Cardiovascular disease: risk assessment and reduction, including

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

1 of 37

2018 surveillance – Cardiovascular disease: risk assessment and reduction, including lipid modification (2014)

NICE guideline CG181

Appendix B: stakeholder consultation comments table

Consultation dates: 19 October to 03 November 2017

Do you agree with the proposal to partially update the guideline?

Stakeholder

Overall

response

Comments

NICE response

Medicines and

Technologies

Programme

Yes

No comments provided

Thank you.

Primary Care

Diabetes Society

Yes

No comments provided

Thank you.

NHS Medway CCG

Yes

No comments provided

Thank you.

Wolfson Institute of

Preventive Medicine

Not

answered

The opportunity to comment on the guideline on cardiovascular disease is welcome.

Thank you.

Boston Scientific

Yes

No comments provided

Thank you.

Association of British

Clinical

Diabetologists

(ABCD)

Yes

No comments provided

Thank you.

Royal College of

Nursing

Yes

There is a strong indication that there is substantial evidence for the required update. The issues

highlighted appear relevant.

Thank you.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

2 of 37

Novo Nordisk

Yes

No comments provided

Thank you.

Public Health

England

Not

answered

No comments provided

Stakeholder provided no comment.

HEART UK- The

Cholesterol Charity

Not

answered

No comments provided

Stakeholder provided no comment.

Amgen Ltd

Yes

We feel that it is essential that the Guideline is reviewed and specifically the following key areas

are covered in the Guideline update (see lines below):

1) Absolute clarity on the frequency of monitoring and follow up of both primary and secondary

prevention patients to ensure that lipid levels are adequately controlled in a timely manner and

that patients receive the appropriate advice, care and medication they need to modify their lipid

levels and reduce their risk of cardiovascular events.

We support expert feedback which highlighted that further guidance was considered necessary

on the methods to use across the healthcare pathway to identify people with an estimated

increased risk of CVD, how frequently this identification should be done and which healthcare

professionals should carry it out. It is disappointing to note (page 5) that despite the fact new

systematic review evidence indicates that more frequent monitoring strategies are cost effective,

NICE seem to have taken the view that this partially supports the current recommendations (i.e.

to use a systematic strategy to identify people who are likely to be at high risk) but that as

CG181 does not stipulate monitoring frequencies new evidence is unlikely to change guideline

recommendations.

We feel that clinical guidelines should provide clear guidance to the NHS thereby avoiding

inappropriate variation in patient treatment and ensuring patients at high risk are both identified

and have their treatment optimised appropriately in an efficient and timely manner to prevent

avoidable events. We therefore recommend that NICE clearly consider monitoring and follow up

frequency of both primary and secondary prevention patients. Clinicians currently have a suite of

lipid modifying therapies available to them which can be used to dramatically decrease the risk

of cardiovascular events. However, without clear and effective monitoring to identify appropriate

patients, initiate treatment and subsequently manage their lipids through to an optimal lipid

lowering regime, patients are left at significant cardiovascular event risk. Cardiovascular events

are life-changing and importantly avoidable, contributing to a considerable burden on the NHS

and society.

With regard to patient follow-up, we note the current guideline recommendation 1.3.28 (as

detailed on page 30) indicates following up patients at 3 months of treatment. However,

Thank you for comments.

1) frequency of monitoring

The surveillance review did not find evidence to impact

on recommendations 1.3.28 and 1.3.29, relating to

initial follow up at 3 months and thereafter annual

medication reviews for people taking statins. Since the

new evidence for annual monitoring was derived from

computer models, there is unlikely to be an impact on

the guideline until further validation studies become

available to substantiate the findings. New research

will be considered in this area at the next surveillance

review.

2) Monoclonal antibodies

The surveillance review acknowledged the potential

value of PSCK9 inhibitors (monoclonal antibodies) in

prevention of CVD, which is captured by the following

technology appraisals:

TA393 Alirocumab for treating primary

hypercholesterolaemia and mixed dyslipidaemia (June

2016)

TA394 Evolocumab for treating primary

hypercholesterolaemia and mixed dyslipidaemia (June

2016)

There is a potential need for CG181 to cross refer to

these technology appraisals in the section on lipid

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(2014) NICE guideline CG181

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assuming patients do not achieve recommended targets, we feel there is unclear guidance on

how to proceed should statin treatment need to be modified or if the patient is already on

maximally tolerated statin therapy, especially as this is followed by recommendation 1.3.29

suggesting provision of annual medication reviews for people taking statins. If treatment is

modified we feel it should be explicitly stated that ongoing follow up at 3 month intervals is

recommended to ensure that optimal lipid modifying treatment is achieved quickly. Once that

has been achieved then annual monitoring is welcome, but not before. In addition, if maximally

tolerated statin therapy has been achieved and target reductions not met then clear guidance on

alternative treatment options or referrals should be made.

2) We note that the surveillance decision was made not to add the review question ‘Monoclonal

antibodies for the primary and secondary prevention of CVD’ as it is felt that new evidence is

unlikely to change guideline recommendations. It was noted however that the technology

appraisals relating to evolocumab (TA394) and alirocumab (TA393) have already been included

in the related NICE Pathway. We firmly believe that the intention of this clinical guideline should

be to provide clear clinical guidance to the NHS on the risk assessment and reduction of

cardiovascular disease, including lipid modification. As an innovative and important treatment

option for the management of patients who remain at very high risk of cardiovascular events due

to elevated LDL-C levels despite treatment with e.g. statins, we therefore feel it is imperative that

the appropriate use of PCSK9 inhibitors is clearly described in the guideline in line with their

current NICE guidance. As indicated in the review proposal, Topic experts noted widespread

confusion over the separate technology appraisals, and as such this guideline offers the perfect

opportunity for NICE to clearly guide the NHS on the most appropriate methods of lipid

modification for patients at high risk of cardiovascular events.

3) We note that the current recommendation 1.3.28 (as detailed on page 30 of the review

proposal) indicates that total cholesterol, HDL cholesterol and non-HDL cholesterol should be

measured. Since the publication of CG181 the use of PSCK9 inhibitors has been approved by

NICE (TA393 and TA394), however, qualification for treatment with a PCSK9 inhibitor is

currently based on LDL-C thresholds. As PCSK9 inhibitors represent an innovative and

important treatment option for the management of lipid levels we would strongly recommend that

LDL-C levels are also routinely measured at treatment initiation and follow up, so that

appropriate clinical decisions can be made in a timely and efficient manner to the benefit of

patients.

4) We welcome (page 39) the statement that new evidence and expert feedback indicated that

patients with statin intolerance are now recognised as a group at increased cardiovascular

disease risk, and that there is a need to set out a clearer definition of statin intolerance.

However, we would strongly challenge the findings that new evidence is unlikely to impact the

modification therapy for the primary and secondary

prevention of CVD. This will be explored in the scoping

process for the update. As noted, the technology

appraisals are already included in the related NICE

Pathway.

3) LDL-cholesterol measurement

Recommendation 1.3.28 refers to follow up of people

started on statin treatment, as distinct from people

started on PCSK9 inhibitors. We did not identify

evidence for measuring LDL-C routinely at follow up for

people started on statin treatment.

In formulating the recommendations for CG181, the

guideline committee discussed that the Friedewald

equation for calculation of LDL-cholesterol as

commonly used for risk assessment requires a fasting

sample and triglycerides below 4.5 mmol/litre. The

committee were aware that a recent very large

database analysis had revealed excess variance and

bias in the calculation of LDL cholesterol such that a

complicated table of correction factors would have to

be applied by clinical laboratories. The formula was

also limited in its utility at low LDL-cholesterol levels as

seen with high-intensity statin treatment. The use of

direct LDL-cholesterol measurement is limited by cost

and availability in the NHS. Meta-analyses of CVD

outcomes in relation to lipid fractions by the Emerging

Risk Factors collaboration and others have consistently

shown the superior predictive value of non-HDL

cholesterol (that is, the difference between total and

HDL cholesterol) on CVD events. Non-HDL cholesterol

does not require a fasting blood sample. The

committee decided that the use of non-HDL cholesterol

was preferable to calculated or measured LDL

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(2014) NICE guideline CG181

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current recommendations (to simply seek specialist advice about other possible treatment

options as there were no alternatives to statins) as no alternative treatments were identified in

the surveillance review. With reference to our comment above (2) current guidance for

evolocumab recommends it as a treatment option for patients if LDL-C concentrations are

persistently above defined thresholds despite maximal tolerated lipid lowering therapy (that is,

either the maximum dose has been reached, or further titration is limited by intolerance). It is

therefore surprising to us that ‘no alternative treatments were identified in the surveillance

review’ when the use of evolocumab is currently recommended by NICE in statin intolerant

patients and that there is clinical trial evidence for the use of evolocumab in statin intolerant

patients (GAUSS-2, J Am Coll Cardiol 2014;63:2541-8; GAUSS-3, JAMA 2016;315:1580-90).

We would recommend that this statement is reviewed and clear guidance given on approved

treatment options.

5) We agree with topic experts who noted that a review of recommendation 1.3.28 for using

high-intensity statins to achieve a percentage reduction, rather than an absolute lipid target level,

should also be undertaken, especially as feedback has indicated that the recommended

approach has not been adopted universally and many in both primary and secondary care are

still treating to target in both primary and secondary prevention. The current recommended

approach has particular issues for those patients who have extremely high lipid levels, whereby

a proportional reduction, even if quite significant, may leave patients with high lipid levels and

therefore they will remain at very high risk of cardiovascular events.

We are concerned however that NICE believes this is not supported by any new evidence

specifically for statin interventions. Given the suite of NICE approved lipid modifying therapies

that are now available to clinicians and the growing body of evidence supporting a ‘lower is

better’ approach to lipid management in order to reduce the risk of avoidable cardiovascular

events (e.g. Giugliano, http://dx.doi.org/10.1016/S0140-6736(17)32290-0; Boekholdt, J Am Coll

Cardiol 2014;64:485-94; Nicholls, JAMA 2016;316:2373-2384; Ference, Eur Heart J

2017;38:2459-2472; JBS3, Heart 2014;100:ii1–ii67) we feel it is essential that NICE reviews this

recommendation to better manage residual risk in very high risk patients.

cholesterol given its greater practicality. No evidence

was identified through surveillance to change this view.

