Lipid clinic experience with bempedoic acid in three UK centres.

OBJECTIVE: Novel lipid-lowering therapies are being introduced. Few studies exist of the real-world effectiveness of adenosine-tri-phosphate citrate lyase inhibition with bempedoic acid. METHODS: This study audited bempedoic acid therapy in 216 consecutive patients from three hospital centres - a university hospital (n = 77) and two district general hospitals (n = 106 and 33). Cardiovascular disease (CVD) risk factors, prescription qualification criteria, efficacy and adverse effects were assessed. RESULTS: The population was aged 65.9 ± 11.0 years, 42% were male, 25% had type 2 diabetes, and 31% had familial hypercholesterolaemia. CVD was present in 19% and multibed vascular disease in 8%. Statin intolerance was reported in 92%. Bempedoic acid reduced total cholesterol by 1.58 ± 1.44 mmol/L (20%), LDL-C by 1.37 ± 1.31 mmol/L (27%), triglycerides by 0.22 mmol/L (2%) with an 0.06 mmol/L (1%) increase in HDL-C after 22 ± 9 months follow-up. An LDL-C <2.5 mmol/L was achieved in 40% and <2 mmol/L in 20%. Efficacy (r2 = .33) was predicted by baseline LDL-C (ß = .54; p <.001). No significant changes were seen in transaminases, creatinine, creatine kinase, urate or HbA1c. Treatment was discontinued by 33% of patients and occurred due to myalgia (43%), lack of efficacy (16%) and gastrointestinal adverse effects (15%). No cases of gout were observed. In a logistic regression only the number of previous drug classes not tolerated (ß = 1.60; p = .009) was a contributing factor to discontinuation. CONCLUSION: This audit suggests that bempedoic acid therapy is effective but that adverse effects and discontinuation are common. This suggests nocebo effects might be generalizable to all lipid-lowering drug therapies in susceptible individuals.

Screening for patients with Gaucher's disease using routine pathology results: PATHFINDER (ferritin, alkaline phosphatase, platelets) study.

AIMS: Lysosomal ß-glucocerebrosidase A (GBA) deficiency causes Gaucher disease (GD), a recessive disorder caused by bi-allelic mutations in GBA. The prevalence of GD is associated with ethnicity but largely unknown and potentially underestimated in many countries. GD may manifest with organomegaly, bone involvement, and neurological symptoms as well as abnormal laboratory biomarkers. This study attempted to screen for GD in patients using abnormal platelet, alkaline phosphatase (ALP), and ferritin results from laboratory databases. METHODS: Electronic laboratory databases were interrogated using a 2- to 4-year time interval to identify from clinical biochemistry records patients with a phenotype of reduced platelets (<150 × 109 /L) and either elevated ALP (>130 iu/L) or ferritin [>150 (female) or >250 µg/L (male)]. The mean value over the screening window was used to reduce variability in results. A dried blood spot sample was collected for the determination of GBA activity in patients meeting these criteria. If low GBA activity was found, then the concentration of the GD-specific biomarker glucosyl-sphingosine (lyso-GB1) was assayed, and the GBA gene sequenced. RESULTS: Samples were obtained from 1058 patients; 232 patients had low GBA activity triggering further analysis. No new cases of GD with homozygosity for pathogenic variants were identified, but 12 patients (1%) were identified to be carriers of a pathogenic variant in GBA. CONCLUSIONS: Pathology databases hold routine information that can be used to screen for patients with inherited errors of metabolism. However, biochemical screening using mean platelets, ALP, and ferritin has a low yield for unidentified cases of GD.

Survival prediction algorithms for COVID-19 patients admitted to a UK district general hospital.

OBJECTIVE: To collect and review data from consecutive patients admitted to Queen's Hospital, Burton on Trent for treatment of Covid-19 infection, with the aim of developing a predictive algorithm that can help identify those patients likely to survive. DESIGN: Consecutive patient data were collected from all admissions to hospital for treatment of Covid-19. Data were manually extracted from the electronic patient record for statistical analysis. RESULTS: Data, including outcome data (discharged alive/died), were extracted for 487 consecutive patients, admitted for treatment. Overall, patients who died were older, had very significantly lower Oxygen saturation (SpO2) on admission, required a higher inspired Oxygen concentration (IpO2) and higher CRP as evidenced by a Bonferroni-corrected (P < 0.0056). Evaluated individually, platelets and lymphocyte count were not statistically significant but when used in a logistic regression to develop a predictive score, platelet count did add predictive value. The 5-parameter prediction algorithm we developed was: [Formula: see text] CONCLUSION: Age, IpO2 on admission, CRP, platelets and number of lungs consolidated were effective marker combinations that helped identify patients who would be likely to survive. The AUC under the ROC Plot was 0.8129 (95% confidence interval 0.0.773 - 0.853; P < .001).

