Rate control in atrial fibrillation, insight into the RACE II study

Currently, in Europe, more than 6 million patients have atrial fibrillation (AF) [1]. It is expected that this number will double in the next 30–50 years [1–3]. With AF, the risk of death, stroke and heart failure is increased [4–6], and exercise capacity and quality of life are reduced [7, 8]. Thus, AF is not a benign disease. Despite efforts to maintain sinus rhythm, AF is a progressive arrhythmia [9–11] and many patients eventually develop permanent AF. Until recently, the treatment of this specific patient group was not evidence based. An evidence-based treatment strategy is indispensable considering the large patient population. It was not until the beginning of this decade that it became apparent that it was not the rhythm that determined the prognosis, i.e. there was no difference in outcome between rate (treatment aimed at heart rate reduction) and rhythm control (treatment aimed at restoration and maintenance of sinus rhythm) [12–18]. However, different definitions of adequate rate control were used in the rate versus rhythm control studies (Table 1). The guidelines at that time advocated a strict rate-control strategy, but this was based on small, short-term studies which did not investigate prognosis [19]. Thus, an evidence-based rate-control strategy was lacking. Studies which investigated different rate-control strategies showed no difference in outcome between patients with a high and low heart rate [20, 21]. However, these were all retrospective analyses. Table 1 Heart rate criteria used in the rate- versus rhythm-control trials Rationale to initiate the RACE II study Drugs frequently used to institute rate control consist of beta-blockers, non-dihydropyridine calcium-channel blockers and digoxin. From the 1970s until now, several studies have been performed evaluating the effect of negative dromotropic drugs (beta-blockers, non-dihydropyridine calcium-channel blockers, digoxin, amiodarone, and dronedarone) on heart rate during AF. At first, the focus was on heart rate at rest and during exercise [22–26]. It was expected that exercise capacity would improve due to a reduction in heart rate. Surprisingly, however, later studies showed no improvement of exercise capacity with a more physiological rate response during exercise [27–33]. The previous guidelines recommended the use of strict rate control [19] to reduce symptoms, improve the quality of life and exercise tolerance, reduce heart failure, and improve survival. On the other hand, strict rate control could cause drug-related adverse effects, including bradycardia, syncope, and a need for pacemaker implantation. Thus, the balance between benefit and risk in terms of cardiovascular morbidity and mortality, quality of life, exercise tolerance, and disease burden remained unknown. One of the first studies on heart rate during AF and prognosis was a large retrospective analysis of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) [20]. All patients randomised to rate control in AFFIRM who were in AF at baseline and at 2 months follow-up were included in this analysis. The patients were stratified according to the quartiles of resting heart rate at 2 months. There was no difference in cardiovascular hospitalisation or death between the quartiles of achieved heart rate at rest at 2-month follow-up. Resting heart rate was not a predictor for all-cause mortality or cardiovascular hospitalisation. Importantly, in AFFIRM a strict rate-control approach was used, as the guidelines advocated at that time (Table 1). To achieve the strict rate-control targets frequent drug changes were needed; eventually, the rate-control criteria were achieved in two-thirds of the patients [34]. In the RAte Control versus Electrical cardioversion (RACE) study the rate-control criterion was a resting heart rate below 100 beats per minute [14]. This criterion was solely established on the basis of the clinical experience of the principal investigators that 100 beats per minute would be most feasible as well as clinically relevant in terms of maintaining. A pooled analysis of AFFIRM and RACE evaluated differences in outcome between the studies [35]. In that study patients were included if they met a combination of overlapping inclusion and exclusion criteria of AFFIRM and RACE. The primary endpoint was a composite of all-cause mortality, cardiovascular hospitalisation, and myocardial infarction. In total, 1091 patients were included, 874 from AFFIRM and 217 from RACE. The mean heart rate in the AFFIRM patients was lower compared with the patients from RACE due to different rate-control definitions (76.1 versus 83.4 beats per minute). There was no difference in outcome between the patients included in AFFIRM or RACE, though a heart rate >100 beats per minute was associated with a worse outcome. Lenient control was associated with far fewer pacemaker implantations than strict control. Thus, all available data showed no clear benefit of strict rate control as compared with lenient rate control; however, only retrospective data were available. Heart rate and quality of life can also be assumed to be related. A higher heart rate could cause more or more severe symptoms than a lower heart rate. However, instituting a stricter rate-control strategy requires more negative dromotropic drugs. Prospective data on quality of life and different rate-control studies were also lacking.