NICE guidelines on CEUS Liver - HD

Introduction

Good afternoon everyone.

I saw the program this morning.

This possibly is not the best talk to follow immediately after lunch.

There are no pretty pictures, no movie clips, just lots of writing as the parasympathetic system kicks in.

Bear with me. Okay.

What is NICE?

First of all, I thought NICE guidelines.

Some of you probably might not be too familiar with.

NICE is the National Institute for Clinical Excellence, as it was back when it first set up in 1999 by the Secretary of State for Health.

The attempt, the intention then was to tackle inequalities in healthcare throughout the UK, the so-called post code lottery of prescriptions.

A lot of new medical technology had come in in the last 10, 15 years, with a lot of it slightly evidenced light, so it was an attempt to try and bring a sort of equality across the UK.

In 2005, this merged with the Health Development Agency.

So it then took on the role of advice in public health and changed its name to the National Institute for Health and Clinical Excellence and more recently, it's actually become a non-departmental public body.

So it's now separated itself from the government.

It is still answerable to the Department of Health, and it also now advises on social care.

So it has a very wide remit and a huge budget, something like 70 million.

This is budget for the year, and it's issuing guidelines, setting standards, advising on performance metrics to both commissioners and providers of healthcare across the whole spectrum.

Public health and social care as well.

Inside NICE, there are, to provide all this data, there are a number of what are known as programs, and one of which of these is the medical technologies program, which was set up in 2010.

And this was to address the sort of increase in emerging medical technologies to try and assess these and equate their value in healthcare.

This has got two limbs to it, one's known as the Medical Technologies Evaluation Program, which looks at sort of equipment, mainly sort of monitoring devices, some of these sort of diagnostic equipment.

And then the diagnostic assessments program, of which we're gonna talk about.

The Diagnostic Assessment Program

The Diagnostic Assessment Program looks at new diagnostic techniques.

It doesn't do it in a simple diagnostic effectiveness outcome study.

It's a much more complicated way.

It looks at a much more complicated way.

It looks at patient pathways and outcomes, as well as the actual effectiveness of the initial diagnostic technique.

And it is supported by a whole raft of independent external assessment groups.

So the committee is made up of both the standing committee and the specialist members it brings in to advise on whichever areas decided to evaluate.

The key issue about this, and this is what ties in with all of NICE, is that all assessments include a cost effectiveness analysis, okay?

The evaluation of the outcome benefits of using that particular diagnostic test.

And these are quoted in quality adjusted life years. Okay?

So the assessments may involve one test or combining a number of tests, and the process works.

The manufacturer provides the relevant data to NICE, the diagnostic assessment team.

But other independent input is also taken on board.

Because this looks at the whole pathway of the patient, often there are modeling techniques that are involved in looking at sort of the pathway that's taken because of diagnostic technique and the final outcome.

So in this cost-effective analysis, as I said, it's not just the diagnostic accuracy that we are interested in when looking at a test, we wanna know how that is going to have impact on treatment decisions and whether those treatment decisions turn out to be the right treatment decisions.

And then looking at the final outcome data for those patients and the quality of life in those patients.

And that measurement is the quality of life year, and that is costed in this cost effective ratio.

So you can bring a uniform unit that you can then compare other tests with if you apply the same modeling techniques to other diagnostic tests.

So these modeling outcome benefits, and we're gonna look at those in a moment.

They typically consider some sort of theoretical cohort of patients entering a model pathway and following them usually until death.

So that's known as the time horizon, lifetime time horizon.

And throughout this pathway, their quality of life is estimated at each turn, whether the way choose, get directed down one treatment pathway or another, and this is summated over their lifetime and used to calculate the quality adjusted life year.

Okay, so let's move on.

NICE Guidelines on SonoVue (2012)

In 2012, NICE published a date there at guidelines on SonoVue, and this was from research carried out in 2011.

So at their base, at their initial meeting, they had consulted with the clinical experts and they'd use the EFSUMB guidelines as well and decided that the area they wanted to focus on in assessing SonoVue as a diagnostic test was really in assessing focal liver lesions.

Namely ones found on unenhanced ultrasound examinations for which the data suggested there's up to 70 to 75% of these are gonna turn out to be benign.

So they're not going to require any further investigation.

And in those that are malignant, the ability of SonoVue to be able to contrast, to characterize what type of malignancy and therefore dictate the correct pathway, care pathway for that patient to enter.

