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Neth Heart J. 2010 November; 18(11): 522–523.
Published online 2011 May 27. doi:  10.1007/s12471-010-0827-9
PMCID: PMC2989488

Upstream therapy in patients with early atrial fibrillation

The relevance of the Routine versus Aggressive upstream rhythm Control for prevention of Early atrial fibrillation in heart failure (RACE 3) study

Atrial fibrillation (AF) is not a benign disease. It is associated with an increased risk of death, stroke, heart failure and hospitalisation, an impaired quality of life, and reduced exercise capacity and left ventricular dysfunction. Development of AF is a result of continuous remodelling of the atria, altered metabolism and autonomic changes secondary to ageing, progression of the underlying heart disease, and genetic and environmental factors. Hypertension, congestive heart failure, ischaemic heart disease, and diabetes are all wellknown risk factors for the development of AF.1 The first manifestation of AF usually occurs after years of atrial and ventricular remodelling, caused by hypertension or heart failure (figure 1).2 Important substrates for AF are fibrosis and inflammation, which form the basis of atrial and ventricular remodelling. One mechanism involved in these processes is activation of the renin-angiotensin-aldosterone system (RAAS), causing increased levels of angiotensin-II and aldosterone, which stimulate fibrosis, hypertrophy and inflammation.3,4

Upstream therapy refers to the use of non-ionchannel-antiarrhythmic drugs that modify the atrial substrate to prevent the occurrence of new onset AF (primary prevention) or recurrence of the arrhythmia (secondary prevention). It includes treatment with RAAS blockers (angiotensin-converting enzyme inhibitors [ACEIs], angiotensin receptor blockers [ARBs], and aldosterone antagonists [ARAs]), statins, and omega-3 polyunsaturated fatty acids. ACEIs, ARBs, and ARAs may prevent or reduce atrial structural remodelling especially by decreasing fibrosis. In addition, these drugs improve haemodynamics by lowering of blood pressure and reduction of left ventricular and atrial wall stress.5 Statins, known for their lipid-lowering capacities, have a variety of pleiotropic properties including attenuation of inflammation through antiatherogenic and antioxidant actions. There is evidence that, through these properties, statins may play a protective role against the development of AF.6 Rehabilitation programs have been introduced as a safe and cost-effective method to increase patients’ well-being and exercise tolerance. Besides an increase of 20% in peak oxygen consumption,7 rehabilitation therapy in patients with heart failure is associated with reversed left ventricular remodelling.8 Interestingly, rehabilitation therapy is associated with significantly lower AF incidence in older adults.9

Figure 1.
Time course of atrial substrate remodelling starting long before the first episode of AF. Substrates for AF include fibrosis and inflammation induced by activation of the renin-angiotensin-aldosterone system, which may be prevented or reduced by upstream ...

Rhythm control is the treatment of choice in patients who are symptomatic due to AF. Outcome of a pharmacological rhythm control strategy, however, is still cumbersome. Upstream therapy may improve outcome of pharmacological therapy and, in the long term, may even prevent the need for pulmonary vein isolation, which is still a complex procedure with possibly severe complications.1 Results of upstream therapy for the prevention of AF in animal experiments, hypothesis-generating small clinical studies and retrospective analyses in selected patient categories have been encouraging. Larger prospective randomised trials, however, did fail to show AF prevention with upstream therapy. 10 This disappointing outcome may have been caused by inclusion of patients in whom the extent of remodelling was more severe and even irreversible due to a longer history of AF and underlying heart disease. In patients with a shorter history of AF, remodelling processes are assumingly less advanced, providing more opportunities for RAAS blockade to be effective. This patient category with a short history of both AF and underlying heart disease has not been studied before. In the RACE 3 study we aim to investigate these patients. It is our hypothesis that in patients with early AF and mild to moderate early systolic or diastolic heart failure, aggressive upstream rhythm control, consisting of non-ion-channel antiarrhythmic drugs (ACEIs and/or ARBs, ARAs, and statins), cardiac rehabilitation therapy, counselling and dietary restrictions besides conventional heart failure drugs, increases persistence of sinus rhythm. The institution of a combination of different classes of upstream therapies may have synergistic effects on the atrial substrate by decreasing AF directly through reduction of atrial remodelling and indirectly through reduction of ventricular remodelling. It is our belief that this may ultimately enhance persistence of sinus rhythm and possibly also improve prognosis.

In RACE 3 patients are included with early symptomatic persistent AF (total AF history <2 years, total persistent AF duration <6 months, and ≤1 previous electrical cardioversion), and mild to moderate early heart failure (total heart failure history <1 year, and left ventricular function ≥45% and NYHA II to III, and signs of heart failure, or left ventricular ejection fraction 25 to 45% and NYHA class I to III). The primary endpoint of the study is sinus rhythm after one year of follow-up, defined as sinus rhythm during ≥6/7th of assessable time of continuous seven-day Holter monitoring during the last week of the study.

Once more, a study on how to improve therapy and outcome in patients with AF is being performed in the Netherlands with financial support of the Netherlands Heart Foundation (NHS), the Interuniversity Cardiology Institute the Netherlands (ICIN) and the Working Group on Cardiovascular Research the Netherlands (WCN). If we succeed in including all 250 patients within the next 18 months, this combined effort of cardiologists throughout the Netherlands may add to our knowledge on optimal therapy of AF and, once again, may alter forthcoming guidelines for AF.


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