3 Evidence

Clinical evidence

The clinical evidence comprises 30 published studies

3.1 The clinical evidence comprises 17 published studies, which include 169,063 patients referred to ambulatory monitoring, and 13 abstracts:

1 UK-based randomised controlled trial (Kaura et al. 2019)
3 prospective within-subject comparative studies (Barrett et al. 2014, Eysenck et al. 2019, Rosenberg et al. 2013)
6 prospective non-comparative studies (Rho et al. 2018; Heckbert et al. 2018, Reed et al. 2018, Schreiber et al. 2014, Steinhubl et al. 2018, Turakhia et al. 2015)
7 retrospective non-comparative studies (Eisenberg et al. 2014, Go et al. 2018, Schultz et al. 2019, Solomon et al. 2016, Tung et al. 2015, Turakhia et al. 2013, Wineinger et al. 2019)
13 abstracts (Agarwal et al. 2015, Chandratheva et al. 2017, Ghosh et al. 2018, Hall et al. 2019, Keibel, et al. 2015, Malhotra et al. 2018, Miller et al. 2014, Norby et al. 2018, Salazar et al. 2011, Sattar et al. 2012, Su et al. 2014, Turakhia et al. 2012, Ullal et al. 2013).

The external assessment centre (EAC) noted that some of the non-comparative studies may have overlapping populations because the data are retrospective. For full details of the clinical evidence, see section 3 of the assessment report, which is in the supporting documents for this guidance.

Four comparative studies are considered pivotal to the decision problem

3.2 Three of the 4 comparative studies compared 14-day Zio XT with a 24‑hour Holter monitor (Barrett et al. 2014, Kaura et al. 2019, Rosenberg et al. 2013) and 1 compared it with an external loop recorder (the Novacor R. Test; Eysenck et al. 2019). The size of the studies varied, with a total of 357 participants, including people with a recent stroke or transient ischaemic attack (TIA), people with pacemakers or diagnosed atrial fibrillation, and people with suspected arrhythmia. The EAC considered the multicentre UK randomised controlled trial to be the highest-quality study (Kaura et al. 2019). The EAC judged the other 3 comparative studies to be of adequate quality. The EAC did not do a meta-analysis because it considered the evidence to be too heterogeneous in terms of populations, methodology, comparators, and outcomes reported.

The UK-based randomised controlled trial has a high withdrawal rate because there was a high refusal rate for the Holter monitor

3.3 The randomised controlled trial compared the diagnostic yield of 14-day Zio XT with 24‑hour Holter monitoring in 116 people with stroke or TIA. There was a high withdrawal rate from the Holter group because 20% of the randomised participants refused to use the 24‑hour Holter monitor. This may have biased results. According to the study authors, the study was adequately powered for the primary outcome. An independent power analysis carried out by the EAC found that the randomised controlled trial was likely to be underpowered because of the high withdrawal rate. The study is underpowered for the secondary outcomes, which included anticoagulation use and mortality.

Evidence suggests that monitoring with Zio XT increases diagnostic yield

3.4 Three studies comparing arrhythmia detection rates for Zio XT with 24‑hour Holter monitoring showed an increased diagnostic yield with Zio XT over total wear time. Results from Eysenck et al. (2019) indicated that Zio XT may be more accurate in detecting the presence or absence of atrial fibrillation than the Novacor R. Test (an external event loop monitor, described as current standard practice) but less accurate than pacemaker data (described as gold standard).

Evidence suggests that patients found Zio XT acceptable and wore it for most of the scheduled days

3.5 Evidence from comparative studies suggests that most patients were happy to wear the Zio XT biosensor, with median wear time ranging from 10.8 days (Rosenberg et al. 2013) to 12.8 days (Eysenck et al. 2019) out of a scheduled 14 days. In Eysenck et al. (2019), the Zio XT biosensor was worn for longer than 3 other continuous cardiac monitors evaluated. In Barrett et al. (2014), 93.7% of participants found the biosensor comfortable to wear compared with 51.7% for the Holter monitor. A survey into patients from a UK cardiology clinic (Hall et al. 2019) found that Zio XT was significantly preferred to Holter monitoring in terms of shape, comfort, practicality and returning method.

