Guidance

3 Clinical evidence

3 Clinical evidence

Summary of clinical evidence

3.2

The key clinical outcomes for the geko device presented in the decision problem were:

  • venous transit time, blood flow and blood velocity

  • incidence of deep vein thrombosis

  • incidence of pulmonary embolism/venous thromboembolism

  • patient adherence.

3.3

In its evidence submission, the sponsor presented 7 studies, an interim report (Khanbhai et al. 2013) and some post-marketing surveillance data about the geko device. Two of the 7 studies were published reports (Tucker et al. 2010 and Warwick et al. 2013) and 3 were unpublished studies (Jawad [cardiac], Jawad [coagulation] and Jawad [versus intermittent pneumatic compression]) based on a PhD thesis by Jawad (2012). The other 2 papers reported results from a study by Williams (a published poster [Williams published, 2013] and an unpublished manuscript [Williams unpublished, 2013]).

3.4

The External Assessment Centre considered that 3 of the 7 sponsor-submitted geko studies provided relevant evidence in line with the comparators and outcomes defined in the scope. The 4 studies excluded from further consideration by the External Assessment Centre were: Tucker et al. (2010), because the comparators were baseline measures and voluntary muscle action (dorsiflexions); Warwick et al. (2013), because of the lack of a proper control arm; Jawad (cardiac) (2012), because of the use of cardiac outcomes not defined in the scope; and Williams (published 2013), because it did not provide sufficient details of how baseline measurements were obtained.

3.5

Jawad (coagulation; 2012) described measurements taken in 10 healthy people using the THRIVE device (a predecessor of the geko device). Participants were placed in airline-style seating for 4 hours with the device activated for 5 minutes, every 15 minutes. All measurements were repeated in a second visit without the device to provide baseline values. Measurements of arterial and venous blood flow were made using colour flow duplex ultrasound and laser doppler flowmetry. A statistically significant increase was observed in mean venous blood flow (p≤0.001) and mean venous peak velocity (p≤0.001) with the device when compared against baseline values in the same leg. The highest increase was found after 3 hours in both measures (+326% and +181% respectively) during the 4-hour session. No statistically significant difference from baseline was observed in mean arterial velocity, although mean arterial volume increased significantly (p≤0.05). The majority of people reported only mild discomfort with the device. During public consultation, the sponsor presented additional results from this study on the changes in the adjusted mean tissue plasminogen activator antigen concentration.

3.6

Jawad (versus intermittent pneumatic compression; 2012) compared the efficacy of the geko device in enhancing lower limb blood perfusion against 2 intermittent pneumatic compression devices (Huntleigh Flowtron Universal and Kendall SCD Express) in 10 healthy people. Measurements were made using colour flow duplex ultrasound and laser doppler fluximetry. The median (and inter-quartile range) values for the venous blood volume flow were 123.5 ml/min (73.4) at baseline, 163 ml/min (105.3) for the geko device at a normal clinical use setting, 129 ml/min (42.7) for the geko device at a threshold setting (the minimum setting to elicit a minor muscular contraction in both the calf and the foot) and 118 ml/min (72.7) and 115 ml/min (60.2) for the 2 intermittent pneumatic compression devices. Therefore, the geko device increased venous blood volume flow by approximately 30% more than intermittent pneumatic compression devices (p≤ 0.001). The geko device also increased arterial blood volume flow by approximately 30% (p≤0.001), arterial blood velocity by 24% (p≤0.001) and total microcirculatory blood velocity by approximately 370% (p≤0.001). When using a visual analogue scale, no statistically significant differences in discomfort were found between the geko device and the intermittent pneumatic compression devices (p≥0.05).

3.7

A study by Williams et al. (2014) compared the geko device against an intermittent pneumatic compression device in 10 healthy volunteers. The study found that venous blood flow was statistically significantly increased with the geko device (101%) compared against the intermittent pneumatic compression device (3%) (p=0.002) and peak venous velocity was statistically significantly increased with the geko device (103%) compared against the intermittent pneumatic compression device (51%) (p=0.002).

3.8

The sponsor presented post-market surveillance data based on self-completed questionnaires from 216 people who had used the geko device in the UK after either vascular or orthopaedic surgery or non-surgical treatment. The data showed that in general the device adhered well to the leg, was easy to apply and use, and was comfortable to wear. At consultation, further data were presented. In response to a question asking how many days the device was worn, 98% (121/123) of patients wore the geko device for 1 or more days. The question was amended during data collection to ask how long the device was worn and 44% (41/93) of patients responded that they wore the device for 24 hours or more.

3.9

As part of its response to consultation, the sponsor also submitted interim unpublished results from 2 ongoing studies. One study was designed to compare lower limb circulation during intermittent pneumatic compression of the foot with the geko device after elective total hip replacement. The study is a single-centre, randomised, intra-patient comparison involving 10 patients in a UK centre. Blood flow is measured using duplex ultrasound, and patient tolerability is measured using a questionnaire. Interim results on 7 patients were submitted as commercial-in-confidence data. The second study, which is described as a pilot involving a planned total of 40 patients, is a multicentre, randomised, open-label investigation comparing the incidence of asymptomatic and symptomatic deep vein thrombosis with the geko device against thromboembolic deterrent stockings after elective total hip replacement. Asymptomatic deep vein thrombosis and blood flow measurements are carried out using duplex ultrasound at baseline, day 2, at discharge and 6 weeks after surgery. Interim results on 16 patients were submitted on a commercial-in-confidence basis.

