The provision of a time-critical elective surgical service during the COVID-19 Crisis: a UK experience

IntroductionWith the emergence of the COVID-19 pandemic, all elective surgery was temporarily suspended in the UK, allowing for diversion of resource to manage the anticipated surge of critically unwell patients. Continuing to deliver time-critical surgical care is important to avoid excess morbidity and mortality from pathologies unrelated to COVID-19. We describe the implementation and short-term surgical outcomes from a system to deliver time-critical elective surgical care to patients during the COVID-19 pandemic.Materials and methodsA protocol for the prioritisation and safe delivery of time-critical surgery at a COVID-19 ‘clean’ site was implemented at the Nuffield Health Exeter Hospital, an independent sector hospital in the southwest of England. Outcomes to 30 days postoperatively were recorded, including unplanned admissions after daycase surgery, readmissions and complications, as well as the incidence of perioperative COVID-19 infection in patients and staff.ResultsA total of 128 surgical procedures were performed during a 31-day period by a range of specialties including breast, plastics, urology, gynaecology, vascular and cardiology. There was one unplanned admission and and two readmissions. Six complications were identified, and all were Clavien-Dindo grade 1 or 2. All 128 patients had preoperative COVID-19 swabs, one of which was positive and the patient had their surgery delayed. Ten patients were tested for COVID-19 postoperatively, with none testing positive.ConclusionThis study has demonstrated the implementation of a safe system for delivery of time-critical elective surgical care at a COVID-19 clean site. Other healthcare providers may benefit from implementation of similar methodology as hospitals plan to restart elective surgery.     

International multicentre comparison of cerivastatin with placebo and simvastatin for the treatment of patients with primary hypercholesterolaemia. International Cerivastatin Study Group

An international multicentre double-blind randomised trial compared the efficacy and safety of cerivastatin (0.025, 0.05, 0.1 and 0.2 mg once daily) with placebo and simvastatin (20 mg) over a period of 12 weeks, with study extensions to 52 and 100 weeks. The primary efficacy parameter was the percentage change in low density lipoprotein cholesterol (LDL-C). This was reduced from the baseline by 12.5% (0.025 mg) to 30.6% (0.2 mg) compared with falls of 2.0% on placebo and 40.3% on simvastatin. All four cerivastatin doses and simvastatin (20 mg) produced significantly greater falls than placebo (p < 0.0001) and the decrease in LDL-C was dose-dependent for cerivastatin. Simvastatin produced significantly greater falls than any cerivastatin dose or placebo (p < 0.0001). The effect was maintained at 1 year but somewhat attenuated at 100 weeks. Significant falls were also seen in serum total cholesterol and triglycerides. High density lipoprotein cholesterol (HDL-C) levels were significantly increased by cerivastatin (0.1 and 0.2 mg) and simvastatin (20 mg) at 12 weeks and increased further by 100 weeks. Mean fasting apolipoprotein A1 and lipoprotein A1 were increased and apolipoprotein B decreased by cerivastatin and simvastatin therapy. All doses of cerivastatin produced significant falls in the total cholesterol/HDL-C ratio at 12 weeks (0.5-1.6) compared with a fall of 2.1 for simvastatin (20 mg). Cerivastatin was well tolerated. Elevations in creatine phosphokinase, aspartate aminotransferase and alanine aminotransferase were mostly minor and transitory. Vital signs, electrocardiogram determinations, urinalysis and ophthalmic assessment showed similar results for both drugs. Cerivastatin, at doses of 0.1 mg and 0.2 mg daily, is considered to be of therapeutic value in the treatment of patients with primary hypercholesterolaemia, with 0.2 mg cerivastatin achieving reductions of LDL-C and total cholesterol similar to those achieved in the WOSCOP and CARE studies.     

Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk

Aims

To determine the relative frequency of mutations in three different genes (low‐density lipoprotein receptor (LDLR), APOB, PCSK9), and to examine their effect in development of coronary heart disease (CHD) in patients with clinically defined definite familial hypercholesterolaemia in UK.

