Familial Hypercholesteraemia Comments from consultation on 1 st draft. 1 of 32

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1 Sectio 1 Full 0 Geera l 2 Full 0 Geera l 3 Full 0 Geera l 4 Full Commet & Dohme Limited (MSD) is pleased that the Guidelie Developmet Group (GDG) recogises that Familial Hypercholesterolaemia (FH) is a severe ad prevalet disease withi the UK. We are disappoited that the guidelie focuses exclusively o low-desity lipoproteis (LDL) cholesterol. With the curret high prevalece of obesity, metabolic sydrome ad diabetes, FH patiets are icreasigly presetig with mixed type hyperlipidaemia, as opposed to the classical presetatio of total cholesterol (TC) ad LDL cholesterol elevatio. We would urge the GDG to recogise that high-desity lipoproteis (HDL) ad triglycerides (TGs) are importat additioal cardiovascular risk factors i such a patiet populatio. We are pleased to ote that the treatmet algorithm icludes icotiic acid as a recommeded treatmet optio for use i patiets who are ot adequately cotrolled o the maximum dose of stati therapy. Nicotiic acid was the first aget demostrated to have cholesterol lowerig effects (Altschul R et al, Arch Biochem 1055). It was also the first aget demostrated to be associated with a reductio of atherosclerotic cardiovascular evets i high risk patiets (The Coroary Drug Research Group, JAMA 1975). Sice the data from 30 trials (4,749 subjects) usig iaci showed a comprehesive lipid modificatio effects ad a sigificat reductio i risk of major coroary evets by (Birjmohu RS, et al, J Am Coll Cardiol 2005). Trials have demostrated icotiic acid is a effective treatmet ot oly for reducig LDL-C ad TG's, but Respose Noted with thaks Noted. Please refer to chapter 1 regardig the diagosis of FH ad the drug treatmet chapters for risk factor stratificatio. We regret that mixed hyperlipidaemia is outside the remit of this guidelie. Noted with thaks Repeated from before 1 of 32

2 Sectio Commet also curretly the most effective aget for raisig HDL- C.Give the severity ad prevalece of familial hypercholesterolaemia i the UK, combied with the high prevalece of obesity, metabolic sydrome ad diabetes with mixed dyslipidaemia, we believe that cliicias should have access to a full rage of treatmet optios that meet the idividual patiet eed, which icludes a effective treatmet optio at the secod lie therapeutic stage that provides a comprehesive approach of lipid lowerig therapy. Respose The treatmet algorithm i sectio 1.7 clearly ad appropriately states icotiic acid as a secod lie therapeutic alterative to stati therapy. We would recommed sectio is rectified to be i lie with sectio Full Furthermore, with the exceptio of flushig, which is beig addressed by compouds i developmet, icotiic acid is ot associated with ay sigificat additioal adverse evets to what is see with statis. Therefore, it is ot clear why the GDG recommed that the decisio to add icotiic acid should be made i a specialist cetre. With the exceptio of flushig, icotiic acid is ot associated with ay cliically sigificat additioal adverse evets to what is see with statis. Therefore, it is ot clear why the GDG recommed that the decisio to add icotiic acid should be made i a specialist cetre. Noted with thaks Nicotiic acid was the first aget demostrated to have cholesterol lowerig effects (Altschul R et al, Arch Biochem 1055). It was also the first aget demostrated to be associated with a reductio of atherosclerotic 2 of 32

3 Sectio Commet cardiovascular evets i high risk patiets (The Coroary Drug Research Group, JAMA 1975). Sice the data from 30 trials (4,749 subjects) usig iaci showed comprehesive lipid modificatio effects ad a sigificat reductio i risk of major coroary evets by (Birjmohu RS, et al, J Am Coll Cardiol 2005). Though iaci iduced flushig, the mai limitatio of iaci use, has bee overcome to some extet by usig modified or exteded release forms of the molecule; there still is some residual flushig that limits its use. Niaci iduced flushig has bee show to be maily due to the release of prostagladi D2 ad bidig to its receptor (DP1) o epimal blood vessels. MSD has a aget which is curretly i phase III developmet which addresses the flushig tolerability to a large degree by combiig a Exteded Release (ER) iaci with a prostagladi D2 receptor (DP1) ihibitor, laropiprat. Respose 1 6 Full We appreciate that icotiic acid is traditioally associated with flushig. However, we would advise the GDG that developmets i this therapeutic area will be available withi the timeframe of this guidelie. Noted with thaks MSD has a aget curretly i phase III developmet which is a fixed dose combiatio of ER iaci/laropiprat. This aget has bee show to overcome most of the tolerability issues related to flushig. ER iaci/laropiprat has already bee assessed i a umber of lipid modificatio & tolerability/safety trials ad is also beig assessed i a log term outcome study, the HPS2-THRIVE study (Heart Protectio Study 3 of 32

4 Sectio Commet 2 Treatmet of HDL to Reduce the Icidece of Vascular Evets) to assess the effects of treatmet with iaci, together with the prostagladi D2 (DP1) ihibitor laropiprat (to reduce iaci-iduced flushig), vs placebo i approximately 20,000 British, Scadiavia, ad Chiese patiets with pre-existig vascular disease maaged usig statis o first major vascular evet (defied as o-fatal myocardial ifarctio or coroary death, o-fatal or fatal stroke, or revascularisatio). LDL cholesterol levels will be cotrolled i all participats by simvastati 40 mg plus ezetimibe 10 mg daily, if required. Respose Secodary aims iclude assessmet of the effects of ER iaci/laopiprat o early safety outcomes; o the separate compoets of the primary edpoit; ad o the primary edpoit withi major baselie disease subgroups. All patiets will be followed up for 4 years. 7 Full We are pleased to ote the treatmet algorithm icludes icotiic acid as a recommeded treatmet optio for use i patiets who are ot adequately cotrolled o the maximum dose of stati therapy. 8 Full We are pleased to ote that the GDG has recogised the use of icotiic acid as a therapy optio for patiets ot toleratig statis i cliical practice. 9 Full Nicotiic acid was the first aget demostrated to have cholesterol lowerig effects (Altschul R et al, Arch Biochem 1055). It was also the first aget demostrated to be associated with a reductio of atherosclerotic cardiovascular evets i high risk patiets (The Coroary Drug Research Group, JAMA 1975). Sice the data from 30 trials (4,749 subjects) usig iaci showed comprehesive lipid modificatio effects ad a sigificat reductio i risk of major coroary evets by (Birjmohu RS, et al, J Am Coll Cardiol 2005). Noted with thaks. Noted with thaks Thak you. Details have ow bee added to the relevat evidece to recommedatios sectio for chapter 5. 4 of 32

