder IC, et al. "Lenient versus Strict Rate Control in Patients with Atrial Fibrillation". The New England Journal of Medicine. 2010. 362(15):1363-73.
PubMed • Full text • PDF

Clinical Question

Among patients with permanent atrial fibrillation, what is the effect of lenient compared to strict rate control strategies on cardiovascular events?

Bottom Line

Among patients with permanent atrial fibrillation, lenient rate control (HR <110 bpm) is as effective as strict rate control (HR <80 bpm) in preventing cardiovascular events.

Major Points

AFFIRM (2002) suggested a mortality benefit in management of AF with rate control over rhythm control. The 2010 Rate Control Efficacy in Permanent Atrial Fibrillation: a Comparison between Lenient versus Strict Rate Control II (RACE II) trial directly addressed the issue of optimal rate control for patients with permanent AF and found that a lenient rate control strategy (resting HR <110 bpm) was noninferior to a strict rate control strategy (resting HR <80 bpm and HR during moderate exercise <110 bpm) in preventing the composite outcome of CV death, CHF hospitalization, stroke, systemic embolism, bleeding, and life threatening arrhythmic events over 3 years.

Of note, the strict rate control group met their resting targets in 78% of cases (compared to 98% in the lenient rate control group) and required nine times as many visits (684 vs. 75) in order to achieve rate control targets.

Based upon the results of RACE II, very stringent HR control is not necessary in many physically active patients with AF who are minimally symptomatic. A more lenient rate control strategy offers the advantages of less medication and fewer outpatient visits to achieve HR control.

Guidelines

AHA/ACC/HRS AF (April 2014, adapted)

• In patients with nonvalvular AF with prior stroke, TIA, or CHA₂DS₂-VASc score ≥2, recommend oral anticoagulation with:
  • Warfarin, goal INR 2-3 (class I, level A)
  • Dabigatran (class I, level B)
  • Rivaroxaban (class I, level B)
  • Apixaban (class I, level B)
• In patients with nonvalvular AF unable to maintain INR 2-3 with warfarin, recommend dabigatran, rivaroxaban, or apixaban (class I, level C)
• In patients with nonvalvular AF with moderate or severe CKD with CHA₂DS₂-VASc score ≥2, consider treatment with reduced doses of dabigatran, rivaroxaban, or apixaban, although safety has not yet been clearly delineated (class IIb, level C)
• In patients with ESRD, dabigatran and rivaroxaban are untested and are not recommended (class III, level C)
• In patients with a mechanical heart valve, do not use dabigatran (class III, level B)
• Rate control with a beta blocker or non-DHP CCB for patients with paroxysmal, persistent, or permanent AF (class I level B)
• HR <80 BPM is reasonable for symptomatic AF management (class IIa level B)
• HR <110 is reasonable if asymptomatic and LV systolic function is preserved (class IIb level B)

Design

• Multicenter, open-label, parallel-group, randomized controlled noninferiority trial
• N=614
  • Lenient rate control (n=311)
  • Strict rate control (n=303)
• Setting: 33 Dutch centers
• Enrollment: January 2005 to June 2007
• Median follow-up: 3 years
• Primary outcome: Composite of CV mortality, CHF, stroke, VTE, major bleeding, and arrhythmic events

Population

Inclusion Criteria

• Age ≤80 years
• Permanent AF for up to 12 months (demonstrated on two consecutive EKGs without known conversion)
• Mean resting HR >80 bpm
• Oral anticoagulation therapy (or aspirin, if no risk factors for thromboembolic complications present)

Exclusion Criteria

• Paroxysmal AF
• Known contraindications to lenient or strict rate control
• NYHA class IV CHF or CHF admission within previous 3 months
• Cardiac surgery within previous 3 months
• History of stroke
• Current or planned pacemaker, ICD, or CRT
• Sick sinus syndrome or AV conduction disturbance
• Untreated hyperthyroidism or euthryoidism within previous 3 months
• Inability to walk or bike

Baseline Characteristics

• Mean age: 68 years
• Male: 66%
• BMI: 29 kg/m²
• BP: 136/83
• Resting HR: 96 bpm
• Symptoms: 57%; palpitations (24%), SOB (35%), fatigue (30%)
• Median duration of permanent AF: 3 months
• Previous electrical cardioversion: 72%
• HTN: 61%
• CAD: 22% vs. 15%
• Valvular heart disease: 20%
• COPD: 13%
• DM: 11%
• Lone AF: 2%
• Previous hospitalization for CHF: 10%
• CHADS2 score: 0 or 1 (61%), 2 (26%), 3-6 (13%)
• NYHA: I (65%), II (30%), III (5%)
• Echocardiographic variables:
  • LA size, long axis: 46 mm
  • LV end-diastolic diameter: 51 mm
  • LV end-systolic diameter: 36 mm
  • LVEF: 52%
  • LVEF ≤40%: 15%

Baseline Medications

• AV nodal blocking agents:
  • None: 10.3%
  • β-blocker alone: 45%
  • Diltiazem or verapamil alone: 6%
  • Digoxin alone: 7%
  • β-blocker and either diltiazem or verapamil: 3%
  • β-blocker and digoxin: 17%
  • Digoxin and either diltiazem or verapamil: 5%
  • β-blocker, digoxin, and either diltiazem or verapamil: 1%
  • Sotalol: 5%
  • Amiodarone: 1.3%
• Other:
  • ARB or ACE inhibitor: 50%
  • Diuretic: 40%
  • Statin: 33% vs. 24%
  • Vitamin K antagonists: 29%
  • Aspirin: 2%

