Alison Pottle

Efficacy criteria and cholesterol targets for LDL apheresis.

Low density lipoprotein (LDL) apheresis is now accepted as the treatment of choice for patients with homozygous familial hypercholesterolaemia and for heterozygotes with cardiovascular disease refractory to lipid-lowering drug therapy. However, a paucity of evidence has meant that detailed guidance on the extent of cholesterol reduction required to prevent the onset or progression of cardiovascular disease in these high risk patients is lacking. This review defines criteria for expressing the efficacy of apheresis, proposes target levels of total and LDL cholesterol for homozygotes and heterozygotes based on recent follow-up studies and suggests a scheme for monitoring cardiovascular disease in these patients. Establishing a uniform approach to data collection would facilitate the setting up of national or multi-national registers and might eventually provide the information needed to formulate evidence-based guidelines for LDL apheresis.

Management of an ABO-Incompatible Lung Transplant

A 24‐year‐old woman with cystic fibrosis underwent bilateral sequential lung transplantation and unintentionally received an ABO incompatible graft (blood type A1 graft into a type O recipient). The recipient had a high titer of IgG anti‐A antibody (256 by the indirect antiglobulin test). Emergency treatment included antibody removal by plasmapheresis and additional immunosuppression with mycophenolate, rabbit antithymocyte globulin and polyspecific intravenous immunoglobulin. Subsequently, immunoadsorption and the anti‐CD20 antibody rituximab were used to remove anti‐A antibody and inhibit its resynthesis. Early graft function was good; one episode of rejection at Day 46 responded promptly to treatment with methylprednisolone. Subsequently, graft function continued to improve and anti‐A antibody titers remained low. No infectious or other complications were encountered. The treatment regimen that we adopted may prove useful in other cases of unplanned ABO‐incompatible organ transplants. The successful outcome suggests that planned ABO‐incompatible lung transplants may be possible.

A Nurse-Led Rapid Access Chest Pain Clinic—Experience from the First 3 Years

Background: The clinical presentation of chest pain is a major problem for primary health care professionals. Rapid access chest pain clinics (RACPC) enable quick assessment, investigation and formation of a treatment plan for such patients without a waiting list. There has been a chest pain clinic in operation at Harefield Hospital since 1988. Until 2001, the cardiology registrars were responsible for the clinic. Beginning in January 2001, the management of the clinic was taken over by the Cardiology Nurse Consultant. This paper will describe the organisation and outcomes of the first 3 years of this nurse-run RACPC. Process: Patients are seen within 2 weeks of referral in line with the National Service Framework for Coronary Heart Disease [Department of Health. National service framework for coronary heart disease. Dept of Health; 2000. London.]. An electrocardiogram (ECG) is recorded on arrival in the clinic and the Nurse Consultant then examines the patients and decides if further investigation is required. Analysis of Results: Four hundred and fifty-four patients were seen in the clinic from January 2001–December 2003. Three hundred and twenty-four patients (71.4%) underwent exercise testing of which 54 (16.7%) had a positive result. One hundred and thirteen patients (24.9%) were referred for angiography. Of these, 75 (66.4%) had coronary heart disease. Thirty-three patients (29.2%) have undergone percutaneous coronary intervention (PCI) and 19 (16.8%) have required coronary artery bypass grafting (CABG). Twenty-three patients (20.4%) are being treated medically. Satisfaction with the service offered by the clinic was high, evidenced by the results of questionnaires sent to patients. Conclusion: This paper demonstrates that nurses can successfully run RACPCs without an increased risk of incorrect diagnosis. These clinics offer patients timely access to assessment of their chest pain and facilitate early diagnosis of cardiac disease. They are also well accepted by the patients attending the clinic.