5 Sectio Commet Respose Trials have demostrated icotiic acid is a effective treatmet ot oly for reducig LDL-C ad TG's, but also curretly the most effective aget for raisig HDL-C.Give the severity ad prevalece of familial hypercholesterolaemia i the UK, combied with the high prevalece of obesity, metabolic sydrome ad diabetes with mixed dyslipidaemia, we believe that cliicias should have access to a full rage of treatmet optios that meet the idividual patiet eed, which icludes a effective treatmet optio at the secod lie therapeutic stage that provides a comprehesive approach of lipid lowerig therapy. The treatmet algorithm i sectio 1.7 clearly ad appropriately states icotiic acid as a secod lie therapeutic alterative to stati therapy. We would recommed this sectio is rectified to be i lie with sectio Full Furthermore, with the exceptio of flushig, which is beig addressed by compouds i developmet, icotiic acid is ot associated with ay cliically sigificat additioal adverse evets to what is see with statis. Therefore, it is ot clear why the GDG recommed that the decisio to add icotiic acid should be made i a specialist cetre. With the exceptio of flushig, icotiic acid is ot associated with ay cliically sigificat additioal adverse evets to what is see with statis. Therefore, it is ot clear why the GDG recommed that the decisio to add icotiic acid should be made i a specialist cetre. Noted with thaks Nicotiic acid was the first aget demostrated to have 5 of 32

6 Sectio Commet cholesterol lowerig effects (Altschul R et al, Arch Biochem 1055). It was also the first aget demostrated to be associated with a reductio of atherosclerotic cardiovascular evets i high risk patiets (The Coroary Drug Research Group, JAMA 1975). Sice the data from 30 trials (4,749 subjects) usig iaci showed comprehesive lipid modificatio effects ad a sigificat reductio i risk of major coroary evets by (Birjmohu RS, et al, J Am Coll Cardiol 2005). Though iaci iduced flushig, the mai limitatio of iaci use, has bee overcome to some extet by usig modified or exteded release forms of the molecule; there still is some residual flushig that limits its use. Niaci iduced flushig has bee show to be maily due to the release of prostagladi D2 ad bidig to its receptor (DP1) o epimal blood vessels. MSD has a aget which is curretly i phase III developmet which addresses the flushig tolerability to a large degree by combiig a ER iaci with a prostagladi D2 receptor (DP1) ihibitor, laropiprat. Respose 1 11 Full We appreciate that icotiic acid is traditioally associated with flushig. However, we would advise the GDG that developmets i this therapeutic area are immiet. Noted with thaks 1 12 Full (page 103) Please refer to our respose to sectio We are pleased to ote that the GDG has recogised that icotiic acid has cliical beefit, ot oly o LDL, but also o HDL ad TG. Noted with thaks FH patiets are icreasigly presetig with mixed dyslipidemia (as opposed to the classical presetatio of TC ad LDL elevatio), largely due to the icreasig prevalece of obesity, metabolic sydrome ad 6 of 32

7 Sectio Commet diabetes. Respose 1 13 Full (page 107-8) Give this chage i presetatio, ad the risk associated with low HDL ad raised TG, we would aticipate a possible wi place for agets affectig LDL-oly i the guidelie. We are pleased to ote that the GDG has idetified studies which show the cliical beefit of icotiic acid i the treatmet of lipid levels, whether used as mootherapy, or i combiatio with a stati. Noted with thaks 1 2 (Hele Johso) Give this cliical beefit, we support the GDGs positioig of icotiic acid i the treatmet algorithm (sectio 1.7). 14 Full We are pleased that the GDG recogises the primary importace of pharmacological treatmet i familial hypercholesterolaemia patiets. The prevalece of diabetes i FH populatio is similar to that i the geeral populatio. Therefore, while we recogise the importace of lowerig LDL-C, we would urge the GDG to also cosi HDL-C ad TG's whe idetifyig the eed for treatmet give the risig prevalece of obesity, metabolic sydrome ad diabetes ad a cosequet presetatio of mixed dyslipidaemia amog 1 Full 0 Geera l FH patiets. There are occasios throughout the draft guidelie where the NICE guidace o the use of ezetimibe for primary hypercholesterolaemia (NICE TA 132) is referred to iaccurately or icompletely. We would therefore urge the Guidelie Developmet Group (GDG) to check all refereces to TA 132 i the fial guidelie for cosistecy, so as to esure that TA 132 is fully icorporated ito the fial guidelie. Thak you. We have added the ratioale for treatmet to page 73 of 193 of the Full Guidelie. The GDG has worked collaboratively with the developers of TA132 ad has take care to icorporate the recommedatios for ezetimibe i primary heterozygous FH ito the guidace. Differeces may occur i the case of homozygotes ad childre. These populatios were outside the scope of TA of 32

