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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.

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Presentation on theme: "RACE II RAte Control Efficacy in Permanent Atrial Fibrillation A Randomized Comparison of Lenient Rate Control versus Strict Rate Control Concerning Morbidity."— Presentation transcript:

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

2 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 2002 Van Gelder et al. New Engl J Med 2002

3 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

4 Strict rate control ? Contra Difficult to achieve Adverse effects drugs More frequent pacemaker implants Higher costs

5 Hypothesis 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

7 Inclusion criteria Permanent AF 12 months Resting heart rate > 80 bpm On oral anticoagulation Age 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

9 Patients were randomized to Lenient rate control Strict rate control Treatment

10 Permanent AF > 80 bpm lenientstrict

11 Permanent AF > 80 bpm lenientstrict HR < 110 bpm (12 lead ECG)

12 Permanent AF > 80 bpm lenientstrict HR < 110 bpm (12 lead ECG)

13 Permanent AF > 80 bpm lenientstrict HR < 110 bpm (12 lead ECG) HR < 80 bpm (12 lead ECG) and HR < 110 bpm (at 25% duration of maximal exercise time)

14 Permanent AF > 80 bpm lenientstrict 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

15 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

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

17 Noninferiority boundary is 10% absolute difference* Statistical hypotheses H o : R lenient - R strict > 10% (inferiority) H 1 : R lenient - R strict < 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

18 Baseline characteristics Lenient controlStrict control n= 311n=303 Age69±867±9 Male66%65% Duration AF Total duration16 (6-54) 20 (6-64) months Permanent AF3 (1-6) 2 (1-5) months

19 Baseline characteristics Lenient controlStrict control n= 311n=303 Hypertension64%58% CAD22%15% Valve disease21%20% COPD12%14% Diabetes mellitus12%11% Lone AF2%2%

20 Baseline characteristics Lenient controlStrict control n= 311n=303 CHADS 2 score 1.4±1.01.4±1.2 0-157%64% 230%22% 3-613%14%

21 Rate control targets at end of dose-adjustment phase Lenient controlStrict control n= 311n=303 Rate control target98%67%* Resting target98%75% Exercise target-73% Visits to achieve target0.2±0.62.3±1.4* Median02* Interquartile range0-01-3 * P<0.001

22 Lenient controlStrict control n= 311n=303 None10%1%* Beta-blocker alone42%20%* Calcium blocker alone6%5% Digoxin alone7%2%* Beta-blocker + calciumblocker4%13%* Beta-blocker + digoxin19%37%* Calciumblocker + digoxin6%10% Beta + calciumblocker + digoxin1%9%* Rate control medication at end of dose-adjustment phase * P<0.01 30% 69%*

23 Lenient controlStrict control n= 311n=303 Beta-blocker (normalized to metoprolol-equivalent doses)120±78162±85 mg* Verapamil166±60217±97 mg* Digoxin0.19±0.80.21±0.8 mg Rate control doses at end of dose-adjustment phase * P<0.001

24 Heart rate during study * * P<0.001 * * * No. At Risk Lenient 311 311 302 291 237 Strict 303 303 284 277 240 Lenient Strict months Heart rate (beats per minute)

25 No. At Risk Strict303 282 273 262 246 212 131 Lenient311 298 290 285 255 218 138 Lenient Strict Cumulative Incidence (%) 14.9% 12.9% months Cumulative incidence primary outcome

26 Lenient controlStrict control 3-y incidence12.9% 14.9% Risk difference-2.0% 90%-CI(-7.6%, 3.5%) Upper limit10% Inferiority hypothesis was rejected (p<0.001) Primary outcome

27 Components of primary outcome Lenient controlStrict control n= 311n=303 Primary outcome12.9%14.9% CV mortality2.9%3.9% Heart failure3.8%4.1% Stroke1.6%3.9% Emboli0.3%0% Bleeding5.3%4.5% Adverse effects RC drugs1.1%0.7% Pacemaker0.8%1.4% Syncope1.0%1.0% ICD0%0.4%

28 Components of primary outcome Lenient controlStrict control n= 311n=303 Primary outcome12.9%14.9% Nonfatal10.0%11.0% Fatal2.9%3.9% Cardiac arrhythmic1.0%1.4% Cardiac nonarrhythmic0.3%0.8% Noncardiac vascular1.7%1.9%

29 3-y incidenceLenient controlStrict control All patients12.9% 14.9% CHADS 2 < 212.4%9.6%* CHADS 2 213.6%25.0%** Inferiority hypothesis rejected for both subgroups (*p=0.02 and **p<0.001) Primary outcome

30 Symptoms Lenient Strict % Symptoms Palpitations Fatigue Dyspnea baseline end of study

31 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

32 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

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

34 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

35 This article is now available on the New England Journal of Medicines website, NEJM.org

36

37 0 5 10 15 minutes 25% exercise duration total exercise recovery 150 100 bpm Heart rate moderate exercise 50 0 2 8

38 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

39 Symptoms Lenient controlStrict control At baseline56%58% Palpitations20%27% Dyspnea34%37% Fatigue28%32% At end of study46%46% Palpitations11%10% Dyspnea30%30% Fatigue24%23%

40 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

41 Primary outcome according to HR at end dose adjustment phase Lenient controlStrict control % (events/total pts) Total group12.9 (38/311)14.9 (43/303) Heart rate < 70- (1/1)20.4 (13/67) Heart rate 70-8020.0 (1/5)11.7 (18/161) Heart rate 81-9015.0 (16/112)10.7 (4/39) Heart rate 91-1009.1 (11/123)5.6 (1/20) Heart rate > 10014.1(9/70)46.4 (7/16)

42 Lenient controlStrict control % (events/total pts) Total group12.9 (38/311)14.9 (43/303) Heart rate < 70- (1/1)20.4 (13/67) Heart rate 70-8020.0 (1/5)11.7 (18/161) Heart rate 81-9015.0 (16/112)10.7 (4/39) Heart rate 91-1009.1 (11/123)5.6 (1/20) Heart rate > 10014.1(9/70)46.4 (7/16) Heart rate d at end of dose adjustment phase

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

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

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

50 Nonfatal and fatal endpoints 5.1% Lenient Strict nonfatal fatal CHADS 2 2 CHADS 2 < 2 10.0% 4.5% 3.5% % Endpoint

51 * * P<0.001 * * months Lenient Strict No. At Risk Lenient 311302 291 237 Strict 303284 277 240 Heart rate (beats per minute) Heart rate during study

52 total exercise recovery 0 5 10 15 minutes 25% exercise duration 0 0 200 150 100 50 bpm

53 total exercise recovery 0 5 10 15 minutes 25% exercise duration 0 0 200 150 100 50 bpm Heart rate 105 bpm

54 0 5 10 15 20 minutes 25% exercise duration total exercise recovery 200 150 100 50 0 bpm Heart rate moderate exercise 13 3.25

55 0 5 10 15 20 minutes 25% exercise duration 200 150 100 50 Heart rate 130 bpm 0 bpm Heart rate moderate exercise 13 3.25 total exercise recovery

56 Baseline characteristics Lenient controlStrict control n= 311n=303 Echocardiograpy (mm) Left atrial size 46±646±7 LV end-diastolic size 51±751±8 LV end-systolic size 36±836±9 LV ejection fraction 52±1152±12


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