Interventions

Dose-adjustment phase

AV nodal blocking agents administered until HR targets achieved via EKG

Lenient control strategy: target resting HR <110 bpm

Strict control strategy: target resting HR <80 bpm and target exercise HR <110 bpm; 24-hour Holter monitoring to check for bradycardia

Resting HR at the end of dose adjustment phase

Target HR achieved: 97.7% vs. 75.2% (P<0.001)

Mean HR: 93 bpm vs. 76 bpm (P<0.001)

HR <80 bpm: 1.9% vs. 75.2% (P<0.001)

HR 80-110 bpm: 75.5% vs. 19.5% (P<0.001)

HR >100 bpm: 22.5% vs. 5.3% (P<0.001)

Exercise HR target achieved: 72.6% in strict control

Rate control medications at the end of dose adjustment phase

None: 10.3% vs. 1.0% (P<0.001)

β-blocker alone: 42.4% vs. 20.1% (P<0.001)

Diltiazem or verapamil alone: 5.8% vs. 5.3% (P=0.78)

Digoxin alone: 6.8% vs. 1.7% (P=0.002)

β-blocker and either diltiazem or verapamil: 3.9% vs. 12.5% (P<0.001)

β-blocker and digoxin: 19.3% vs. 37.3% (P<0.001)

Digoxin and either diltiazem or verapamil: 5.8% vs. 9.6% (P=0.08)

β-blocker, either diltiazem or verapamil, and digoxin: 1.0% vs. 8.9% (P<0.001)

Dose

β-blocker: 120 vs. 162 mg (P<0.001)

Diltiazem: 232 vs. 217 mg (P=0.72)

Verapamil: 166 vs. 217 mg (P<0.001)

Digoxin: 0.19 vs. 0.21 mg (P=0.06)

Follow-up phase

Visits every 2 weeks to adjust rate control agents until HR targets achieved

Visits after 1, 2, and 3 years

Follow-up terminated after 3 years or June 30, 2009

If HR targets could not be achieved or patients symptomatic, protocol permitted further adjustment of drugs/doses, electrical cardioversion, or ablation

At the end of the followup phase

Resting HR: 85 bpm vs. 75 bpm (P<0.001)

Visits to achieve rate-control target(s): 75 vs. 684 (P<0.001)

Outcomes

Comparisons are lenient vs. strict rate control.

Primary Outcomes

Composite of CV mortality, CHF, stroke, VTE, major bleeding, and arrhythmic events including syncope, sustained VT, cardiac arrest, life-threatening adverse effects of rate control agents, and implantation of a pacemaker or cardioverter-defibrillator

12.9% vs. 14.9% (HR 0.84; 95% CI 0.58-1.21; P<0.001)

HR 0.80, after statistical adjustment for the unbalanced distribution of the presence of CAD, use of statins, and DBP

Secondary Outcomes

CV mortality

2.9% vs. 3.9% (HR 0.79; 0.38-1.65)

From arrhythmia: 1.0% vs. 1.4%

From cardiac cause other than arrhythmia: 0.3% vs. 0.8%

From noncardiac vascular cause: 1.7% vs. 1.9%

CHF

3.8% vs. 4.1% (HR 0.97;0.48-1.96)

Stroke

1.6% vs. 3.9% (HR 0.35; 0.13-0.92)

Ischemic: 1.3% vs. 2.9%

Hemorrhagic: 0.3% vs. 1.5%

VTE

0.3% vs. 0%

Major bleeding

5.3 %vs. 4.5% (HR 1.12; 0.60-2.08)

Intracranial: 0% vs. 1.0%

Extracranial: 5.3% vs. 3.5%

Syncope

1.0% vs 1.0%

Life-threatening adverse effect of rate control agents: 1.1% vs. 0.7%

Sustained VT or VF: 0% vs. 0.3%

Cardioverter-defibrillator or pacemaker implantation: 0.8% vs. 1.7%

All-cause mortality

5.6% vs. 6.6% (HR 0.91; 90% CI 0.52-1.59)

Symptoms associated with AF

45.6% vs. 46.0% (P=0.92)

Dyspnea: 30.0% vs. 29.6% (P=0.90)

Fatigue: 24.4% vs. 22.6% (P=0.93)

Palpitations: 10.6% vs. 9.5% (P=0.66)

NYHA I: 70.0% vs. 70.4% (P=0.74)

NYHA II: 23.3% vs. 23.4% (P=0.74)

NYHA III: 6.7% vs. 6.2% (P=0.74)

Hospitalizations

25.1% vs. 27.4% (P=0.5)

Subgroup analysis

Primary composite outcome, among CHADS₂ ≥2

12.8% vs. 23% (P<0.001 for noninferiority)

Primary composite outcome, among CHADS₂ <2

11.8% vs. 9.2% (P=0.02 for noninferiority)

Adverse events

Any

19.9% vs. 23.8% (P=0.2)

Dizziness

2.9% vs. 5.3% (P=0.1)

Fatigue

1.6% vs. 3.0% (P=0.1)

Dyspnea

3.5% vs. 3.6% (P=0.9)

Funding

Supported by Netherlands Heart Foundation and unrestricted educational grants from multiple companies, including AztraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Medtronic, Roche, and Sanofi Aventis France.