Lenient versus Strict Rate Control in Patients with Atrial Fibrillation

(NEJM April 15, 2010 )

Piti Niyomsirivanich ,MD.

• Atrial Fibrillation is NOT a benign condition– Stroke– Heart failure

Treatment

• Rate Control• Rhythm Control

RACE trialRAte Control versus Electrical cardioversion for persistent atrial fibrillation study group

A Comparison of Rate Control and Rhythm Control in Patients with Recurrent Persistent Atrial FibrillationNEJM Volume 347:1834-1840 December 5, 2002

AFFIRM TrialAtrial Fibrillation Follow-up Investigation of Rhythm Management

Cumulative Mortality from Any Cause in the Rhythm-Control Group and the Rate-Control Group.

A Comparison of Rate Control and Rhythm Control in Patients with Atrial Fibrillation

NEJM Volume 347:1825-1833 December 5, 2002

Rate Control has become front-line therapy

• BUT….

– The level of heart rate control is remain UNKNOWN

Strict rate control VS Lenient ???

Criteria for rate control vary with patient age but usually involve achieving ventricular rates between 60 and 80 beats per minute at rest and between 90 and 115 beats per minute during moderate exercise.

Rate Control• Guidelines (No Evidence-based)

– Suggest…Strict rate control – 60 and 80 beats per minute at rest– between 90 and 115 beats per minute during moderate

exercise.• Reduce symptom• Improve QOL & Exercise tolerance• Reduce heart failure• Improve survival

– Harm ??• Drug-relate adverse effect

– Bradycardia , Need for pacemaker implantation

To determine

• Hypothesis

Whether Lenient rate control is not inferior to strict rate control.

RACE II

• The RAte Control Efficacy in Permanent Atrial Fibrillation: a Comparison between Lenient versus Strict Rate Control II

• A Prospective, multicenter, randomized, open-label, noninferiority trial

Participation

• Interuniversity Cardiology Institute of the Netherlands• University Medical Center Groningen• Working Group on Cardiovascular Research of the

Netherlands

• Founded by Natherlands Heart Foundation– Unrestricted educational grants from pharmaceutical and

device companies

– None were involved in the study design, data collection, data analysis manuscript preparation

Methods33 Centers in the Netherlands

Jan 2005 - June 2007

Eligibility criteriaAF up to 12 months

Age <80Resting rate > 80

Current use of anticoagulant therapy or aspirin

Randomization And Treatment

• Informed consent

• Randomization– accomplished by means of a central telephone

system with use of permuted blocks of various size

• Dose Adjustment phase– Pts. Were administered [alone or combination]

• Beta-blocker , non-dihydropyridine CCB , digoxin • Until the heart –rate target were achieved

Randomization And Treatment

Lenient ControlVentricular rate <110 bpm

(Resting)

Strict ControlVentricular rate <80 bpm

(Resting)

(Determine by ECG after 2-3 min of rest in supine position)

• Follow-up outpatient visits occurred every 2 wks until the ventricular rate targets were archived

• During follow-up period– Resting ventricular rate was assessed by attending

physician at each visit– If heart rate target could not be achieved

• The study protocol permitted further adjustment of rate control drugs.

Randomization And Treatment

Primary outcomeme

•Death from cardiovascular causes•Hospitalization for heart failure•Stroke •Systemic embolism•Major bleeding•Arrhythmic events (syncope,VT,cardiac arrest)•Implantation of Pacemaker/Cardioverter

Death from any causeSymptoms

Functional Status

secondary outcome

Statistical analysis

Non inferiority trial

Study size was determined by expected rate of primary outcome 25% at 2.5 yrs(based on the observed events rate in the rate control group of RACE trial)

A sample size of 250 patients with a median follow up of 2.5 years satisfied the statistical requirements

Statistical analysis

• Primary analysis : Kaplan-Meier curves

614 patients enrolled33 Centers in the Netherlands

Jan 2005 - June 2007

Lenient control311

Strict control303

Randomization

Randomization and Follow-up of the Study Patients.

Heart rates

• Resting Ventricular Rate– lenient control group 93+-9 beats per min– Strict control group 76+-12 beats per min

Nine patients of both group were in sinus rhythm at the end of follow up

Rate Control Targets and Drug Therapy at the End of the Dose-Adjustment Phase

Primary outcome

Hazard ratio 0.84

95%CI 0.58 to 1.21

Lenient Control is NONINFERIOR to Strict Control

Secondary Outcome

Lenient Control Strict ControlDeath from any cause

17 (5.6%) 18 (6.6%)

Death from CVS 8 7Symptom associate with AFDyspnea 30% 29.6%Fatigue 24.4% 22.6%palpitation 10.6% 9.5%

Secondary OutcomeNYHA classification

Lenient Control Strict ControlClass I 70.0% 70.4%

Class II 23.3% 23.4%Class III 6.7% 6.2%

Class IV 0 % 0 %

Subgroup Analysis (CHADS2 score =2 or more)

Lenient Control Strict ControlPrimary outcome 17/133 25/108

Subgroup Analysis (CHADS2 score <2)

Lenient Control Strict ControlPrimary outcome 21/178 18/195

Criticized Paper

Is the study VALID ?

• Was the assignment of patients to treatment randomized?– Yes , the assignment of patients was randomized.

• Was the randomization concealed– The randomization accomplished by means of a

central telephone system with use of permuted blocks of various size.

Is the study VALID ?

• Were the groups similar at the start of the trial ?– The groups were similar except

• In the lenient rate control group has more patients with cardiovascular disease than strict rate control (67 vs 44)

– AND

• In the lenient rate control group has more usage of statin than strict rate control 103 vs 74

Is the study VALID ?

• Was the follow up complete?– Yes ,Study size was determined by expected rate of

primary outcome 25% at 2.5 yrs(based on the observed events rate in the rate control group of RACE trial)

Is the study VALID ?

• Were patients, their clinicians, and study personel “blind” to treatment ?– The patients were not blind to treatment

medication.– Their clinicians were not blinded.

• Were they analysed in the groups to which they were randomised- Intention to treat analysis

Is the study VALID ?

• Aside from the experimental treatment, were the groups treated equally?

– The other medications of both group were slightly different.

• Patients in lenient control group receive ARB/ACEI (166 VS 140) and Statins (103 VS 74) more than patient in strict control group slightly.

What were the results• How large was treatment effect?

– Primary outcome• Death from cardiovascular cause• Hospitalization due to heart failure• Stroke• Systemic embolism• Major bleeding• Arrhythmic Events• Life threatening adverse effects of rate control drugs• Implantation of a pacemaker or cardioverter-defibrillator

– Hazard ratio of Lenient control compare with Strict control is 0.84 (95% CI 0.58 to 1.21)

Can the results be applied to our patient care ?

• Is our patient so different from those in the study ?– Not so different , the pathophysiology are similar.

• Is the treatment feasible in our setting ?– Yes , the treatment is feasible in our setting.

Thank you