Genetic risk scores in lipid disorders.

PURPOSE OF REVIEW: Extensive work has gone into understanding the genetics of cardiovascular disease (CVD) and implicating genes involved in hyperlipidaemia. Translation into routine practise involves using genetic risk scores (GRS) to identify high-risk individuals in the general population. Some of these risk scores are beginning to disentangle the complex nature of CVD and inherited dyslipidaemias. RECENT FINDINGS: GRS of varying complexity have been used to identify high-risk groups of patients with polygenic CVD including some individuals with risk equivalent to monogenic disease. In phenotypic familial hypercholesterolaemia a six or 12 gene lipid GRS may identify polygenic cases that comprise up to 50% of cases. In high triglyceride syndromes including even cases of familial chylomicronaemia syndrome more than 80% of cases are polygenic and not even associated with rare variants. In both familial hypercholesterolaemia and familial chylomicronaemia syndrome individuals with polygenic disease have a lower risk than those with monogenic disease. SUMMARY: GRS show promise in identifying individuals with high risks of CVD. They have a close relationship with imaging markers. It is unclear whether GRS, imaging or both will be used to identify individuals at high risk of future events.

An update on trials of novel lipid-lowering drugs.

PURPOSE OF REVIEW: A number of novel trials have assessed the efficacy of new lipid-lowering therapies in cardiovascular disease (CVD). RECENT FINDINGS: Proprotein convertase subtilisin kexin-9 inhibitors reduce low-density lipoprotein cholesterol (LDL-C) by 50-55%. A CVD outcome trial in patients with acute coronary syndromes with evolocumab achieved a LDL-C of 0.8 mmol/l (31 mg/dl) and a 20% relative risk reduction in CVD events in 2.2 years. Cholesterol ester transfer protein inhibitors raise high-density lipoprotein cholesterol and can lower LDL-C. Anacetrapib reduced coronary artery disease events by 7%, but not wider composite CVD outcomes, in a population with chronic CVD with pretreatment LDL-C of 1.6 mmol/l (62 mg/dl). The conflicting outcomes of cholesterol ester transfer protein inhibitor trials means these compounds are not being developed further. Trials using lipid drugs targeting inflammation have previously been generally unsuccessful, but recent data on the interleukin-1B receptor antagonist canakinumab has proven the concept of intervention on inflammation in atherosclerosis by showing a reduction in acute coronary interventions, but at the predictable cost of increased infections. SUMMARY: Despite the success of proprotein convertase subtilisin kexin-9 inhibition, the ability to achieve low LDL-C with off-patent medications and the costs of novel therapies will limit their use even in high-risk patients and confine them to the highest-risk sub-groups of patients.

Identification of rare diseases by screening a population selected on the basis of routine pathology results-the PATHFINDER project: lysosomal acid lipase/cholesteryl ester storage disease substudy.

AIMS: Lysosomal acid lipase deficiency (LALD) is an autosomal recessive disorder of cholesterol ester storage associated with hepatic disease, cirrhosis and accelerated atherosclerosis. Its prevalence in the general population, patients with dyslipidaemia and raised transaminases is unclear. This study attempted to identify the prevalence of LALD from patients with abnormal results in laboratory databases. METHODS: Electronic laboratory databases were interrogated to identify from clinical biochemistry records patients with a phenotype of low high-density lipoprotein-cholesterol (≤0.85 mmol/L; 33 mg/dL) and with elevated alanine or aspartate transaminases (≥60 IU/L) on one occasion or more over a 3-year time interval. Patients were recalled, and a dried blood spot sample was collected for lysosomal acid lipase determination by a fluorimetric enzyme assay. Histopathology databases of liver biopsies were interrogated for patients with features of 'microvesicular cirrhosis' or 'cryptogenic cirrhosis' in the report. Histological blocks were sampled, and samples were analysed by next-generation sequencing for the presence of mutations in the LAL gene. RESULTS: Samples were obtained from 1825 patients with dyslipidaemia and elevated transaminases. No cases of LALD were identified. Liver biopsies were obtained from six patients. DNA extraction was successful from four patients. Two patients were homozygous for the LAL c.46A>C;p.Thr16Pro unclassified variant in exon 2. CONCLUSIONS: Pathology databases hold routine information that can be used to identify patients with specific patterns of results or those who had biopsies to allow targeted testing for possible causes of disease. Biochemical screening suggests that the gene frequency of LAL deficiency in adults is less than 1 in 100.