The diagnostic accuracy of Zio XT and the impact of the technology on clinical outcomes are uncertain

3.6 The diagnostic accuracy of Zio XT compared with standard care was not clearly defined in any study. Barrett et al. (2014) and Rosenberg et al. (2013) carried out some analysis comparing a Holter monitor and Zio XT over the same 24‑hour period with different results. Rosenberg et al. (2013) reported that there was significant agreement between Zio XT and the Holter monitor recordings over the same 24‑hour period. However, Barrett et al. (2014) reported the Holter monitor detected 11 arrhythmia events that were not detected by Zio XT over a simultaneous 24‑hour monitoring period. The authors stated that 2 were caused by Zio XT algorithm misclassification, which was then corrected, and 7 were errors made by the company's report reviewer. A technical study by Hannun et al. (2019) reported good diagnostic performance for the deep neural network used as part of Zio XT compared with a committee of cardiologists. There is no evidence to show that an increased diagnostic yield with Zio XT improves clinical outcomes. The EAC considered that, without more information about diagnostic accuracy, it's not clear if the changes to treatment reported in the studies were an appropriate response to the patient's condition.

The evidence for Zio XT is broadly generalisable to NHS practice

3.7 Five studies were done in the UK and the EAC considered the evidence is generalisable to the NHS: 2 comparative studies (Kaura et al. 2019, Eysenck et al. 2018), 1 prospective non-comparative study (Reed et al. 2018), and 2 conference abstracts (Chandratheva et al. 2017 and Ghosh et al. 2018). The 2 remaining comparative studies were in the USA.

Cost evidence

The cost evidence comprises 5 published studies

3.8 Five published studies reported the economic impact of the technology:

a UK budget impact analysis (Kaura et al. 2019)
a UK study reporting technology costs using data from the REMAP-AF trial (Eysenck et al. 2019)
a prospective matched cohort study reporting healthcare resource use (Steinhubl et al. 2018)
2 conference abstracts (Ghosh et al. 2018, Chandratheva et al. 2017).

Two studies reported that the technology was cost saving. Two reported it was not compared with other devices including Holter monitoring. Studies consistently reported that Zio XT is the most efficient in terms of avoiding delays between clinic and diagnosis confirmation.

The company presented 3 cost models showing that monitoring with Zio XT saves between £55 and £85 per patient over 1 year

3.9 The company created 3 de novo cost analyses comparing the 14-day Zio XT with blended strategies, based on a 24‑hour Holter monitor or a cardiac event recorder, in different care pathways:

The cardiology model (presented as a base case) considered people with symptomatic palpitations or syncope and assessed the costs associated with the diagnostic process only.
The stroke model (presented as a base case) considered people who have had a stroke or TIA and assessed the costs associated with the diagnostic process only.
The downstream stroke model was presented as a scenario analysis and extrapolated the economic consequences of the extra risk of recurrent stroke because of delayed or missed diagnosis of atrial fibrillation.

All models had a time horizon of 1 year. Overall, the company's models showed that using Zio XT saves between £55 and £85 per patient because of reductions in repeat testing, referrals or cardiology outpatient review, and events in stroke populations. For full details of the cost evidence, see section 4 of the EAC's assessment report in the supporting documents for this guidance.

The EAC's changes to the models make monitoring with Zio XT cost incurring

3.10 The EAC revised the base-case (cardiology and stroke) models to address some potential limitations:

the proportion of patients having repeat Holter tests after 24‑hour Holter monitoring was changed to 27%
NHS reference costs were used for Holter monitoring rather than Patient Level Information and Costing System (PLICS) data
the cost of an outpatient visit before discharge was included for all tests.

The EAC revised the downstream stroke model to:
include the cost of anticoagulants (and their side effects)
lower the estimated stroke risk
include repeated diagnostic test costs.

The EAC considered the downstream stroke cost model the most informative. After these revisions, the EAC concluded that Zio XT is unlikely to be cost saving when compared with current practice. Zio XT became cost incurring by:
£0.82 per patient per year in the cardiology model
£70.81 per patient per year in the stroke model
£20.83 per patient per year in the downstream stroke model.

Scenario analyses suggest that cost saving is influenced by the number of repeat tests and outpatient follow-up visits

3.11 The EAC did a scenario analysis to explore the impact of repeat monitoring after a negative test. Zio XT was cost incurring when all monitoring was repeated after a negative test. When monitoring with a 24‑hour Holter or a 7-day cardiac event recorder was repeated after a negative first test, but Zio XT was not repeated, the technology was cost saving. The EAC also explored the impact of excluding follow-up outpatient visits after monitoring for some or all tests. It also modified the model structure to include the sensitivity and specificity parameters of the tests. For full details, see the addendum to the EAC's assessment report in the supporting documents for this guidance.

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Zio XT for detecting cardiac arrhythmias