The comparators that they use were what is the conventional way of assessing these indeterminate liver lesions on ultrasound, namely contrast enhanced CT and contrast enhanced MRI.

The clinical indications having discussed, consulted with the expert on the expert panel.

They felt that the main areas to focus on were the detection of HCC in patients who are being monitored for cirrhosis in a screening pathway, the detection of liver metastases in patients who have known primary colorectal cancer and just characterization of incidental focal liver lesions found by pure chance.

Again, these were very much supported by the EFSUMB guidelines deciding this.

There was an attempt also to look at the use of contrast ultrasound to assess treatment response or assessment for recurrence in patients being given local treatment for liver tumors.

And we'll touch on that in a moment.

So the test comparators have already said we're going to be contrast CT contrast enhanced MRI both using gadolinium, but also the newer liver specific agents were looked at in some of the studies.

Biopsy obviously was not considered a comparator because indeterminate focal liver lesions on ultrasound do not immediately move on to biopsy.

NICE then thought about possible diagnostic pathways for how we could examine the use of contrast enhanced ultrasound.

And here are the two that they considered the one where contrast ultrasound replaces contrast enhanced CT or contrast enhanced MRI as the next test, or one where it is used to screen out patients prior to moving on to CT or MRI.

Subsequent data analysis failed to produce enough data to be able to model that particular pathway, so that was dropped.

They also considered the care pathways for cirrhosis surveillance, the detection of focal liver lesions in cirrhosis, and the surveillance of patients with possible colorectal metastases that the treatment pathways and final outcomes for the modeling that subsequently happened.

The Research Group

So this was the group that did the research for this.

They are from the Health Technology Assessment program and a part of the National Institute for Health Research, and they were commissioned by NICE to carry out this data review.

So they looked at clinical effectiveness of the test of contrast ultrasound in the clinical areas we've already looked at and its cost effectiveness.

Clinical Effectiveness Outcomes

So looking at the clinical effectiveness, the outcomes that they were interested in was the effect of the test on planning treatment and whether that treatment turns out to be the appropriate treatment for that patient, the effect of the test on the final clinical outcome for that patient, the ability of the test to predict the clinical outcome for that patient, and a standard sort of test accuracy assessment.

But what they were also interested in was the non-diagnostic lesions that came out of the contrast ultrasound examination.

Additional outcomes that they were interested in was the acceptability patient acceptability for this test.

Anxiety levels. These all factor into the quality adjusted life year calculation.

Adverse events were also recorded, although there weren't many in the data they collected, and whether contrast ultrasound was able to identify any additional focal liver lesions over the ones that they were targeting at their time.

Methods for Clinical Effectiveness

So the methods they used, they used a database search looking at a number of databases, trial registers, conference abstracts, looking for randomized controlled trials, non randomized controlled trials, observational studies and test accuracy studies.

They use an extraction, a screening process where two of the members of the team screened out all of the studies, and then those that were accepted, the data was extracted and a quality assessment was made on that data using a model called the QUADAS 2 model, which looks at possibilities of bias in patient recruitment, how the trial runs, et cetera.

The clinical conditions for each of those studies was recorded.

IE was a cirrhosis patients, colorectal cancer screening, the type of target lesion and which comparative test was used.

And for all of these, the true positive, true negative false positive, false negative sensitivity and specificity were calculated if there was possible, they tried to pool data where similar studies were using similar techniques and similar definitions or pathology to generate combined sensitivity and specificity calculations.

So out of it. So I got 859 documents.

I think they originally identified, they actually got down to 21 studies out of 22 publications.

And not surprisingly, most of those were data test accuracy, diagnostic test accuracy studies.

So we had seven that were looking at characterizing lesions and cirrhosis monitoring.

Four in patients, people with known primary cancer, not all colorectal cancer.

Six where there was just an incidental liver lesion found.

And then there were two other additional, three studies and a further study looking at patients looking at assessing treatment response in patients with known liver cancer or predicting the effectiveness of treatment with a pre-treatment scan.

Focal Liver Lesions in Cirrhosis

So looking at the focal liver lesions in cirrhosis, there were seven studies that diagnosed 369 malignancies and in all these focal liver lesions detected at baseline ultrasound, they were all less than 30 millimeter.

There was some variation across the studies about the definition of what a positive IE looks like an HCC diagnosis was.

So that was a bias in this group.

However, there was across the board no significant difference in test performance between CT and contrast ultrasound.