4) Statin intolerance

Recommendation 1.3.43 relating to statin intolerance

advises that specialist advice is sought about options

for treating people at high risk of CVD such as those

with CKD, type 1 diabetes, type 2 diabetes or genetic

dyslipidaemias, and those with CVD, who are intolerant

to 3 different statins. Advice can be sought for

example, by telephone, virtual clinic or referral.

In the section of the surveillance review on lipid

modification therapy for the primary and secondary

prevention of CVD, it has been acknowledged that

there is a potential need for CG181 to cross refer to the

technology appraisals:

TA385 Ezetimibe for treating primary heterozygous-

familial and non-familial hypercholesterolaemia;

TA393 Alirocumab for treating primary

hypercholesterolaemia and mixed dyslipidaemia (June

2016)

TA394 Evolocumab for treating primary

hypercholesterolaemia and mixed dyslipidaemia (June

2016)

This will be explored in the scoping process.

5) Percentage and absolute lipid level reduction

Topic expert feedback indicated the need to review

recommendation 1.3.28 for using high-intensity statins

to achieve a percentage reduction rather than an

absolute lipid target level. This was not supported by

any new evidence in the surveillance review

specifically for statin interventions. The initial

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(2014) NICE guideline CG181

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conclusion from the surveillance review was therefore

that there is a potential future impact on this

recommendation if new evidence emerges that is

directly relevant to statins. However, the studies by

Boekholdt et al. (2014) and Ference et al. (2017) cited

in the stakeholder consultation have a potential impact

on recommendation 1.3.28, and will be considered in

the update of this areas. The other evidence cited is

either not specific to statin treatment or does not meet

the study design eligibility criteria for the surveillance

review.

For any evidence relating to published or ongoing

NICE technology appraisals, the guideline surveillance

review deferred to the technology appraisal decision.

This included evidence on alirocumab and

evolocumab.

South Asian Health

Foundation

Yes

No comments provided

Thank you.

British

Cardiovascular

Society

Yes

There have been important developments in CVD prevention in the last few years. Especially

need to incorporate new trial data on Ezetemibe and PCSK9 inhibitors and seamlessly cross

reference to relevant TAs

Thank you for the opportunity to comment on the NICE Consultation on CG181 (cardiovascular

disease: risk assessment and reduction, including lipid modification) on behalf of the British

Cardiovascular Society.

1. Multiple risk factor measurement (QRISK) screening versus age-screening

In selecting people for statin treatment age-screening has been inappropriately removed from

consideration in the proposed review of the Guideline. This needs to be rectified. The following

points are relevant to this:

I. Statins are safe and highly effective, but under-used in the prevention of cardiovascular

disease. Any new guideline should aim to simplify access to such treatment. The current

guideline is too complicated, requiring two risk factor based assessments before a person can

be considered for preventive treatment.

Thank you for your comments.

1) Age screening

The guideline committee had requested information on

age screening as part of the evidence review for

CG181. They acknowledged that since age is the most

important contributor to CVD risk, an age-alone

strategy would identify most people at risk. The

committee were concerned however that an age-alone

strategy would not allow identification of people with

increased risk at a younger age whose risk is

increased by ethnicity, comorbidity or lifestyle factors.

Younger people will also gain from treatment over a

longer time period. The only evidence available for age

was from a simulated cohort. The committee

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(2014) NICE guideline CG181

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II. A simpler approach is to offer statins according to age-alone. The most recent JBS3

Guideline acknowledges that this is a reasonable approach given that age is the dominant risk

factor determining a person’s risk of CVD. Research has shown that other risk factors (eg.

cholesterol, blood pressure etc) included in QRISK scores (the system currently recommended

by NICE) add little discrimination, but add considerable complexity. QRISK also adds

considerable cost, but NICE ignore this extra cost. This needs to be included in any comparison

of screening strategies.

III. NICE reject age-screening without giving a justification. This is wrong.

IV. NICE plan to remove any mention of age-screening, even as a research plan, without

giving a justification.

V. NICE ignore research papers that directly compare age-screening and risk factor-based

screening (eg. QRISK) both in terms of screening performance and cost. These papers

(referenced below) should be included in the new NICE guideline review, as they provide the

answer.

VI. In the previous NICE guideline, an expert advocate of QRISK (Gary Collins) was invited

to speak to the NICE Guideline Development Group more than once. Experts on age-screening

were not invited, even once. This was wrong. There is an opportunity to rectify this in this

Guideline update.

VII. In the new Guideline review process, a fair balance should be reached between the two

screening approaches. The researchers, Professor Joan Morris or Professor Sir Nicholas Wald,

who are experts on age-screening for CVD should be invited to present the relevant research to

group, so this is properly understood and included in the assessment.

VIII. Senior NICE management (eg. Mark Baker) should consider the appropriateness of

including on the NICE Guideline Development Group a member who may have an interest in risk

factor measurement for the purposes of selecting who is offered a statin. For example, anyone

who may have a professional or pecuniary interest in cholesterol measurement (eg. runs a lab

that performs such measurements) has a clear conflict of interest in seeing cholesterol

measurement remaining part of the selection process, even though cholesterol is known to be a

poor screening test.

Conclusion:

Screening based on age-alone should be on the NICE agenda.

2. Blood pressure Reduction

It is a mistake to consider cholesterol reduction in the prevention of CVD separately from blood

pressure reduction. Both risk factors should be lowered in anyone who is considered to be at

sufficient risk of a future CVD event. Both risk factors show the same log-linear relationship

between risk factor and risk of CVD, without a threshold. Both lowering cholesterol and blood

pressure have been shown to reduce risk of CVD in randomised trials. The JBS3 guidelines

considered the two risk factors together and so too should NICE.

considered it worthwhile to develop a research

recommendation to use a prospective cohort to

compare age and other simplified methods of risk

assessment with validated risk tools. The surveillance

review proposal to withdraw this research

recommendation will be reconsidered in the light of

stakeholder feedback.

It should be noted that QRISK 2 has an upper limit of

84 years. All people of 85 years and older are at high

risk of CVD by virtue of age alone. The guideline

committee stated that decisions about interventions

should be made on a clinical basis according to

proposed treatments and other factors such as

comorbidities and patient choice.

2) Blood pressure measurement

In developing CG181, the guideline committee

emphasised that lipid modification should take place as

part of a programme of risk reduction which also

include attention to the management of all other known

CVD risk factors.

Recommendation 1.3.13 states that before starting

statin treatment baseline blood tests and clinical

assessment should be performed, and comorbidities

and secondary causes of dyslipidaemia should be

treated. All of the following are recommended for

assessment:

•smoking status

•alcohol consumption

•blood pressure (see hypertension [NICE guideline

CG127])

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(2014) NICE guideline CG181

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Conclusion:

Blood pressure reduction should be considered as well as cholesterol reduction.

3. Precision of risk estimation versus estimation of health gain from preventive treatment

NICE focus on the precision of risk estimation when what is important is the benefit gained from

adopting a preventive intervention which is simply and accurately summarised with two

numbers, (i) the proportion who will benefit from adopting the intervention (realise this gain the)

and (ii) among these the average years of life gained without a heart attack or stroke. These two

metrics are the most useful in enabling a provider to recommend a preventive treatment and

helping an individual chose whether to use it (eg. statin). NICE should consider, introducing

these two metrics in their guideline update.

Conclusion

What is important is the benefit rather than the precision of risk estimation prior to preventive

treatment.

Summary

The previous iteration of the NICE Guideline sensibly reduced the risk threshold for statin

treatment, but increased the complexity of assessments needed before a statin is offered by a

GP. Recent evidence suggests that statins are only offered to 1/5th of those eligible for them.

The NICE review should consider whether this complexity is obstructing prevention. NICE

should consider focusing more on cardiovascular disease prevention and less on risk factor

measurements. Simply refining what has been done in the past is not adequate in dealing with

the public health problem.

References to be considered in this Guideline review.

1. Wald NJ, Simmonds M, Morris JK (2011). Screening for future cardiovascular disease using

age alone compared with multiple risk factors and age.PLoS One vol. 6, (5)

This paper shows that screening performance is similar using age alone compared with multiple

risk factors, but one is considerably more complex and costly than the other.

2. Simmonds MC, Wald NJ (2012) . Risk estimation versus screening performance: a

comparison of six risk algorithms for cardiovascular disease. J Med Screen vol. 19, (4) 201-205.

This paper shows that different risk algorithms (including QRISK2) have similar screening

performances. The accuracy (calibration) of CVD risk estimation does not materially affect

•body mass index or other measure of obesity (see

obesity [NICE guideline CG43])

•total cholesterol, non‑HDL cholesterol, HDL

cholesterol and triglycerides

•HbA1c

•renal function and eGFR

•transaminase level (alanine aminotransferase or

aspartate aminotransferase)

•thyroid‑stimulating hormone. [new 2014]

The related NICE guideline on hypertension covers

identifying and treating primary hypertension in people

aged 18 and over. It aims to reduce the risk of CVD by

helping healthcare professionals to diagnose

hypertension accurately and treat it effectively. Both

lipid lowering and blood pressure reduction are

included in NICE’s CVD prevention interactive

flowchart.

3) Precision of risk estimation versus estimation

of health gain from preventive treatment

In developing the guideline, the committee concluded

that primary prevention of CVD should make use of

strategies to prioritise patients likely to be at highest

risk and to invite patients in descending order of CVD

risk estimated from available data in the GP database.

Recommendation 1.1.1 advises the use of a

systematic strategy to identify people who are likely to

be at high risk.

Recommendation 1.1.5 advises discussing the process

of risk assessment with the person identified as being

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(2014) NICE guideline CG181

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screening performance. In distinguishing who will and will not develop CVD it is screening

performance that matters rather than the accuracy of the risk estimation.

3. Wald NJ, Morris JK (2014) . Quantifying the health benefits of chronic disease prevention: a

fresh approach using cardiovascular disease as an example.European journal of epidemiology

vol. 29, (9) 605-612.

