Authors' objectives: Objective The aim of this health technology assessment (HTA) report is to evaluate the efficacy, effectiveness, safety, cost-effectiveness and budget impact of direct oral anticoagulants (DOACs) compared to vitamin K antagonists (VKA) in patients with nonvalvular atrial fibrillation (NVAF). In addition, ethical, legal, social and organisational issues related to DOAC and VKA use are explored.

Authors' results and conclusions: Clinical results Randomised controlled trials In total, 9 RCTs were included (n=74,472), all of which compared DOAC to warfarin: 2 evaluated warfarin compared to apixaban (n=18,423), 2 compared it to dabigatran (n=18,283), 3 compared it to edoxaban (n=22,224) and 2 compared it to rivaroxaban (n=15,542). Of the included RCTs, 3 were considered to have a low risk of bias and 6 a high risk of bias. All-cause mortality slightly favoured DOACs, reaching statistical significance for edoxaban at 30 mg once daily (7 fewer deaths per 1,000 patients [from 13 fewer to 0 fewer], moderate certainty evidence). Compared to warfarin, there was a reduction in reported events of major/life-threatening bleeding for a number of DOACs (apixaban 5 mg twice daily, dabigatran 110 mg twice daily, edoxaban 30 mg and edoxaban 60 mg), with an estimated effect size of 3 to 20 fewer events per 1,000 patients. All DOACs showed a statistically significant reduction in the rate of intracranial bleeding compared to warfarin, with the effect size ranging from 6 to 13 fewer events per 1,000 patients. The impact of DOACs on GI bleeding varied—edoxaban 30 mg showed statistically significant reductions compared to warfarin. Dabigatran 150 mg, rivaroxaban 20 mg and edoxaban 60 mg showed a statistically significant increase in GI bleeding. There was no statistically significant difference with apixaban. Edoxaban (30 and 60 mg) significantly reduced the number of clinicallyrelevant bleeding events (58 fewer per 1,000, from 68 fewer to 48 fewer; and 25 fewer per 1,000, from 37 fewer to 14 fewer, respectively). All other DOACs, where reported, showed no significant difference compared to warfarin. Across all DOACs (type and dose) there was no difference in total stroke and SE compared to warfarin. Non-randomised controlled trials In total, 10 NRSIs were included that compared DOACs to either phenprocoumon, acenocoumarol or an unspecified VKA from a country that primarily uses one of these 2 drugs (n=1,772,002). Of these, 8 NRSIs evaluated apixaban (n=183,780), 9 evaluated dabigatran (n=144,742), 2 evaluated edoxaban (n=16,531) and 7 evaluated rivaroxaban (n=417,689). All studies were at a high or critical risk of bias, primarily due to unmeasured confounding and significant, unbalanced dropouts between treatment groups. The NRSI results were difficult to interpret due to the risk of bias and conflicting results depending on the choice of outcome measure (i.e. hazard ratio [HR] or risk ratio [RR]). Economic results Under base-case assumptions, all DOACs were found to be cost-saving compared to VKAs while improving patient outcomes (quality-adjusted life years lived). All DOACs increased drug costs relative to VKAs but were cost-saving in terms of monitoring and clinical event costs. Sensitivity analyses found the dominance of each DOAC to be robust. The relative efficacy of each DOAC with respect to all-cause mortality was the key model driver in all 4 comparisons. The high monitoring costs associated with VKAs proved influential; removing this reverted the dominance of all 4 DOACs. Use of relative effect estimates from NRSIs, rather than RCTs, impacted the economic outcomes. Nevertheless, the conclusions regarding the cost-effectiveness of DOACs were drawn based on the RCT-based analyses alone because the NRSI evidence itself was conflicting and difficult to interpret. Under current policy conditions, OACs for patients with AF were estimated to be responsible for a cost of CHF128.0 million in 2021, increasing to an anticipated cost of CHF188.2 million in 2026. Expected monitoring costs were projected to decline; however, overall treatment costs (i.e. drug and monitoring costs combined) were projected to rise to an anticipated CHF233.0 million in 2026. Ethical, legal, social and organisational issues A total of 21 studies relevant to the ELSO domains were identified from systematic and targeted, non-systematic keyword searches. No legal issues were identified. Social issues associated with DOAC include patient-related, physician-related and healthcare system-related factors that affect adherence. An ethical issue around DOAC use relates to their benefit/harm profile. Although a favourable benefit/harm profile of DOACs was demonstrated from the RCT evidence, the NRSI data was difficult to interpret. In relation to the main organisational impacts on practice, DOACs have fewer monitoring requirements compared to VKAs, which require international normalised ratio (INR) testing approximately every 20 days. Conclusions The RCT evidence demonstrated favourable outcomes for the use of DOACs, noting that the evidence had a mixed risk of bias (ranging from low to very high). The NRSI evidence was difficult to interpret due to unmeasured confounding, significant unbalanced dropouts between treatment groups, and conflicting results depending on the choice of outcome measure (i.e. HR or RR). As such, the RCT evidence was deemed to provide more reliable results and was used as the basis for the economic evaluation. The economic evaluation supports the cost-effectiveness of DOACs. This finding is driven primarily by small improvements in all-cause mortality and high costs associated with INR monitoring for VKAs. Overall, payer costs for OAC use in AF are expected to increase due to (anticipated) continued growth in the relative use of DOACs and expected demographic changes.