Apheresis as novel treatment for refractory angina with raised lipoprotein(a): a randomized controlled cross-over trial

Aims To determine the clinical impact of lipoprotein apheresis in patients with refractory angina and raised lipoprotein(a) > 500 mg/L on the primary end point of quantitative myocardial perfusion, as well as secondary end points including atheroma burden, exercise capacity, symptoms, and quality of life. Methods We conducted a single-blinded randomized controlled trial in 20 patients with refractory angina and raised lipoprotein(a) > 500 mg/L, with 3 months of blinded weekly lipoprotein apheresis or sham, followed by crossover. The primary endpoint was change in quantitative myocardial perfusion reserve (MPR) assessed by cardiovascular magnetic resonance. Secondary endpoints included measures of atheroma burden, exercise capacity, symptoms and quality of life. Results The primary endpoint, namely MPR, increased following apheresis (0.47; 95% CI 0.31-0.63) compared with sham (-0.16; 95% CI - 0.33-0.02) yielding a net treatment increase of 0.63 (95% CI 0.37-0.89; P < 0.001 between groups). Improvements with apheresis compared with sham also occurred in atherosclerotic burden as assessed by total carotid wall volume (P < 0.001), exercise capacity by the 6 min walk test (P = 0.001), 4 of 5 domains of the Seattle angina questionnaire (all P < 0.02) and quality of life physical component summary by the short form 36 survey (P = 0.001). Conclusion Lipoprotein apheresis may represent an effective novel treatment for patients with refractory angina and raised lipoprotein(a) improving myocardial perfusion, atheroma burden, exercise capacity and symptoms.

HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom.

This consensus statement addresses the current three main modalities of treatment of homozygous familial hypercholesterolaemia (HoFH): pharmacotherapy, lipoprotein (Lp) apheresis and liver transplantation. HoFH may cause very premature atheromatous arterial disease and death, despite treatment with Lp apheresis combined with statin, ezetimibe and bile acid sequestrants. Two new classes of drug, effective in lowering cholesterol in HoFH, are now licensed in the United Kingdom. Lomitapide is restricted to use in HoFH but, may cause fatty liver and is very expensive. PCSK9 inhibitors are quite effective in receptor defective HoFH, are safe and are less expensive. Lower treatment targets for lipid lowering in HoFH, in line with those for the general FH population, have been proposed to improve cardiovascular outcomes. HEART UK presents a strategy combining Lp apheresis with pharmacological treatment to achieve these targets in the United Kingdom (UK). Improved provision of Lp apheresis by use of existing infrastructure for extracorporeal treatments such as renal dialysis is promoted. The clinical management of adults and children with HoFH including advice on pregnancy and contraception are addressed. A premise of the HEART UK strategy is that the risk of early use of drug treatments beyond their licensed age restriction may be balanced against risks of liver transplantation or ineffective treatment in severely affected patients. This may be of interest beyond the UK.

Low-density lipoprotein apheresis is effective in reducing lipoprotein(a) levels and in improving symptoms in a patient with refractory angina secondary to accelerated coronary artery disease

Coronary artery disease remains a significant cause of morbidity and mortality in the Western world. High plasma Lp(a) concentrations are related to the risk of cardiovascular disease, but Lp(a) is rarely assayed and treated. We present the case of a 50-year-old gentleman with refractory angina, whose coronary disease continued to progress despite optimal medical and surgical therapy. We show that the aggressive reduction of Lp(a) successfully ameliorated the progression of coronary stenosis and provides effective and durable relief of symptoms.

LDL‐apheresis: indications and clinical experience in a tertiary cardiac centre

Objective:  To determine the efficacy and safety of liposorber D low‐density lipoprotein (LDL) apheresis system in high‐risk cardiac patients.

Prevalence of obstructive coronary artery disease and prognosis in patients with stable symptoms and a zero-coronary calcium score

