Dr Dev Datta Consultant in Metabolic Medicine

Ysbyty Athrofaol Llandochau University Hospital Llandough

Penlan Road, Llandough Heol Penlan, Llandochau Penarth, Vale of Glamorgan Penarth, Bro Morgannwg CF64 2XX CF64 2XX Phone 029 2071 1711 Ffôn 029 2071 1711 Eich cyf/Your ref Fax 029 2070 8973 Ffacs 029 2070 8973 Ein cyf/Our ref Welsh Health Telephone Network Direct Line/Llinell uniongychol

LLANDOUGH LIPID UNIT Dr Dev Datta Consultant in Metabolic Medicine Tel: 02920 716844/Fax 02920 712942 Suzanne Watkins Nurse Specialist Lipid Unit Tel: 02920 715047

11th December 2013

Dear Dr,

Thank you for referring patient *** for consideration of lipoprotein apheresis. I will include details of the treatment and anonymised information on your patient. This is in addition to my recent clinic letter, which indicates that we have reviewed your patient in Cardiff.

Patient *** has familial hypercholesterolaemia and significant vascular disease. She had an MI in 2001 and 2012, CABG in 2006 and redo CABG in 2006. She has also had subclavian arterial disease requiring stenting in 2006 and furthermore required percutaneous coronary intervention with stenting in 2012. Despite this, she remains well and active. She is reported to have diabetes, but is on no medication for this and her recent HbA1c was actually within the non-diabetic range. Despite maximal lipid lowering therapy with Rosuvastatin 40mg OD and Ezetimibe 10 mg OD her total cholesterol is 5.6 mmol/L, LDL 3.5 mmol/L. She would not be a suitable candidate for any of our active commercial clinical trials in Cardiff. In view of her aggressive vascular disease, you were keen to consider apheresis as an approach to reduce her risk of further events.

I am sure that our colleagues who will be reviewing the use of lipoprotein apheresis in *** will have to hand the NICE guidance for identification and management of FH, which references the use of lipoprotein apheresis and was published in August 2008. This provides the relevant background, although there is some up to date information which I will mention in this letter. You will also be familiar with the HEART UK guidelines for use of lipoprotein apheresis published in 2009, which we utilise as our template to ensure any appropriate patients are considered for apheresis. As you will

Bwrdd Iechyd Prifysgol Caerdydd a’r Fro yw enw gweithredol Bwyrdd Iechyd Lleol Prifysgol Caerdydd a’r Fro Cardiff and Vale University Health Board is the operational name of Cardiff and Vale University Local Health Board Ysbyty Athrofaol Llandochau University Hospital Llandough

be aware I have disseminated this document to relevant colleagues to ensure our unit receives appropriate referrals.

The indications for apheresis are expanded upon within the documents referred to above, however I will describe how the service in Cardiff informs local practice. At present 18 patients are treated in the Cardiff unit and one third are from the Cardiff area, one third are from England and the rest are from other parts of Wales. The unit was first established by my predecessor, Stephanie Matthews in 1990 and indeed we do have some patients who have been treating since that time. As the indications for apheresis have become better known in recent times, our approach to selection and monitoring of patients has become more stringent. Given the nature of the atherosclerotic process i.e. it is the chronic deposition of atherogenic lipoproteins such as those contained within LDL-C which is important in the genesis of atherosclerosis in FH, it is long term interventions which are appropriate. This of course in the vast majority of patients entails the use of lipid lowering tablets, however apheresis remains an option for a small minority. Most of our patients either have homozygous FH or have severe heterozygous FH with aggressive coronary disease. In the long term we achieve an average 63.5% reduction in LDL-C with each treatment. This is comparable with other units in the world. We utilise the mean LDL-C value to chart progress and despite the rebound of LDL-C production in between fortnightly therapies we see on average a 25% reduction in the mean circulating LDL-C concentration as well as a 70% reduction in atherogenic lipoprotein Lp(a). The incidence of complications related to therapy are low and treatment is generally well tolerated with most patients being able to drive home after a 2 – 3 hour treatment. All of our data is recorded and averaged over a 6 monthly cycle and this information relayed to the referring physician and GP. Anonymised data are inputted into a national database.