8 2 (Hele Johso) Sectio 2 Full.25 Key prioritie s for implem etatio - Maag emet Commet We would questio the GDG s coclusio that a more potet stati is the oly treatmet optio i a situatio where the goal is to achieve LDL-C reductios of greater tha 50% from baselie. First, NICE guidace TA 132 clearly states that ezetimibe, coadmiistered with iitial stati therapy, is recommeded as a optio i these circumstaces, as per its licesed idicatios, ad we are pleased to ote that this recommedatio is reflected i sectio of the draft guidelie. Secodly, NICE TA 132 recommeds ezetimibe as a optio i circumstaces where cosiatio is beig give to chagig, ot to a more potet stati, but to a alterative stati. Respose Thak you. Recommedatio refers to iitial stati drug therapy ad ot chage from existig stati therapy. The NICE Techology Appraisal 132 advises that it should be read i the cotext of the cliical guidelie for the relevat area. TA 132 ad the guidelie recommedatios are complemetary ad subject to stakehol commet by NICE. We have also cosied the results of the ENHANCE study, although this has ot bee raised i this istace. 2 (Hele Johso) 2 (Hele Johso) We would suggest that this key priority is reworded to take accout of these two poits. 3 Full NICE guidace TA 94 recommeds that, where stati therapy is iitiated i patiets at risk of cardiovascular evets, the prescriber should use a stati of low acquisitio cost. We appreciate that NICE TA 94 applies to patiets with o-familial hypercholesterolaemia, but would suggest that the same caveat should apply here, i the iterests of esurig cosistecy of guidace. 4 Full We would questio the GDG s coclusio that a more potet stati is the oly treatmet optio i a situatio where the goal is to achieve LDL-C reductios of greater tha 50% from baselie. Commet oted. Please see the ecoomic modellig re high dose low dose statis. Thak you. NICE TA 132 also advises that it should be read i the cotext of the cliical guidelie for the relevat area. First, NICE TA 132 clearly states that ezetimibe, coadmiistered with iitial stati therapy, is recommeded as a optio i these circumstaces, as per its licesed idicatios, ad we are pleased to ote Techology Appraisal 132 ad the the guidelie recommedatios are complemetary ad subject to stakehol commet by NICE. 8 of 32

9 Sectio Commet that this recommedatio is reflected i sectio of the draft guidelie. As curretly worded, sectio is icosistet with sectio which makes it clear that ezetimibe ca be cosied i situatios where serum LDL-C cocetratio is ot appropriately cotrolled by a stati aloe ad whe cosiatio is beig give to chagig from iitial stati therapy to a alterative stati. Respose Please see the updated cosiatio of the ENHANCE study. The drug treatmet recommedatios guide selectio of iitial drug therapy for this populatio. I NICE TA 132, the Appraisal Committee cocluded that: whereas doublig the dose of stati therapy or switchig to a alterative stati geerally leads to a further reductio i baselie LDL cholesterol cocetratios of approximately 6% ad 8%, respectively, the Committee cocluded that the additio of ezetimibe to stati therapy is likely to lead to greater icremetal reductios i LDL cholesterol cocetratios (NICE TA 132, sectio 4.3.2). Moreover, the Appraisal Committee also cocluded that: addig ezetimibe to iitial stati therapy as a treatmet optio is a cost-effective use of resources whe compared with switchig to a alterative stati (NICE TA 132, sectio ). Secodly, NICE TA 132 recommeds ezetimibe as a optio i circumstaces where cosiatio is beig give to chagig, ot to a more potet stati, but to a alterative stati. 9 of 32

10 Sectio Commet Respose 2 (Hele Johso) 2 (Hele Johso) 2 (Hele Johso) 2 (Hele Johso) 5 Full Full Full Sectio Lie Full Care Pathwa ys We would suggest that sectio is reworded accordigly. This setece should be ameded to read whe serum total or LDL-C cocetratio is ot appropriately cotrolled i accordace with NICE TA 132. This sectio ifers that resis, icotiic acids ad fibrates should oly be cosied as maagemet optios i patiets who are otherwise itolerat to statis ad ezetimibe, or i whom both statis ad ezetimibe are cotraidicated. We believe that this is the correct iferece ad is i lie with existig NICE ad atioal guidace. However, we do feel that there is some potetial for cofusio here, particularly whe oe compares the wordig of sectio to the treatmet algorithm o page 31. We would strogly recommed that the GDG makes the sequece of treatmets more explicit i this sectio. Sectio seems to be icosistet with sectio The drug therapy box (adults) of the FH maagemet algorithm o page 31 of the guidelie does ot accurately reflect the recommedatio i sectio , amely that ezetimibe ca be cosied as a treatmet optio after iitial stati therapy, but that resis, icotiic acids ad fibrates should oly be cosied by a specialist i FH if both statis ad ezetimibe are cotraidicated or ot tolerated. The same commet applies to the box titled optimisig The focus of FH treatmet is LDL-C lowerig as FH is specifically a coditio which affects LDL-C absorptio. Thak you. Recommedatio idicates whe referral should be utake whe prescribig specific drugs. Selectio of drug treatmet is idividualised to the patiet i accordace with recommedatio ad as described i the treatmet algorithm. Thak you. The recommedatio has bee moved to the adult treatmet sectio. Thak you. The recommedatios for lipid lowerig drug therapy do ot specify the sequece of drugs that should be adopted i all healthcare settigs, oly the poit of referral for particular drugs. We have ot made ay recommedatios for sequecig i relatio to ay drug other tha statis. 10 of 32

11 Sectio Commet drug therapy (adults). Respose We have chaged the algorithm to esure the recommedatios are cogruet. 2 (Hele Johso) 9 Full We are cocered that the GDG has take a somewhat selective approach to its health ecoomic aalysis. I particular, we do ot believe it is helpful to compare, ad make recommedatios about, the cost effectiveess of high itesity statis with low itesity statis exclusively without a) utakig a direct compariso of all the treatmet optios for FH, icludig ezetimibe, ad b) coductig a comprehesive ecoomic aalysis, commesurate with the aalyses that have bee coducted o statis ad ezetimibe as part of TA 94 ad TA 132, respectively. NICE TA 132 is fully icorporated withi this guidelie. Although you have ot raised the ENHANCE study, the GDG have cosied this evidece at the request of multiple stakehols. I NICE TA 132, a comprehesive pharmacoecoomic evaluatio was carried out, comparig ezetimibe as mootherapy ad as a add-o to stati therapy i five differet treatmet scearios. The Appraisal Committee cocluded that addig ezetimibe to iitial stati therapy as a treatmet optio is a cost-effective use of resources whe compared with switchig to a alterative stati (NICE TA 132, sectio ). Upo Tye Foudatio 1 NICE 1 1 Itrodu ctio We believe that this recommedatio should be take fully ito accout i the fial guidelie. It should be emphasised i the opeig paragraphs of the Itroductio or u Patiet Cetred Care that as Familial Hypercholesterolaemia is clearly recogised to be a autosomal co-domiat iherited coditio, this kowledge places a obligatio o the Natioal Service to esure that patiets ad their close relatives, who are at 50% (first degree) or 25% (secod degree) risk of iheritig the coditio, should be idetified Noted. The recommedatios for idetificatio, maagemet ad referral are made throughout the guidelie, ad are supported by cliical ad cost effectiveess evidece available. Where appropriate, heterogeeity i cliical ad cost effectiveess has bee highlighted. 11 of 32

