1. 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
Mr chairmen ladies and gentlemen
It is my pleasure to present to you the results of the RACE II study, that is Rate control efficacy in permanent atrial fibrillation, a randomized comparison of lenient versus strict rate control concerning morbidity and mortality, carrying the acronym RACE II

2. 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
AFFIRM and RACE showed that 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, however, is still unknown
Wyse et al. New Engl J Med 2002
Van Gelder et al. New Engl J Med 2002

3. ACC/AHA/ESC 2006 Guidelines
Strict rate control
At rest:
During moderate exercise:
The present guidelines advocate a strict rate control approach with control of heart rate at rest between 60 and 80 and at moderate exercise between 90 and 115 beats per minute
However, these guidelines are not evidence based
Fuster et al. Guidelines J Am Coll Cardiol 2006

4. Strict rate control ? Contra Difficult to achieve
Adverse effects drugs
More frequent pacemaker implants
Higher costs
But even if strict rate control is the standard of care today,
It is difficult to achieve
There is a higher chance on adverse effects of rate control drugs
leading to more pacemaker implants
And associated with higher costs
Pro weglaten, beginnen met conThis slide shows the arguments pro and con strict rate control
wer strokes (en fewer bleeding) nog uitleggen via lower chads2score omdat minder hartfalen en ook vanwege fewer drugs and therefore less INR instability
irregular HR still present?? Is dat een verschil waar je op wil wijzen? M.a.w. waarom zou je strict doen als HF toch irregulr blijft? OK ….

5. Hypothesis
Lenient rate control is not inferior to strict rate control in patients with permanent AF in terms of cardiovascular morbidity and mortality
Therefore it was our hypothesis that Lenient rate control is not inferior to strict rate control in patients with permanent AF in terms of cardiovascular morbidity and mortality

6. RACE II trial
Prospective, randomized, open trial with blinded endpoint evaluation
Multicenter, noninferiority trial conducted in The Netherlands
2-3 years follow-up
The RACE II trial is
A prospective randomized open trial with blinded endpoint evaluation
is a multicenter noninferiority trial
With a follow of 2 to 3 years

7. Inclusion criteria Permanent AF ≤ 12 months
Resting heart rate > 80 bpm
On oral anticoagulation
Age ≤ 80 years
Inclusion criteria were
Permanent atrial fibrillation with a duration of a maximum of 12 months
A resting heart rate above 80 beats per minute
Patients had to be on oral anticoagulation
And have a maximal age of 80 years

8. 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
We excluded patients who satisfied any of these exclusion criteria:
Paroxysmal or transient atrial fibrillation
Known contra indications for either strict or lenient rate control, e.g.previous adverse effects on rate control drugs
Unstable heart failure
Cardiac surgery during the last 3 months
Previous stroke
Current or foreseen pacemaker, ICD or CRT therapy
Inability to walk or bike

9. Treatment Patients were randomized to Lenient rate control
Strict rate control
Patients were randomized to lenient or strict rate control

10. Permanent AF > 80 bpm lenient strict
Patients randomized to lenient rate control

11. Permanent AF > 80 bpm lenient strict HR < 110 bpm (12 lead ECG)
Were treated with rate control drugs aiming at a RESTING heart rate below 110 beats per minute

12. Permanent AF > 80 bpm lenient strict HR < 110 bpm (12 lead ECG)
Patients randomized to strict rate control

13. Permanent AF > 80 bpm lenient strict HR < 110 bpm (12 lead ECG)
and
HR < 110 bpm (at 25% duration of maximal exercise time)
Were treated with negative dromotropic drugs in order to achieve 2 targets:
a resting heart rate below 80 beats per minute, and
a heart rate during moderate exercise, which was defined as the heart rate at 25% duration of the maximal exercise time, below 110 beats per minute

14. Permanent AF > 80 bpm lenient strict HR < 110 bpm (12 lead ECG)
and
HR < 110 bpm (at 25% duration of maximal exercise time)
After achieving rate control target: Holter for safety
a Holter was performed for safety

15. 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.
To achieve the targets patients were treated with negative dromotropic drugs, being beta-blockers, non dihydropyidine calcium channel blockers and digoxin, alone or in combination
Dosages of drugs were increased or drugs combined until the heart rate target or targets in the strict control group were achieved

16. 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
Primary outcome was a composite of
Cardiovascular mortality
Hospitalization for heart failure necessitating start or dose increase of treatment with diuretics
And hence stroke, systemic emboli, major bleeding
Syncope, sustained ventricular arrhythmia and cardiac arrest
Life threatening adverse effects of rate control drugs
PM implantation for bradycardia and ICD implantation for ventricular arrhythmias, thus not if part of regular treatment