Authors' methods: Methods Systematic searches were conducted in 4 databases (PubMed, Embase, Cochrane Library, INAHTA) up to 29 March 2022. In addition, grey literature sources and ongoing clinical trials up to 29 August 2022 were retrieved. Publications were limited to English, German, French and Italian. Systematic reviews, randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSI) were included that investigated the use of a DOAC currently reimbursed in Switzerland (i.e. apixaban, dabigatran, edoxaban, rivaroxaban), compared to a VKA currently reimbursed in Switzerland (i.e. phenprocoumon, acenocoumarol) or warfarin in patients with NVAF. Warfarin is not used in Swiss practice but is considered to be equivalent to other VKAs; therefore, studies that used warfarin as the main comparator were only included in the absence of evidence for acenocoumarol or phenprocoumon. Outcomes included all-cause mortality; bleeding, including major/life-threatening, gastrointestinal (GI), intracranial and clinically-relevant; stroke or systemic embolism (SE), including ischaemic and haemorrhagic stroke; health-related quality of life; adherence to treatment plan; persistence with therapy; and discontinuations due to adverse events. Risk of bias was evaluated using AMSTAR-II (systematic reviews), Cochrane RoB 2.0 tool (RCTs), ROBINS-I tool (NRSIs). GRADE was used to determine the overall strength of evidence for selected outcomes. Separate pairwise meta-analyses were conducted at longest follow-up (range 3–30 months) for RCTs and NRSIs, per outcome. Meta-analyses were conducted using random effects inversevariance models. Heterogeneity was evaluated visually and quantitatively (i.e. I2, Chi2, Tau2 and I2). A Markov model was developed to evaluate the cost-effectiveness of apixaban, dabigatran, edoxaban and rivaroxaban relative to VKAs. Four pairwise analyses—from the perspective of the Swiss healthcare payer—were conducted. The robustness of the economic findings was explored via deterministic and probabilistic sensitivity analysis. In addition, expected payer costs for OAC therapies in patients with atrial fibrillation (AF), under current policy and practice conditions, were extrapolated over the period 2022 to 2026. The financial implications of potential policy changes were not considered given the clinical and economic findings favoured the use of DOACs.

Project Status: Completed

URL for project: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-projekte/oraleblutverduenner.html

URL for protocol: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0060obvv-hta-protocol.pdf.download.pdf/h0060obvv-hta-protocol.pdf

Year Published: 2023

URL for published report: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0060obvv_hta-report.pdf.download.pdf/h0060obvv_hta-report.pdf

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Switzerland

Organisation Name: Swiss Federal Office of Public Health (FOPH)

Contact Address: Federal Office of Public Health, Schwarzenburgstrasse 157, CH-3003 Berne, Switzerland

Contact Name: Stephanie Vollenweider

Contact Email: hta@bag.admin.ch

Copyright: Swiss Federal Office of Public Health