12 Upo Tye Foudatio Upo Tye Foudatio Upo Tye Foudatio Upo Tye Foudatio Upo Tye Foudatio Upo Tye 2 NICE 3 NICE 4 NICE 5 NICE 6 NICE 7 NICE Sectio 1 1 Itrodu ctio 2 1 Key Prioritie s 2 1 Key Prioritie s 111, & Commet without uecessary delay ad offered diagostic testig ad treatmet if affected, to prevet avoidable morbidity ad mortality. Lie 14: Chage serum cholesterol to serum LDLcholesterol. Total cholesterol is less specific, beig elevated i several other primary hyperlipidaemias. Page 7, Lie 10: youg people should be defied by a upper age limit. Page 7. Lie 19. (ad also sectio likewise). Take out the word treated sice a patiet with FH may ot be o treatmet because of side effects or at their request. Coreal arcus is ot part of the Simo Broome Diagostic criteria for FH diagosis ad it should be omitted from this sectio. Respose Several research questios have also bee idetified that address areas where importat evidece was lackig. Icompletely refereced LDL-C has ow bee used throughout, except where specifically appropriate. Defiitio added please see glossary. Chage made. Chage made Suggest DNA testig istead of molecular techiques Chage made Precisely what iformatio should be recorded? Rec 1.1.0, chage utake refer to Simo broome criteria added. 12 of 32

13 Foudatio Upo Tye Foudatio Upo Tye Foudatio Upo Tye Foudatio 8 NICE 9 NICE 10 NICE Sectio Commet Page 9, Lie 8: coroary heart disease should be cardiovascular disease. Also applies i may places throughout. A variety of abbreviatios are used i the documet icludig CHD, CAD, CVD ad could be defied i the glossary What should be icluded i the DNA test, precisely? This is addressed i the mai documet (Sectio ) but deserves a brief metio here The use of the term uequivocal FH risks implyig a additioal category of FH i additio to those defied i the Simo Broome Criteria. Some relatives of a FH probad may be foud to have the family mutatio but may ot have typically elevated LDL-Cholesterol. If these relatives are to be diagosed with FH i all cases the phrase regardless of LDL- Cholesterol cocetratio should be added. It should also be stated here, as i the mai documet, that i idividuals who have a cliical diagosis of FH the absece of a diagostic mutatio does ot exclude the diagosis. They should be give a cliical diagosis of FH (either Defiite or Possible) accordig to the Simo Broome Criteria ad maaged accordigly. Respose The GDG has purposely used CHD as this is the site of FH morbidity. Rates of stroke ad peripheral does ot icrease i these idividuals, this is cosistet with the Simo Broome defiitio. See evidece to recommedaito page 31 of 193. Abbreviatios will be added to the glossary The specific varieties of DNA tests was outside the scope of the guidelie. The full guidelie gives a brief outlie of the priciples behid the test but this is ot appropriate for the NICE versio due to the eed for brevity. Chages made. We have added a ew recommedatio for the cliical diagosis of Fh i the absece of a mutatio see rec of 32

14 Upo Tye Foudatio Upo Tye Foudatio Upo Tye Foudatio Upo Tye Foudatio 11 NICE 12 NICE 13 NICE 14 NICE Sectio Commet We agree this is importat as other forms of hyperlipidaemia are frequetly foud i families with premature coroary disease ad may co-exist with FH Chage to the mutatio ad ot LDL-cholesterol should be used to idetify affected relatives. See previous poit u There is metio of the creatio of a atioal system for co-ordiatig cascade testig, this of course already exists ad is called the regioal geetic services, who already do this very effectively for other heritable diseases. Why should FH be ay differet? I fact there is o metio i this of the role of geetic services i the maagemet of cascade testig. I am surprised at this give that there was a cliical geeticist o the pael who wrote the draft. It is likely that a typical lipidologist will kow o more about cascade screeig tha a typical geeticist kows about FH. I the same way that there is metio of the role of cardiologists ad obstetricias i the maagemet of FH there surely eeds to be ackowledgemet that it makes sese to ivolve geetic services i the maagemet of a archetypal sigle gee disease I most cases the decisio to treat FH is ot difficult oe, however i some cases carriers of FH mutatios may ot have typically elevated LDL-Cholesterol cocetratios. We would suggest that where there is doubt about the diagosis or the eed to iitiate stati treatmet i such cases, this should prompt referral to a specialist with expertise i FH Respose Noted with thaks Chage made. The GDG did cosi the issue of geetic cousellig. See page 119 of 193. We have ot attempted to utake service specificatio, the term healthcare with expertise i FH is iclusive of all people with the competece to utake this role. Thak you. The recommedatios for diagosis assume that the patiets meet the Simo Broome criteria at the outset, ad therefore all idex idividuals will have a elevated cholesterol. Recommedatios have bee made for family members who do 14 of 32

