Van Gelder Race

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


lenient strict

HR < 110 bpm(12 lead ECG)


lenient strict



lenient strict


HR < 80 bpm (12 lead ECG)and

HR < 110 bpm (at 25% duration of maximal exercise time)


lenient 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

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


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%



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


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


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%*


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


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


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


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


150

100

bpm


50

0

Heart rate 95 bpm

2 8

Symptoms


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


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)


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


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


0 5 10 15 minutes


0 0

200

150

100

50

bpm


0 5 10 15 minutes


0 0

200

150

100

50

bpm

Heart rate 105 bpm

0 5 10 15 20 minutes



200

150

100

50

0

bpm


133.25

0 5 10 15 20 minutes


200

150

100

50

Heart rate 130 bpm

0

bpm


133.25




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

Documents

Van Gelder Race