RACE II
RAte Control Efficacy in Permanent Atrial
Fibrillation
A Randomized Comparison of Lenient Rate Control
versus Strict Rate Control Concerning Morbidity and
Mortality
Isabelle C Van Gelder, Hessel F Groenveld, Harry J Crijns, Jan G Tijssen,
Hans H Hillege, Ype Tuininga, Marco Alings, Hans Bosker, Jan Cornel,
Raymond Tukkie, Otto Kamp, Dirk J Van Veldhuisen, Maarten P Van den Berg,
on behalf of the RACE II Investigators
AFFIRM, RACE
 Rates of complications and death were similar
in patients treated with rate-control and rhythmcontrol therapy
 Since then, rate control has become front-line
therapy in the management of AF
The optimal level of heart-rate control during
AF is unknown
Wyse et al. New Engl J Med 2002
Van Gelder et al. New Engl J Med 2002
ACC/AHA/ESC 2006 Guidelines
 Strict rate control
 At rest: 60 - 80
 During moderate exercise: 90-115
Fuster et al. Guidelines J Am Coll Cardiol 2006
Strict rate control ?
 Contra
 Difficult to achieve
 Adverse effects drugs
 More frequent pacemaker implants
 Higher costs
Hypothesis
Lenient rate control is not inferior to
strict rate control in patients with
permanent AF in terms of
cardiovascular morbidity and mortality
RACE II trial
 Prospective, randomized, open trial with
blinded endpoint evaluation
 Multicenter, noninferiority trial conducted in
The Netherlands
 2-3 years follow-up
Inclusion criteria
 Permanent AF ≤ 12 months
 Resting heart rate > 80 bpm
 On oral anticoagulation
 Age ≤ 80 years
Exclusion criteria
 Paroxysmal or transient AF
 Known contra-indications for either strict or
lenient rate control (e.g. previous adverse
effects on rate control drugs)
 Unstable heart failure
 Cardiac surgery < 3 months
 Stroke
 Current or foreseen PM/ ICD/ CRT
 Inability to walk or bike
Treatment
 Patients were randomized to
 Lenient rate control
 Strict rate control
Permanent AF > 80 bpm
lenient
strict
Permanent AF > 80 bpm
lenient
HR < 110 bpm
(12 lead ECG)
strict
Permanent AF > 80 bpm
lenient
HR < 110 bpm
(12 lead ECG)
strict
Permanent AF > 80 bpm
lenient
HR < 110 bpm
(12 lead ECG)
strict
HR < 80 bpm (12 lead ECG)
and
HR < 110 bpm (at 25% duration of
maximal exercise time)
Permanent AF > 80 bpm
lenient
HR < 110 bpm
(12 lead ECG)
strict
HR < 80 bpm (12 lead ECG)
and
HR < 110 bpm (at 25% duration of
maximal exercise time)
After achieving rate control target:
Holter for safety
Treatment
 Patients were treated with negative
dromotropic drugs (i.e. beta-blockers, nondihydropyridine calcium-channel blockers and
digoxin, alone or in combination).
 Dosages of drugs were increased or drugs
combined until the heart rate target or targets
were achieved.
Primary outcome (composite)
 Cardiovascular mortality
 Hospitalization for heart failure
 Stroke, systemic emboli, major bleeding
 Syncope, sustained VT, cardiac arrest
 Life-threatening adverse effects of RC drugs
 Pacemaker implantation for bradycardia
 ICD implantation for ventricular arrhythmias
Statistical analysis
Noninferiority boundary is 10% absolute difference*
Statistical hypotheses
Ho: Rlenient - Rstrict > 10% (inferiority)
H1: Rlenient - Rstrict < 10% (non-inferiority)
The null hypothesis of inferiority will be rejected
when the upper limit of the 2-sided 90%-confidence
interval of the risk difference does not exceed 10%.