15 Upo Tye Foudatio Upo Tye Foudatio Upo Tye Foudatio Upo Tye Foudatio 15 NICE 16 NICE 17 NICE 18 NICE Sectio Commet The full rage of available statis should be ope to cosiatio as a alterative to low acquisitio cost statis i these are ieffective of ot tolerated. The ascertaimet of a greater tha 50% reductio is depedet o establishig a accurate baselie, pretreatmet LDL-cholesterol for the purpose of goal settig. This is ofte uavailable ad uless treatmet is withdraw temporarily to establish it, i practice it is ecessary to work towards a absolute LDL-Cholesterol target (see below u ) A reductio of 51% may be far from sufficiet i severe cases. Istead recommed i additio the same absolute targets as for o-fh i.e. LDL-C < 3 (or ideally <2), to achieve whichever represets the greater reductio. It is ot clear what (See At least five a week ) is referrig to. Superscript 4 referrig to footote required The term child-focussed settig is uclear ad requires defiitio Respose ot have raised cholesterol but carry a mutatio equivocal diagosis of FH. Examples of statis ow give. The GDG cosied the issue of what should be doe for patiets already takig treatmet. Expert advice suggested that a phoe call to the relevat biochemical laboratory would be usually beig sufficiet to cofirm the diagosis. Expert opiio also suggested that treatmet ad referral for subsequet cascade testig without cofirmatio of the diagosis would be poor practice. See page 73 Full Guidelie. We ote you have ot provided ay scietific evidece. A risk stratificatio approach to treatmet is described i the treatmet recommedatios. Rec This is uclear, we were uable to determie the purpose of this commet. Added to glossary 15 of 32

16 Upo Tye Foudatio Upo Tye Foudatio Upo Tye Foudatio Upo Tye Foudatio Upo Tye Foudatio 19 NICE 20 NICE 21 NICE 22 NICE 23 NICE Sectio Commet Please specify which vitami supplemets should be cosied It is most importat that relatives are be provided with appropriate documetatio icludig cotact letters. A direct approach should be offered as a alterative where estraged relatives may ot wish to make persoal cotact There is little evidece to justify avoidace of combied oral cotraceptio which is usually more secure ad better tolerated tha other forms of cotraceptio. Suggest iclude here the evidece statemet from the Full guidelie, Sectio If treated optimally, wome with FH will have ormalised lipid cocetratios, so combied oral cotraceptio is ot routiely cotraidicated We agree that a structured review should be required aually as a miimum oce the patiet is stable o maiteace therapy A fastig blood specime is ot essetial for moitorig lipid cocetratios i typical FH patiets i whom triglyceride cocetratio are low ormal but it should be recogised that calculated LDL-Cholesterol is subject to egative bias i o-fastig specimes (i iverse proportio to the post-pradial triglyceride icrease) ad might lead to u-treatmet if used iappropriately. Total ad HDL-cholesterol ca be estimated o a ofastig specime ad are usually sufficiet for Respose We have added details of the vitamis required. The BNF states that resis may affect vitami absorptio ad that vitamis A, D ad K may be required with log term use. We have used the term facilitate to capture the sesitivities of the umerous variatios i persoal circumstaces. See page 119. Absece of evidece is ot evidece of absece - see evidece to recommedatios page 172 for the GDGs updated ad detailed aalysis of this area.. Chage made. Noted. A fastig sample is ot ureasoable give that the patiet may oly have a aual review ad that LDL-C cocetratios are the basis of this coditio. See page of 32

17 Sectio Commet moitorig patiets o stable maiteace therapy. Respose Upo Tye Foudatio Upo Tye Foudatio Upo Tye Foudatio 24 NICE 25 NICE 26 NICE Appropriate specialist referral should be arraged if there are sigs or symptoms of ANY cardiovascular disease. (NB Already chaged i care pathway o page 31) A more explicit defiitio is required for a family history of coroary heart disease i early adulthood with a upper age limit if this criterio is to be applied i cliical practice. Coroary heart disease should be chaged to cardiovascular disease. As diabetes is uusual i associatio with FH ad is a potet cardiovascular risk factor which overcomes ge related risk differetials, diabetes by itself should be cosied as a idicatio for specialist referral. Diagosis of FH may be poorly recogised amog patiets attedig diabetes services Appe dix C Page 34. Coreal arcus is ot icluded i the Simo Broome diagostic criteria ad it is ot possible to examie for symptoms. Suggest replace Examie for cliical sigs ad symptoms icludig coreal arcus ad tedo xathomata with Examie for tedo xathomata ad cliical sigs of cardiovascular disease. Take persoal ad family medical history, especially CHD should be placed before the cliical examiatio. The term CHD has bee used based o the Simo Broome data. See evidece to recommedatio page 31 of 193. See Full Guidelie page 136 for explaatio fo why this has bee used. Chages have bee made. Upo Tye 27 NICE Appe dix D Note that there are some differeces betwee the iformatio i the boxes ad i the related body text of the guidelies. LDL-cholesterol calculatio by the Friedewald formula is ivalid uless the lipid measuremets are performed o a fastig specime. Noted with thaks 17 of 32

18 Foudatio Upo Tye Foudatio Upo Tye Foudatio Upo Tye Foudatio Nursig 28 NICE Sectio Appe dix E 29 Full 0 Geera l 30 Full 0 Geera l 1 Itrodu ctio Commet As preseted, diagosis of Possible Familial Hypercholesterolaemia requires 2 of the 3 bulleted criteria as for Defiite Familial Hypercholesterolaemia AND oe or the two bulleted family history criteria. It would be clearer if the criteria were ot bulleted but umbered 1-5; the Defiite FH is 1 + (2or 3) ad possible is 1 + (4 or 5). The guidelies will be of cosiable practical value if they are used to form the basis for commissioig of a itegrated care pathway which liks together the existig secodary care services (icludig Adult ad Paediatric Lipid Cliic Services, Cliical Geetics ad Cardiology) ad primary care services. Abbreviatios are ot used cosistetly throughout ad are frequetly ot defied at first use. Tables are give umbers ad titles i some cases ad ot others i a icosistet fashio, especially see Sectios 3 ad 8. 0 With a membership of over 400,000 registered urses, midwives, health visitors, ursig studets, health care assistats ad urse cadets, the Nursig (RCN) is the voice of ursig across the UK ad the largest professioal uio of ursig staff i the world. RCN members work i a variety of hospital ad commuity settigs i the ad the idepedet sector. The RCN promotes patiet ad ursig iterests o a wide rage of issues by workig closely with the Govermet, the UK parliamets ad other atioal ad Europea political istitutios, trade uios, professioal bodies ad volutary orgaisatios. Respose Noted with thaks Noted ad will be passed to the NICE implemetatio team. Noted ad correctios made. Noted with thaks The RCN welcomes this guidelie. 18 of 32