You will be aware that there are no published, blinded randomised control trials evaluating the use of apheresis for aggressive FH, in the same way as there are no such trials evaluating the use of statin therapy in FH as to pursue such trials have not been considered ethical. It is important to note that in homozygous and aggressive heterozygous FH, lipoprotein apheresis represents the final opportunity for meaningful lipid lowering therapy, where other avenues have been exhausted.

Older data have suggested lack of progression of angiographic coronary disease with other reports showing no significant angiographic disease regression or stabilisation compared to tablet therapy, however in the modern era, what is perhaps more compelling is data indicating the reduction in major adverse cardio vascular events (MACE) with the use of apheresis. Note that these data were published after the publication of the NICE guidance for FH.

Koziolek et al, described their experience in a German unit, mainly treating a case mix such as our own i.e. 38 patients with mainly heterozygous FH, with an LDL-C >3.4 mmol/L on appropriate drug therapy. Retrospective analysis over 20 years demonstrated a statistically and clinically significant reduction in MACE from 7% to 1.2% per annum and a decrease in the need for revascularisation from 23% to 3.8% per annum.

Jaeger et al, again in Germany demonstrated a reduction in MACE from 1.056 per patient per annum on drug therapy to 0.144 per patient per annum (p<0.0001) when on apheresis and drug therapy.

The cost-effectiveness of this has not been full appraised. The potential health economic argument is likely to be derived from reduction in MACE and the implication for clinical progress with aggressive cholesterol lowering. This is our own observation, but hitherto unpublished experience in the Cardiff unit.

NICE in CG71 recommends consideration of apheresis as follows “ In exceptional instances (such as when there is progressive, symptomatic coronary heart disease, despite maximal tolerated lipid-modifying drug therapy and optimal medical and surgical therapy), healthcare professionals should consider offering LDL apheresis for the treatment of people with heterozygous FH. This should take place in a specialist centre on a case-by-case basis and data recorded in an appropriate registry.”

HEART UK, and other authoritative bodies in the developed world including European countries, United States and Australasia pursue lipoprotein apheresis for FH patients. This is recognised by European health insurance companies and those in the United States.

We are also aware that all interventions which reduce cholesterol in FH, have contributed to long term benefit, as manifest by the improvement of mortality and cardiovascular morbidity in this condition. In a condition which targets LDL cholesterol, there is confidence in that aggressively targeting the mediator of the disease is of benefit and has translated into significant improvements in mortality and morbidity in FH patients worldwide. Thus for an individual patient who has severe FH and significant coronary disease, aggressive lowering of LDL-C by apheresis, whilst reasonably considered as a treatment of ‘last resort’, if not offered in patients with severe FH which is inadequately treated, puts the patient at risk of atherosclerotic disease progression and MACE, the risk of which may be reduced with apheresis.

We have therefore applied relevant guidance in pursuing lipoprotein apheresis for ***. I would therefore argue that long term treatment with lipoprotein apheresis would be clinically appropriate and should be supported.

Yours sincerely

Dr Dev Datta MD MRCP FRCPath Consultant in Metabolic Medicine

References

DeMott K, Nherera L, Shaw EJ, Minhas R, Humphries SE, Kathoria M, Ritchie G, Nunes V, Davies D, Lee P, McDowell I, Neil A, Qureshi N, Rowlands P, Seed M, Stracey H, Thorogood M, Watson M. Clinical Guidelines and Evidence Review for Familial hypercholesterolaemia: the identification and management of adults and children with familial hypercholesterolaemia. 2008. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners.

Thompson, GR. Recommendations for the use of LDL apheresis. Atherosclerosis (2008); 198: 247-55

Koziolek MJ et al. Retrospective analysis of long term lipid apheresis at a single centre. Ther Aph Dial (2009); 14;143-52

Jaeger B et al. Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein (a) levels and prevent major adverse coronary events. Nat Clin Prac Cardiovasc Med (2009);6:229-239

Bwrdd Iechyd Prifysgol Caerdydd a’r Fro yw enw gweithredol Bwyrdd Iechyd Lleol Prifysgol Caerdydd a’r Fro Cardiff and Vale University Health Board is the operational name of Cardiff and Vale University Local Health Board