Patients and methods

409 patients with familial hypercholesterolaemia patients (158 with CHD) were studied. The LDLR was partially screened by single‐strand conformational polymorphism (SSCP) (exons 3, 4, 6–10 and 14) and by using a commercial kit for gross deletions or rearrangements. APOB (p.R3500Q) and PCSK9 (p.D374Y) were detected by specific assays. Coding exons of PCSK9 were screened by SSCP.

Results

Mutations were detected in 253 (61.9%) patients: 236 (57.7%) carried LDLR, 10 (2.4%) carried APOB p.Q3500 and 7 (1.7%) PCSK9 p.Y374. No additional mutations were identified in PCSK9. After adjusting for age, sex, smoking and systolic blood pressure, compared to those with no detectable mutation, the odds ratio of having CHD in those with an LDLR mutation was 1.84 (95% CI 1.10 to 3.06), for APOB 3.40 (0.71 to 16.36), and for PCSK9 19.96 (1.88 to 211.5; p = 0.001 overall). The high risk in patients carrying LDLR and PCSK9 p.Y374 was partly explained by their higher pretreatment cholesterol levels (LDLR, PCSK9 and no mutation, 10.29 (1.85), 13.12 and 9.85 (1.90) mmol/l, respectively, p = 0.001). The post‐statin treatment lipid profile in PCSK9 p.Y374 carriers was worse than in patients with no identified mutation (LDL‐C, 6.77 (1.82) mmol/l v 4.19 (1.26) mmol/l, p = 0.001, HDL‐C 1.09 (0.27) mmol/l v 1.36 (0.36) mmol/l, p = 0.03).

Conclusions

The higher CHD risk in patients carrying PCSK9 p.Y347 or a detected LDLR mutation supports the usefulness of DNA testing in the diagnosis and management of patients with familial hypercholesterolaemia. Mutations in PCSK9 appear uncommon in patients with familial hypercholesterolaemia in UK.Familial hypercholesterolaemia is an autosomal dominant disorder associated with increased risk of coronary heart disease (CHD), with an estimated prevalence in the UK of 1 in 500 to 1 in 600.¹ Roughly half of the men with familial hypercholesterolaemia, if untreated, will have developed clinically evident CHD by the age of 55 years. Affected women from the same families typically develop CHD about 9 years later than their affected male relatives, but again, often remarkably prematurely.² The proportion of patients with familial hypercholesterolaemia identified and being treated in lipid clinics to date in the UK is, at best, 15% of the predicted number, with most of these being young people.¹ Because lipid‐lowering drug treatment with statins substantially reduces coronary morbidity and mortality,³ identification of affected people by screening is crucially important. To this end, the Department of Health has recently funded five pilot sites in the UK to determine the efficiency of cascade testing in the current social structure and the framework of the National Health Service. Cascade testing is a cost‐effective method of finding additional patients with familial hypercholesterolaemia,⁴ and has been used extensively in other countries in Europe, most notably in Holland,⁵ for the past 5 years.

Key points

• Patients with familial hypercholesterolaemia with a detectable LDLR mutation have a higher risk of early CHD than those in whom no mutation was detected.
• Patients with the pD374Y mutation in PCSK9 have the highest pretreatment and post‐treatment levels of plasma cholesterol and the highest risk of early CHD.
• Mutations in PCSK9 appear to be uncommon in patients with familial hypercholesterolaemia in UK.

