Discussion
Model and statistical analyses results discussion
The aim of this study was to explore the clinical and economic implications of implementing cryoablation as an alternative first-line therapy for symptomatic PAF versus first-line AADs from an English NHS perspective.
The results from the economic analysis indicated that cryoablation is estimated to be more costly than AADs over a patient’s lifetime. However, cryoablation is predicted to yield higher QALYs, resulting in an ICER of £3783 per QALY gained. Similarly, these findings were consistent with the scenario analyses (table 4), with cryoablation predicted to be cost-effective in all scenarios explored. This suggests that the results are robust to parameter uncertainty. Thus, the ICER for cryoablation (using the pooled trials efficacy data) was below the lower threshold used in the UK cost-effectiveness decision-making (£20 000 per QALY gained),20 indicating that cryoablation would be considered a highly cost-effective alternative to AADs as an initial rhythm control therapy.
Statistical modelling using the pooled clinical trial data showed that cryoablation was associated with a statistically significant reduction in the rate of reablation and AF recurrence. There were 0.89 fewer reablations per person and a 45% relative reduction in the amount of time spent in AF health states over a lifetime for patients who had cryoablation compared with those who received AADs. Additionally, it was predicted that those receiving cryoablation in the ST-episodic health state would have a 4.26% higher 12-month utility than those receiving AADs. Consequently, patients in the cryoablation arm incurred lower utility decrements in the ST-episodic health state. The higher estimated QALY yield in the cryoablation arm is, therefore, attributable to the reduction in time spent in AF health states that are associated with higher utility decrements. This finding aligns with the Euro Heart Survey, which showed that the decrease in HRQoL associated with AF progression is attributed to a minor effect of the associated symptoms and a major effect of associated adverse events due to AF.21
Clinical effectiveness
While the cost-effectiveness of second-line cryoablation compared with second-line AADs has previously been shown to fall within the range that is acceptable to NICE,15 this study highlights that first-line cryoablation treatment is also highly cost-effective and clinically pertinent. Since AF is a progressive disease, minimising the time from diagnosis to treatment is crucial to improve clinical outcomes. Recently, the Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST-AFNET 4) showed that early rhythm control is associated with a significantly lower risk of adverse cardiovascular outcomes compared with usual care.22 Further cost-effectiveness analysis of a subset of the data generated by the EAST-AFNET 4 trial projected fewer cardiovascular death and hospitalisation and stroke events over a 72-month follow-up period for those receiving early rhythm control.23 Moreover, as an initial first-line rhythm control strategy, cryoablation is associated with a significant reduction in atrial arrhythmia recurrence and rehospitalisation compared with AAD therapy in patients with PAF.24 Cryoablation has also been shown to significantly lower the risk of progression from PAF to persistent AF compared with AAD therapy, suggesting that ablation is disease modifying.25 Importantly, AF progression is associated with higher risk for stroke, heart failure and healthcare utilisation, underscoring the clinical and economic importance of intervening early.26–28
Economic effectiveness
In addition to the clinical advantages of early ablation, this model shows that ablation is economically advantageous for the UK NHS Setting. A recent economic evaluation by NICE (2021) comparing cryoablation as second-line therapy with AADs concluded that cryoablation was cost effective, with a reported ICER of £11 687 per QALY gained.29 The total costs and QALYs from this model also align with those described by Rodgers et al (2008), who reported stroke risk-dependent lifetime costs of £14 415 to £18 107 for AADs.30
The results of this model are also similar to the cost-effectiveness outcomes of RFA as a first-line treatment compared with first-line AADs31; however, the cited study notes that the cost-effectiveness of RFA in older patients (≥50 years) is uncertain. This outcome was not observed in the current study, which included a lifetime time horizon with a baseline age of 57.5 (ie, based on the characteristics from the pooled RCT sample), suggesting that cryoablation, as a first-line initial rhythm control strategy, may be a cost-effective intervention in older patients (≥50 years). The cited economic analyses were, however, undertaken before the completion of the three RCTs that informed the analysis conducted in this study. Additionally, it is important to note that the EARLY AF 3-year results demonstrate that the clinical effects of ablation persist beyond the 12 months that were analysed for the model.25
Similar outcomes have been observed for second-line RFA versus AAD therapy. Leung et al demonstrated that, despite the high initial cost associated with ablation, a significant reduction in CV-related AEs and AF recurrence resulted in a higher QALY yield in the ablation arm, ultimately producing a cost-effective result (ICER = £8614).32 The authors note, however, that the model only considered one repeat ablation, in contrast to the maximum of two repeat procedures (ie, three total procedures) captured in the current study.