This paper shows that what is important in helping a person decide on preventive treatment is

not the precision of risk estimation but the proportion of people who will benefit from a preventive

treatment and the number of years they gain without a heart attack or stroke from this treatment.

People see what they could potentially gain not just what their starting risk is.

at risk, including the option of declining any formal risk

assessment.

The surveillance review did not identify any new

evidence to impact on these recommendations, or to

support the replacement of risk estimation with the use

of estimated health gain. The studies cited in the

stakeholder consultation either preceded the

surveillance literature search period, or did not meet

the eligibility criteria. Further evidence in this area will

be considered in future surveillance reviews.

Royal College pf

Physicians and

Surgeons of Glasgow

Yes

No comments provided

Thank you.

Merck Sharp &

Dohme Limited

Yes

No comments provided

Thank you.

Sanofi

Yes

Sanofi welcomes the proposal to partially update the guideline.

Sanofi welcomes the recommendation of the topic experts that

PCSK9 inhibitors are within the scope of NICE guideline CG181 and have advised that these

should be incorporated into the guideline recommendations as part of an update.

Thank you for your comments.

Do you agree with the proposal to update the review question?

181-02 Which risk assessment tools are the most accurate for predicting the risk of CVD events in adults without established CVD (primary prevention)?

Stakeholder

Overall

response

Comments

NICE response

Medicines and

Technologies

Programme

Yes

Yes, include QRISK3 and what to do in high risk groups not covered by QRISK3.Eg. RA and

SLE are covered but not psoriatic arthritis.

Need to be clear on what to do in over 84s and people with FH.

Thank you for your comments. The surveillance review

did not identify evidence for risk assessment beyond

QRISK3 for people with psoriatic arthritis.

QRISK3 has an upper limit of 84 years. All people of

85 years and older are at high risk of CVD by virtue of

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age alone. Decisions about interventions should be

made on a clinical basis according to proposed

treatments and other factors such as comorbidities and

patient choice.

Risk assessment of people with familial

hypercholesterolaemia are covered by Familial

hypercholesterolaemia (NICE NG71).

Primary Care

Diabetes Society

Yes

No comments provided

Thank you.

NHS Medway CCG

Yes

The recommendations from the review should inform the CVD prevention rules which are

currently being developed to support the 5YFV aspirations. Contact Dr Matt Kearney NHSE, Dr

Judith Richardson NICE.

Risk should be expressed as the risk amenable to an intervention, not just as absolute risk.

This allows care to be focused on those individuals who will benefit most, it allows better

resource allocation and will therefore will produce better outcomes, given limited resources.

I can’t change a person’s age, sex, family history, ethnicity or pre-existing illnesses. Even though

this combination of factors may contribute all or most of an individual’s risk.

Thank you for your comments. The recommendations

from the review will be circulated to relevant internal

and external stakeholders.

Regarding risk assessment, in developing the

guideline, the committee concluded that primary

prevention of CVD should make use of strategies to

prioritise patients likely to be at highest risk and to

invite patients in descending order of CVD risk

estimated from available data in the GP database.

Recommendation 1.1.1 advises the use of a

systematic strategy to identify people who are likely to

be at high risk.

Recommendation 1.1.5 advises discussing the process

of risk assessment with the person identified as being

at risk, including the option of declining any formal risk

assessment.

The surveillance review did not identify any new

evidence to impact on these recommendations, or to

support the replacement of risk estimation with the use

of estimated health gain. Further evidence in this area

will be considered in future surveillance reviews.

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(2014) NICE guideline CG181

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Wolfson Institute of

Preventive Medicine

Not

answered

No comments provided

Stakeholder provided no comment.

Boston Scientific

Yes

We welcome the update of this Clinical Guideline and we would like to emphasize the

importance of access to screening for higher risk patients at the primary care level. We think

access to screening for this group of patients needs better sign posting to reduce future major

complications such as myocardial infarction or ischaemic stroke from this higher risk group (e.g.

Type 1 Diabetes and in particular female patients) (1.1.9).

Thank you for your comments. Screening is outside the

remit of the guideline but risk assessment in primary

care is covered by QRISK2, to be replaced by QRISK3

in 2018.

Association of British

Clinical

Diabetologists

(ABCD)

Yes

No comments provided

Thank you.

Royal College of

Nursing

Yes

This is a critical consideration in terms of the health promotion and will provide invaluable to the

practitioner when review differing assessment tools.

Thank you for your comments.

Novo Nordisk

Yes

1.1.10. Use the QRISK2 risk assessment tool to assess CVD risk in people with type 2 diabetes.

Although this tool in its current form allows for the additional risk of diabetes, clinicians need to

be aware that there are a number of parameters which render the resulting risk less accurate

and are likely to under-estimate the risk and these include people already taking medication for

hypertension or for cholesterol1 As this includes the majority of those with type 2 diabetes

universal use of this tool will result in widespread underestimation of risk and consequential

effects on clinical management. Guiding clinicians to use a risk assessment tool is then

confounded if they are expected to use their clinical judgement to interpret the CVD scores

On page 11 it is stated that “Topic expert feedback also highlighted that people with type 2

diabetes should not have cardiovascular risk assessment – they should be considered

automatically at high risk, but no evidence was cited in support of this”.

Evidence does exist to support this as demonstrated in a meta-analysis reviewing nearly 700

000 UK patient records from 102 prospective studies concluding that “diabetes confers with

about a two-fold excess risk for a wide range of vascular diseases, independently from other

conventional risk factors

.” It has also been long accepted that diabetes is associated with an

increased risk of MI whether or not the individual has had a prior MI.

A review to simplify this section of the guideline is necessary to fully explore the evidence to

support the recommendation that patients with diabetes are already at risk and do not require a

risk assessment. Indeed the recently updated SIGN guideline SIGN 149 • Risk estimation and

the prevention of cardiovascular disease recognises the need to automatically assess people

Thank you for your comments, which we are in broad

agreement with, as reflected by the proposal to update

this review question and to consider the use of

QRISK3 in place of QRISK2.

The guideline advises that risk assessment tools

provide only an approximate value of CVD risk, and

that risk will be underestimated in people who are

already taking antihypertensive or lipid modification

therapy:

 Recommendation 1.1.7: Be aware that all

CVD risk assessment tools can provide only

an approximate value for CVD risk.

Interpretation of CVD risk scores should

always reflect informed clinical judgement.

 Recommendation 1.1.19: Recognise that

CVD risk will be underestimated in people

who are already taking antihypertensive or

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(2014) NICE guideline CG181

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with diabetes over the age of 40 (or those under the age of 40 with >20 years duration of

diabetes or microvascular complications) as being at high risk of cardiovascular events

1.Silvia Rabar, Martin Harker, Norma O’Flynn, Anthony S Wierzbicki (2014) Lipid modification

and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular

disease: summary of updated NICE guidance

2.N.Sawar et al, Lancet 2010;Volume 375, No. 9733, p2215–2222, available at

http://dx.doi.org/10.1016/S0140-6736(10)60484-9

3.Hafner SM. N Engl J Med 1998;339:229–342

4.SIGN 149 Risk estimation and prevention of cardiovascular disease; available at

http://www.sign.ac.uk/assets/sign149.pdf

lipid modification therapy, or who have

recently stopped smoking. Use clinical

judgement to decide on further treatment of

risk factors in people who are below the CVD

risk threshold for treatment. [2008, amended

2014]

The cited studies either precede the surveillance

search period, or do not meet the study design

eligibility criteria for the surveillance review. However,

the points highlighted by the consultee specifically on

type 2 diabetes will be passed to developers for

consideration in the update.

Public Health

England

Yes

This is an important question, particularly for those in groups where Cardiovascular Disease

(CVD) risk may be higher at a younger age than those in the general population i.e. people with

severe mental illness (SMI), such as psychosis, schizophrenia, bipolar disorder.

We know that QRISK2 underestimates risk in young women, even where they have abnormal

risk factor profiles. Since this guidance was published the Joint British Cardiovascular Society

published their third set of guidelines recommending the use of lifetime rather than 10-year risk

(http://heart.bmj.com/content/100/Suppl_2/ii1 ).

Therefore, it would also be helpful to consider which is most accurate and the limitations of both

CVD risk scores in predicting risk in different groups.

The current guidance recognises that CVD risk scores will underestimate people who have

additional risk and includes people with serious mental health problems (1.1.18). Therefore, It

would be helpful to review available risk assessment tools, both developed and in use, and

those reviewed in the literature, to determine whether any are fit for purpose to be recommended

for people with SMI and younger women.

QRISK3 has been updated recently and now includes SMI as an additional risk factor and

consideration of this would be timely.

The current guidance also mentions that risk assessment tools are not appropriate for people

who have familial hypercholesterolemia (FH) (1.1.16). New NICE guidance is about to be

published on FH and this should be referenced and any updates CG181 should be aligned,

particularly 1.1.16 and 1.3.7 in the current version of CG181.

Thank you for your comments.

 Severe mental illness (SMI) and smoking status

SMI and smoking status are included as additional

variables in the QRISK3 tool. Alternative tools and

additional biomarkers are unlikely to impact on CG181

for people with additional risk, such as those with SMI,

because QRISK3 has been validated in these groups

in England and Wales, and there does not appear to

be any evidence that any of the alternative tools or

variables have been shown to improve on QRISK3.

 Familial hypercholesterolemia (FH)

The existing cross reference from the guideline to

NICE’s guideline on familial hypercholesterolemia from

recommendation 1.1.16 does not require updating as

the corresponding recommendation in the FH guideline

were not updated and remain extant.

The potential amendment to recommendation 1.3.7 to

reflect the updated recommendation in the FH

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(2014) NICE guideline CG181

12 of 37

In considering this question it would be helpful to reflect on the feasibility/cost effectiveness of

using the tools. Currently, QRISK2 is used for the NHS Health Check programme. While it is

essential that the risk score is as accurate as possible, it would be beneficial to understand the

cost effectiveness of tools that require additional information.

We would recommend interventions to identify tobacco smokers are included in the review of

tools for risk assessment. In particular, we would welcome a robust assessment of the Lester

Tool and its effect on outcomes for smoking cessation and how it compares to other

interventions such as Very Brief Advice.

guideline (NICE CG71) will be noted for consideration

in the guideline update.