The extent to which DNA testing for familial hypercholesterolaemia complements cholesterol measurement in cascade screening to identify affected patients is unclear, as is its role in determining the risk of CHD and response to treatment. In the current study, we carried out molecular genetic testing in patients recruited from the Simon Broome familial hypercholesterolaemia register⁶ in the UK as a cross‐sectional cohort study to identify risk factors for premature CHD in patients with familial hypercholesterolaemia.⁷ Primary results from this study indicated that the conventional cardiovascular risk factors of age, sex, smoking, pretreatment cholesterol levels and low levels of high‐density lipids (especially in women) were all associated with higher risk of CHD,⁷ confirming associations reported in other studies, for example.⁸ When this UK study was started, mutations at two loci causing familial hypercholesterolaemia had been identified, with mutations in the low‐density lipoprotein receptor gene (LDLR) accounting for most of the identified mutations,⁹ whereas one particular mutation in the gene encoding the ligand for the low density lipoprotein (LDL) receptor—namely apolipoprotein B (FDB)—occurs in about 5% of patients in the UK.¹⁰ This mutation, which alters a single amino acid (p.R3500Q), has been shown to reduce the affinity of the LDL cholesterol particle,¹⁰ where ApoB is the single‐protein component for the receptor. For the LDLR, currently >100 mutations have been reported in UK patients to date^9,11 (see also www.ucl.ac.uk/FH). A commercially available kit for screening for deletions and rearrangements of the LDLR gene has become available, and it is known that up to 5% of patients with familial hypercholesterolaemia in patients in the UK may have such a deletion.¹²Recently, defects in a third gene causing monogenic hypercholesterolaemia have been identified.¹³ The gene protein convertase subtilisin/kexin type 9 (PCSK9) codes for an enzyme that has also been called “neural apoptosis regulated convertase 1”, which has recently been proposed to be involved in degrading the LDLR protein in the lysosome of the cell and preventing it from recycling.¹⁴ Gain‐ of‐ function mutations in the PCSK9 gene could therefore cause increased degradation of LDLRs, reduced numbers of receptors on the surface of the cell, and monogenic hypercholesterolaemia. An alternative mechanism has also been proposed for the hypercholesterolaemic effect, whereby the gain of function causes increased secretion of apoB‐containing lipoproteins from the liver, with this being supported by in vivo turnover studies in patients carrying PCSK9 missense mutations¹⁵ and by in vitro studies in transiently transfected rat liver cells.¹⁶ One mutation in this gene, p.D374Y, has been reported in several independent families^16,17,18 and we therefore also tested for this cause of familial hypercholesterolaemia in this group of patients, as well as using single‐strand conformational polymorphism (SSCP) analysis and direct sequencing to screen all coding exons of the gene.Although patients with no identified mutation may have a monogenic cause of the disorder in an as yet undiscovered gene, it is also possible that some may have polygenic hypercholesterolaemia and have been misclassified using current clinical diagnostic criteria. These patients would be expected to have a milder degree of hyperlipidaemia, possibly not present from birth but only developing in later life, and would therefore be predicted to have a lower risk of CHD. The hypothesis we set out to test was that patients with identified mutations in the LDLR, PCSK9 or APOB genes would be at greater risk of CHD than patients with no identified mutation.     

Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset confirmed Alzheimer's disease

The allelic frequency of the gene for the K variant of butyrylcholinesterase (BCHE-K) was 0.17 in 74 subjects with late-onset (age > 65 years) histopathologically diagnosed Alzheimer's disease (AD), which was higher than the frequencies in 104 elderly control subjects (0.09), in 14 early-onset cases of confirmed AD (0.07) and in 29 confirmed cases of other dementia (0.10). The association of BCHE-K with late-onset AD was limited to carriers of the epsilon 4 allele of the apolipoprotein E gene (APOE), among whom the presence of BCHE-K gave an odds ratio of confirmed late-onset AD of 6.9 (95% C.I. 1.65-29) in subjects > 65 years and of 12.8 (1.9-86) in subjects > 75 years. In APOE epsilon 4 carriers over 75 years, only 1/22 controls, compared with 10/24 confirmed late-onset AD cases, had BCHE-K. We suggest that BCHE-K, or a nearby gene on chromosome 3, acts in synergy with APOE epsilon 4 as a susceptibility gene for late-onset AD.