17. 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%.
The aim of the study was to show that lenient rate control is not inferior to strict rate control
Therefore the statistical approach was that of testing for noninferiority.
The noninferiority boundary was set at 10 percentage point absolute difference, comparable to the noninferiority boundary in the first RACE trial.
The null hypothesis of inferiority will be rejected when the upper limit of the 2-sided 90% confidence interval of the risk difference between lenient and strict rate control does not exceed 10%
The null hypothesis was that the risk of an endpoint event under lenient rate control minus the risk under strict rate control was larger than 10%. In that case lenient rate control would be inferior to strict rate control.
H0 en H1 H0 inferiority 0 hypothyss niet noemen
H1 inferiority
ndary of non inferiority is 10%
Aim of the study is to reject the nil hypothesis.
This means that the incidence of the primary endpoint in the rate control group must be <10% than the incidence on a primary endpoint in the rhythm control group.
* Comparable to the noninferiority boundary in the first RACE trial

18. 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) (6-64) months
Permanent AF 3 (1-6) (1-5) months
we included 614 patients.
The baseline profile was typical for an AF population
69 and 678 years of age, 66% males.
Duration of permanent AF was 3 and 2 months in the lenient and strict group, respectively

19. 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%
the underlying cardiac conditions were also typical as is shown here
Being predominantly hypertension but also coronary artery disease and valve disease.
In this population only a few had lone AF.
(There was one major imbalance
22% of the lenient and 15% of strict control patients had coronary artery disease.)

20. Baseline characteristics
Lenient control Strict control
n= 311 n=303
CHADS2 score 1.4± ±1.2
0-1 57% 64%
2 30% 22%
3-6 13% 14%
We included relatively low risk patients, mean CHADS2 score was 1.4.
The majority of patients had a score of zero or 1, 13% and 14% had a score of 3 or more.

21. Rate control targets at end of dose-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± ±1.4*
Median 0 2*
Interquartile range
At the end of the dose adjustment phase the rate control target was achieved in 98% of the patients randomized to lenient rate control versus 67% in the patients randomized to strict rate control.
Also the number of visits necessary to achieve the heart rate target was lower in the lenient group, 0.2 versus 2.3 visits.
* P<0.001

22. Rate control medication at end of dose-adjustment phase
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 the end of dose adjustment phase was used more intensive in the strict RC patients.
- 10% of the pts in the lenient group did not need any medication against 1% if the strict group.
69% needed a combination of 2 or 3 RC drugs versus 30% in the lenient group
and beta-blockers alone sufficed in 42% in the lenient pts versus 20% in the strict group.
30%
69%*
* P<0.01

23. 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 mg
At the end of dose adjustment phase the doses of the drugs used were higher in the strict control group.
160 against 120, 217 against 166 milligrams
* P<0.001

24. Heart rate during study
Lenient * *
Heart rate (beats per minute) * *
Strict
Achieved heart rates were substantially different between the treatment groups.
During the titration phase pts in the strict group went down from 96 to 75 bpm whereas in the lenient there was a reduction from 96 to 93 bpm. Thereafter the differences remained constant.
* P<0.001
months
No. At Risk
Lenient
Strict

25. Cumulative incidence primary outcome
Strict
14.9%
12.9%
Lenient
Cumulative Incidence (%)
This slide shows the KM curves in the strict and lenient group over 3 years of follow up.
The 2 Kaplan-Meijer curves were superimposible with a slight trend favoring lenient control
with a cumulative incidence of the primary outcome of 12.9% for the lenient and 14.9% for the strict group.
months
No. At Risk
Strict
Lenient

26. Primary outcome Lenient control Strict control
3-y incidence 12.9% %
Risk difference -2.0%
90%-CI (-7.6%, 3.5%)
Upper limit 10%
Inferiority hypothesis was rejected (p<0.001)
The difference between the lenient and strict group was minus 2.0 %
With a 90% confidence interval ranging from -7.6 to plus 3.5%
The upper limit was way below the boundary for nonferiority of 10%
Which means that the inferiority hypothesis was rejected, with a p value for noninferiority of less than 0.001
12.9 en 14.9 hier niet meer herhalen

27. 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%
this slide shows the distribution of morbidity and mortality over the various components of the primary endpoint
adds up to 16,8% and 20,3%
CV mortality was seen in 2.9% and 3.9% in lenient and strict group, respectively.
HF occurred in 3.8 and 4.1%, stroke in 1.6 and 3.9%, systemic embolism in 0.3% n the lenient group, and bleeding in 5.3 and 4.5%.
Adverse effects of rate control drugs in 1.1% versus 0.7% in the lenient and strict group, pacemakers in 0.8% in the lenient group versus 1.4% in the strict group. Syncope and ICD implantation were also low in both groups.
No double counts within lines
between lines double counts are possible
The individual components of the primary outcome were also not significantly different.

