Van Gelder IC et al Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med. 2010 Apr 15;362(15):1363-73. The RACE II Study

Article: http://content.nejm.org/cgi/content/abstract/362/15/1363

Editorial: http://content.nejm.org/cgi/content/extract/362/15/1439

 

Evidence from several RCTs (on an intention to treat basis) have now demonstrated that restoring and maintaining sinus rhythm (rhythm strategy) is not superior (in terms of stroke, death and bleeding rates) to the alternative of accepting the rhythm and controlling the ventricular rate (rate control strategy) in the management of patients with Atrial Fibrillation.

Clearly there is still a role for a rhythm strategy in selected patients and in more symptomatic or younger patients and those with favourable echo parameters (non-dilated LA etc) are all worthy of a serious consideration of a rhythm control strategy. With respect to the rate control strategy the optimal level of HR control is not clearly defined but it is widely held that lower is better which is nicely discussed in the accompanying editorial. The joint ACC/AHA/ESC guidelines (revised 2006) on AF stipulate that HR of <80bpm at rest and <110 on exercise should be aimed for. However whether the benefits of intensive rate control outweigh the potential adverse effects associated with achieving this remains unclear. Thus the RACE II study was undertaken to address this issue.

The RACE II study asked the question whether a lenient strategy (resting HR<110) was as effective (i.e. non inferior) to strict HR control strategy (rest< 80 and exercise <110) in AF.

It was a prospective, multicentre (33 centres) national (Netherlands) study that randomly assigned 614 patients (n=311 Lenient, n=303 strict) with permanent AF either strategy in an open label fashion. FU was for 3 years

Primary (adjudicated by independent committee blind to Rx) : Composite of CV death, hospitalisation for HF, stroke, major bleeding, arrhythmic events, VT, syncope, cardiac arrest, life threatening adverse events of rate control drugs, implantation of PPM or ICD

Secondary: death any cause, symptoms and functional status

Patients <80 years with permanent AF (all <12 months but median 3mo vs. 2mo) with 72% received previous attempt at electrical cardioversion. Overall mean age 68(8) years and 65% male. Overall prevalence of hypertension (61%), diabetes (11%) HF hospitalisation (10%) lone AF (<2%). Patients with previous stroke excluded so the majority of patients in either group were classified as low-mod stroke risk (CHADS2 score 0-1) 57% vs. 64% but over 98% patients/gp were prescribed vitamin K antagonist. Symptoms (palpitations, fatigue and dyspnoea) were present in 56 vs. 58% at baseline. 66% patients were classified as NYHA I and 5% NYHA III. Baseline HR (ECG) was 96bpm and equal in groups.

Echo parameters between groups balanced. LA size 46mm with 45v 48% patients having LVEF<45%.

10% of group were not taking any rate control agent at baseline with 45% beta-blocker, 7% digoxin and 3% CCB, 1% amiodarone, 5% sotalol on monotherapies. 17% were on combined BB/Dig. Interestingly 1% were on the triple combo of BB/Dig and verapamil or diltaizem!

 

Overall groups were well balanced but with lenient group having higher prevalence of CAD and statin use. No statistics were reported for baseline parameters between 2 groups.

 

Patients in each group were administered one or more negative chronotropic drugs, listed above used alone or in combination during the dose adjustment phase. 2 weekly FU was done until HR targets for each group were achieved. Every patient had yearly FU thereafter. Holter monitoring was also used to verify and look for arrhythmias. Exercise HR was determined during moderate exercise performed on bicycle testing.

Results: Heart rates achieved/ primary outcomes?                                        

                                                                                                               

 

At study end more patients in the lenient group achieved HR targets (304, 98% vs. 203, 67%). A combination of AV nodal blockers was required in 30% vs 69%.In the strict control group the reason the target was not achieved was due to drug related adverse events in 25% or the target was impossible to achieve with drugs available (22%).

 

No differences in Hazard Ratios were seen for each of the component of the pre-specified primary endpoints except in stroke rates. The lenient rate control strategy fulfilled the prespecified criteria of non inferiority compared to the strict rate control group. Furthermore the lenient group had fewer hospital visits to titrate drugs. No significant differences were seen for the primary outcome when sub grouped for CHADS score. In post-hoc analyses when the incidence of the primary outcome was stratified based on HR achieved after dose adjustment phase the lowest event rate was seen in the HR 91-100bpm (8.6%) in both groups, compared to <70bpm (13.9%) or >100 bpm (19.9%). No significant differences were seen in secondary endpoints.

 

Patients tended to be somewhat younger (mean 68) with only 1/3 women (who are more symptomatic) and excluded patients with previous stroke (reported rationale of physically active patients) thus the overall population had a lower risk profile than perhaps encountered in wider practice. Furthermore baseline heart rates were less than 100 in both groups. The study did not include patients in acute HF where rapid ventricular rates are deleterious and in whom stricter rate control would be advantageous. The mean HR for the lenient group was somewhat closer to the strict group target (85 v 76bpm) than just below the target of <110. The accompanying editorial speculated whether a longer FU may have shown more detrimental effect of faster HR on deterioration of cardiac function and health.

In patients with permanent AF in whom a rate control strategy has been accepted aiming for stricter heart rate control (<80bpm at rest <110 exercise) confers no advantage over a more relaxed target of <110 (study achieved mean of 86) in terms of hard end points with a potential for more adverse events with a higher stroke rate, and greater need to stop because of adverse drug effects (p<0.001). A lenient strategy would also reduce the need for OPD visits/ monitoring etc. It is important to note that this study specifically excluded patients with prior stroke.

 

Take Home: Dont push too hard to get ventricular Rates down in AF but most desirable is to get to between 90-100.