Review of referral criteria to lipid clinics and outcomes of treatment in four UK centres.

BACKGROUND: Little data exist on the referral patterns and effectiveness of lipid clinics. METHODS: An audit was conducted in four clinics of 100 consecutive referrals each. Data were recorded on referral criteria, cardiovascular disease (CVD) risk factors, drug history, investigations, diagnoses, therapies, results and referrals. RESULTS: Patients were aged 56 ± 14 years, 47% were male and 87% were primary prevention. Risk factors included smoking (16%), type 2 diabetes (13%) and hypertension (13%). Referrals were made for hypercholesterolaemia (68%), diagnosis of FH (31%), statin intolerance (23%) and hypertriglyceridaemia (23%). Initial total cholesterol (TC) was 7.65 ± 2.64 mmol/L, triglycerides (TG) 2.17 (0.41-76.9 mmol/L) mmol/L, HDL-C 1.53 ± 0.71 mmol/L, LDL-C 4.57 ± 1.66 mmol/L with non-HDL-C 5.90 ± 2.09 mmol/L. Criteria for FH were met in 21% with genetic testing in 13% and lipid cascade testing in 30% of index cases. Triglycerides >20 mmol/L were present in 4%. The diagnosis was changed in 21%: hypercholesterolaemia (7%), mixed hyperlipidaemia (7%) and hypertriglyceridaemia (7%). Hepatic steatosis was identified in 14.5%. Lipoprotein(a) levels >125 nmol/L occurred in 41% in one clinic. Therapy changes included altered statins (40%), addition of a fibrate (11%) or ezetimibe (8%). These reduced TC by 1.92 mmol/L (19%; P = 0.0001), LDL-C 1.07 mmol/L (15%; P = 0.02), non-HDL-C 1.50 mmol/L (16%; P < 0.001), and TG 2.3 (-4 to 38) mmol/L (16%; P < 0.001) with 11% extra achieving TG <5 mmol/L while HDL-C increased by 7% (P = 0.37). CONCLUSIONS: Lipid clinics have diverse functions including diagnosis of FH, managing severe hypercholesterolaemia, mixed hyperlipidaemia and statin intolerance. Effectiveness criteria of average reductions of 1.5 mmol/L in TC or non-HDL-C, 1 mmol/L in LDL-C and 2 mmol/L in TG would be reasonable for newly referred patients.

Pro-protein subtilisin kexin-9 (PCSK9) inhibition in practice: lipid clinic experience in 2 contrasting UK centres.

BACKGROUND: Prescribing criteria have been suggested for proprotein convertase subtilisin kexin-9 (PCSK-9) inhibitors but few studies exist of their real-world effectiveness. METHODS: This study audited PCSK-9 inhibitor therapy in 105 consecutive patients from two hospital centres-a university hospital (UH; n = 70) and a district general hospital (DGH; n = 35). Baseline characteristics including cardiovascular disease risk factors, NICE qualification criteria, efficacy and side effects were assessed. RESULTS: Baseline LDL-C levels were similar in both centres. NICE criteria were met for 2.05 items in the whole study (UH patients 1.7 and DGH patients 2.7). District general hospital patients were more likely to have familial hypercholesterolaemia (89 vs 69%; P = .02); intolerance to statins (94 vs 52%; P < .001) and polyvascular disease (42% vs 17%; P = .005). Prescriptions (evolocumab 73%; alirocumab 23%) were collected by 76% of patients (UH 64% vs DGH 100%). Therapy was discontinued by time of review in 15% of patients (UH 7% vs DGH 25%; P = .02). In adherent patients PCSK-9 inhibitor treatment reduced TC by 28% (2.24 ± 2.39 mmol/L; P < .001) and LDL-C by 49% (2.10 ± 1.33 mmol/L; P < .001). A LDL-C < 2.5 mmol/L was achieved in 30% of patients and <2.0 mmol/L in 20%. PCSK-9 therapy was effective and safe in patients with increased lipoprotein (a), diagnosed muscle diseases (including myopathies and muscular dystrophy) or poststatin rhabdomyolysis, nephrotic syndrome or HIV disease. Mixed results were obtained in patients with significant mixed hyperlipidaemia. CONCLUSIONS: This study suggests that PCSK-9 inhibitors are effective but that prescriptions should not be changed to long-term delivery until patients have been reviewed and shown to be adherent.

Views of general practitioners on the role of CA125 in primary care to diagnose ovarian cancer.