There was one study that subdivided this 30 millimeter cutoff group into less than 10 millimeter, greater than 10, who felt the contrast ultrasound might not have any sensitivity to satisfactorily exclude an HCC in these smaller group.

Some of the studies combined the imaging and showed there was increased sensitivity by combining subsequent tests for identifying HCCs.

The summary of that data was that contrast ultrasound is probably adequate for focal liver lesions between 11 and 30 millimeters.

Identifying HCCs those incidental lesions in the potential liver metastasis group, they had four studies, one, two looking at CT and MR two including those specific liver specific contrast agents in MR.

Again, there was variation in the description of enhancement for what's defining a metastasis.

However, again, across the board, no significant difference in performance between the contrast enhanced ultrasound CT and MRI or with sensitivities around 83%.

And in fact, in one study the sensitivities rose to 95%, comparing contrast ultrasound with CT in the incidental liver lesions.

There was no significant difference across the board for the different techniques.

They were able here to do a pooled sensitivity analysis 'cause some of the studies that very similar and used the same diagnostic criteria for positives, where they produced for contrast ultrasound and CT 95% sensitivities with similar specificities.

And then looking at the liver specific agents, it didn't really seem to buy any advantage with contrast ultrasound performing with 91% sensitivity compared to 82%, sensitivity for the liver specific agents, but specificity also very similar in this study.

Combining the techniques didn't seem to improve sensitivity over using contrast on its own.

Now, I touched on those studies that I mentioned.

The ones looking at use of contrast agents for assessing treatment and predicting treatment outcomes.

The data here was not felt to be adequate to go on and do the cost effectiveness calculations.

And so these were dropped from the report after that.

Cost Effectiveness

Now moving on to the cost effectiveness, and this is the key thing because this is what drives a NICE's guidelines very much it's the rock base of it.

So they did an initial literature search, database search and national guidelines search, looking for studies that describe cost effectiveness with using contrast enhanced ultrasound.

And although they found four studies that met the inclusion criteria, what they didn't have is the outcome data and the necessary detail on the patient pathways to be able to calculate those quality adjusted life years.

So the external assessment group went on and performed the de novo Health economic Analysis on various models.

The three models they used cirrhosis surveillance looking for liver metastases, detecting liver metastases in patients with known colorectal cancer.

And another pathway in the incidentally detected focal liver lesion.

In each, for each of those models, they compared contrast enhanced ultrasound with contrast enhanced CT MRI and MRI with liver specific agents.

They calculated the average costs for all these different pathways, expected life years and the quality life years for each of those different possible pathways.

For the cost of adding in contrast ultrasound, they quoted 65 pounds.

That's the cost of the agent in the UK plus loan and the slightly extra time, this is another key factor.

This was based on the idea that you would do the contrast study.

At the same time having identified the indeterminate lesion, on your screening or on your GP patient, you would immediately go on and do the contrast study there.

And then rather than rebook the patient, the cirrhosis surveillance model they used was one that already existed from peninsula.

Technology assessment group with patients entering with compensated cirrhosis being having six monthly ultrasounds up until 70.

During that time they may develop decompensated cirrhosis, they may develop an HCC, they may have resection, they may have treatment.

There's multiple stems to this model.

They used a sensitivity for non-contrast ultrasound.

The screening ultrasound for small lesions IE under 10 millimeter of 10%, 29% for medium sized lesions and lesions over 30 millimeter was 75%.

That's based on that data. I'll just show you the Bennet Atal.

And they worked in the principle that 43% of these lesions you'll are going to identify in cirrhosis patients are going to be characterized as inconclusive and therefore will go on and have some form of characterization study.

The data they use for the sensitivity of these various tests came from Leoni here, and fairly similar except MRI stands out as a little bit better for the sensitivity of detection of HCC, the initial cost effect list analysis for these three models, either IE using contrast ultrasound versus CT or MRI, which suggests that ultrasound has the edge.

It's out there as being slightly more cost effective over the lifetime of that patient.

And the initial cost effect in this ratio calculation for MRI comes out at 48,454 pounds per quality adjusted life year.

For those of you not familiar nice likes it to be 20,000 the I, and it definitely has to be less than 30,000 for it to get nice approval.

However, on subsequent modeling, they decided that if all ultrasound positive lesions, including the ones that you go to do a contrast ultrasound on subsequently then have to go on and have a second line of imaging.

And that if you reduce the percentage of inconclusive lesions, the 43% was suggested by brca, the expert panel review suggested it might be less than that.

