Dia 1

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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
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AFFIRM, RACE

• 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

Wyse et al. New Engl J Med 2002 Van Gelder et al.
New Engl J Med 2002
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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
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Strict rate control ?

• Contra
• Difficult to achieve
• Adverse effects drugs
• More frequent pacemaker implants
• Higher costs

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Hypothesis
Lenient rate control is not inferior to strict
rate control in patients with permanent AF in
terms of cardiovascular morbidity and mortality
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RACE II trial

• Prospective, randomized, open trial with blinded
  endpoint evaluation
• Multicenter, noninferiority trial conducted in
  The Netherlands
• 2-3 years follow-up

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Inclusion criteria

• Permanent AF 12 months
• Resting heart rate gt 80 bpm
• On oral anticoagulation
• Age 80 years

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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 lt 3 months
• Stroke
• Current or foreseen PM/ ICD/ CRT
• Inability to walk or bike

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Treatment

• Patients were randomized to
• Lenient rate control
• Strict rate control

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Permanent AF gt 80 bpm lenient strict
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Permanent AF gt 80 bpm lenient strict
HR lt 110 bpm (12 lead ECG)
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Permanent AF gt 80 bpm lenient strict
HR lt 110 bpm (12 lead ECG)
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Permanent AF gt 80 bpm lenient strict
HR lt 110 bpm (12 lead ECG)
HR lt 80 bpm (12 lead ECG) and HR lt 110 bpm (at
25 duration of maximal exercise time)
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Permanent AF gt 80 bpm lenient strict
HR lt 110 bpm (12 lead ECG)
HR lt 80 bpm (12 lead ECG) and HR lt 110 bpm (at
25 duration of maximal exercise time) After
achieving rate control target Holter for safety
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Treatment

• 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.

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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

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Statistical analysis
Noninferiority boundary is 10 absolute
difference Statistical hypotheses Ho Rlenient
- Rstrict gt 10 (inferiority) H1 Rlenient -
Rstrict lt 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
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Baseline characteristics
Lenient control Strict control n
311 n303 Age 698 679 Male 66 65 Dura
tion AF Total duration 16 (6-54) 20
(6-64) months Permanent AF 3 (1-6) 2
(1-5) months
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Baseline characteristics
Lenient control Strict control n
311 n303 Hypertension 64 58 CAD 22 15
Valve disease 21 20 COPD 12 14 Diabetes
mellitus 12 11 Lone AF 2 2
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Baseline characteristics
Lenient control Strict control n
311 n303 CHADS2 score 1.41.0 1.41.2
0-1 57 64 2 30 22 3-6 13 14
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Rate control targets at end ofdose-adjustment
phase
Lenient control Strict control n
311 n303 Rate control target 98 67
Resting target 98 75 Exercise
target - 73 Visits to achieve
target 0.20.6 2.31.4 Median 0 2
Interquartile range 0-0 1-3
Plt0.001
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Rate control medication at end ofdose-adjustment
phase
Lenient control Strict control n
311 n303 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
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69
Plt0.01
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Rate control doses at end ofdose-adjustment phase
Lenient control Strict control n
311 n303 Beta-blocker (normalized to
metoprolol-equivalent doses) 12078 16285
mg Verapamil 16660 21797 mg Digoxin 0.19
0.8 0.210.8 mg
Plt0.001
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Heart rate during study
Lenient



Heart rate (beats per minute)

Strict
Plt0.001
months
No. At Risk Lenient 311 311 302
291 237 Strict 303 303
284 277 240
25
Cumulative incidence primary outcome
Strict
14.9
12.9
Lenient
Cumulative Incidence ()
months
No. At Risk Strict 303 282 273
262 246 212 131 Lenient 311
298 290 285 255 218
138
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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 (plt0.001)
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Components of primary outcome
Lenient control Strict control n
311 n303 Primary outcome 12.9 14.9 CV
mortality 2.9 3.9 Heart failure 3.8 4.1 Stro
ke 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
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Components of primary outcome
Lenient control Strict control n
311 n303 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
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Primary outcome
3-y incidence Lenient control Strict
control All patients 12.9 14.9 CHADS2 lt
2 12.4 9.6 CHADS2 2 13.6 25.0 Inferi
ority hypothesis rejected for both subgroups
(p0.02 and plt0.001)
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Symptoms
baseline
end of study
Symptoms
Palpitations Fatigue Dyspnea
Lenient Strict
Lenient Strict
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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

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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

