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
Rates of complications and death were similar in patients treated with rate-control and rhythm-control 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
AFFIRM, RACE
Wyse et al. New Engl J Med 2002Van 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
Patients were randomized to
Lenient rate control
Strict rate control
Treatment
Permanent AF > 80 bpm
lenient strict
Permanent AF > 80 bpm
lenient strict
HR < 110 bpm(12 lead ECG)
Permanent AF > 80 bpm
lenient strict
HR < 110 bpm(12 lead ECG)
Permanent AF > 80 bpm
lenient strict
HR < 110 bpm(12 lead ECG)
HR < 80 bpm (12 lead ECG)and
HR < 110 bpm (at 25% duration of maximal exercise time)
Permanent AF > 80 bpm
lenient strict
HR < 110 bpm(12 lead ECG)
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
Patients were treated with negative
dromotropic drugs (i.e. beta-blockers, non-
dihydropyridine 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.
Treatment
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
Noninferiority boundary is 10% absolute difference*
Statistical hypothesesHo: 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%.
Statistical analysis
* Comparable to the noninferiority boundary in the first RACE trial
Baseline characteristics
Lenient control Strict
control
n= 311 n=303
Age 69±8 67±9
Male 66% 65%
Duration AF
Total duration 16 (6-54) 20 (6-64)
months
Permanent AF 3 (1-6) 2 (1-5)
months
Baseline characteristics
Lenient control Strict control
n= 311 n=303
Hypertension 64% 58%
CAD 22% 15%Valve disease 21% 20%COPD 12% 14%Diabetes mellitus 12% 11%Lone AF 2% 2%
Baseline characteristics
Lenient control Strict
control
n= 311 n=303
CHADS2 score 1.4±1.0 1.4±1.2
0-1 57% 64%
2 30% 22%
3-6 13% 14%
Rate control targets at end ofdose-adjustment phase
Lenient control Strict control
n= 311 n=303
Rate control target 98% 67%* Resting target 98% 75% Exercise target - 73%
Visits to achieve target 0.2±0.6 2.3±1.4* Median 0 2* Interquartile range 0-0 1-3
* P<0.001
Lenient control Strict control
n= 311 n=303
None 10% 1%*
Beta-blocker alone 42% 20%*
Calcium blocker alone 6% 5%
Digoxin alone 7% 2%*
Beta-blocker + calciumblocker 4% 13%*
Beta-blocker + digoxin 19% 37%*
Calciumblocker + digoxin 6% 10%
Beta + calciumblocker + digoxin 1% 9%*
Rate control medication at end ofdose-adjustment phase
* P<0.01
30% 69%*
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
Rate control doses at end ofdose-adjustment phase
* P<0.001
0 3 12 24 3650
60
70
80
90
100
110
*
**
*
Heart rate during study
*
* P<0.001
* *
*
No. At RiskLenient 311 311 302 291 237Strict 303 303 284 277 240
Lenient
Strict
months
Hea
rt r
ate
(bea
ts p
er m
inut
e)
0
5
10
15
20
0 6 12 18 24 30 36
No. At RiskStrict 303 282 273 262 246 212 131Lenient 311 298 290 285 255 218 138
Lenient
StrictC
umul
ativ
e In
cide
nce
(%)
14.9%
12.9%
months
Cumulative incidence primary outcome
Lenient control Strict control
3-y incidence 12.9% 14.9%
Risk difference -2.0%90%-CI (-7.6%, 3.5%)
Upper limit 10%
Inferiority hypothesis was rejected (p<0.001)
Primary outcome
Components of primary outcome
Lenient control Strict control
n= 311 n=303
Primary outcome 12.9% 14.9%
CV mortality 2.9% 3.9%Heart failure 3.8% 4.1%Stroke 1.6% 3.9%Emboli 0.3% 0%Bleeding 5.3% 4.5%Adverse effects RC drugs 1.1% 0.7%Pacemaker 0.8% 1.4%Syncope 1.0% 1.0%ICD 0% 0.4%
Components of primary outcome
Lenient control Strict control
n= 311 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%
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)
Primary outcome
Symptoms
0
20
40
60
80
100
120
palpitations
fatigue
dyspnea
Lenient Strict Lenient Strict
% S
ymp
tom
s
PalpitationsFatigueDyspnea
baseline
end of study
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
Conclusions
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
Clinical implications
Van Gelder,Groenveld,Van Veldhuisen, Van den Berg University Medical Center Groningen