That definitely that has a big impact on the final calculated quality adjusted life year and that MR then comes out as superior contrast enhanced ultrasound, The colorectal surveillance, there was another model they used by a group called brush et al.

Again, a lifetime model of following up patients who've had colorectal cancer resected having ultrasounds to assess for liver metastases.

This was the study they based the test performance on.

And as you can see, one thing that stands out slightly is this issue of specificity.

The contrast ultrasound slightly lower than the comparator tests.

The baseline assessment of lifetime costs, however, still would seem to favor contrast ultrasound.

It sits there next to CT at a similar value compared to MRI.

And all of these different test pathways have similar quality adjusted life years.

But if they theorized that if contrast ultrasound diagnosed a liver metastasis when it was not a liver metastasis and the patient then subsequently went on to have inappropriate treatment for that, this would make a massive difference.

Contrast ultrasound would drop down.

That table become very costly and very least effective as a diagnostic test.

However, subsequent sensitivity analysis showed that at the cutoff this 20,000 pounds per quality adjusted life year, both CT had the edge slightly for the probability of being cost effective.

Just over contrasting ultrasound.

Incidental Focal Liver Lesion Model

Now finally the incidental focal liver lesion.

For this, they combine those two models.

We've already talked about the cirrhosis and the colorectal cancer model with an analytical model that they devise for a decision tree when you come across an incidental focal liver lesion, which has increasing branches of diagnostic choices, starting with the unexplained focal liver lesion, for all other cancers other than metastases that might be discovered along these incidental focal liver lesions.

They used the same quality adjusted life year calculations they used for HCCs.

This was the pooled multivariate analysis study that they used for their input data for sensitivity of contrast ultrasound and of CT.

And they worked in the principle of a very low probability and the incidental liver lesions a very low probability of actually being malignant.

The cost analysis of this showed that contrast ultrasound came out as very cost effective compared to CT compared to MR and throughout whatever modeling they used with the sensitivity analysis, they subsequently went on contrast ultrasound did favor over all the other, both other techniques, so with a more than 95% guarantee of it being a 20,000 pounds per quality adjusted life year gained.

Committee Review and Final Guidelines

So that was the data presented to the committee and when they reviewed it, these are the factors that came out when they were just making the final decision.

They identified that the studies were flawed.

There is a lot of bias in patient selection.

A lot of patients potentially excluded.

Patients who didn't have any tumor in the liver would possibly skew the specificity data.

However, for contrast ultrasound in the incidental focal liver lesion, the cost advantage was seen as quite clear over the other two parameters.

We saw that the colorectal cancer and metastases, they were CT and contrast ultrasound were extremely similar.

However, there already exist NICE guidelines where the recommendation for the investigation of metastatic disease and colorectal cancer is contrast enhanced CT.

And I think that's possibly what pushed it in that direction.

However, they acknowledged that contrast enhanced ultrasound would be a good test still for this if there was some reason that the patient couldn't have a CT.

Likewise for the cirrhosis model, MR as we saw for the quality adjusted life years did come out on top after that modeling that they formed where they reduced the number of indeterminate focal liver lesions.

But they acknowledged they didn't really know what that value was.

And this is something that needs further looking into the number of inconclusively lesions at a non-contrast ultrasound examination.

Other issues that were discussed with the training to support the service if we were to develop this service across the UK and the emphasis on the costing fact.

The fact that this has all been costed on the fact of the contrast ultrasound being performed at the same time as the initial scan.

So those are the guidelines written out, but I'm sure you are all very familiar with them.

Namely number one, contrast ultrasound with SonoVue is indicated for characterizing the incidental focal liver lesion in number two.

In patients who have potential metastasis from known primary cancer, it is indicated it can be used if for some reason the patient cannot have a CT, CT is inappropriate possibly 'cause of renal function or patient choice.

And likewise with cirrhotic patients with cirrhosis, having a screening for the characterization of the indeterminate liver lesion, MR is first line choice, but contrast ultrasound is acceptable if for some reason accessibility is an issue, which it is in this country, or there is some contraindication to the patient having an MRI scan.

Research Recommendations

The research recommendations that came out of this, and we touched on them already, was Why are lesions inconclusive and the true number of inconclusive lesions that we come across on unenhanced ultrasound and they wanted more information on patient preference because as I said, patient preference reduced anxiety.

These have influence on the final calculated quality adjusted life years along with those guidelines that came out in 2012 were a number of other documents which I'm just gonna touch on quickly.