28. 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%
this slide shows the split of the primary outcome in terms of fatal and non fatal events.
Non fatal events occurred in 10% in the lenient group and in 11% in the strict group.
fatal cardiovascular events occurred in 2.9% in the lenient versus 3.9% in the strict group, 9 and 11 patients respectively.
Cardiovascular mortality was predominantly of noncardiac vascular origin, rather than due to lethal arrhythmias or heart failure

29. Primary outcome 3-y incidence Lenient control Strict control
All patients 12.9% %
CHADS2 < % 9.6%*
CHADS2 ≥ % 25.0%**
Inferiority hypothesis rejected for both subgroups (*p=0.02 and **p<0.001)
Subanalysis shows that the primary outcome event in patients with a CHADS 2 below 2 occurred in 12.4 in the lenient and 9.6% in the strict group.
In patients with a high CHADS 2 score, i.e. high risk patients the difference was more outspoken 13.6 versus 25%.
For both subgroups the inferior hypothesis could be rejected, indicating that lenient was noninferior to strict rate control in low and high risk patients

30. Symptoms baseline end of study % Symptoms Palpitations Fatigue Dyspnea
No differences were observed in symptoms associated with AF between both groups, at baseline and end of study.
At end of study the was a small decline in both group, predominantly due to a reduction of palpitations from 20 and 27% in the lenient and strict group at baseline to 11% and 10% at end of study
Palpitations
Fatigue
Dyspnea
Lenient Strict
Lenient Strict

31. 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

32. 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

33. 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
we thank all the investigators in The Netherlands that contributed patients to the study

34. Adjudication Committee
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
we also thank the DSMB, adjudication committee and finally we thank the people of the Trial Coordination Center in Groningen who took care of data collection and analysis the TCC

35. This article is now available on the
New England Journal of Medicine’s website, NEJM.org
Finally,
This article is now available on the NEJM’s website, NEJM.org
I thank you for your attention

37. Heart rate moderate exercise
150
bpm
100 50
Heart rate during moderate exercise was assessed by using this figure provided after the exercise test.
In this example, the patient exercised for a total of 8 minutes. At 25% of the total exercise duration, in this case 2 minutes
total exercise recovery 2 8
minutes
25% exercise duration

38. Heart rate moderate exercise
150
bpm
100
Heart rate 95 bpm 50
The heart rate was about 95 beats per minute, implying achievement of the exercise heart rate target in this patient. Thereafter, and in the strict group only
total exercise recovery 2 8
minutes
25% exercise duration

39. 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%
No differences were observed in symptoms associated with AF between both groups, at baseline and end of study.
At end of study the was a small decline in both group, predominantly due to a reduction of palpitations from 20 and 27% in the lenient and strict group at baseline to 11% and 10% at end of study

40. 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
Patients were seen every 2 weeks until the rate control target was achieved and after 1, 2 and 3 years of follow up.

41. Primary outcome according to HR at 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 (1/5) 11.7 (18/161)
Heart rate (16/112) 10.7 (4/39)
Heart rate (11/123) 5.6 (1/20)
Heart rate > (9/70) 46.4 (7/16)

42. Heart rate d at end of 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 (1/5) 11.7 (18/161)
Heart rate (16/112) 10.7 (4/39)
Heart rate (11/123) 5.6 (1/20)
Heart rate > (9/70) 46.4 (7/16)

43. total exercise recovery
25% exercise duration

44. 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
Pro weglaten, beginnen met conThis slide shows the arguments pro and con strict rate control
wer strokes (en fewer bleeding) nog uitleggen via lower chads2score omdat minder hartfalen en ook vanwege fewer drugs and therefore less INR instability
irregular HR still present?? Is dat een verschil waar je op wil wijzen? M.a.w. waarom zou je strict doen als HF toch irregulr blijft? OK ….

45. 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

46. 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

47. Severe adverse effects RC drugs
Digitalis intoxication
Conduction disturbances necessitating hospitalization

48. Cardiovascular death 3.9% 2.9% noncardiac vascular
tabel
2.9%
noncardiac vascular
% Endpoint
cardiac nonarrhythmic
cardiac arrhythmic
Lenient control
Strict control

49. Nonfatal and fatal endpoints
14.9%
12.9%
% Endpoint
nonfatal
fatal
Lenient control
Strict control

50. Nonfatal and fatal endpoints
CHADS2 < 2
CHADS2 ≥ 2
10.0%
% Endpoint
5.1%
4.5%
Ik zou chads > 2 rechts in fuguur zetten en chads2 , 2 links;
Getallen (%) in kolom centreren en niet tegen rand aanzetten
3.5%
nonfatal
fatal
Lenient Strict
Lenient Strict

51. Heart rate during study
Lenient
Heart rate (beats per minute) * * *
Strict
* P<0.001
months
No. At Risk
Lenient
Strict

52. 200
bpm
150
100 50
total exercise recovery
minutes
25% exercise duration

53. 200
bpm
150
Heart rate 105 bpm
100 50
total exercise recovery
minutes
25% exercise duration

54. Heart rate moderate exercise
200
bpm
150
100 50
Heart rate during moderate exercise was assessed looking at this figure provided immediately after an exercise test. In this example, the patient exercised for a total of 13 minutes. At the 25% of the total exercise duration, in this case 3.25 minutes
total exercise recovery
3.25 13
minutes
25% exercise duration

55. Heart rate moderate exercise
200
bpm
150
Heart rate 130 bpm
100 50
The heart rate was about 130 beats per minute, thus in this patient the heart rate target was not achieved, and dose adjustment of negative dromotropic drugs or addition of another drug was done and repeated until the heart rate target eventually was achieved
total exercise recovery
3.25 13
minutes
25% exercise duration

56. 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