Abstract Aims CT calcium scoring (CTCS) and CT cardiac angiography (CTCA) are widely used in patients with stable chest pain to exclude significant coronary artery disease (CAD). We aimed to resolve uncertainty about the prevalence of obstructive coronary artery disease and long-term outcomes in patients with a zero-calcium score (ZCS). Methods and results Consecutive patients with stable cardiac symptoms referred for CTCS or CTCS and CTCA from chest pain clinics to a tertiary cardiothoracic centre were prospectively enrolled. In those with a ZCS, the prevalence of obstructive CAD on CTCA was determined. A follow-up for all-cause mortality was obtained from the NHS tracer service. A total of 3914 patients underwent CTCS of whom 2730 (69.7%) also had a CTCA. Half of the patients were men (50.3%) with a mean age of 56.9 years. Among patients who had both procedures, a ZCS was present in 52.2%, with a negative predictive value of 99.5% for excluding ≥70% stenosis on CTCA. During a mean follow-up of 5.2 years, the annual event rate was 0.3% for those with ZCS compared with 1.2% for CS ≥1. The presence of non-calcified atheroma on CTCA in patients with ZCS did not affect the prognostic value (P = 0.98). Conclusion In patients with stable symptoms and a ZCS, obstructive CAD is rare, and prognosis over the long-term is excellent, regardless of whether non-calcified atheroma is identified. A ZCS could reliably be used as a ‘gatekeeper’ in this patient cohort, obviating the need for further more expensive tests.

The impact of lipoprotein apheresis in patients with refractory angina and raised lipoprotein(a): Objectives and methods of a randomised controlled trial

It is well established that Lipoprotein(a) [Lp(a)] is an independent cardiovascular risk factor and predictor of major adverse cardiovascular events. Lipoprotein apheresis is currently the most effective approved treatment available, with minimal effect conferred by conventional lipid lowering agents. A growing body of evidence suggests that aggressively lowering raised Lp(a) may improve cardiovascular and clinical outcomes, although more prospective research is required in this field. Angina which is refractory to conventional medical therapy and revascularisation is extremely challenging to manage. There is a significant unmet need to establish therapeutic options. Our goal is to determine the impact of lipoprotein apheresis on clinical parameters and symptoms of patients with refractory angina secondary to advanced coronary disease and raised Lp(a). Determining whether we should aggressively lower Lp(a) in such patients remains a very important question, which could potentially impact on the management of a large population. We will also gain insight into how this treatment works and the mechanisms via which Lp(a) increases cardiovascular risk. We are currently conducting a prospective, randomised controlled crossover study of patients with refractory angina and raised Lp(a), randomised to undergoing three months of weekly lipoprotein apheresis or sham apheresis. Patients will then crossover to the opposite study arm after a 1 month wash-out phase. We will assess myocardial perfusion, carotid atherosclerosis, endothelial vascular function, thrombogenesis, oxidised LDL and their antibodies, exercise capacity, angina and quality of life at the beginning and end of treatment, to determine the net true treatment effect on the above parameters. This is a novel area of research, as previous studies have not assessed the role of lipoprotein apheresis in patients with refractory angina and raised Lp(a) in a prospective randomised controlled manner.

The expanding role of lipoprotein apheresis in the treatment of raised lipoprotein(a) in ischaemic heart disease and refractory angina

It is increasingly recognised that lipoprotein(a) [Lp(a)], an inherited, genetically-determined form of LDL-cholesterol, is an independent cardiovascular risk factor and predictor of adverse cardiovascular outcomes. Lp(a) is felt to increase cardiovascular risk via its pro-thrombotic effect and by enhancing intimal lipoprotein deposition. Lipoprotein apheresis is currently the most effective treatment for raised Lp(a). There is a growing body of evidence suggesting that aggressively lowering raised Lp(a) may improve cardiovascular and clinical outcomes, although much more research is required in this field. Angina which is refractory to conventional medical therapy and revascularisation, is extremely challenging to manage. Treatment options for such patients remain very limited. We describe the case of a patient with refractory angina and raised lipoprotein(a) in whom aggressive reduction of Lp(a) with lipoprotein apheresis successfully ameliorated the progression of coronary stenosis and provided effective and durable relief of angina symptoms. In our centre, we are currently conducting a prospective, randomised controlled cross-over study of patients with refractory angina and raised Lp(a), randomised to undergoing lipoprotein apheresis or ‘sham’ apheresis with assessment of myocardial perfusion, carotid atherosclerosis, endothelial vascular function, thrombogenesis, oxidised phospholipids and their antibodies, exercise capacity, angina symptoms and quality of life at the beginning and end of treatment.