* Comparable to the noninferiority boundary in the first RACE trial
Baseline characteristics
Age
Male
Duration AF
Total duration
Permanent AF
Lenient control
n= 311
Strict control
n=303
69±8
66%
67±9
65%
16 (6-54)
3 (1-6)
20 (6-64) months
2 (1-5) months
Baseline characteristics
Hypertension
CAD
Valve disease
COPD
Diabetes mellitus
Lone AF
Lenient control
n= 311
Strict control
n=303
64%
22%
21%
12%
12%
2%
58%
15%
20%
14%
11%
2%
Baseline characteristics
Lenient control
Strict control
n= 311
n=303
1.4±1.0
1.4±1.2
0-1
57%
64%
2
30%
22%
3-6
13%
14%
CHADS2 score
Rate control targets at end of
dose-adjustment phase
Lenient control
n= 311
Strict control
n=303
98%
98%
-
67%*
75%
73%
0.2±0.6
0
0-0
2.3±1.4*
2*
1-3
Rate control target
Resting target
Exercise target
Visits to achieve target
Median
Interquartile range
* P<0.001
Rate control medication at end of
dose-adjustment phase
Lenient control Strict control
n= 311
n=303
None
Beta-blocker alone
Calcium blocker alone
Digoxin alone
Beta-blocker + calciumblocker
Beta-blocker + digoxin
Calciumblocker + digoxin
Beta + calciumblocker + digoxin
10%
42%
6%
7%
4%
19%
30%
6%
1%
1%*
20%*
5%
2%*
13%*
37%*
69%*
10%
9%*
* P<0.01
Rate control doses at end of
dose-adjustment phase
Lenient control Strict control
n= 311
n=303
Beta-blocker (normalized to
metoprolol-equivalent doses) 120±78
162±85 mg*
Verapamil
166±60
217±97 mg*
Digoxin
0.19±0.8
0.21±0.8 mg
* P<0.001
Heart rate during study
Heart rate (beats per minute)
110
100
90
Lenient
*
*
**
80
**
**
70
Strict
60
* P<0.001
50
0
3
No. At Risk
Lenient 311 311
Strict
303 303
12
24
302
284
291
277
36 months
237
240
Cumulative incidence primary outcome
Cumulative Incidence (%)
20
Strict
15
14.9%
12.9%
Lenient
10
5
0
0
No. At Risk
Strict
303
Lenient 311
6
12
18
282
298
273
290
262
285
24
30
246
255
212
218
36 months
131
138
Primary outcome
3-y incidence
Risk difference
90%-CI
Upper limit
Lenient control
12.9%
Strict control
14.9%
-2.0%
(-7.6%, 3.5%)
10%
Inferiority hypothesis was rejected (p<0.001)
Components of primary outcome
Lenient control
n= 311
Primary outcome
CV mortality
Heart failure
Stroke
Emboli
Bleeding
Adverse effects RC drugs
Pacemaker
Syncope
ICD
12.9%
2.9%
3.8%
1.6%
0.3%
5.3%
1.1%
0.8%
1.0%
0%
Strict control
n=303
14.9%
3.9%
4.1%
3.9%
0%
4.5%
0.7%
1.4%
1.0%
0.4%
Components of primary outcome
Lenient control
n= 311
Strict control
n=303
Primary outcome
12.9%
14.9%
Nonfatal
10.0%
11.0%
Fatal
2.9%
3.9%
Cardiac arrhythmic
1.0%
1.4%
Cardiac nonarrhythmic
0.3%
0.8%
Noncardiac vascular
1.7%
1.9%
Primary outcome
3-y incidence
Lenient control
Strict control
All patients
12.9%
14.9%
CHADS2 < 2
12.4%
9.6%*
CHADS2 ≥ 2
13.6%
25.0%**
Inferiority hypothesis rejected for both subgroups
(*p=0.02 and **p<0.001)
Symptoms
120
baseline
% Symptoms
100
end of study
80
60
40
palpitations
Palpitations
Fatigue
fatigue
Dyspnea
dyspnea
20
0
Lenient
Strict
Lenient
Strict