BACKGROUND: NICE guidance on the investigation and treatment of ovarian cancer advocates that the tumour marker CA125 should be the first line investigation for women suspected of having ovarian cancer. METHODS: An internet-based survey, of primary care doctors in the West Midlands, was conducted in order to ascertain the views of general practitioners (GPs) of NICE guidance on the use of CA125 to triage suspected ovarian cancer cancers and the impact that this may have on referral pathways. RESULTS: In total 258 GPs responded to the questionnaire. Although 219 (84.9%) responders reported awareness of the NICE guidance only 146 (56.6%) had personally read the document. The majority 187 (72.5%) of respondents anticipated that their use of CA125 would increase as a result of the new guidance. Abdominal bloating (>50 years), persistent abdominal distension and the presence of an abdominal or pelvic mass/swelling were the symptoms felt to be most associated with ovarian cancer. When questioned on the management of a woman with a raised CA125 the majority of respondents reported that a normal ultrasound scan would not stop an urgent secondary care referral if the CA125 was raised. There was no significant difference in the opinions of GPs with <5 years primary care experience compared to GPs with 6+ years. CONCLUSION: The symptoms associated with ovarian cancer are well understood by the GPs that responded however, a coordinated programme of education and training is needed for GPs on the role of CA125 in ovarian cancer, in addition to clearly defined referral pathways, in order to address a likely significant increase in suspected ovarian cancer referrals to secondary care, most of whom will not have ovarian cancer.

The ethics of antenatal screening: lessons from Canute.

Modern medicine has given us the power to identify many diseases before they occur and apply preventative measures so that morbidity and mortality may be avoided. When these screening measures are offered to someone who is capable of making an informed decision to proceed, they may be uncontroversial but may actually cause more harm than good. In antenatal screening, it is difficult to define who the patient is, because there are several possibilities: the pregnant woman, the foetus, or the family. Consequently, it can be difficult to identify whether the treatment offered is in the best interest of all concerned. Our growing knowledge about the human genome will in future give us more power to be able to identify undesirable traits, but there is no strict definition where the line of acceptability lies. The eugenic excesses of the mid-20(th) century are often cited as a reason why antenatal screening is bad. The story of King Canute informs us that defining a 'line in the sand' cannot prevent the rising tide of medical capability overwhelming any arbitrary level of acceptability. This paper discusses the history of eugenics from Sparta to the modern day and attempts to give some perspective on this crucial policy area. No one paper can provide the answer: it is necessary that society as a whole debates where it wishes to go...

Targeted versus global approaches to the management of hypercholesterolaemia.

AIMS: The role of statins in secondary prevention of cardiovascular disease is well established. However, there is debate about the most effective approach to primary prevention. This study simulated the effects of directed versus global approaches for intervention on coronary heart disease (CHD) event rates. METHODS: A primary prevention population was generated by computer simulation derived from data from the National Health Survey for England. The efficacy of reductions in cholesterol, treatment to cardiovascular risk targets and effects of phytosterols or statins were assessed. RESULTS: A 0.5 mmol/L reduction in population total cholesterol would result in a 10.4% reduction in CHD events, while 1.0 mmol/L, 1.5 mmol/L and 2.0 mmol/L reductions would achieve 21.0%, 30.6% and 41.9% reductions respectively. In statin-based cardiovascular risk targeted strategies, use of simvastatin 40 mg would result in 1.8% reduction by UK National Service Framework targets of 30%/decade CHD risk and 7.2% reduction in events for a 20%/decade target assuming perfect adherence. Similarly, aggressive primary prevention with 40 mg atorvastatin would result in a 2.5% or 10% reduction in events. Universal use of 10 mg simvastatin following an over-the-counter approach would result in a 25% reduction in CHD events. In contrast, whole population consumption of sitostanol/sitosterol products would result in 11.8% reduction. CONCLUSION: Targeting and treating high-risk individuals may be beneficial for them and rewarding for medical practitioners. However, this approach has minimal effects on the population burden of atherosclerotic disease. This study suggests that universal therapy with phytosterols and/or wider availability of statins has the potential to dramatically decrease rates of CHD.

Non-ceruloplasmin-bound copper in routine clinical practice in different laboratories.

