Sex differences in cardiovascular morbidity associated with familial hypercholesterolaemia: A retrospective cohort study of the UK Simon Broome register linked to national hospital records (2020)

Type of publication:
Journal article

Author(s):
Barbara Iyen, Nadeem Qureshi, Stephen Weng, Paul Roderick, Joe Kai, *Nigel Capps, Paul N. Durrington, Ian FW. McDowell, Handrean Soran, Andrew Neil, Steve E. Humphries

Citation:
Atherosclerosis, Nov 2020 [epub ahead of print]

Abstract:
Background and aims: The UK Simon Broome (SB) familial hypercholesterolaemia (FH) register previously reported 3-fold higher standardised mortality ratio for cardiovascular disease (CVD) in women compared to men from 2009 to 2015. Here we examined sex differences in CVD morbidity in FH by national linkage of the SB register with Hospital Episode Statistics (HES).
Methods: Of 3553 FH individuals in the SB register (aged 20–79 years at registration), 2988 (52.5% women) had linked HES records. Standardised Morbidity Ratios (SMbR) compared to an age and sex-matched UK general practice population were calculated [95% confidence intervals] for first CVD hospitalisation in HES (a composite of coronary heart disease (CHD), myocardial infarction (MI), stable or unstable angina, stroke, TIA, peripheral vascular disease (PVD), heart failure, coronary revascularisation interventions).
Results: At registration, men had significantly (p < 0.001) higher prevalence of previous CHD (24.8% vs 17.6%), previous MI (13.2% vs 6.3%), and were commenced on lipid-lowering treatment at a younger age than women (37.5 years vs 42.3 years). The SMbR for composite CVD was 6.83 (6.33–7.37) in men and 7.55 (6.99–8.15) in women. In individuals aged 30–50 years, SMbR in women was 50% higher than in men (15.04 [12.98–17.42] vs 10.03 [9.01–11.17]). In individuals >50 years, SMbR was 33% higher in women than men (6.11 [5.57–6.70] vs 4.59 [4.08–5.15]).
Conclusions: Excess CVD morbidity due to FH remains markedly elevated in women at all ages, but especially those aged 30–50 years. This highlights the need for earlier diagnosis and optimisation of lipid-lowering risk factor management for all FH patients, with particular attention to young women with FH.

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Non-HDL or LDL cholesterol in heterozygous familial hypercholesterolaemia: findings of the Simon Broome Register (2020)

Type of publication:
Journal article

Author(s):
Soran H.; Durrington P.N.; Cooper J.A.; Humphries S.E.; *Capps N.; McDowell I.F.W.; Neil A.

Citation:
Current Opinion in Lipidology; August 2020, Volume 31, Issue 4, p. 167-175

Abstract:
PURPOSE OF REVIEW: The role of non-HDL-C in the identification and management of lipid disorders is not clearly defined, although UK guidelines recommend its wider use in assessing the need for lipid-lowering therapy and as a treatment target. RECENT FINDINGS: We examined the implications of the use of non-HDL-C as opposed to LDL-C in 253 people with hypercholesterolaemia before treatment and 573 after treatment in whom fasting total serum cholesterol, HDL-C and LDL-C had been recorded and the diagnosis of heterozygous familial hypercholesterolemia (heFH) was investigated by genetic testing. The difference and the limits of agreement between non-HDL-C and LDL-C calculated using the Friedewald formula were assessed in those with and without heFH-causing mutations. SUMMARY: There were 147 mutation-positive and 106 mutation-negative pretreatment participants and 395 mutation-positive and 178 mutation-negative patients receiving treatment. The difference between non-HDL-C and LDL-C pretreatment in mutation-positive people (mean LDL-C 7.73 mmol/l) was 0.67 mmol/l (95% CI 0.62-0.73) and posttreatment (mean LDL-C 4.71 mmol/l) was 0.62 mmol/l (95% CI 0.59-0.65) with wide limits of agreement of -0.02 to 1.37 and 0.07-1.18 mmol/l, respectively. Among patients with heterozygous familial hypercholesterolaemia, use of estimated LDL-C derived from non-HDL-C in place of calculated LDL-C may result in diagnostic misclassification and difficulty in assessing the true reduction in LDL-C with treatment, because of the wide inter-individual limits of agreement around the mean difference between non-HDL-C and LDL-C.

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Current management of children and young people with heterozygous familial hypercholesterolaemia – HEART UK statement of care (2019)

Type of publication:
Journal article

Author(s):
Ramaswami U.; Humphries S.E.; Priestley-Barnham L.; Green P.; Wald D.S.; *Capps N.; Anderson M.; Dale P.; Morris A.A.

Citation:
Atherosclerosis; Nov 2019; vol. 290 ; p. 1-8 [epub ahead of print]

Abstract:
This consensus statement on the management of children and young people with heterozygous familial hypercholesterolaemia (FH) addresses management of paediatric FH in the UK, identified by cascade testing when a parent is diagnosed with FH and for those diagnosed following incidental lipid tests. Lifestyle and dietary advice appropriate for children with FH; suggested low density lipoprotein cholesterol (LDL-C) targets and the most appropriate lipid-lowering therapies to achieve these are discussed in this statement of care. Based on the population prevalence of FH as ~1/250 and the UK paediatric population, there are approximately 50,000 FH children under 18 years. Currently only about 550 of these children and young people have been identified and are under paediatric care.

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Coronary heart disease mortality in treated familial hypercholesterolaemia: Update of the UK Simon Broome FH register (2018)

Type of publication:
Journal article

Author(s):
Humphries S.E.; Cooper J.A.; Seed M.; *Capps N.; Durrington P.N.; Jones B.; McDowell I.F.W.; Soran H.; Neil H.A.W.

