Early rhythm control for atrial fibrillation: looking cost-effective, at least from one direction

This editorial refers to ‘Cost-effectiveness of early rhythm control vs. usual care in atrial fibrillation care: an analysis based on data from the EAST-AFNET 4 trial’, by S. Gottschalk et al., https://doi.org/10.1093/europace/euad051.

In the coming years, the intensifying endemic of atrial fibrillation (AF) is likely to consume an increasingly large fraction of health care resources.¹ In addition to causing disabling symptoms in some cases, uncontrolled AF comes with a higher incidence of stroke, heart failure, and mortality. The available therapeutic options are growing rapidly, leading to increased need for their responsible application.

While for decades, both rhythm control and rate control strategies were considered equally acceptable modalities of treatment for atrial fibrillation,² recent years’ improvements in the efficacy and safety of rhythm control therapies have been tipping the balance in the direction of rhythm control. Growing evidence supports the use of either medical therapy or procedural therapy (largely, catheter-based ablation) to effect maintenance of sinus rhythm.³

The randomized trial EAST-AFNET 4 found that the application of early rhythm control therapy (ERC) reduced adverse cardiovascular outcomes when applied to patients with recent-onset AF and cardiac risk factors but without severe symptoms related to heart rhythm.⁴ Importantly, these inclusion criteria may describe over 70% of newly-diagnosed patients with AF, which makes this trial broadly applicable.⁵ In EAST-AFNET 4, rhythm control therapy could take the form of antiarrhythmic medication and/or ablation, and participants in the rate control arm only received rhythm control in the case of uncontrolled symptoms despite adequate control of heart rate. Participants were followed for up to 6 years (median: 5.1 years) for the combined endpoint of cardiovascular death, stroke, or hospitalization for heart failure or acute coronary syndrome. The ERC strategy resulted in primary-endpoint relative risk reduction of 21%, with absolute risk reduction of 1.1% (number needed to treat [NNT] = 91). The risk of death from cardiovascular causes was 28% lower with ERC, and the risk of stroke was 35% lower. Early rhythm control was clearly superior, and the trial was stopped early due to overwhelming evidence of efficacy.

Nearly all therapy comes at a price, however, and treatment of AF is no exception to this rule.

In this issue of EP Europace, Gottschalk et al. report on their cost-effectiveness analysis of ERC among a sizeable portion of the EAST-AFNET 4 population.⁶ The authors evaluated data from the 1664 EAST-AFNET 4 participants who were enrolled within Germany. This subpopulation represents a majority (59.7%) of the entire multinational study population, and the restriction to one country of origin enabled some amount of uniformity in the analysis. The authors tallied costs related to hospitalization, based on diagnosis-related groups, as well as the cost of medication, as paid by the German health care insurance system. The ERC group incurred higher mean medication cost (€1218 more) and numerically higher mean hospitalization-related cost (€976 more), though this latter difference did not reach statistical significance.

Analysis of incremental cost-effectiveness ratios (ICERs) revealed that under most tested conditions, ERC was more costly but probably worth it. In the base case, the incremental cost of one additional life-year free from the primary outcome was calculated to be €10 538 in 2021 euros, and the cost was €22 536 per year of life gained. The authors calculated the probability of willingness-to-pay based on a range of hypothetical values of costs and benefits that could be incurred by using ERC rather than primarily rate control, and found ERC 95% likely to be cost-effective when the cost of ERC was €55 000 or lower per endpoint-free year. Cost-effectiveness was maintained even during broad sensitivity analyses assuming variation in economic discount rates, cost of rehabilitation following strokes or myocardial infarction, and cost of hospitalization. The authors are congratulated on their robust evaluation of the data, including their detailed and thorough sensitivity analysis.

It is important to recognize that rhythm control strategy can take various forms, which may have a profound effect on the cost and effectiveness of that strategy. Some centres may be more likely to pursue ablation as first-line therapy, while others may habitually reserve ablation for when antiarrhythmic medication fails. Catheter ablation is becoming an increasingly important tool in many places. Thus, the cost-effectiveness described by Gottschalk et al. may differ within other health systems, with varying cost and reimbursement systems, or with varying aggressiveness regarding ablation therapy. However, the authors’ detailed description of the mix of care strategies employed, and the associated cost/benefit relationship of targeting rhythm control rather than rate control, will be a useful point of consideration for decision-makers within a broad array of healthcare systems.

In a prior analysis of the EAST-AFNET 4 data, Eckardt et al. found that the key determinant of outcome reduction in the ERC arm was the presence of sinus rhythm (SR) at the 1-year follow-up.⁷ This effect was seen regardless of whether (and what type of) therapy was required to achieve sinus rhythm. The ERC group had a higher incidence of SR at 1 year (86% vs. 66%, P < 0.001).^4,7 Thus, it is ERC’s effect on achieving SR that is to be credited for ERC’s reduction in adverse outcomes.

Despite evidence that ablation is superior to medical therapy for achieving and maintaining sinus rhythm, the penetration of AF ablation in the entire EAST-AFNET 4 population was only 24% (and not reported for the German subpopulation).^8–10 Thus, EAST-AFNET 4 could be considered primarily a trial of drug-based AF suppression. Gottschalk et al. did not specifically evaluate the impact of medical vs. procedural-based therapies. The utilization of ablation, an initially costly procedure that likely results in long-term savings, is expected to increase in Germany as well as in other places. Considerable evidence has found ablation therapy to be cost-effective, including in an analysis of CABANA data showing favourable ICER per QALY gained, as well as other analyses, meta-analyses, and national treatment recommendations.^11–14 While the present analysis provides an informative snapshot given recent German care strategies, updated cost-effectiveness analyses will be required as practice patterns change.

A significant limitation of the EAST-AFNET 4 data is the absence of quality-of-life information. While avoidance of the hard outcomes examined in EAST-AFNET 4 is very important, at present, the most common reason for pursuing rhythm control is improvement in quality of life via symptom reduction. In addition, this analysis gathered cost information only related to hospitalizations and medications. While these are major determinants of the cost of care, clearly some important expense categories were not available, such as outpatient hospital-based care, imaging studies, and medical therapy not directly related to care of atrial fibrillation. It is unclear whether any ablations were done on an outpatient basis (i.e. without overnight hospitalization, as is increasingly done in contemporary practice), but if so, then those costs may not have been captured in this analysis.

Cost-effectiveness analyses evaluate willingness to pay, and they help to decide whether investing in a perhaps costlier therapy results in overall savings through avoidance of adverse outcomes. The conclusions may vary greatly depending on who is doing the paying, and who reaps the benefits or suffers the adverse outcomes. The current analysis adopted a healthcare payer perspective, so only the effect on those payers’ bottom line was evaluated. Broader societal-based evaluation of ERC’s cost-effectiveness would need to account for quality of life as well as loss of work productivity related to illness or hospitalization, as was recently performed in the United Kingdom for various forms of not-necessarily-early rhythm control for paroxysmal atrial fibrillation.¹⁵ These costs would be expected to be especially important in younger, pre-retirement, populations, and in those with significant comorbidities (especially heart failure).

This robust analysis by Gottschalk et al. is an additional pillar supporting the pursuit of rhythm control, here with an economic rationale. As rhythm control strategies become more efficient, effective, and (hopefully) cheaper, ERC is expected to be even more cost-effective in the future.