BACKGROUND: Copper is an essential nutrient but is toxic when the free form is in excess. Wilson's disease (WD) is an autosomal recessive disorder of copper excess. Its diagnosis is a challenge, especially in the absence of obvious neurological changes, or Kayser-Fleischer rings. Non-ceruloplasmin-bound copper is a calculated parameter devised for the investigation of patients who potentially have WD. METHODS: We compared non-ceruloplasmin-bound copper from three different laboratories. We retrospectively reviewed paired ceruloplasmin and copper data and calculated non-ceruloplasmin-bound copper. Comparative statistics, linear regression, chi-square test and graphical techniques were employed to compare the data. RESULTS: All three assays had negative results for over 20% of the non-ceruloplasmin-bound copper concentrations; this was not significantly different. However, there were statistically significant differences for the 97.5th percentile. When plotted against the ceruloplasmin and copper concentrations, significant differences existed for both the visual and linear regression data between the three different laboratories. CONCLUSIONS: Non-ceruloplasmin-bound copper cut-offs may not be transferable between laboratories. Each laboratory should derive its own cut-offs for the 97.5th percentile, as there are differences due to assays, populations or both.

Implications of method specific creatinine adjustments on General Medical Services chronic kidney disease classification.

AIMS: To evaluate the impact of different equations for calculation of estimated glomerular filtration rate (eGFR) on general practitioner (GP) workload. METHODS: Retrospective evaluation of routine workload data from a district general hospital chemical pathology laboratory serving a GP patient population of approximately 250 000. The most recent serum creatinine result from 80 583 patients was identified and used for the evaluation. eGFR was calculated using one of three different variants of the four-parameter Modification of Diet in Renal Disease (MDRD) equation. RESULTS: The original MDRD equation (eGFR(186)) and the modified equation with assay-specific data (eGFR(175corrected)) both identified similar numbers of patients with stage 4 and stage 5 chronic kidney disease (ChKD), but the modified equation without assay specific data (eGFR(175)) resulted in a significant increase in stage 4 ChKD. For stage 3 ChKD the eGFR(175) identified 28.69% of the population, the eGFR(186) identified 21.35% of the population and the eGFR(175corrected) identified 13.6% of the population. CONCLUSIONS: Depending on the choice of equation there can be very large changes in the proportions of patients identified with the different stages of ChKD. Given that according to the General Medical Services Quality Framework, all patients with ChKD stages 3-5 should be included on a practice renal registry, and receive relevant drug therapy, this could have significant impacts on practice workload and drug budgets. It is essential that practices work with their local laboratories.

Can we manage demand for allergy testing by restricting requests to a small number of prime target allergens?

BACKGROUND: Demand for expensive tests such as allergen-specific IgE is expanding far faster than for cheaper tests: at Burton Hospital the annual growth rate is 24%. Different hospitals have different policies on allergen testing. We report a comparison of the effect of requesting policy on diagnostic yield. METHODS: All results from five years of allergen testing were downloaded from the data warehouse at Burton, and a representative sample of recent results was evaluated from Ipswich Hospital. Statistical analysis by chi(2) test and significance tests for differences of proportions were carried out. RESULTS: Ipswich hospital used a standard four-allergen panel for respiratory patients and demonstrated a statistically significantly lower positivity rate for three of those four allergens. No relationship between the number of allergens tested and the probability of a positive result was shown - the probability of a positive result was approximately 0.3. Number of allergen-specific IgE tests requested/patient have remained roughly constant over 5(1/2) years but total demand has increased. CONCLUSIONS: Selective requesting for allergen-specific IgE testing may be more effective than use of a standard panel but this cannot be conclusively proven. It is not appropriate to attempt to limit workload by specifying a maximum number of tests that are allowed for any individual patient.

Percentage non-caeruloplasmin bound copper.

OBJECTIVES: To compare percentage non-caeruloplasmin bound copper (%NCC) to generally accepted values. DESIGN AND METHODS: Using data for 338 normal individual patients, we calculated the %NCC. RESULTS: The %NCC ranged (median) from -59.75% to 51.98% (8.75%) respectively. The non-parametric reference interval was -23.44% to 22.99% with 43.8% of the %NCC values >10%. CONCLUSIONS: We found the %NCC to be higher than generally accepted. This may be due to uncertainty from precision, bias and specificity.

Copper:caeruloplasmin ratio.

Investigation of copper status can be a diagnostic challenge. The non-caeruloplasmin-bound copper (NCC) has deficiencies; accordingly, the copper:caeruloplasmin ratio has been suggested as an alternative index of copper status. A reference interval for this index was derived. In addition to making the interpretation of copper easier, the copper:caeruloplasmin ratio should also enable adjustment for relatively high caeruloplasmin concentrations without recourse to producing gender- and age-derived intervals. The copper:caeruloplasmin ratio has weaknesses similar to those identified for NCC in that immunological methods used for caeruloplasmin can cross react with apocaeruloplasmin and there is no standardised method for caeruloplasmin. Caeruloplasmin assays also have uncertainty from precision, bias and specificity and, accordingly, method-related differences may have a large effect on the copper:caeruloplasmin ratio in a manner similar to the NCC.