3.10

A meeting abstract (Barnes et al. 2014) became available after the medical technologies consultation document was issued. This described a study in which blood flow in people with peripheral arterial disease wearing the geko device for 40 minutes was compared with baseline values. Results for 16 patients showed a statistically significant increase in arterial, venous and microcirculatory flow.

3.11

The External Assessment Centre noted a number of limitations of the clinical evidence presented in the sponsor's original evidence submission:

  • All the geko studies included only healthy people: there were no studies on patients or in clinical settings.

  • In some of the studies, people were positioned in economy-style airline seating, which is not representative of a typical hospital setting.

  • In the submitted evidence, the longest period of time for which the device was continuously active was 30 minutes.

3.12

The External Assessment Centre critically appraised all of the additional evidence and information submitted during consultation. It concluded that, although relevant to the scope, it did not provide conclusive evidence for the clinical effectiveness of the geko device, or for its mechanism of action. The External Assessment Centre considered that the new evidence submitted during consultation was promising because the studies were conducted in a patient population with an activated geko device. However, it noted significant limitations in the study methodology and the level of information provided. In particular, the External Assessment Centre judged that the additional information contained conflicting information and was inconclusive about the effect of shear stress on the endothelium. It noted that the Barnes et al. (2014) abstract contained very few details of the study, that it was not on people at risk of deep vein thrombosis, and that it showed an increase in venous blood flow comparable to that demonstrated in existing studies. The External Assessment Centre also reviewed the additional post-market surveillance information presented during consultation. It considered that these data did not provide a sufficiently detailed description of either how long the geko device was activated, or if acceptability and tolerability for patients were related to the period for which the geko device was activated. The External Assessment Centre also noted that the number of patients who stopped using the geko device, or the rationale for stopping use, were not reported in the post-market surveillance report.

Evidence on other neuromuscular stimulation devices

3.13

In its submission, the sponsor presented evidence on other mechanical venous thromboembolism prophylaxis methods including neuromuscular electrostimulation and intermittent pneumatic compression studies. Using the sponsor's search strategy, the External Assessment Centre identified a total of 22 studies (15 neuromuscular electrostimulation and 7 intermittent pneumatic compression). It excluded 10 of these (4 neuromuscular electrostimulation and 6 intermittent pneumatic compression) and identified, from its own literature search, 5 further studies. Of the resulting 17 studies, 6 presented evidence on the effect of neuromuscular electrostimulation on the incidence of deep vein thrombosis with all but 1 (Moloney et al. [1972]) showing a reduction.

3.14

The External Assessment Centre judged that the efficacy demonstrated by other neuromuscular electrostimulation or intermittent pneumatic compression devices currently in use could not be generalised to the geko device. It noted that other devices use different methodologies that introduce uncertainties related to the type of muscle contractions caused by the geko device.

Committee considerations

3.15

The Committee noted that most of the studies on the geko device involved healthy people, but acknowledged that there were some relevant data on patients (see sections 3.8 to 3.10). The Committee was advised by clinical experts that it is likely that the blood flow results from healthy people are generalisable to patients at high risk of venous thromboembolism. The Committee judged that, on balance, the generalisability of the blood flow results to patients was plausible and concluded that the increased blood flow benefits of geko should be realisable in patients who are unable to receive other methods of mechanical prophylaxis.

3.16

The Committee debated at length whether evidence of increased blood flow during use of the geko device could be used as a surrogate for effectiveness in reducing the risk of venous thromboembolism. The Committee heard a range of expert opinions, a majority of which advised that this assumption was reasonable. It therefore accepted that the available data on measurements of blood flow provide some support for the claim that the device reduces the risk of venous thromboembolism. However, further research is needed to confirm that the geko device reduces the incidence of venous thromboembolism in clinical practice, and to demonstrate conclusively the size of the risk reduction associated with its use.

3.17

The Committee noted no evidence of harm to patients from the geko device. It heard expert advice that the risk of harm is very low and the expert advisers had no concerns about possible side effects. The Committee considered that this was particularly important in the context of the population in the scope, who might otherwise not be offered prophylaxis.

3.18

The Committee was mindful that the population in the decision problem included only people who have a high risk of venous thromboembolism and for whom other mechanical and pharmacological methods of prophylaxis are impractical or contraindicated. It considered that the incidence of venous thromboembolism in this population, without any prophylaxis, is likely to be high and that the geko device offers plausible benefit with a low risk of harm.

3.19

The Committee discussed other potential benefits of the geko device for patients. It noted the post-market surveillance data and heard expert advice that the geko device is simple to use and offers advantages in terms of mobility and comfort, which may help improve adherence to its use. The Committee judged that the geko device may offer an acceptable alternative means of prophylaxis to those who are unable to use current methods. It noted that the benefits to patients of this device should become clearer as the evidence base in hospitalised patients matures.

3.20

The Committee noted that there were a number of ongoing studies and considered that further research on the geko device, in clinical settings, would be useful in resolving the uncertainties about how much it reduces the risk of venous thromboembolism. The Committee recognised the practical difficulties of conducting studies in people who cannot receive existing methods of venous thromboembolism prophylaxis because of the small numbers and particular circumstances of such people. However, data on its use could be collected and audited, and could contribute to the evidence base. If research demonstrated that the geko device is as effective as other mechanical methods of prophylaxis, particularly intermittent pneumatic compression, then its use might be supported in a broader population. The Committee wished to give strong encouragement to both research and data collection.