The US lifetime model used in this study indicates that, from a health care payer’s perspective, dronedarone is a cost-effective treatment option to manage paroxysmal/persistent AF/AFL in the US. The base-case scenario cost/QALY was $19,520, and 85% of the probabilistic sensitivity analysis simulations fell well below the commonly used threshold of $50,000/QALY.31
A feature of this cost-effectiveness model is that it was sensitive to the reduction in cardiovascular mortality associated with dronedarone therapy. The relatively minor cost for 3-monthly ECG monitoring did not change the results of the model in any appreciable way, and the monitoring cost used was most likely an overestimation for current US practice costs.
The finding that cost-effectiveness is below current thresholds is consistent with the conclusions of a similar assessment of dronedarone in Canada, Italy, Sweden, and Switzerland, where the costs/QALY gained were €5828, €5873, €14,970, and €8554, respectively.25
Variation across countries is largely attributed to differences in treatment costs, which were markedly higher in the US and Sweden. The cost-effectiveness results from the current model were also stable across the examined subgroups, and the incremental cost-effectiveness ratios were lower in patients with a higher risk of cardiovascular events, as anticipated.
We believe that the cost-effectiveness estimates provided by this model are of relevance to patient care, given the long-term control of arrhythmia that may be required by AF/AFL patients. This study used robust clinical trial data from one of the largest datasets on patients with paroxysmal/persistent AF/AFL (ATHENA),13
to provide the assessment of cost-effectiveness over the patients’ lifetime.
The conclusions of this study are consistent with those of an evaluation of dronedarone in non-permanent AF conducted by the National Institute for Health and Clinical Excellence (NICE). Based on several evaluations, including a United Kingdom lifetime model, NICE concluded that dronedarone was a cost-effective treatment option in patients with similar characteristics to those of the ATHENA population.32
However, following a review of its benefit–risk balance conducted in light of the Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) trial results,26
the European Medicines Agency has recommended that use of dronedarone should be restricted to patients with paroxysmal/persistent AF who are in sinus rhythm and only after other antiarrhythmic drugs have been tried.27
Similarly, the US Food and Drug Administration now recommends that dronedarone should be initiated only in nonpermanent AF patients who are in sinus rhythm and that it should be discontinued in patients whose AF becomes permanent (ie, cannot or will not be cardioverted).33
It is acknowledged that the US lifetime model assumes that there is no change in effect of treatment when extrapolating beyond the ATHENA trial data. The use of data from this large trial permits greater precision than the use of data from either a smaller study or the collection of data from multiple published studies. Also, the approach of extrapolating to consider cost-effectiveness over a lifetime is considered a requirement to assist health care decision makers in identifying appropriate and cost-effective treatments for cardiovascular disease.34
The current model assesses the cost-effectiveness of dronedarone in its currently approved indications of paroxysmal and persistent AF/AFL. While a moderate proportion of patients with paroxysmal and persistent AF/AFL eventually progress to permanent AF/AFL,35
within the base case of this model, symptomatic patients who developed permanent AF/AFL (15.2% of patients) were assumed to have discontinued dronedarone. This differentiates this study from the recent investigation of the use of dronedarone in patients aged ≥ 65 years with permanent AF (the PALLAS trial), which was stopped after unexpected findings of an increase in cardiovascular events with dronedarone in comparison with placebo.26
We conclude that the findings of this study are relevant to patients with paroxysmal or persistent AF/AFL.
Published information on the cost-effectiveness of treatments for AF/AFL is limited. The Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study concluded that rhythm control was more costly and less effective than rate control, with an incremental cost difference of $5077 between the two treatment classes.38
The probability of rhythm control being more cost-effective than rate control was reportedly <0.01, even at a value of $100,000/QALY gained.38
This evaluation was for a 3.5-year follow-up period rather than being a lifetime model.
A major difference between AFFIRM and ATHENA is in the direction of survival trends. In AFFIRM, all-cause mortality was numerically higher in the rhythm control arm than in the rate control arm (23.8% versus 21.3% at 5 years, P
Thus, in the AFFIRM health economic analysis there was a low probability that rhythm control was more effective in terms of LYG.38
In ATHENA, the dronedarone treatment arm had numerically lower all-cause mortality than the control group (5.0% versus 6.0%; P
= 0.18) and a statistically significantly lower cardiovascular mortality rate (2.7% versus 3.9%; P
As expected, our model projected higher LYG with dronedarone therapy, consistent with the ATHENA results, but the model results are sensitive to assumptions about the magnitude of the survival benefit.
The findings of this study should be considered in the context of certain limitations that are consequential of basing the cost-effectiveness model on clinical trial data. It is well recognized that discontinuation rates are higher in routine clinical practice than in clinical trials. Also, given that dronedarone is relatively new to the market, it is not possible to accurately assess how trial-based efficacy data compare with the effectiveness of dronedarone in the real-world setting. Another possible limitation of using trial data is that the inclusion and exclusion criteria used in these trials provide a restriction not present in clinical practice. For example, to be included in the ATHENA trial patients were required to be over 75-years old or over 70-years old with one or more additional cardiovascular risk factor. Also, the ATHENA trial excluded patients with unstable hemodynamic conditions; New York Heart Association class IV congestive heart failure; acute myocarditis; bradycardia with a heart rate of <50 beats per minute or a PR interval of >0.28 seconds; previous clinically significant sinus-node disease (if not currently treated with a pacemaker); planned major surgery; any (non-cardiac) severe illness that limited life expectancy; limited kidney function; or who were in need of prohibited concomitant medication (other class I or III antiarrhythmic drugs). For this reason, external sources of mortality data were used as model parameters.
The multinational nature of the ATHENA trial may also impact the applicability of some of the results of this trial to the US population. For example, approximately 20% of the patients enrolled in ATHENA were from Russia, and mortality rates in these patients may differ considerably from those in the US. To compensate for this limitation, US-specific data were used for noncardiac mortality data, and the characteristics of the subgroup of ATHENA patients from the US (27% of the ATHENA cohort) were used in this study rather than data from all of the patients enrolled in ATHENA.
This model did not include hospital readmissions or additional costs for subsequent events after baseline, for stroke, or congestive heart failure in the assessment of cost-effectiveness. Our estimates of cost-efficiency can therefore be considered conservative, as rehospitalization of US AF/AFL patients occurs frequently.9
There is also some evidence that AF readmissions are more costly than the initial admission.42
Additionally, the model also used the lower range of commonly reported 1-month stroke fatality rates.
Certain assumptions made in the model may not be representative of clinical practice; for example, that there is no change in health state transition probability over the 21-month period of dronedarone treatment. It should also be noted that cardiovascular mortality was only one of several mortality risks in the cost-effectiveness model and the model’s sensitivity to the assumed reduction in all-cause mortality with dronedarone is uncertain.