 Cost effectiveness of risk tools

Alternative risk tools are unlikely to impact on the

guideline, since none have been shown to perform

better than QRISK3, and no cost effectiveness

evidence was identified to inform a health economic

analysis of the different tools.

 Lifetime risk

New evidence supporting the use of lifetime risk

calculation to more accurately assess patients for

lifestyle changes and eventually lipid lowering drugs

was not specific to the UK population. However, topic

expert and stakeholder feedback indicating the need to

review this area, combined with the fact that the

surveillance literature search strategy did not extend to

observational studies, raises a potential impact on

recommendation 1.1.4 to consider lifetime risk as an

alternative to 10-year risk. This may also have

consequential impacts on recommendation 1.1.26 for

communicating risk and on recommendations 1.3.18

and 1.3.26 for primary prevention of CVD.

HEART UK- The

Cholesterol Charity

Yes

1.1.8 QRisk 3 should be recommended instead of QRisk 2

Thank you for your comment.

Amgen Ltd

Not

answered

No comments provide

Stakeholder provided no comment.

South Asian Health

Foundation

Yes

Yes based on evidence that need to focus on most at high risk and need to review

weighting of risk scores for South Asians

Thank you for your comment.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

13 of 37

British

Cardiovascular

Society

Yes

Agree there has been sufficient new work in this area to warrant an update, especially using

novel biomarkers, imaging and including patient groups with diabetes and renal disease in risk

models

Thank you for your comment, which we are in broad

agreement with, as reflected by the proposal to update

this review question and to consider the use of

QRISK3 in place of QRISK2. Alternative tools and

additional biomarkers are unlikely to impact on CG181,

because QRISK3 has been validated in England and

Wales, and the surveillance review did not identify any

evidence indicating that any alternative tools or

biomarkers have been shown to improve on QRISK3

Royal College pf

Physicians and

Surgeons of Glasgow

Yes

No comments provided

Thank you.

Merck Sharp &

Dohme Limited

Yes

No comments provided

Thank you.

Sanofi

Not

answered

No comments provide

Stakeholder provided no comment.

Do you agree with the proposal to update the review question?

181-11 What is the clinical and cost effectiveness of statin therapy for adults without established CVD (primary prevention) and with established CVD

(secondary prevention)?

Stakeholder

Overall

response

Comments

NICE response

Medicines and

Technologies

Programme

Yes

No comments provided

Thank you.

Primary Care

Diabetes Society

Yes

No comments provided

Thank you.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

14 of 37

NHS Medway CCG

Yes

No comments provided

Thank you.

Wolfson Institute of

Preventive Medicine

Not

answered

No comments provided

Stakeholder provided no comment.

Boston Scientific

Yes

No comments provided

Thank you.

Association of British

Clinical

Diabetologists

(ABCD)

Yes

No comments provided

Thank you.

Royal College of

Nursing

Yes

This is an important consideration for the practitioner considering the correct use of limited

resources. The review question provides extensive exploration of the relevant primary data.

There is clear justification for the revision of established review question.

Thank you for your comment.

Novo Nordisk

Not

answered

No comments provide

Stakeholder provided no comment.

Public Health

England

Yes

It would be helpful for this to include cost-effectiveness for groups who have additional risk

because of underlying medical conditions or treatments (outlined in 1.1.18). If cost-effectiveness

is shown to be equal to or exceed that of estimates for the general adult population, it may help

make the case for targeting and developing specific services (or pathways into services) to focus

on these groups which may not always be well-served or prioritised by mainstream services.

Thank you for your comment. The surveillance review

did not identify cost effectiveness evidence for the

specific groups with additional risk. Evidence in this

area will be monitored for consideration in the next

surveillance review.

HEART UK- The

Cholesterol Charity

Not

answered

No comments provide

Stakeholder provided no comment.

Amgen Ltd

Not

answered

No comments provide

Stakeholder provided no comment.

South Asian Health

Foundation

Yes

Comment as above

Thank you.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

15 of 37

British

Cardiovascular

Society

Yes

Clinical effectiveness is well established, but patent expiry on high potency statins will change

cost-effectiveness estimates

Thank you for your comment.

Royal College pf

Physicians and

Surgeons of Glasgow

Yes

No comments provided

Thank you.

Merck Sharp &

Dohme Limited

Yes

No comments provided

Thank you.

Sanofi

Not

answered

No comments provide

Stakeholder provided no comment.

Do you agree with the proposal to remove the research recommendation?

RR–01 What is the effectiveness of age alone and other routinely available risk factors compared with the formal structured multifactorial risk assessment

to identify people at high risk of developing CVD?

Stakeholder

Overall

response

Comments

NICE response

Medicines and

Technologies

Programme

answer

No comments provided

Stakeholder provided no comment.

Primary Care

Diabetes Society

Yes

No comments provided

Thank you.

NHS Medway CCG

Yes

No comments provided

Thank you.

Wolfson Institute of

Preventive Medicine

Not

answered

The focus continues to be on estimating cardiovascular risk but public health priority is

administering effective and safe preventive medication to the population at risk determined as

simply as possible which in primary prevention is age. The focus should be more on intervention

combining blood pressure lowering with LDL cholesterol reduction.

Thank you for your comments. This research

recommendation will be retained and if needed, a new

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

16 of 37

research recommendation may be made as part of the

update process.

Boston Scientific

Yes

No comments provided

Stakeholder provided no comment.

Association of British

Clinical

Diabetologists

(ABCD)

Further research into uptake and effectiveness of statins in high risk ethnic groups such as

South Asian and Black groups is needed.

Thank you for your comments. This research

recommendation will be retained and if needed, a new

research recommendation may be made as part of the

update process.

Royal College of

Nursing

Yes

This research recommendation does not now appear relevant in terms of the guidelines and

therefore it is appropriate for its removal.

Thank you for your comment. Other feedback has

indicated value in retaining the research

recommendation. It will therefore be retained and if

needed, a new research recommendation may be

made as part of the update process.

Novo Nordisk

Not

answered

No comments provide

Stakeholder provided no comment.

Public Health

England

Not

answered

No comments provide

Stakeholder provided no comment.

HEART UK- The

Cholesterol Charity

Not

answered

No comments provide

Stakeholder provided no comment.

Amgen Ltd

Not

answered

No comments provide

Stakeholder provided no comment.

South Asian Health

Foundation

Still need for research into black and S Asian groups on statin uptake and even

effect

Thank you for your comments. This research

recommendation will be retained and if needed, a new

research recommendation may be made as part of the

update process.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

17 of 37

British

Cardiovascular

Society

Yes

None

Thank you.

Royal College pf

Physicians and

Surgeons of Glasgow

Yes

No comments provided

Thank you.

Merck Sharp &

Dohme Limited

Yes

No comments provided

Thank you.

Sanofi

Not

answered

No comments provide

Stakeholder provided no comment.

Do you agree with the proposal to remove the research recommendation?

RR–02 What is the improvement in the cost‑effectiveness metrics for statin therapy in reducing CVD that can be obtained when using a complete individual patient‑based outcomes

meta‑analysis data set compared with using published outcomes data?

Stakeholder

Overall

response

Comments

NICE response

Medicines and

Technologies

Programme

answer

No comments provided

Stakeholder provided no comment.

Primary Care

Diabetes Society

Yes

No comments provided

Thank you.

NHS Medway CCG

answer

No comments provided

Stakeholder provided no comment.

Wolfson Institute of

Preventive Medicine

Not

answered

It is, in our view, a mistake to remove research recommendations from screening based on the

use of age alone and hence remove discussion of this strategy. Publications have shown that in

terms of risk prediction this is nearly as effective as more complex risk estimation using multiple

Thank you for your comments, which apply more

directly to research recommendation RR-01. No new

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

18 of 37

variables including blood pressure and cholesterol. There is an urgent need to simplify the

screening process, avoid the process that creates patients as a result and a need to offer

preventive medication more widely for a disease that remains a major burden of illness and

mortality in Britain. We believe that NICE should examine approach more closely and take

evidence from a wide circle of experts in this area.

We did not understand the second bullet point regarding withdrawing research recommendation.

However, the focus should not be simply on statin therapy, it should be statin therapy combined

with blood pressure reduction.

There is an increasing body of opinion that considers so-called “risk scores” as unnecessarily

fussy in relation to public health intervention and wasteful of scarce medical resources. One of

us (NW) recently met Dr Frieden, former head of CDC in the USA. Dr Frieden has the same

view that what is urgent is global reduction of adult blood pressures and LDL cholesterol levels

rather than trying to improve the precision of risk estimates. The general topic needs further

discussion and consideration in NICE.

evidence relevant to the research recommendation

RR-02 was found and no ongoing studies were

identified in the surveillance review. Therefore the

research recommendation will be removed from the

NICE version of guideline and the NICE research

recommendations database because there is no

evidence of research activity in this area. It will,

however, remain in the full versions of the guideline.

See NICE’s research recommendations process and

methods guide 2015 for more information.

Boston Scientific

Yes

No comments provided

Thank you.

Association of British

Clinical

Diabetologists

(ABCD)

Yes

No comments provided

Thank you.

Royal College of

Nursing

Yes

Outdated findings and therefore less relevant in terms of the review.

Thank you for your comment.

Novo Nordisk

Not

answered

No comments provide

Stakeholder provided no comment.

Public Health

England

Not

answered

No comments provide

Stakeholder provided no comment.

HEART UK- The

Cholesterol Charity

Not

answered

No comments provide

Stakeholder provided no comment.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

19 of 37

Amgen Ltd

Not

answered

No comments provide

Stakeholder provided no comment.

South Asian Health

Foundation

Yes

No comments provide

Thank you.

British

Cardiovascular

Society

Yes

None

Thank you.

Royal College pf

Physicians and

Surgeons of Glasgow

Yes

No comments provided

Thank you.

Merck Sharp &

Dohme Limited

Yes

No comments provided

Thank you.

Sanofi

Not

answered

No comments provide

Stakeholder provided no comment.

Do you agree with the proposal to remove the research recommendation?

RR–03 What is the effectiveness of statin therapy in older people?