Conclusions
 The RACE II study shows that lenient rate
control is not inferior to strict rate control
 Lenient rate control is more convenient since
fewer outpatient visits, fewer examinations,
lower doses and less often combination of
drugs are needed
Clinical implications
 Lenient rate control may be adopted as first
choice rate control strategy in patients with
permanent atrial fibrillation
 This applies for high and low risk patients
Van Gelder,Groenveld,Van Veldhuisen,
Van den Berg
Janssen, Tukkie
Bendermacher, Olthof
Robles de Medina
Kuijer, Zwart
Crijns
Alings
Post
Peters, Van Stralen, Buys
Daniëls
Timmermans
Kuijper, Van Doorn
Hoogslag
Den Hartog
Van Rugge
Derksen, Bosker
Hamraoui
De Milliano
Kamp
Kragten
Linssen
Tuininga, Badings
Nierop
Gratama
Nio, Muys, Van den Berg
Thijssen
Van Dijkman
Cornel
Van der Galiën
Boersma
Bronzwaer
Spanjaard
Bartels
University Medical Center Groningen
Kennemer Hospital Haarlem
Elkerliek Hospital Helmond
Hospital Leyenburg The Hague
Hospital Bernhoven Oss
Maastricht University Medical Center
Amphia Hospital Breda
Hospital Hengelo
Hospital Gooi Noord Blaricum
Jeroen Bosch Hospital Den Bosch
Medical Spectrum Twente Enschede
Spaarne Hospital Hoofddorp
Diaconessen Hospital Meppel
Hospital Gelderse Vallei Ede
Diaconessen Hospital Leiden
Rijnstate Hospital Arnhem
Tweesteden Hospital Tilburg
Hospital Hilversum
VU Medical Center Amsterdam
Atrium Medical Center Heerlen
Twenteborg Hospital Almelo
Deventer Hospital Deventer
St. Franciscus Hospital Rotterdam
VieCurie Hospital Venlo
IJsselland Hospital, Capelle aan de IJssel
Maxima Medical Center Veldhoven
Bronovo Hospital The Hague
Medical Center Alkmaar
St.Lucas Hospital Winschoten
St.Antonius ospital Nieuwegein
Zaans Medical Center De Heel Zaandam
Delfzicht Hospital Delfzijl
Martini Hospital Groningen
Steering Committee
Isabelle C Van Gelder
Harry JGM Crijns
Jan GP Tijssen
Hans L Hillege
Ype S Tuininga
A Marco Alings
Hans A Bosker
Jan H Cornel
Otto Kamp
Dirk J Van Veldhuisen
Maarten P Van den Berg
Thesis of
Hessel F Groenveld
Data Safety and
Monitoring Board
Hein J Wellens
Richard N Hauer
Arthur A Wilde
Adjudication Committee
Jan Van der Meer†
Gert J Luijckx
Johan Brügemann
Trial Coordination Center
Hans L Hillege
Janneke A Bergsma
Marco Assmann
Olga Eriks-De Vries
Myke Mol
This article is now available on the
New England Journal of Medicine’s
website, NEJM.org
Heart rate moderate exercise
150
bpm
100
50
total exercise
0
2
0
recovery
8
5
10
25% exercise duration
15 minutes
Heart rate moderate exercise
150
bpm
100
Heart rate 95 bpm
50
total exercise
0
2
0
recovery
8
5
10
25% exercise duration
15 minutes
Symptoms
At baseline
Palpitations
Dyspnea
Fatigue
Lenient control
56%
20%
34%
28%
Strict control
58%
27%
37%
32%
At end of study
Palpitations
Dyspnea
Fatigue
46%
11%
30%
24%
46%
10%
30%
23%
Follow up visits
 Patients were seen
 Every 2 weeks until the rate control target