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Van Gelder,Groenveld,Van Veldhuisen, Van
den Berg University Medical Center
Groningen Janssen, Tukkie Kennemer
Hospital Haarlem Bendermacher, Olthof
Elkerliek Hospital Helmond Robles de Medina
Hospital Leyenburg The Hague Kuijer,
Zwart Hospital Bernhoven
Oss Crijns Maastricht University
Medical Center Alings Amphia Hospital
Breda Post Hospital Hengelo Peters,
Van Stralen, Buys Hospital Gooi Noord
Blaricum Daniëls Jeroen Bosch
Hospital Den Bosch Timmermans Medical
Spectrum Twente Enschede Kuijper, Van Doorn
Spaarne Hospital Hoofddorp Hoogslag
Diaconessen Hospital Meppel Den Hartog
Hospital Gelderse Vallei Ede Van Rugge
Diaconessen Hospital Leiden Derksen,
Bosker Rijnstate Hospital
Arnhem Hamraoui Tweesteden Hospital
Tilburg De Milliano Hospital
Hilversum Kamp VU Medical Center
Amsterdam Kragten Atrium Medical
Center Heerlen Linssen Twenteborg
Hospital Almelo Tuininga, Badings
Deventer Hospital Deventer Nierop St.
Franciscus Hospital Rotterdam Gratama
VieCurie Hospital Venlo Nio, Muys, Van den
Berg IJsselland Hospital, Capelle aan de
IJssel Thijssen Maxima Medical Center
Veldhoven Van Dijkman Bronovo Hospital
The Hague Cornel Medical Center
Alkmaar Van der Galiën St.Lucas
Hospital Winschoten Boersma
St.Antonius ospital Nieuwegein Bronzwaer
Zaans Medical Center De Heel Zaandam Spanjaard
Delfzicht Hospital Delfzijl Bartels
Martini Hospital Groningen
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Data Safety and Monitoring Board Hein J
Wellens Richard N Hauer Arthur A Wilde

• 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

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
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This article is now available on the New England
Journal of Medicines website, NEJM.org
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(No Transcript)
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Heart rate moderate exercise
150
bpm
100
50
total exercise recovery
0
2
8
0 5 10 15 minutes
25 exercise duration
38
Heart rate moderate exercise
150
bpm
100
Heart rate 95 bpm
50
total exercise recovery
0
2
8
0 5 10 15 minutes
25 exercise duration
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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 3
0 Fatigue 24 23
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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

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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 lt
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 gt
100 14.1(9/70) 46.4 (7/16)
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Heart rate d at end ofdose adjustment phase
Lenient control Strict control
(events/total pts) Total
group 12.9 (38/311) 14.9 (43/303) Heart rate lt
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 gt
100 14.1(9/70) 46.4 (7/16)
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total exercise recovery
25 exercise duration
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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

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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

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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

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Severe adverse effects RC drugs

• Digitalis intoxication
• Conduction disturbances necessitating
  hospitalization

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Cardiovascular death
3.9
tabel
2.9
noncardiac vascular
Endpoint
cardiac nonarrhythmic
cardiac arrhythmic
Lenient control
Strict control
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Nonfatal and fatal endpoints
14.9
12.9
Endpoint
nonfatal
fatal
Lenient control
Strict control
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Nonfatal and fatal endpoints
CHADS2 lt 2
CHADS2 2
10.0
Endpoint
5.1
4.5
3.5
nonfatal
fatal
Lenient Strict
Lenient Strict
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Heart rate during study
Lenient
Heart rate (beats per minute)



Strict
Plt0.001
months
No. At Risk Lenient 311 302 291
237 Strict 303 284 277
240
52
200
bpm
150
100
50
total exercise recovery
0
0
0 5 10 15 minutes 25
exercise duration
53
200
bpm
150
Heart rate 105 bpm
100
50
total exercise recovery
0
0
0 5 10 15 minutes 25
exercise duration
54
Heart rate moderate exercise
200
bpm
150
100
50
0
total exercise recovery
13
3.25
0 5 10 15 20
minutes 25 exercise duration
55
Heart rate moderate exercise
200
bpm
150
Heart rate 130 bpm
100
50
0
total exercise recovery
13
3.25
0 5 10 15 20
minutes 25 exercise duration
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Baseline characteristics
Lenient control Strict control n
311 n303 Echocardiograpy (mm) Left
atrial size 466 467 LV end-diastolic
size 517 518 LV end-systolic size
368 369 LV ejection fraction 5211 5212