Citation:
Atherosclerosis; Jul 2018; vol. 274 ; p. 41-46

Abstract:
Background and aims: Patients with familial hypercholesterolaemia (FH) have an elevated risk of coronary heart disease (CHD). Here we compare changes in CHD mortality in patients with heterozygous (FH) pre 1992, before lipid-lowering therapy with statins was used routinely, and in the periods 1992-2008 and 2008-2016. Methods: 1903 Definite (DFH) and 1650 Possible (PFH) patients (51% women) aged 20-79 years, recruited from 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2016 for 67,060 person-years. The CHD standardised mortality ratio (SMR) compared to the population in England and Wales was calculated (with 95% Confidence intervals). Results: There were 585 deaths, including 252 from CHD. Overall, the observed 2.4-fold excess coronary mortality for treated DFH post-1991 was significantly higher than the 1.78 excess for PFH (35% 95% CI 3%-76%). In patients with DFH and established coronary disease, there was a significant excess coronary mortality in all time periods, but in men it was reduced from a 4.83-fold excess (2.32-8.89) pre-1992 to 4.66 (3.46-6.14) in 1992-2008 and 2.51 (1.01-5.17) post-2008, while in women the corresponding values were 7.23 (2.65-15.73), 4.42 (2.70-6.82) and 6.34 (2.06-14.81). Primary prevention in men with DFH resulted in a progressive reduction in coronary mortality over the three time-periods, with no excess mortality evident post-2008 (0.89 (0.29-2.08)), although in women the excess persisted (post-2008 3.65 (1.75-6.72)). Conclusions: The results confirm the benefit of statin treatment in reducing CHD mortality, but suggest that FH patients with pre-existing CHD and women with FH may not be treated adequately.

Coronary heart disease mortality in treated Familial Hypercholesterolaemia: Update of the UK Simon Broome FH Register (2017)

Type of publication:
Conference abstract

Author(s):
Humphries S.E.; Cooper J.A.; Seed M.; *Capps N.; Durrington P.N.; Jones B.; McDowell I.F.W.; Soran H.; Neil

Citation:
Atherosclerosis Supplements; 2017; vol. 28, Pages 41-46

Abstract:
Background: Guidelines for the management of patients with Familial Hypercholesterolaemia (FH) recommend the use of high intensity statin therapy to reduce subsequent risk of Coronary Heart Disease (CHD). Here we compare changes in CHD mortality in patients with heterozygous (FH) pre 1992 before lipid-lowering therapy with statins was used routinely, and in the periods 1992-2008 and 2008 till the present. Methods: Analysis used 1903 Definite (DFH) and 1650 Possible (PFH) patients (51% women) aged 20-79 years, recruited from 21 lipid clinics in the United Kingdom and followed prospectively between 1980-1991 (6627 personyears) 1992-2008 (43117 person-years) and 2009-2016 (17317 person-years). The excess CHD standardised mortality ratio (SMR) compared to the population in England and Wales was calculated (with 95% Confidence intervals). Results: There were 252 deaths from CHD. Overall, treated DFH patients had a higher CHD SMR than PFH patients (post 1991 35% higher 2.40 (2.00-2.86) vs 1.78 (1.44-2.19) p = 0.03). In treated DFH patients with previous CHD the CHD SMR was significantly elevated at all time periods but in men fell from a 4.83-fold excess (2.32-8.89) pre-1992 to 4.66 (3.46-6.14) in 1992-2008 and 2.51 (1.01-5.17) post 2008, while in women these values were 7.23 (2.65-15.73), 4.42 (2.70-6.82) and 6.34 (2.06-14.81)). In treated DFH men with no previous CHD the CHD SMR fell over the three time periods, and was not significantly elevated post 2008 (0.89 (0.29-2.08), but in women the SMR remained significantly elevated (post 2008 3.65 (1.75-6.72)). Conclusions: The data confirm the major benefit in CHD mortality associated with statin treatment, but suggest that FH patients with pre-existing disease, and women with FH may not be being treated adequately.

Knowledge gaps in the management of familial hypercholesterolaemia. A UK based survey (2016)

Type of publication:
Journal article

Author(s):
Jonathan Schofield, See Kwok, Michael France, *Nigel Capps, Ruth Eatough, Rahul Yadav, Kausik Ray, Handrean Soran

Citation:
Atherosclerosis (2016) [article in press]

Abstract:
Background and aims: Untreated individuals with familial hypercholesterolaemia (FH) are at increased
risk of developing premature cardiovascular disease (CVD). Early diagnosis and treatment can result in a
normal life expectancy. A recent survey commissioned by the European Atherosclerosis Society (EAS)
reported a lack of awareness of FH in the general population.We conducted a survey to assess knowledge
among healthcare professionals involved in the assessment and management of cardiovascular risk and
disease in the United Kingdom.
Methods: A survey designed to assess knowledge of diagnostic criteria, risk assessment, the role of
cascade screening, and management options for patients with FH was distributed to 1000 healthcare
professionals (response rate 44.3%). The same survey was redistributed following attendance at an
educational session on FH.
Results: 151 respondents (40.5%) reported having patients under their care who would meet the diagnostic criteria for FH, but just 61.4% recognized that cardiovascular risk estimation tools cannot be
applied in FH, and only 22.3% understood the relative risk of premature CVD compared to the general
population. Similarly, just 65.9% were aware of recommendations regarding cascade screening.
Conclusions: The prevalence and associated risk of FH continue to be underestimated, and knowledge of
diagnostic criteria and treatment options is suboptimal. These results support the recent Consensus
Statement of the EAS and production of quality standards by the National Institute for Health and Care
Excellence. Further work is required to formulate interventions to improve FH awareness and knowledge, and to determine the effect these interventions have on patient outcomes.