https://orcid.org/0000-0002-4881-720X
Atrial fibrillation (AF) constitutes one of the most common cardiac rhythm irregularities and it is estimated to affect more than 60 million people worldwide. In Japan alone, by 2050 one million patients will be diagnosed with AF.
AF carries an increased risk for stroke, which is interlaced with substantial mortality and morbidity, while the incurred medical costs are estimated around Japanese yen (JPY) 137 and 191 billion for Japan alone.
The gold standard of treatment is the administration of anticoagulation, either warfarin or Novel oral anticoagulants (NOACs). However, these agents have demonstrated an increased risk of bleeding and suboptimal adherence, further compounded in warfarin patients owing to the need for regular INR tests.
In 2015, the Percutaneous Left Atrial Appendage Closure (LAAC), WATCHMAN device (Boston Scientific Corporation, Marlborough, MA, USA), alternative to NOACs for patients with Non-valvular atrial fibrillation (NVAF) who are at risk for stroke and systemic embolism, was approved by the FDA, based on the outcomes of PROTECT AF trial, along with its FDA mandated registry CAP, and PREVAIL trial, with its corresponding CAP2 registry.Citation1–4 The PREVAIL trial showed that LAA was not inferior to warfarin for ischemic stroke prevention, but failed to demonstrate non-inferiority for overall efficacy. The PROTECT trial reported that after 3.8 years of follow-up in NVAF patients, with elevated risk for stroke, percutaneous LAAC proved both noninferiority and superiority, vs warfarin, in the composite endpoint of stroke, systemic embolism, and cardiovascular death. LAAC was proved to be superior with regards to cardiovascular mortality and all-cause mortality.
The high acquisition and up-front cost of the technology constitutes a decisive factor in the decision-making process. To this direction, Kamae et al. published a cost-effectiveness analysis in the Journal of Medical economics, of LAA from a Japanese perspective, in order to cast light to its efficiency profile vs oral treatment modalities.Citation5
Authors elaborated a Markov Model, which compared LAAC Watchman device to NOACs and warfarin, in NVAF patients. The demographic data of the patients were set as per the SALUTE trialCitation6 and a single center observational Japanese Study.Citation7 Authors adopted a lifetime (30-year) time horizon and a 2% discount rate. Patients could be allocated to LAAC WATCHMAN device, NOACs and warfarin. The LAAC arm was associated with once-off procedure-related complications and after the implantation, patients could receive warfarin for 45 days, aspirin and clopidogrel until the 6th month and aspirin afterwards. The successful implantation rate was set at 92.5%. The LAAC complications were mined from the pooled PROTECT AF and PREVAIL trials at 5-years follow-up while the commensurate data on warfarin and NOACs were derived from published metaanalyses. All event probabilities were extrapolated over a lifetime horizon. Mortality rates for non-AF related causes were assumed to follow Japan life tables.
SALUTE trial provided also the baseline risks of stroke and bleeding for the LAAC WATCHMAN device patients with NVAF. It was assumed that the rates of ischemic and hemorrhagic stroke increased with age by 1.4- and 1.97-fold per decade, respectively and the risk of a secondary event was higher compared to a primary ischemic event by 2.6-fold.
The utilities values were transferred from available literature. The LAAC intervention was associated with disutility as well, applicable to 2 weeks post-procedure, along with stroke, major bleeding, systemic embolism, transient ischemic attack and myocardial infarction.
Costs were calculated from the perspective of Japanese public payer (2020 yen) and included therapy costs, costs of LAAC WATCHMAN device and procedure-related complications, related medical activities, including long-term care of disabling stroke, pharmaceutical cost and laboratory costs. The willingness-to-pay threshold was set at five million JPY.
Results
The results were time-dependent: LAAC dominated warfarin by year 13, following the operation, while it was established as a cost-effective option by year 8 (JPY 3,867,297/QALY).
The same pattern was evinced in the LAAC vs NOAC branch. LAAC surpassed NOACs’ conferred utility by year 4 (3.067 vs. 3.056 QALY). At year 10, LAAC demonstrated a cost-effective profile compared to NOACs (3,961,249/QALY). By year 15, LAAC dominated NOACs, a pattern which sustained by the end of the study.
For both scenarios, results were sensitive to the utility value of “feeling well” state of LAAC, number of LAAC patients with severely disabling stroke and the consequent long-term care costs for these patients.
These findings align with previously published studies, as by Lee et who demonstrated cost-effectiveness vs warfarin and dominance over NOACs.Citation8 This was reverberated by Kreidieh et al. who reported that by 6th year, LAAC is cost-effective vs warfarin and by 10th year a dominance is established, a pattern reported by Kamae et al., albeit at a later time period.Citation9
Policy implications
The results carry certain implications. Current clinical guidelines recommend LAAC in patients who cannot tolerate or do not want per-os treatment.Citation10 However, there is growing evidence that LAAC is dominant vs both warfarin and NOACs. Nevertheless, cost-effectiveness and consequent dominance, are established sequentially, due to high upfront cost of the watchman. It’s trivial how to incorporate thistime dependent economic outcome in the health policy.
As per the basics of health economics, LAAC should be considered for first line therapy, a statement that has its own repercussions. Primarily, is it legitimate to rank an interventional approach as a first-line treatment? People would prefer an oral treatment vs a more interventional approach. This was broadcasted in the patients’ preference towards TAVI rather than CABG, due to the former being less interventional.Citation11 Moreover, given the affected population and the unabated rising incidence of AF, we should contemplate whether any given country has the capacity to establish, run, and also sustain the expertise of the necessary centers.
Finally, the age of patients seems to be a critical factor. The older the patient, the lower the probability that LAAC would suffice to demonstrate cost-effectiveness. As a result, the age of the patient should be a part of the therapeutic algorithm. In younger patients, the LAAC should carry a stronger recommendation.
Any decision should be preceded by a shared-decision making process between the treating doctor and the patient.
Transparency
Reviewer disclosures
A reviewer on this manuscript has disclosed that they have worked as a statistician for Pfizer before retirement and have co-authored publications on apixaban (Eliquis) using Real World Data. The other peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.
Acknowledgements
None stated.
Additional information
Funding
References
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- Reddy VY, Holmes D, Doshi SK, et al. Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry. Circulation. 2011;123(4):417–424. doi: 10.1161/CIRCULATIONAHA.110.976449.
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- Glikson M, Wolff R, Hindricks G, et al. EHRA/EAPCI expert consensus statement on catheter-based left atrial appendage occlusion - an update. Europace. 2020;22(2):184–184. Epub 2019 Aug 31. PMID: 31504441. doi: 10.1093/europace/euz258.
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