The findings of this analysis can be generalised to other healthcare systems. A recently published adaptation of this economic model from a United States Medicare perspective also found that first-line cryoballoon ablation is cost-effective compared with first-line AAD therapy.33 Further adaptations of the economic model from a Canadian and German healthcare perspective are in preparation for publication. The current findings are also consistent with that of cost-effectiveness analyses examining catheter ablation in other regions. Chew et al, in a retrospective analysis of the CABANA (Catheter Ablation vs Anti-arrhythmic Drug Therapy for Atrial Fibrillation Trial) clinical trial, evaluating the cost-effectiveness of second-line ablation versus AAD therapy for treating AF in a US setting, found that, despite ablation being more costly than AADs, the treatment provided a substantial enough improvement in patient HRQoL to generate a cost-effective result.34 Similarly, supportive economic evidence—demonstrating ablation (RFA and cryoballoon) yields higher costs and QALYs versus AAD therapy—has been observed from the perspective of the Chinese and South Korean healthcare systems in populations with PAF.35 36 Therefore, while the implementation and cost-effectiveness of an intervention in different regions can vary substantially due to factors such as treatment pathway and source of reimbursement not being directly comparable, the current study joins a growing body of evidence demonstrating the potential economic benefits of adopting catheter ablation as a method of rhythm control in AF populations.
Assumptions
Numerous parameters, including the relative risk of AF recurrence and resolution, stroke, heart failure and reablation success according to the number of ablations received and the health state occupied, were based on assumptions. Namely, the cited parameters, which were validated by the clinical authors to ensure clinical plausibility, were included as conservative estimates. Similarly, the stroke rates applied in the model are based on clinical opinion due to a failure to identify appropriate parameters in the literature. Despite a reportedly greater risk of complication from a single instance with ablation, the greater frequency of treatment administration with AADs compounds the risk of complication. This is supported in contemporary literature, where the risk of complication from AAD administration was double that of ablation at a 3-year follow-up.25 The utility decrement applied to the ST-episodic and LT-persistent states was assumed equivalent.
Despite the necessity of adopting assumptions, the scenario analyses (table 4) demonstrated that the results are robust to parameter uncertainty. A cost-effective result was maintained when the relative risk of AF recurrence and resolution was increased by 10% and when the relative risk of heart failure was increased by 10% in the permanent AF state. A cost-effective result was also maintained when the health state-specific relative risk of stroke was changed to alternative values sourced from the literature, when the success rate of reablations was reduced by 30% (proportionally) and when applying alternative EHRA class-specific decrements.
Strengths
A key strength of this model is that the parameter estimates were derived from the statistical analysis of IPD from three RCTs (Cryo-FIRST, STOP AF First and EARLY-AF) where possible.
Despite the necessity of adopting some assumptions, the PSA and scenario analyses showed that the model results were robust across all sets of results and throughout all plausible scenarios. In addition, the model structure, parameter estimates and assumptions were reviewed and validated by clinical experts.
Limitations
The data used to parameterise this model were subject to limitations. The AF health state data were derived by ECG monitoring in the trials. As ECG monitors detect both symptomatic and asymptomatic PAF events, the rate of AF recurrence and, consequently, the retreatment costs may be overestimated. However, it should be noted that this overestimation will be present in both treatment arms. Additionally, all three RCTs employed different ECG monitoring methods; however, said methods were consistent between treatment arms within each trial. These limitations may be mitigated by the trials’ inclusion criteria, which specified the enrolment of symptomatic patients. The analysis also did not estimate cryoablation to be cost-saving (in the base case or scenario analyses). Thus, it is unlikely that the model outcomes were affected by overestimated retreatment costs. Prior literature has also demonstrated no differences in major clinical outcomes for patients who present as asymptomatic versus symptomatic, suggesting that management strategies should not be based on symptomatic clinical status.37 Regardless, the ECG monitoring method was included as a confounding effect in the regression models to account for any impact this may have on the results.
In addition, variation may exist between guideline recommendations and clinical practice (eg, regarding AAD prescription) that could affect the applicability of the methods used in the economic model to clinical practice. However, to minimise this, the opinions of clinical experts were used in the design of this model. Clinical coauthors were interviewed until a consensus for all inputs was achieved and based on their clinical experience these inputs were considered both reasonable and conservative. The same panel of clinical experts also validated the structure of the economic model to ensure it was reflective of the clinical pathway for PAF. Scenario analyses were used where there was variation between clinical expert opinions to ensure that the economic model covered a broad range of real-world practices.
Conclusion
This analysis illustrates that cryoablation is cost-effective compared with AADs as a first-line therapy in a PAF population. This study also generated results that were consistent with previous economic evaluations of cryoablation versus AADs in a second-line setting. The ICER in this study was lower, suggesting that earlier intervention is an even more cost-effective option versus delaying and treating initially with AADs. However, further studies and economic modelling are required to confirm the cost-effectiveness of early versus delayed ablation intervention. In summary, this study has shown that cryoablation is a highly cost-effective option for PAF, compared with first-line AAD treatment in the UK NHS healthcare setting.