Stakeholder

Overall

response

Comments

NICE response

Medicines and

Technologies

Programme

answer

No comments provided

Stakeholder provided no comment.

Primary Care

Diabetes Society

No comments provided

Thank you. This research recommendation will be

retained and if needed, a new research

recommendation may be made as part of the update

process.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

20 of 37

NHS Medway CCG

answer

No comments provided

Stakeholder provided no comment.

Wolfson Institute of

Preventive Medicine

answer

No comments provided

Stakeholder provided no comment.

Boston Scientific

Yes

No comments provided

Thank you.

Association of British

Clinical

Diabetologists

(ABCD)

Research is needed on risk/benefits ratio of statins usage in CVD risk reduction and the use of

statins on quality of life in elderly population.

Thank you for your comments. This research

recommendation will be retained and if needed, a new

research recommendation may be made as part of the

update process.

Royal College of

Nursing

Yes

The conceptual basis of statin therapy needs to be the central concern here rather than

peripheral considerations

Thank you for your comments. This research

recommendation will be retained and if needed, a new

research recommendation may be made as part of the

update process.

Novo Nordisk

Not

answered

No comments provide

Stakeholder provided no comment.

Public Health

England

Not

answered

No comments provide

Stakeholder provided no comment.

HEART UK- The

Cholesterol Charity

Not

answered

No comments provide

Stakeholder provided no comment.

Amgen Ltd

Not

answered

No comments provide

Stakeholder provided no comment.

South Asian Health

Foundation

There remains need for research in those over 80 on overall improvement of

treatment on quality of life and research on informing patient choice and

partnership.

Thank you for your comments. This research

recommendation will be retained and if needed, a new

research recommendation may be made as part of the

update process.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

21 of 37

British

Cardiovascular

Society

Yes

None

Thank you.

Royal College pf

Physicians and

Surgeons of Glasgow

Yes

No comments provided

Thank you.

Merck Sharp &

Dohme Limited

Yes

No comments provided

Thank you.

Sanofi

Not

answered

No comments provide

Stakeholder provided no comment.

Do you agree with the proposal to remove the research recommendation?

RR–04 What is the effectiveness of statins and/or other LDL‑cholesterol‑lowering treatment in people with type 1 diabetes?

Stakeholder

Overall

response

Comments

NICE response

Medicines and

Technologies

Programme

answer

No comments provided

Stakeholder provided no comment.

Primary Care

Diabetes Society

answer

No comments provided

Stakeholder provided no comment.

NHS Medway CCG

answer

No comments provided

Stakeholder provided no comment.

Wolfson Institute of

Preventive Medicine

answer

No comments provided

Stakeholder provided no comment.

Boston Scientific

Yes

No comments provided

Thank you.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

22 of 37

Association of British

Clinical

Diabetologists

(ABCD)

The use of statins in various subgroups of Type 1 diabetes defined by age, duration of diabetes

and other risk factors needs to be clarified.

Thank you for your comments. This research

recommendation will be retained and if needed, a new

research recommendation may be made as part of the

update process.

Royal College of

Nursing

Yes

Type I diabetes needs to be recommendation for therapy rather than a research debate

correctly removed.

Thank you for your comment. Other feedback has

indicated value in retaining the research

recommendation. It will therefore be retained and if

needed, a new research recommendation may be

made as part of the update process.

Novo Nordisk

Not

answered

No comments provide

Stakeholder provided no comment.

Public Health

England

Not

answered

No comments provide

Stakeholder provided no comment.

HEART UK- The

Cholesterol Charity

Not

answered

No comments provide

Stakeholder provided no comment.

Amgen Ltd

Not

answered

No comments provide

Stakeholder provided no comment.

South Asian Health

Foundation

It remains unclear what age the statins should be started in type 1 and need to

refine the risk in this group

Thank you for your comments. This research

recommendation will be retained and if needed, a new

research recommendation may be made as part of the

update process.

British

Cardiovascular

Society

Yes

None

Thank you.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

23 of 37

Royal College pf

Physicians and

Surgeons of Glasgow

Yes

No comments provided

Thank you.

Merck Sharp &

Dohme Limited

Yes

No comments provided

Thank you.

Sanofi

Not

answered

No comments provide

Stakeholder provided no comment.

Do you agree with the proposal to remove the research recommendation?

RR–05 What is the clinical effectiveness and rate of adverse events of statin therapy using atorvastatin 20 mg per day compared with atorvastatin 40 mg per day and atorvastatin 80 mg per

day in people without established CVD?

Stakeholder

Overall

response

Comments

NICE response

Medicines and

Technologies

Programme

answer

No comments provided

Stakeholder provided no comment.

Primary Care

Diabetes Society

answer

No comments provided

Stakeholder provided no comment.

NHS Medway CCG

answer

No comments provided

Stakeholder provided no comment.

Wolfson Institute of

Preventive Medicine

answer

No comments provided

Stakeholder provided no comment.

Boston Scientific

Yes

No comments provided

Thank you.

Association of British

Clinical

Yes

As above

Thank you.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

24 of 37

Diabetologists

(ABCD)

Royal College of

Nursing

Yes

Relates to older research and therefore needs to be removed from consideration of these

guidelines.

Thank you.

Novo Nordisk

Not

answered

No comments provide

Stakeholder provided no comment.

Public Health

England

Not

answered

No comments provide

Stakeholder provided no comment.

HEART UK- The

Cholesterol Charity

Not

answered

No comments provide

Stakeholder provided no comment.

Amgen Ltd

Not

answered

No comments provide

Stakeholder provided no comment.

South Asian Health

Foundation

Yes

Appears to have been answered

Thank you.

British

Cardiovascular

Society

Yes

None

Thank you.

Royal College pf

Physicians and

Surgeons of Glasgow

Yes

No comments provided

Thank you.

Merck Sharp &

Dohme Limited

Yes

No comments provided

Thank you.

Sanofi

Not

answered

No comments provide

Stakeholder provided no comment.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

25 of 37

Do you have any comments on areas excluded from the scope of the guideline?

Stakeholder

Overall

response

Comments

NICE response

Medicines and

Technologies

Programme

Yes

Will there be any recommendations for end of life care or a reference to 1.5.1 NG31?

Thank you for your comment. NG31 recommendation

1.5.1 is a generic recommendation and is not specific

to end of life care in cardiovascular disease. The NICE

pathway on Patient experience in adult NHS services,

which refers to end of life care in addressing patient

concerns, is linked to the NICE pathway on

Cardiovascular disease prevention.

Primary Care

Diabetes Society

Yes

1. It is well established that diabetes carries a significant cardiovascular risk as

demonstrated with the Haffner (1) data.

2. It has become common practice to risk stratify people with diabetes at an earlier age

with lifestyle modification and the addition of preventative agents.

New therapies and studies have come to light suggesting reduced cardiovascular outcomes if

some of the newer agents are introduced. The newer agents of note are Sodium-glucose

transport inhibitors and GLP-1 agonists. The evidence has been compelling enough to change

guidelines in other Western countries to promote the earlier introduction of these agents.

Regulatory authorities in the US, Canada, Japan , Switzerland, Italy and France have already

recognised this new evidence and their guidelines now support the use of SGLT2 inhibitors and

the GLP-1 RA liraglutide at 1.8mg dose for cardioprotection in high risk individuals. NICE has not

yet done so and indeed has stated that it will not consider the question of CV protection with

these agents until all studies have reported i.e. after 2019/2020.

3. Cardiovascular safety trials ,to ensure no harm comes from taking these newer agents

,have demonstrated protection of significant level that we feel should not be overlooked when

putting together cardiovascular protection guidelines that involve people with diabetes.

4. EMPA-REG (2) – study looked at patients with established cardiovascular disease and

demonstrated a significant reduction in heart failure , MACE and mortality that appears more

favourable than the use of statin therapy. This study has recently been supported with the

CANVAS (3) study and the real world publication of CVD-REAL (4).

5. New studies have also demonstrated significant benefit in cardiovascular outcomes in

people who have diabetes and treated with GLP1-RA . The two agents with current data are

Liraglutide (5) ( LEADER study ) and the new once weekly Semaglutide (6) (SUSTAIN-6)

Thank you for your comments. The remit of CG181

covers lipid modification in the prevention of CVD and

therefore other pharmacological treatments, including

those specific to type 2 diabetes, are outside the remit.

These treatments are covered by the following NICE

guidelines:

Type 2 diabetes management (NICE NG28)

Canagliflozin in combination therapy for treating type 2

diabetes (NICE TA315)

Dapagliflozin in combination therapy for treating type 2

diabetes (NICE TA288)

Empagliflozin in combination therapy for treating

type 2 diabetes (NICE TA336)

Dapagliflozin in triple therapy for treating type 2

diabetes (TA418)

Empagliflozin for reducing the risk of cardiovascular

events in type 2 diabetes (in process)

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

26 of 37

Many prescribers working within Primary Care are constrained in their prescribing by LHB and

CCG medicine management formularies. These formularies will often not be changed unless

there has been NICE approval or endorsement of a therapy. This will lead to many at risk

patients not having access to therapies that are likely to lead to a significant reduction in

morbidity and mortality.

1. Haffner SM. N Engl J Med. 1998 :339;229-234

2. Zinman B, Wanner C, Lachin J M et al. Empagliflozin, Cardiovascular Outcomes and

Mortality in Type 2 Diabetes. N Engl J Med 2015;373:2117-28

3. Bruce N, Perkovik V, Mahaffey KW et al. Canagliflozin and Cardiovascular and renal

events in type 2 Diabetes. N Engl J Med 2017;377:644-657

4. Kosiborod M., Cavander,M.A.,Fu,A.Z.,Wilding,J.P. et al. Lower risk of heart failure and

death in patients initiated on SGLT-2 inhibitors versus other Glucose –lowering drugs: The CVD-

REAL Study. Circulation 2017

5. 7 Marso, S.P., Daniels,G.H., Brown-Frandsen, K. et al. Liragluitide and Cardiovascular

Outcomes in Type 2 Diabetes. (LEADER) N Engl J Med 2016 375; 4: 311-321

6. Marso SP, Bain SC, Consoli A et al. Semaglutide and Cardiovascular Outcomes in

Patients with Type 2 Diabetes (SUSTAIN 6). N Engl J Med 2016 375;19:1834-44

The feedback and evidence will be noted for

consideration in the next review of the clinical and

technology appraisal guidance on Type 2 Diabetes.