19 Nursig 2 Geera l Sectio Commet 0 This guidelie is much eeded. We feel it is easy to follow ad it should be easy for healthcare professioals to decide what to do whe followig the guidelie. Respose Noted with thaks Nursig Nursig ad Child ad Child ad Child It will also hopefully result i better ad more uiform care of patiets with Familial Hypercholesterolaemia ad those with suspected Familial Hypercholesterolaemia. 3 NICE If DNA testig is carried out o both possible a defiite FH patiets ad a mutatio is ot idetified there could be potetial for cofusio o the part of the idividual ad the possibility that they may the uestimate 4 NICE Full versio their risk. Where paediatric/child focused services are ot available where should childre be see? Could there ot be family FH cliics? No studies foud o the use of icotiamide. There are o RCTs but Colletti et al reported i Pediatrics : Full 0 Geera l 2 0 Geera l Icludig childre s guidelies i the body of a adult guidelie is geerally ot good practice. It would be better for the Paediatric guidace to be separate ad easily idetifiable. It would also limit cofusio. The paediatric guidelies are ot specific eough ad could be cofusig ad do ot have eough precautios to safeguard childre. Holistic paediatric care may also ot be possible if this service is delivered by adult traied specialists; shared care with a geeral practitioer/paediatricia may provide the solutio. We agree. Both cliical ad molecular testig are recommeded i Commet will be passed to the NICE implemetatio team. Our searches were limited to RCTs with regard to drug itervetios. Thak you. The recommedatios will be colour coded i the fial guidelie, ad recommedatios that are specific to childre/youg people oly are clearly marked. Thak You. The recommedatios for childre were based o the best available (limited) evidece i this age group. The role of the Natioal Service Framework for Childre, Youg People ad Materity Services i the delivery of care for childre ad youg people has ow bee emphasised. We regret 19 of 32

20 ad Child ad Child ad Child ad Child Sectio 3 0 Geera l 4 0 Geera l 5 Full 0 Geera l 6 Full 0 Geera l 7 Full versio ad Commet Excludig the post mortem data collected from childre is a error i my view as the evidece for early oset disease is elimiated by this assumptio. I fid it disappoitig that the America NCEP program was ot used i the process especially as this is the logest ruig Cholesterol program for childre ad they have recetly reviewed it after beig i use for early 515 years. Their reviewers felt that childre were ot diagosed early eough ad ot treated adequately, ad that was usig guidelies much stricter tha those suggested here. See: ad Julia Steiberger ad Aaro S. Kelly. Challeges of Existig Pediatric Dyslipidemia Guidelies: Call for Reappraisal Circulatio, Jauary 1/8, 2008; 117: The guidelie highlights throughout the documet where there are gaps i the evidece to support cliical practice. Although these areas are i the mai text of the documet, it would be helpful if there could be a additioal sectio at the ed of each chapter with areas where further research would be helpful. This would support the research ageda ad maximise resources. There eeds to be more metio of patiet /paret orgaisatios who play a importat part of support i maagig families It would be detrimetal to oly cofirm the diagosis of FH after puberty, especially as childre with Homozygous status therapy should be iitiated before Respose that are uable to offer advice of service specificatio. Our searches did ot exclude post mortem data but o was idetified. We do have evidece of early oset disease from studies of carotid itima thickess. We have excluded studies i the geeral populatio ad looked istead at studies specific to childre with FH. We have recommeded treatmet as early as age 10 i childre with kow FH. Although we appreciate the opiios of Steiberger ad Kelly our process is to review the origial research which upis the recommedatios. Please refer to the guidelie research recommedatios. This will appear i the Ustadig NICE Guidace (UNG) publicatio. Thak you. We have ow provided advice for childre at risk of homozygous FH (see 20 of 32

21 ad Child ad Child ad Child ad Child ad Child Sectio Commet NICE the age of 5. Please see: Atherosclerosis Feb 19. Recommedatios for the use of LDL apheresis. Thompso GR; HEART-UK LDL Apheresis Workig Group. Respose recommedatio ). 8 IFP A secod paragraph should state This should iclude The geeral iclusios for the FH guidelie are idetified i paragraph 2. Further detail is available i the scope. 9 Full Full versio ad NICE 11 Full versio ad NICE What exactly is a specialist with expertise i FH for childre? This should be a paediatricia (preferably with metabolic expertise) at least. This recommedatio eeds to be cosiably stregtheed to esure that childre are see by paediatricias who the have extra expertise. There is referece to patiets beig see i a child friedly area, but that eeds to be with a paediatricia. This has to be take seriously as we have cocers that adult practitioers may feel that a paediatricia is ot essetial from the way this guidace is writte at preset, which caot be allowed. Specialist with expertise i child focused settig should be expaded to protect childre. The specialist would eed to be actively maagig at least 25 childre with FH, should have experiece i prescribig drugs i childre, should be ehaced CRB checked to work with childre ad have received child protectio traiig at level 2 as a miimum. Facilities should be available to have access to paediatric dieticias as the eeds ad maagemet of dietary itervetio are differet i childre. How did the team arrive at this value of LDL-C as most of the quoted evidece i childre looked at total cholesterol? Is this typig error? Total Cholesterol of 6mmol/l would be more appropriate for childre. Especially as that would be way above the 95th cetile Thak you. We are uable to address service specificatio however the stadards for service delivery withi the Natioal Service Framework for Childre, Youg People ad Materity Services are sigposted. This commet will be referred to the NICE implemetatio team This is a icorrect recommedatio ad has bee revised. 21 of 32