was achieved
 After 1, 2 and 3 years of follow-up
Primary outcome according to HR
at end dose adjustment phase
Lenient control
Strict control
% (events/total pts)
Total group
Heart rate < 70
12.9 (38/311)
- (1/1)
14.9 (43/303)
20.4 (13/67)
Heart rate 70-80
20.0 (1/5)
11.7 (18/161)
Heart rate 81-90
15.0 (16/112)
10.7 (4/39)
Heart rate 91-100
9.1 (11/123)
5.6 (1/20)
Heart rate > 100
14.1(9/70)
46.4 (7/16)
Heart rate d at end of
dose adjustment phase
Lenient control
Strict control
% (events/total pts)
Total group
Heart rate < 70
12.9 (38/311)
- (1/1)
14.9 (43/303)
20.4 (13/67)
Heart rate 70-80
20.0 (1/5)
11.7 (18/161)
Heart rate 81-90
15.0 (16/112)
10.7 (4/39)
Heart rate 91-100
9.1 (11/123)
5.6 (1/20)
Heart rate > 100
14.1(9/70)
46.4 (7/16)
total exercise
recovery
25% exercise duration
Strict rate control ?
 Pro

 lower incidence CHF
 fewer strokes
 fewer bleeding
 better survival
 fewer symptoms
 improved quality of life
Contra
 difficult to achieve
 adverse effects drugs
 pacemaker implants
 higher costs
Stroke
 Sudden onset of focal neurological deficit
consistent with occlusion major cerebral artery
 Documented by CT or MR imaging
 Categorized as ischemic, hemorrhagic or
indeterminate
Major bleeding
 Requiring hospitalization with reduction of
hemoglobin level of at least 20 mg/L
 Requiring transfusion of at least 2 units
 Symptomatic bleeding in critical area or organ
 Fatal
Severe adverse effects RC drugs
 Digitalis intoxication
 Conduction disturbances necessitating
hospitalization
Cardiovascular death
4
tabel
% Endpoint
3
3.9%
2.9%
non
cardiac
noncardiac
vascular
vascular
cardiac
non
cardiac
arrhythmic
nonarrhythmic
carciac
cardiac
arrhythmic
arrhythmic
2
1
0
Lenient control
Strict control
Nonfatal and fatal endpoints
15
14.9%
% Endpoint
12.9%
10
5
nonfatal
nonfatal
fatal
fatal
0
Lenient control
Strict control
Nonfatal and fatal endpoints
12
% Endpoint
10
CHADS2 < 2
CHADS2 ≥ 2
10.0%
8
6
5.1%
4
4.5%
3.5%
nonfatal
nonfatal
2
fatal
fatal
0
Lenient
Strict
Lenient
Strict
Heart rate during study
Heart rate (beats per minute)
110
100
Lenient
90
**
80
**
**
Strict
70
60
* P<0.001
50
No. At Risk 0
Lenient 311
Strict
303
12
302
284
24
36
291
277
237
240
months
200
bpm
150
100
50
total exercise
recovery
00
0
5
10
25% exercise duration
15 minutes
200
bpm
150
Heart rate 105 bpm100
50
total exercise
recovery
00
0
5
10
25% exercise duration
15 minutes
Heart rate moderate exercise
200
bpm
150
100
50
total exercise
0
0
3.25
5
10
recovery
13
15
25% exercise duration
20 minutes
Heart rate moderate exercise
200
bpm
150
Heart rate 130 bpm
100
50
total exercise
0
0
3.25
5
10
recovery
13
15
25% exercise duration
20 minutes
Baseline characteristics
Lenient control Strict control
n= 311
n=303
Echocardiograpy (mm)
Left atrial size
LV end-diastolic size
LV end-systolic size
LV ejection fraction
46±6
51±7
36±8
52±11
46±7
51±8
36±9
52±12