NHS Medway CCG

answer

No comments provided

Stakeholder provided no comment.

Wolfson Institute of

Preventive Medicine

answer

No comments provided

Stakeholder provided no comment.

Boston Scientific

answer

No comments provided

Stakeholder provided no comment.

Association of British

Clinical

Diabetologists

(ABCD)

Yes

Diabetes, especially T2 diabetes is a major risk factor for the development of cardiovascular

disease (CVD) conferring approximately a two-fold increase in the risk of developing CVD

including potentially fatal presentation of myocardial infarction (1,2). The 2016 Scottish Diabetes

Survey noted that 9.7 % of patients with T2 Diabetes have had a myocardial infarction and

survived, 7.5% cardiac revascularisation and 5.3% a stroke (3). Diabetes and impaired glucose

tolerance are very common among people with CVD - seen in almost two-thirds of the patients

at presentation with manifest coronary heart disease - and are associated with an approximately

two-fold increase in mortality rate compared to those with normoglycaemia (2, 4). Aggressive

management of multiple cardiovascular risk factors of hyperglycaemia, hypertension and

hyperlipideamia have shown to improve CVD outcomes in people with type 2 diabetes (5,6 ).

While improved management of these risk factors have improved CVD outcomes in recent

Thank you for your comments. The remit of CG181

covers lipid modification in the prevention of CVD and

therefore other pharmacological treatments, including

those specific to type 2 diabetes, are outside the remit.

These treatments are covered by the following NICE

guidelines:

Type 2 diabetes management (NICE NG28)

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(2014) NICE guideline CG181

27 of 37

years, rising rates of diabetes and obesity are threatening to reverse the recent trends of

improvement in CVD mortality seen over the last few decades (7). Urgent actions are therefore

needed exploring various strategies to tackle this challenge.

Over the last two years large, well-conducted trials have showed that glucose lowering agents

SGLT2 inhibiotors (8,9,10) and GLP-1 analogues (11,12,13) offer substantial cardiovascular

protection, bringing new hopes in improving CV outcomes in people with type 2 diabetes. Such

cardiovascular benefits are of similar scale to that offered by statins and therefore needs to be

passed on to diabetes patients without further delay.

In the EMPA-REG trial involving about 7000 patients with type 2 diabetes and established CVD,

compared with placebo, patients on SGLT2 inhibitor Empagliflozin significantly benefited from

relative risk reduction in cardiovascular (CV) deaths, admission for heart failure and all-cause

mortality by 38%, 35% and 32% respectively (8). The NNT to prevent one death with

Empagliflozin in this trial was 39 over 3 years compared to 30 for statins. The benefit of this

glucose lowering therapy was over and above that from blood pressure control and lipid

lowering. About 80% and 77% of patients were treated with ACE inhibitors/Angiotensin receptor

blockers and statins respectively in this trial (8). Similar findings of reductions in CV deaths,

heart failure and all-cause mortality has been seen with another SGLT2 inhibitor Canagliflozin in

the CANVAS randomised controlled trial (n=6000) (9). Furthermore in a real-world multinational

observational study, CV protective effects were observed for all currently licensed SGLT2

inhibitors (10).

Looking at the CV protection offered by the GLP-1 analogues, four large trials have been

reported thus far of which two (11,12) have shown clear CV reduction in people with type 2

diabetes and in the third trial (13) a trend towards improved CV outcomes was observed. In the

LEADER study, compared with placebo, Liraglutide 1.8mg once a day significantly reduced

composite outcome of CV death, non-fatal MI and stroke in people with type 2 diabetes and

established CVD or CV risk factors (11). The NNT to avoid the composite of major

cardiovascular event with Liraglutide was 66 in this trial. Similar results were observed with

once weekly Semaglutide in the SUSTAIN -6 trial (12). In the EXSCEL trial, the direction and

scale of the CV benefits with weekly use of extended-release exenatide were in line with those

seen in the LEADER and the SUSTAIN-6 trials but the findings did not reach a statistically

significant level (13). In the ELIXA trial though, only non-inferiority of the less potent Lixisenatide

versus placebo (i.e. demonstrate CV safety) but no evidence for cardioprotection was observed

(14). The mechanisms behind these differences in achieved CV outcomes among various GLP-1

analogues are a matter of further research but likely to related to difference in their molecular

structures and affinity towards receptors in the heart and other body tissues. Overall though, the

evidence for use of Liraglutide and also Semaglutide for CV protection in patients with a high risk

of cardiovascular disease is undisputable (11,12).

Moreover there is now a drive worldwide to use SGLT2 inhibitors and GLP-1 analogues,

especially Liraglutide 1.8mg, for CV risk reduction with national and international guidelines from

the USA, Canada, Japan , Switzerland, Italy and France supporting their use in high risk

individuals with type 2 diabetes. On this background, the decision by the NICE to not address

the subject of CV benefits offered by these agents until all studies have been reported over next

Canagliflozin in combination therapy for treating type 2

diabetes (NICE TA315)

Dapagliflozin in combination therapy for treating type 2

diabetes (NICE TA288)

Empagliflozin in combination therapy for treating

type 2 diabetes (NICE TA336)

Dapagliflozin in triple therapy for treating type 2

diabetes (TA418)

Empagliflozin for reducing the risk of cardiovascular

events in type 2 diabetes (in process)

The feedback and evidence will be noted for

consideration in the next review of the clinical and

technology appraisal guidance on Type 2 Diabetes.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

28 of 37

2-3 years is alarming, ignores high quality randomised controlled trials, places the NICE

guidelines out of kilter with international guidelines and denotes them as being outdated from

their launch. Furthermore this decision is not in our patient’s best interest and the Scottish Data

from 2016 highlights that these medications are highly appropriate for 10% of those with T2

diabetes (3). In view of a very strong current evidence favouring use of these agents to reduce

CV events including deaths, any decision depriving high-risk individual of these potentially life-

saving therapies raises serious concerns around neglecting our duty of care towards these

patients. A timely approval of use of these agents from the NICE at this stage is also extremely

important to avoid further procedural delays usually incurred during implementing the change in

clinical practice at local level through CCG and medicines management.

Delaying the use of these agents in CV protection also has implications on cost saving since

substantial savings could be made from avoiding deaths and admissions with heart failure. For

example, based on the findings of EMPA-REG trial, by treating the 525,000 patients with type 2

diabetes in the UK who are known to have cardiovascular disease, an estimated 4375 deaths

per annum could be avoided. Furthermore, as highlighted by a recent audit (15), 6164

admissions from heart failure per year would be avoided potentially saving 73968 bed days (£26

million annually), thereby offsetting any increase in treatment costs associated with use of these

agents.

On the whole, the current evidence certainly makes a very strong clinical, economic and moral

case for the NICE to recommend the use of GLP-1 analogues especially Liraglutide 1.8 mg in

both those with established CVD or with CV risk factors and that of SGLT2 inhibitors in at least

in those with established CVD. Any further delay in making such recommendations until all the

evidence in this area becomes available is really unwarranted. Further studies and economic

analysis however will be needed before the use of SGLT2 inhibitors could be broadened to also

include those without established CVD but harbouring one or more CV risk factors.

In summary, we believe, in accordance with other national and international guidelines that

advice from NICE must include the currently available, well conducted and robust evidence of

cardioprotective benefits of SGLT-2 inhibitors and the GLP-1 analogue Liraglutide in high risk

patients with T2DM. We strongly request the NICE to incorporate recommendations on use of

these agents in secondary prevention of CVD in patients with T2DM in their update of NICE

CG181. This will empower clinicians within both primary and secondary care in the UK to

appropriately use these agents in high-risk individuals with type 2 diabetes improving their

mortality and morbidity from CVD.

REFERENCES

1. The Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose

concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective

studies. Lancet 2010; 375: 2215-2222.

2. Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, et al. ESC Guidelines on

diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD:

the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

29 of 37

of Cardiology (ESC) and developed in collaboration with the European Association for the Study

of Diabetes (EASD). Eur Heart J 2013;34:3035-3087

3. Scottish Diabetes Survey Monitoring Group. Scottish Diabetes Survey 2016.

http://www.diabetesinscotland.org.uk/Publications/Scottish%20Diabetes%20Survey%202016.pdf

4. Gholap NN, Achana FA, Davies MJ, Ray KK, Gray L and Khunti K. Long-term mortality

after acute myocardial infarction among individuals with and without diabetes: A systematic

review and meta-analysis of studies in the post-reperfusion era. Diabetes Obes Metab. 2016 doi:

10.1111/dom.12827.

5. Gæde P, Lund-Andersen H, Parving H, Pedersen O. Effect of a multifactorial

intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580-591.

6. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year follow-up of

intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359:1577-1589.

7. Bottle A, Millett C, Khunti K & Majeed A.Trends in cardiovascular admissions and

procedures for people with and without diabetes in England, 1996–2005. Diabetologia 2009;

52:74–80.

8. Zinman B, Wanner C, Lachin J M et al. Empagliflozin, Cardiovascular Outcomes and

Mortality in Type 2 Diabetes. N Engl J Med 2015;373:2117-2

9. Bruce N, Perkovik V, Mahaffey KW et al. Canagliflozin and Cardiovascular and renal

events in type 2 Diabetes. N Engl J Med 2017;377:644-657

10. Kosiborod M., Cavander,M.A.,Fu,A.Z.,Wilding,J.P. et al. Lower risk of heart failure and

death in patients initiated on SGLT-2 inhibitors versus other Glucose –lowering drugs: The CVD-

REAL Study. Circulation 2017 Https://doi.org/10.1161/CIRCULATIONAHA.117.029190

11. Marso, S.P., Daniels,G.H., Brown-Frandsen, K. et al. Liragluitide and Cardiovascular

Outcomes in Type 2 Diabetes. (LEADER) N Engl J Med 2016 375; 4: 311-321

12. Marso SP, Bain SC, Consoli A et al. Semaglutide and Cardiovascular Outcomes in

Patients with Type 2 Diabetes (SUSTAIN 6). N Engl J Med 2016 375;19:1834-44

13. Holman RR, Bethel MA, Mentz RJ et al. Effects of once –weekly Exenatide on

Cardiovascular Outcomes in type 2 Diabetes. N Engl J Med 2017 ;377 :1228-39

14. Pfeffer MA, Clagget B, Diaz R et al. Lixisenatide in patients with type 2 Diabetes and

acute coronary syndrome. N Engl J Med 2015;373:2247-57

15. https://www.ucl.ac.uk/nicor/audits/heartfailure/documents/annualreports/hfannual12-

13.pdf

Royal College of

Nursing

No comments provided

Thank you.