22 Sectio Commet for childre of all ages. Respose ad Child ad Child ad Child ad Child ad Child 12 Full versio ad NICE Pravastati have a licece from the age of 8, but all stati therapy should be iitiated by a expert i lipid disors i childre. 13 Full More emphasis is eeded o educatig of childre about FH lifestyle/diet as this is oe of the mai aims of early itervetio. 14 Full versio ad NICE The use of staols i childre may lead to Vitami deficiecies ad their use is geerally ot ecouraged i childre u the age of 8.This is ot clear from curret guidace. 15 Full Whilst we agree i priciple with... example ad commet. 16 Full There is o recommedatio regardig the frequecy of moitorig cholesterol levels, what to moitor ad what target levels to aim for i the paediatric populatio Noted. This is also the GDG recommedatio. Thak you. The GDG have specifically cosied this issue ad this is explaied withi the evidece to recommedatios o page 125 of the Full Guidelie. There was o evidece re childre with FH ad staols or of vitami deficiecies i the paediatric populatio. See page 125 of the Full Guidelie. Commet is icomplete Thak you. The guidelie provides moitorig recommedatios for all people with FH (icludig childre). Target levels were ot specified i this guidelie for childre as values chage with growth. This iformatio has bee added to page 81 of 193. ad Child 17 Full versio ad NICE Lifestyle chages should be started earlier i childre ad chage durig adolescece is ot well tolerated. Idetifyig childre at youger age may be a greater beefit i view of the lack of evidece. Lifestyle chages before the age of 5 are more likely to have a impact. Thak you. The GDG cosied this specific issue ad their cosesus view is ow described i the guidelie. Please page 125 of Full Guidelie. 22 of 32

23 ad Child ad Child ad Child ad Child 18 Full versio Sectio 19 Full Full versio 21 Full versio Commet Multiple paediatric refereces ca be foud o this topic. The sesitivity of cholesterol value is also higher i the pre-pubertal age, supportig the fact that childre should be diagosed earlier tha suggested i the guidace The NSF for childre should have bee cosulted for the paediatric guidelies Who should orgaise mutatio aalysis? Has full cosiatio bee give to geetic cosequeces of this ivestigatio ad eed for geetic cousellig? Who would pay for testig? This statemet is ot true. Most childre with Homozygous hypercholesterolaemia actually have lower values tha the adults. The youger they are the lower the cocetratio, ad with this value may childre will be missed. A value of 12mmol/l for total cholesterol has previously bee agreed by cosesus for the trials i childre. See: The Metabolic& Molecular Bases of iherited Disease 8th editio Volume 11 p 2865 table Goldstei, Hobbs ad Brow How were 8 studies idetified as there are 12 RCT studies o the subject i? It may ot ifluece the guidace but the RCT studies published by Couture et al, Koeijvoets et al, Rodeburg et al ad Respose The eed to refer to this has ow bee made clear withi the Itroductio ad the relevat recommedatios. The issue of geetic cousellig was cosied by the GDG ad a recommedatio made that iformatio ad educatio should be give by a idividual with expertise i FH. Please see page 119 of the Full Guidelie for the evidece to recommedatio for this area. The orgaisatio ad fudig of services is beyod our remit. Your query will be referred to the NICE implemetatio team. Thak you. We have ow adopted a recommedatio that defies a LDL-C level i childre with homozygous FH. Please also see page 28 ad 31of the Full Guidelie for the explaatio for this figure. These were studies which met the iclusio criteria for the Arambepola et al systematic review. This well coducted systematic review 23 of 32

24 Pathologists Sectio Commet Kwiterovich et al seem to have bee excluded. As they represet RCT s ad, except for Couture et al, the others have follow up i excess of 2 years it seems strage ot to metio them. 1 NICE 0 The College recommeds a iterpretative commet o ay cholesterol of 7.5 mmol/l or above recommedig family history screeig ad screeig of family members if there is a family history of IHD. Respose represets the highest level of evidece ad therefore idividual RCTs were ot extracted. Thak you. A ew recommedatio has bee made that addresses this issue (see first recommedatio u diagosis ). This is supported by the HEART UK laboratory subcommittee. South Asia Foudatio Trafford Primary Care Trafford Primary Care s 1 NICE 0 Geera l 1 Full ; Full 25 Appe dix E A comprehesive guidelie for which the GDG must be cogratulated. We are pleased to particularly see the low threshold for ivestigatio coupled to the fact that symptoms ad sigs sigal the eed for further o ivasive ivestigatio of coroary disease ad that asymptomatic idividuals should ot automatically be ivestigated. We are also delighted to see emphasised that the use of stadard risk predictio charts is ot advocated i FH. This will eed sigificat educatio as relatively youg patiets with FH will score low i terms of CV risk ad therefore receive iappropriate reassurace ad eglect if practitioers are uaware of the possible diagosis of FH. Thus, educatio is key to this guidelie. We would like to have see a statemet regardig the place of the restig ECG i maagemet. Although the exercise ECG is metioed, there is o statemet (positive or egative) regardig the restig ECG. We feel there is a error i "Appedix E: Diagostic criteria for probads (Simo Broome) ad relatives". We do't ustad how "Possible FH" ca require more criteria tha "Defiite FH". Goig back to earlier Noted with thaks. Will pass commets to the NICE Implemetatio team. A recommedatio has made i the moitorig sectio that this should be cosied ad please also see page 136 of the Full Guidelie. Thak you. This has bee ameded. 24 of 32

25 UK Natioal Screeig Committee Sectio 1 Full 0 Geera l Commet publicatios of the Simo Broome criteria these show possible FH to iclude the FIRST bullet poit i the "Defiite" list plus oe of the bullet poits i the "Possible" list. We thik there may have bee a trascriptio error ad would like NICE to review the appedix ad compare it to published Simo Broome criteria. The UK NSC otes that populatio screeig is outside the remit of this guidelie. The Committee welcomes the guidelie s distictio betwee targeted testig or cascade testig of relatives positively diagosed with FH which is recommeded ad populatio screeig which is ot. This helpful distictio is maitaied withi the guidelie s recommedatios. However the glossary defiitio of targeted testig refers to targeted cascade screeig. We would be grateful if this could be replaced with targeted cascade testig. Respose Correctios made. Edocrie ad Diabetes 1 NICE versio 1 1 Itrodu ctio There are other examples of this slidig termiology, eg page 23 lie 2/3 refers to cascade screeig. We would be grateful if the Guidelie Developmet Group could refer to testig, targeted or cascade cosistetly throughout the documet. Lie 11: It is stated that rarely a idividual will iherit a geetic defect from both parets ad will have homozygous FH. As iheritace of two differet defects from each paret (compoud heterozygosity) is likely to occur at least as ofte as iheritig the same defect from both patiets (homozygosity). The cliical equivalece of these is oted i the Full Guidelie Sectio 1.10, Glossary, but for clarity this paragraph Thak you. This has bee ameded. 25 of 32