Janssen, Tukkie Kennemer Hospital HaarlemBendermacher, Olthof Elkerliek Hospital HelmondRobles de Medina Hospital Leyenburg The HagueKuijer, Zwart Hospital Bernhoven OssCrijns Maastricht University Medical CenterAlings Amphia Hospital BredaPost Hospital HengeloPeters, Van Stralen, Buys Hospital Gooi Noord BlaricumDaniëls Jeroen Bosch Hospital Den BoschTimmermans Medical Spectrum Twente EnschedeKuijper, Van Doorn Spaarne Hospital HoofddorpHoogslag Diaconessen Hospital MeppelDen Hartog Hospital Gelderse Vallei EdeVan Rugge Diaconessen Hospital LeidenDerksen, Bosker Rijnstate Hospital ArnhemHamraoui Tweesteden Hospital TilburgDe Milliano Hospital HilversumKamp VU Medical Center AmsterdamKragten Atrium Medical Center HeerlenLinssen Twenteborg Hospital AlmeloTuininga, Badings Deventer Hospital DeventerNierop St. Franciscus Hospital RotterdamGratama VieCurie Hospital VenloNio, Muys, Van den Berg IJsselland Hospital, Capelle aan de
IJsselThijssen Maxima Medical Center VeldhovenVan Dijkman Bronovo Hospital The HagueCornel Medical Center AlkmaarVan der Galiën St.Lucas Hospital WinschotenBoersma St.Antonius ospital NieuwegeinBronzwaer Zaans Medical Center De Heel
ZaandamSpanjaard Delfzicht Hospital DelfzijlBartels Martini Hospital Groningen
Steering CommitteeIsabelle C Van GelderHarry JGM CrijnsJan GP TijssenHans L HillegeYpe S TuiningaA Marco AlingsHans A BoskerJan H CornelOtto KampDirk J Van VeldhuisenMaarten P Van den Berg
Thesis ofHessel F Groenveld
Data Safety and Monitoring BoardHein J WellensRichard N HauerArthur A Wilde
Adjudication CommitteeJan Van der Meer†
Gert J LuijckxJohan Brügemann
Trial Coordination CenterHans L HillegeJanneke A BergsmaMarco AssmannOlga Eriks-De VriesMyke Mol
This article is now available on the
New England Journal of Medicine’s
website, NEJM.org
0 5 10 15 minutes 25% exercise duration
total exercise recovery
150
100
bpm
Heart rate moderate exercise
50
02 8
0 5 10 15 minutes 25% exercise duration
total exercise recovery
150
100
bpm
Heart rate moderate exercise
50
0
Heart rate 95 bpm
2 8
Symptoms
Lenient control Strict control
At baseline 56% 58%Palpitations 20% 27%Dyspnea 34% 37%Fatigue 28% 32%
At end of study 46% 46%Palpitations 11% 10%Dyspnea 30% 30%Fatigue 24% 23%
Patients were seen
Every 2 weeks until the rate control target
was achieved
After 1, 2 and 3 years of follow-up
Follow up visits
Primary outcome according to HRat end dose adjustment phase
Lenient control Strict
control
% (events/total pts)
Total group 12.9 (38/311) 14.9 (43/303)
Heart rate < 70 - (1/1) 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)
Lenient control Strict
control
% (events/total pts)
Total group 12.9 (38/311) 14.9 (43/303)
Heart rate < 70 - (1/1) 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 ofdose adjustment phase
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
0
1
2
3
4
non cardiacvascular
cardiac nonarrhythmic
carciacarrhythmic
2.9%
3.9%
Lenient control
noncardiac vascularcardiac nonarrhythmiccardiac arrhythmic
Strict control
% E
nd
po
int
Cardiovascular death
tabel
Nonfatal and fatal endpoints
0
5
10
15
nonfatal
fatal
12.9%
14.9%
fatal
nonfatal
Strict controlLenient control
% E
nd
po
int
Nonfatal and fatal endpoints
0
2
4
6
8
10
12
nonfatal
fatal
5.1%
Lenient Strict Lenient Strict
nonfatalfatal
CHADS2 ≥ 2CHADS2 < 210.0%
4.5%
3.5%
% E
nd
po
int
0 12 24 3650
60
70
80
90
100
110
**
**
* P<0.001
* *
months
Lenient
Strict
No. At RiskLenient 311 302 291 237Strict 303 284 277 240
He
art
ra
te (
be
ats
pe
r m
inu
te)
Heart rate during study
total exercise recovery
0 5 10 15 minutes
25% exercise duration
0 0
200
150
100
50
bpm
total exercise recovery
0 5 10 15 minutes
25% exercise duration
0 0
200
150
100
50
bpm
Heart rate 105 bpm
0 5 10 15 20 minutes
25% exercise duration
total exercise recovery
200
150
100
50
0
bpm
Heart rate moderate exercise
133.25
0 5 10 15 20 minutes
25% exercise duration
200
150
100
50
Heart rate 130 bpm
0
bpm
Heart rate moderate exercise
133.25
total exercise recovery
Baseline characteristics
Lenient control Strict
control
n= 311 n=303
Echocardiograpy (mm)
Left atrial size 46±6 46±7
LV end-diastolic size 51±7 51±8
LV end-systolic size 36±8 36±9
LV ejection fraction 52±11 52±12
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