Novo Nordisk

Yes

In relation to the scope of this guideline, drugs specifically for lipid management are no longer

the only compounds with proven reduction in cardiovascular morbidity and mortality. In two

large randomised controlled cardiovascular outcomes trials, empagliflozin and liraglutide have

shown significant reductions (38%1 and 22%2 respectively) in cardiovascular death in patients

with high CV risk and type 2 diabetes. The 2016 European Guidelines on Cardiovascular

Thank you for your comments. The remit of CG181

covers lipid modification in the prevention of CVD and

therefore other pharmacological treatments, including

those specific to type 2 diabetes, are outside the remit.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

30 of 37

Disease Prevention in Clinical Practice3 and the joint AHA/ADA4 have updated their guidelines

to include this new data and provide specific recommendations for high risk patients with type 2

diabetes. Such an update should be considered within this guideline as it is currently not

addressed in any other UK guideline.

1.Zinman B et al. N Engl J Med 2015;373:2117–2128

2.Marso SP et al. N Engl J Med 2016;375:311–322

3. Piepoli MF et al. Eur Heart J 2016;37:2315–2381

4.Fox CS et al. Diabetes Care 2015;38:1777–1803

These treatments are covered by the following NICE

guidelines:

Type 2 diabetes management (NICE NG28)

Canagliflozin in combination therapy for treating type 2

diabetes (NICE TA315)

Dapagliflozin in combination therapy for treating type 2

diabetes (NICE TA288)

Empagliflozin in combination therapy for treating

type 2 diabetes (NICE TA336)

Dapagliflozin in triple therapy for treating type 2

diabetes (TA418)

Empagliflozin for reducing the risk of cardiovascular

events in type 2 diabetes (in process)

The feedback and evidence will be noted for

consideration in the next review of the clinical and

technology appraisal guidance on Type 2 Diabetes.

Public Health

England

Not

answered

In addition to considering the risk calculators it would be helpful to consider how the information

about CVD risk is communicated. There is some evidence that people do not understand their

CVD risk score and therefore may not be likely to take their advice of their General Practitioner

regarding lifestyle or clinical management. Understanding whether other methods of

communication such as Heart Age have an impact on understanding and behaviour would be

beneficial.

Thank you for your comments. NICE has produced

guidance on Patient experience in adult NHS services.

(NICE CG138) which includes recommendations on

communication and information in section 1.5 Enabling

patients to actively participate in their care. This

guidance is listed as related guidance in CG181 for

GPs and other health professionals to refer to.

HEART UK- The

Cholesterol Charity

Not

answered

1.2.1 advises mono and polyunsaturated fats as replacements for saturated fats and this is

absolutely correct but 1.2.2 only talks about monounsaturated fats and gives rapeseed and olive

oil as examples. We consider that this should be extended to include polyunsaturated fats and

sunflower oil given as the example. Most spreads are sunflower based, although some spreads

do contain olive oil it is usually only there as a percentage of the total fat. Research shows that

replacing saturated fat with polyunsaturated fats has a bigger effect on cholesterol than

replacing with monounsaturated fats, but both are needed as there are issues with too high a

PUFA intake.

Thank you for your comments.

Section 1.2 Lifestyle modifications for the primary and

secondary prevention of CVD

 Cardioprotective diet

The collective new evidence and topic expert feedback

in the surveillance review were consistent with

recommendations in the section of the guideline on

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

31 of 37

1.2.4 Advice to limit oily fish to 2 portions in pregnant women should be extended to all children

and women of child bearing age. https://www.nhs.uk/Livewell/Goodfood/Pages/fish-

shellfish.aspx

1.2.3 Could there be a reference to “sustainable fish”

1.2.3 Also could we have a reference to either eating more meat free meals please or

alternatively less red and processed meat. See Eatwell Plate

https://www.nhs.uk/Livewell/goodfood/Pages/the-eatwell-guide.aspx

1.2.13 Advice on alcohol needs updating as guidelines on units are now the same for both men

and women. Also a reference to having alcohol free days please

1.2.17 There is a blanket reference to not recommending plant sterols and stanols which should

also including consideration during pregnancy and breastfeeding. It also should be considered

that foods fortified with plant sterols and stanols may be used on top of first line drug and more

basic dietary measures to help manage lifetime risk from raised cholesterol in people with

Familial Hypercholesterolaemia and other similar lipid conditions provided they are taken

routinely and as part of a healthy diet and lifestyle. Advice on plant sterols and stanols for people

with Familial Hypercholesterolaemia also should be consistent NICE guidelines on the

management and treatment of FH

This section should also highlight the concerns about coconut oil and its adverse effect on

cholesterol, which is a growing problem seen in many lipid clinics.

1.3 There needs to be consistency with NICE technology appraisal guidance for alirocumab

(TA393) and evolocumab (TA394)

1.3.23 says consider treating all T1DM with a statin. This is a superfluous statement as

1.3.24 then goes on to dictate which Type 1s should be offered statins

1.3.33 should consider adding: exclude effects of strenuous exercise on CK

1.3.46 Nicotinic acid no longer has a UK licence

1.3.7 Should be consistent with 2017 NICE guidelines on the management and treatment of FH,

which states:

Suspect familial hypercholesterolaemia (FH) as a possible diagnosis in adults with:a total

cholesterol level greater than 7.5 mmol/l and/ora personal or family history of premature

coronary heart disease (an event before 60 years in an index individual or first-degree

relative).[2008, amended 2017]

cardioprotective diet, which cross refer to NHS choices

advice on healthy eating and NICE guideline PH6

behaviour change: the principles for effective

interventions.

New evidence in the areas highlighted will be

considered at the next surveillance review.

 Alcohol consumption

The feedback relating to advice on alcohol in

recommendation 1.2.13 will be noted for amendment in

the update of the guideline.

 Alirocumab and evolocumab technology appraisals

New evidence and topic expert feedback indicates the

potential value of PSCK9 inhibitors (monoclonal

antibodies) in prevention of CVD and is captured by

the following technology appraisals:

TA393 Alirocumab for treating primary

hypercholesterolaemia and mixed dyslipidaemia (June

2016)

TA394 Evolocumab for treating primary

hypercholesterolaemia and mixed dyslipidaemia (June

2016)

There is a potential need for CG181 to cross refer to

these technology appraisals in the section on lipid

modification therapy for the primary and secondary

prevention of CVD. This will be explored as part of the

guideline update. The technology appraisals are

already included in the related NICE interactive

flowchart.

 Type 1 diabetes

Recommendation 1.3.23 states that statin treatment for

the primary prevention of CVD in all adults with type 1

diabetes should be considered. However,

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

32 of 37

Systematically search primary care records for people:

younger than 30 years, with a total cholesterol concentration greater than 7.5 mmol/l and30

years or older, with a total cholesterol concentration greater than 9.0 mmol/las these are the

people who are at highest risk of FH. [2017]

For people with a personal or family history of premature coronary heart disease (an event

before 60 years in an index individual or first-degree relative), but whose total cholesterol is

unknown, offer to measure their total cholesterol. [2017]

recommendation 1.3.24 is a stronger recommendation

stating that statins should be offered to adults with type

1 diabetes and with additional risk factors.

The guideline committee agreed using informal

consensus that all adults with type 1 diabetes may

benefit from treatment with a statin and that statin

treatment should be considered. They agreed that

statin treatment should be offered to adults with any

additional risk factors to their type 1 diabetes and

made a recommendation listing common factors such

as age over 40 years, length of time people have had

diabetes for, presence of additional CVD risk factors

and evidence of abnormal renal function.

 Nicotinic acid

Although nicotinic acid is no longer licensed in the UK,

it is widely available as a dietary supplement. It is

therefore possible that a GP could prescribe or

recommend it, and recommendation 1.3.46 advising

against this is therefore still relevant.

 Familial Hypercholestrolaemia

The existing cross reference from the guideline to

NICE’s guideline on familial hypercholesterolemia from

recommendation 1.1.16 does not require updating as

the corresponding recommendation in the FH guideline

were not updated and remain extant.

The potential amendment to recommendation 1.3.7 to

reflect the updated recommendation in the FH

guideline (NICE CG71) will be noted for consideration

in the guideline update.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

33 of 37

Amgen Ltd

Not

answered

No comments provide

Stakeholder provided no comment.

South Asian Health

Foundation

Yes

We believe this guideline needs to recognise that in addition to statins there are now SGLT1

inhibitors and GLP1 inhibitors that afford cardioprotection and that advice to use these agents for

primary prevention in type 2 diabetes should be included.

We believe there have recently been major breakthroughs in treatments which include SGLT-2

inhibitors and GLP-1 Receptor Agonists (GLP-1 RAs) that can provide significant

cardioprotection for patients with diabetes with established cardiovascular disease. Large RCTs

with SGLT-2 inhibitors (3, 4) suggest that in terms of cardiovascular (CV) mortality and CV

events and protection from heart failure, this treatment approach appears almost as powerful as

that seen with statin treatment and indeed complements and adds to this protection. THE NNT

prevent one death with an SGLT2 inhibitor was 39 over 3 years compared to 30 for statins

(3).The convincing results of the EMPA-REG study of Empagliflozin in 7000 patients all of whom

had established cardiovascular disease (3) have now been reinforced by the CANVAS study

with Canagliflozin in 6000 with established cardiovascular disease (4) confirming the lowering of

cardiovascular and heart failure events from this class.. These studies are complemented by the

evidence from a large real-world CVD-REAL study (5) looking at all licensed drugs in the SGLT2

class and confirming almost exactly the same relative and absolute risk reduction for both CV

mortality and events and hospitalisation for heart failure shown in EMPA-REG (3).In summary,

this class of drugs reduced all-cause mortality by 32%, CV death by 30% and hospitalisations for

heart failure (an increasing cost pressure to the NHS) by 35% (3,4,5). In addition, the

subanalysis forest plots showed greater reductions for south Asians for the primary MACE

outcomes compared to white populations. (3)

Two large cardiovascular outcome RCTs (6,7) looking at the GLP1RAs liraglutide 1.8

mg(LEADER) and the once weekly Semaglutide (SUSTAIN) which is not yet licensed in the UK

have shown significant reductions in cardiovascular deaths, all-cause mortality and

cardiovascular events with NNT over 3 years of 66.