26 Edocrie ad Diabetes Edocrie ad Diabetes Edocrie ad Diabetes Edocrie ad Diabetes Edocrie ad Diabetes 2 NICE versio 3 NICE versio 4 NICE versio 5 NICE versio 6 NICE versio Sectio 1 1 Itrodu ctio 2 1 Key Prioritie s & Commet could be reworded to state rarely a idividual will iherit a geetic defect from each paret ad will have homozygous or compoud heterozygous FH, which will be collectively termed homozygous FH for the purpose of this guidelie. Lie 14: The statemet The elevated serum cholesterol cocetratios that characterise heterozygous FH should be modified to read The elevated serum LDLcholesterol cocetratios that characterise heterozygous FH as the latter are much more specific for FH. Page 7. Lie 19. (ad also sectio likewise). Take out the word treated sice a patiet with FH may ot be o treatmet because of side effects or at their request. Arcus is listed with tedo xathoma as a cliical sig for FH, Tedo xathoma is cosied pathogomic for FH, but coreal arcus lipidus lacks specificity ad is therefore ot part of the Simo Broome Diagostic criteria for FH diagosis Rather tha molecular techiques why ot just say DNA testig? Page 9. Lie 8. coroary heart disease should be cardiovascular disease. Also applies i may places throughout. Respose We appreciate this is true, however this sectio is the itroductio to the guidelie ad therefore for reasos of ease of comprehesio we have used the term cholesterol here, but i all evidece appraisal through the guidelie, ad i recommedatios, we have used LDL-cholesterol where possible. Chage made. Chage made. Chage made. The GDG has purposely used CHD as this is the site of FH morbidity. Rates of stroke ad peripheral does ot icrease i these idividuals, this is cosistet with the Simo Broome defiitio. See evidece to recommedatio page 31 of of 32

27 Edocrie ad Diabetes 7 NICE versio Sectio Commet The phrase relatives who have a detected mutatio would be more clearly expressed as relatives who have a diagostic FH mutatio detected o DNA testig. The use of the term uequivocal FH is appropriate i this cotext but there is a risk of implyig a additioal category of FH i additio to those defied i the Simo Broome Criteria. Respose Chage made. Edocrie ad Diabetes Edocrie ad Diabetes Edocrie ad Diabetes Edocrie ad Diabetes Edocrie 8 NICE versio 9 NICE versio 10 NICE versio 11 NICE versio 12 NICE versio It should also be stated here, as i the mai documet, that i idividuals who have a cliical diagosis of FH the absece of a diagostic mutatio does ot exclude the diagosis. They should be give a cliical diagosis of FH accordig to the Simo Broome Criteria ad maaged accordigly We agree this is importat as other forms of hyperlipidaemia are frequet i families with premature coroary disease ad may co-exist with FH The itetio of statemet would be clearer if modified to read I families i which a mutatio has bee idetified, the mutatio ad ot LDL-cholesterol should be used to idetify affected relatives. See previous poit u A reductio of 51% may be far from sufficiet. Istead recommed i additio the same absolute targets as for o-fh ie LDL-C < 3 (or ideally <2), to achieve whichever represets the greater reductio Should t limit exercise to 30 mis i.e. chage to at least 30 mis Specify arterio-veous fistulae. There are other varieties. Also i Full Guidelie Page 186, Lie 17: Commet oted. Thak you. Icorporated. We ote you have ot provided ay scietific evidece. A risk stratificatio approach to treatmet is described i the treatmet recommedatios. Rec Chage utake. Chage utake. 27 of 32

28 ad Diabetes Edocrie ad Diabetes Edocrie ad Diabetes Edocrie ad Diabetes Edocrie ad Diabetes 13 NICE versio 14 NICE versio 15 NICE versio 16 NICE versio Sectio Commet Structured review should be required aually as a miimum oce the patiet is stable o maiteace therapy A fastig blood specime is oly essetial for assessmet of LDL-Cholesterol usig the Friedewald calculatio, as required for the applicatio of the Simo Broome criteria i or to establish a diagosis. A fastig blood specime is seldom essetial for moitorig lipid cocetratios i typical FH patiets i whom triglyceride cocetratio are low ormal ad to isist o fastig may be detrimetal to patiet compliace ad overall service delivery. HDL- Cholesterol remais importat but ca be estimated o a o-fastig specime. As ay reductio i total cholesterol i the absece of hypertriglyceridaemia is likely to be due to reductio of LDL-Cholesterol or icrease of HDL-cholesterol, estimatio of VLDL cholesterol (by Friedewald calculatio o a fastig specime) is ot required routiely This statemet is vague ad requires a more explicit defiitio of what is meat by a family history of coroary heart disease i early adulthood. Coroary heart disease should be chaged to cardiovascular disease. As diabetes is uusual i associatio with FH ad is a potet cardiovascular risk factor which overcomes ge related risk differetials, diabetes by itself should be cosied as a idicatio for specialist Appe dix C referral Page 34. Coreal arcus is ot icluded i the Simo Broome diagostic criteria ad it is ot possible to examie for symptoms. Suggest replace Examie for cliical sigs ad symptoms icludig coreal arcus ad Respose Chage made. Noted. A fastig sample is ot ureasoable give that the patiet may oly have a aual review ad that LDL-C cocetratios are the basis of this coditio. See page 136. See Full Guidelie page 136 for explaatio fo why this has bee used. Chages have bee made. 28 of 32