Implementation Advice Document

This one was an implementation advice document that was produced in collaboration with these hospitals where there was already a lot of expert experience in the use of SonoVue.

They again highlighted the fact that the majority of focal liver lesions are gonna be benign.

They are not going to go any further down a pathway if they're characterized correctly.

They advocated that contrast ultrasound therefore be used as an alternative to the conventional pathway back then, which was still very much CT or MRI for characterizing indeterminate focal liver lesion.

It avoids secondary referral, it avoids specialist referral and expedites the result to the patient reduced patient anxiety, less appointments for the patient.

So their suggested actions about instigate, and this is for people wanting to instigate it, obviously getting very familiar with the EFSUMB guidelines is a key factor and there are a number of things set into the general framework.

But this one I would really want to emphasize 'cause this is my personal experience is something that really will of course want to fault at the beginning is agreeing a diagnostic pathway within your trust.

I'm afraid to say in my trust I still have not achieved that because there are some people who have very strong views about the use of MR in characterizing focal liver lesions and we have not yet reached an agreement on that, but I think that's probably the most key thing if you want it to succeed because it really has sort of impacted on how we can set up our program at St. George's.

All these other things listed, yes, they're important I think, but I think that's the absolute number one, getting an agreement on the diagnostic pathway within your department or across the trust even The other issue they targeted, which is very important to meet this you know these calculations of efficiency costs in that the study has to ideally be done at the same time as that initial non-contrast study.

And these were suggested ways of having flexible clinics where there's always someone in the department who's able to perform the study.

'cause we are aware that it is still fairly specialized.

Not a large number of people still can perform this as yet.

Ability to review images and decide there, and then whether a patient needs to have it or the possibility of dedicated clinics as some people run.

There's also an electronic audit tool that's on the NICE website if you want to audit it, if you're providing your meeting, those recommendations, those guidelines and a costing template is provided, which you can enter the data for your, the area that you work in, in the UK and model how you are going to change your use of contrast ultrasound to give, produce a costing sheet as that to give to your managers to show that you are going to save the trust loads of money.

Recent Studies and Updates

Now finally, there's just a couple of studies looking back at those areas that required sort of further investigation.

There was a study published in this research in research notes recently.

And this was based around some targeted interviews performed around those trusts that we saw that developed those advice document.

And it really was looking at the pathway, our pathways for the investigation of focal liver lesions was across the UK and the results that came out of it really were that yes, there's a huge still massive heterogeneity of the way we investigate focal liver lesions in the UK.

Something that we certainly ought to address.

And that contrast enhanced ultrasound really at the moment is still probably being used as a triage test rather than the correct alternative test to CT and MR what also came out of it though was that they had a lot of evidence to say that patients preferred using contrast ultrasound.

They found it less stressful, they liked the instant result providing it was normal.

And so a lot of positive feedback on that question.

The other bit of data that came out of Newcastle, and I was published in ultrasound last year looking at these inconclusive lesions, trying to get a handle on how many inconclusive lesions we are looking at with focal liver lesions.

And they did a huge retrospective review back through all their ultrasound reports going back 21 and just over 20, well over nearly 20, nearly 22,000 outpatient general and GP ultrasound records and identified these where focal liver lesions had been described in the report.

And then these were individually read through and they interestingly found that for GP ultrasound generated about 18%, just over 18% of indeterminate focal liver lesions as opposed to outpatient ultrasound.

That's probably not surprising, a slightly higher percentage of indeterminate focal liver lesions in patients referred from outpatients.

What is interesting though is that in the cirrhosis group of those outpatient ultrasounds, which made up about 10% of the outpatient ultrasounds, indeterminate liver lesions came out as 47%.

So not the 20% that the remodeling was done to give that quality adjusted life year, which favored MR for.

So that's certainly something to think about.

However, with that in mind, the final, the guidelines have been finally reviewed this at the end of 2015.

The feeling was there was no change in the evidence of the technology, the costs to lead to any changes and recommendation.

And that evidence that addressed the research questions, namely the sort of indeterminate liver lesions and patient preference satisfaction reduced anxiety had been addressed.

So these guidelines have now been moved over to what is known as the static guidance list.

It sits next to CT scanners, I think on next, the only other one on it at the moment.

And unless there's some dramatic change in the data, that's where they'll stay as they are for now.

Thank you very much. That's their website if you want to go and read about it, there's.