Regulatory authorities in the US, Canada, Japan , Switzerland, Italy and France have already

recognised this new evidence and their guidelines now support the use of SGLT2 inhibitors and

the GLP-1 RA liraglutide at 1.8mg dose for cardioprotection in high risk individuals. NICE has not

yet done so and indeed has stated that it will not consider the question of CV protection with

these agents until all studies have reported i.e. after 2019/2020.

We believe that this excessively cautious approach and delay is likely to harm many patients by

failing to endorse proven life-saving treatments. Many GPs directed by their CCGs through their

Medicine Management Teams will not change their management practice until approved by

NICE, licences reflect new indications and there is endorsement from local formulary groups-all

adding to further delays!. This will deprive potentially life-saving treatments for many of our most

vulnerable South Asian patients with established cardiovascular disease. We believe that the

Thank you for your comments. The remit of CG181

covers lipid modification in the prevention of CVD and

therefore other pharmacological treatments, including

those specific to type 2 diabetes, are outside the remit.

These treatments are covered by the following NICE

guidelines:

Type 2 diabetes management (NICE NG28)

Canagliflozin in combination therapy for treating type 2

diabetes (NICE TA315)

Dapagliflozin in combination therapy for treating type 2

diabetes (NICE TA288)

Empagliflozin in combination therapy for treating

type 2 diabetes (NICE TA336)

Dapagliflozin in triple therapy for treating type 2

diabetes (TA418)

Empagliflozin for reducing the risk of cardiovascular

events in type 2 diabetes (in process)

The feedback and evidence will be noted for

consideration in the next review of the clinical and

technology appraisal guidance on Type 2 Diabetes.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

34 of 37

evidence for using these agents for secondary prevention is overwhelming and that it would be a

neglect of duty of care to further delay their endorsement.

On the basis of the NNT of 39 over 3 years for people with cardiovascular disease (secondary

prevention) with Empagliflozin, plus the reduction of hospitalisation for heart failure by 35% (3)

CV events could be prevented and the lives of our patients prolonged. Substantial savings would

also be made on avoidance of hospital treatment for heart failure. Based on the criteria used in

these studies (3), if the 525,000 patients with Type 2DM in the UK who are known to have

cardiovascular disease were treated, it is estimated that 4375 deaths per annum could be

avoided. In addition, 6164 admissions from heart failure per year would be avoided saving

73968 bed days (£26 million annually). This is highlighted by a recent audit (8) which suggested

that the savings would offset increased treatment costs. We believe that for patients with

established cardiovascular disease, the moral and economic case for treatment is overwhelming

and further delay unjustified. This is particularly the case in South Asians with their very great

susceptibility to and high mortality from CVD.

There is also an argument from the studies of SGLT-2 inhibitors that these agents should be

recommended more widely to people with T2DM who have 1 or 2 cardiovascular risk factors (as

described in the CANVAS Study (4). We accept that extending to this at risk group may require

more studies and more health economic analysis before adoption as a NICE recommendation.

The picture is somewhat more complex with GLP-1 RAs. Two studies, one with Liraglutide

(LEADER) (6), and the other with Semaglutide (SUSTAIN 6) (7) demonstrated both non-

inferiority (safety) and superiority for reduction of the composite primary endpoint of CV death

and non-fatal MI and stroke versus placebo. LEADER also reported significant reduction in CV

mortality. The two other long term cardiovascular safety studies with Lixisenatide (ELIXA) (9)

and long acting once weekly Exanetide (EXSCEL) (10) studies showed non-inferiority versus

placebo (ie demonstrate CV safety) but no evidence for cardioprotection. The explanation and

mechanisms to explain these differences within class are not understood and require further

research but the molecular structures of these GLP- 1 analogues and their ability to bind the

receptors in the heart and in different body tissues appear to differ. The evidence from LEADER

has, however, been thought

sufficient by many national and international guideline bodies to recommend Liraglutide 1.8 mg

as a treatment for patients with T2DM at high CV risk. We believe that a similar approach should

be taken by NICE particularly in the context of our very high CV risk South Asian patients.

In summary, we believe that there is sufficient evidence from well-conducted cardiovascular

outcome studies, to recommend that both SGLT-2 inhibitors and/or the GLP-1 RA Liraglutide be

considered as part of the management regime for secondary prevention in patients with T2DM

and specifically in those at particularly high risk including the South Asian population. These

issues MUST be considered by NICE in their update of NICE CG181. This will then guide UK

healthcare professionals to introduce these treatments appropriately to help reduce

cardiovascular events, mortality and heart failure in our most vulnerable patients.

REFERENCES

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

35 of 37

1 Bellary S, O’Hare JP, Raymond NT et al. Premature cardiovascular events and mortality in

South Asians with type 2 diabetes in the United Kingdom Asian Diabetes Study Current Medical

Research and Opinion 2010 ;26 (8):1873-1879

2 Barnett A H, Dixon A N, Bellamy S et al. Type 2 Diabetes and cardiovascular risk in the UK

South Asian community. Diabetologia 2006;49:2234-46

3 Zinman B, Wanner C, Lachin J M et al. Empagliflozin, Cardiovascular Outcomes and Mortality

in Type 2 Diabetes. N Engl J Med 2015;373:2117-28

4 Bruce N, Perkovik V, Mahaffey KW et al. Canagliflozin and Cardiovascular and renal events in

type 2 Diabetes. N Engl J Med 2017;377:644-657

5 Kosiborod M., Cavander,M.A.,Fu,A.Z.,Wilding,J.P. et al. Lower risk of heart failure and death

in patients initiated on SGLT-2 inhibitors versus other Glucose –lowering drugs: The CVD-REAL

Study. Circulation 2017 Https://doi.org/10.1161/CIRCULATIONAHA.117.029190

British

Cardiovascular

Society

Yes: 181-

Dietary

advice,

especially

saturated

fats

There has been significant controversy about this in the wider media in the last few years, with

an opposite view supported by some doctors. The high profile PURE study from Salim Yusuf

(Dehghan M et al. Associations of fats and carbohydrate intake with cardiovascular disease and

mortality in 18 countries from five continents (PURE): a prospective cohort study. Lancet. 2017

Aug 28. pii: S0140-6736(17)32252-3) has added to the debate. The committee may wish to

update this section. Some acknowledgment of the issue should be made and countered with

evidence to support NICE’s position (which is shared by BHF, AHA etc).

Thank you for your comments.

 Cardioprotective diet

The collective new evidence and topic expert feedback

in the surveillance review were consistent with

recommendations in the section of the guideline on

cardioprotective diet, which cross refer to NHS choices

advice on healthy eating and NICE guideline PH6

behaviour change: the principles for effective

interventions.

New evidence in the areas highlighted will be

considered at the next surveillance review.

Royal College of

Physicians and

Surgeons of Glasgow

Yes

While the issue of smoking and cessation is fully explored and dealt with by this and previous

guidelines, there may be scope to add a Research Question on the usefulness of Vapourisers

when trying to quit smoking. There is little guidance for clinicians on the benefits or harms of this

practice on CV risk.

Thank you for your comments. The addition of this

research recommendation on this topic will be

considered during the update scoping process.

Merck Sharp &

Dohme Limited

No comments provided

Thank you.

Sanofi

Not

answered

No comments provide

Stakeholder provided no comment.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

36 of 37

Do you have any comments on equalities issues?

Stakeholder

Overall

response

Comments

NICE response

Medicines and

Technologies

Programme

No comments provided

Thank you.

Primary Care

Diabetes Society

Yes

Diabetes and ethnicity carry a higher risk of cardiovascular disease with poorer results. It does

not appear to have been included within this document as a special consideration.

Thank you for your comments. The QRISK2 risk

assessment tool, and its successor QRISK3, include

ethnicity as a risk factor in calculating overall risk of

CVD.

NHS Medway CCG

answer

No comments provided

Stakeholder provided no comment.

Wolfson Institute of

Preventive Medicine

answer

No comments provided

Stakeholder provided no comment.

Boston Scientific

answer

No comments provided

Stakeholder provided no comment.

Association of British

Clinical

Diabetologists

(ABCD)

No comments provided

Thank you.

Royal College of

Nursing

No comments provided

Thank you.

Novo Nordisk

No comments provided

Thank you.

Appendix B: stakeholder consultation comments table for 4-year surveillance of – Cardiovascular disease: risk assessment and reduction, including lipid modification

(2014) NICE guideline CG181

37 of 37

Public Health

England

answer

No comments provided

Stakeholder provided no comment.

HEART UK- The

Cholesterol Charity

answer

No comments provided

Stakeholder provided no comment.

Amgen Ltd

Not

answered

No comments provide

Stakeholder provided no comment.

South Asian Health

Foundation

Yes

South Asians with type2 diabetes need to be treated with the newer flozins as

primary protection and this could be as powerful an addition to preventing deaths

and heart failure as the use of statins. Inclusion in this guideline will help to reverse

the inequity in treatment this group suffers.

Thank you for your comments. Treatments for diabetes

are not included in the remit of CG181, but are covered

in NICE’s guideline on type 2 diabetes management.

British

Cardiovascular

Society

No comments provided

Thank you.

Royal College pf

Physicians and

Surgeons of Glasgow

No comments provided

Thank you.

Merck Sharp &

Dohme Limited

No comments provided

Thank you.

Sanofi

Not

answered

No comments provide

Stakeholder provided no comment.

Comments:

RCN Unfortunately we have no comments to submit to inform on the above review proposal at this present time