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The impact of lipoprotein apheresis in patients with refractory angina and raised lipoprotein(a): Objectives and methods of a randomised controlled trial
Atherosclerosis Supplements 18 (2015) 103e108 www.elsevier.com/locate/atherosclerosis
The impact of lipoprotein apheresis in patients with refractory angina and raised lipoprotein(a): Objectives and methods of a randomised controlled trial Tina Z. Khan a,*, Alison Pottle a, Dudley J. Pennell b, Mahmoud S. Barbir a b
a Harefield Hospital, Hill End Road, Uxbridge UB9 6JH, UK Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
Abstract 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. Ó 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Lipoprotein(a); Lipoprotein apheresis; Ischaemic heart disease; Refractory angina
1. Introduction 1.1. Lipoprotein(a) * Corresponding author. Tel.: þ44 (0)1895 82 37 37; fax: þ44 (0)1895 82 88 96. E-mail addresses: [email protected] (T.Z. Khan), A.Pottle@rbht. nhs.uk (A. Pottle), [email protected] (D.J. Pennell), M.Barbir@ rbht.nhs.uk (M.S. Barbir). http://dx.doi.org/10.1016/j.atherosclerosissup.2015.02.019 1567-5688/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
Lipoprotein(a) [Lp(a)] is a plasma lipoprotein consisting of a cholesterol-rich LDL particle with one molecule of apolipoprotein B100 and a protein, apolipoprotein(a), attached via a disulphide bond. [See Fig. 1]. An elevated Lp(a) level (>500 mg/L) is established as an important
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Fig. 1. The structure of lipoprotein(a).
independent cardiovascular risk factor and predictor of adverse outcome in atherosclerotic disease [1,2]. A large epidemiological study demonstrated that the relative risk of CHD per 3.5-fold higher Lp(a) level adjusted for age and sex only was 1.16 and 1.13 (95% CI: 1.09e1.18) following further adjustment for systolic blood pressure, smoking, history of diabetes and total cholesterol [3]. Elevated Lp(a) is believed to promote atherosclerosis via Lp(a)-derived cholesterol entrapment in the intima, inflammatory cell recruitment and/or via the binding of proinflammatory-oxidised phospholipids, such as oxidised LDL.[4] In addition, elevated Lp(a) is felt to be prothrombotic via the inhibition of fibrinolysis with enhancement of clot stabilisation as well as via enhanced coagulation via the inhibition of tissue factor pathway inhibitor [4]. An increased level of Lp(a) is highly heritable. Two variants of the LPA locus on 6q26-27 encoding Lp(a) lipoprotein (rs10455872) and (rs3798220) were strongly associated with both an increased level of Lp(a) and risk of coronary disease [5]. Most patients with raised LDL-cholesterol can be adequately treated with appropriate dietary measures and lipid lowering drug therapy [6]. However, the conservative therapy of elevated Lp(a) is unsatisfactory [7]. Data assessing the impact of statins on Lp(a) are limited and highly variable [4] and overall, statins are ineffective at significantly lowering Lp(a). Nicotinic acid based treatment (eg. Tredaptive) was previously felt to be modestly effective at lowering Lp(a), however the European Medicines Agency have withdrawn it based on preliminary findings from the HPS2-THRIVE trial showing that this drug does not reduce major adverse cardiac events and causes a higher incidence of serious non-fatal side effects [8]. 1.2. Lipoprotein apheresis Lipoprotein apheresis is a selective lipid-lowering extracorporeal treatment by which excess atherogenic
ApoB100-containing lipoproteins, including Lp(a) and LDL are removed from blood or plasma.[9] Currently it remains the most effective means of lowering Lp(a) levels [9]. The European Atherosclerosis Society Consensus Panel recommended that Lp(a) levels should be reduced below 500 mg/L, in extreme cases, by lipoprotein apheresis [4]. The HEART UK guidelines recommend lipoprotein apheresis for patients with Lp(a) levels >600 mg/L with progressive coronary heart disease and LDL levels >3.2 mmol/L despite treatment with maximally tolerated combined drug therapy. However, objective prospective evidence to support these recommendations is limited. A potential pharmacological treatment that holds promise for the future are antisense oligonucleotides (ASO) directed to apolipoprotein (a) [apo(a)], thereby reducing apo(a) and Lp(a) levels. So far, animal studies have shown that this may provide an effective approach to lower elevated Lp(a) levels [10]. However, phase 1 and 2 human studies are needed to determine safety and efficacy of this treatment before it can be established for widespread use. 1.3. Refractory angina Cardiovascular disease remains a leading cause of death in the western world [11]. Most patients with angina are successfully treated with conventional medical therapy and revascularisation techniques such as coronary artery bypass graft (CABG) surgery or percutaneous coronary interventions (PCI) [12]. However, there is a group of patients who are particularly challenging to manage, who have severe disabling angina from coronary artery disease which is refractory to conventional therapy [13]. There is a real need for effective treatment options for patients with refractory angina. Estimates suggest that between 30,000 and 50,000 patients per year develop the condition [13]. 1.4. The impact of lipoprotein apheresis on refractory angina with raised lipoprotein(a): A case history In our centre, we have experience of treating a patient with refractory angina and raised Lp(a) with lipoprotein apheresis and demonstrated that aggressive reduction of Lp(a) successfully ameliorated the progression of coronary stenosis and provided effective and durable relief of angina [14]. Aged 42, this gentleman presented with unstable angina and diffuse multi-vessel coronary disease. Subsequently, he was treated with quadruple CABG and a total of 12 stents over a three year period. Despite these multiple coronary interventions and optimal medical therapy, he continued to experience angina which was adversely affecting his quality of life. His Lp(a) was screened and was found to be significantly elevated at 1200 mg/L (normal range: 0e300 mg/L). The remainder of his fasting lipid profile revealed normal total cholesterol (TC) 3.2 mmol/L, LDL-C (1.5 mmol/L) and plasma triglycerides (TG)
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(1.4 mmol/L). He was started on a fortnightly regimen of lipoprotein apheresis which reduced the plasma levels of Lp(a) by an average of 70%. He has since experienced significant improvement of his angina and quality of life. Lipoprotein apheresis has slowed the rate of progression of his coronary disease, with a reduction in the rate of revascularisation procedures. During the five year period the patient has undergone lipoprotein apheresis, he has had four prophylactic stents in an in-stent stenosis; in contrast to the multiple frequent interventions he was requiring prior to apheresis. Our case study, in combination with the existing evidence described below provide rationale for our study, specifically to assess the impact of lipoprotein apheresis on patients with isolated raised Lipoprotein(a) in the context of refractory angina, a condition which affects a substantial population and which is challenging to manage. Our study aims to confirm a positive treatment effect in these individuals on a larger scale. 1.5. Existing evidence Although it is confirmed that raised Lp(a) is an important independent cardiovascular risk factor and predictor of adverse cardiovascular events, more research is required to demonstrate that vigorously treating it can objectively improve clinical outcomes. Recently, Leebmann et al. performed a prospective observational multi-center study [15] in which 170 patients were investigated who commenced lipoprotein apheresis (LA) because of Lp(a)-hyperlipoproteinemia and progressive cardiovascular disease. The incidence rates of cardiovascular events 2 years before (y-2 and y-1) and prospectively 2 years during LA treatment (yþ1, yþ2) were compared. Mean annual rates for major adverse coronary events declined from 0.41 for 2 years before LA to 0.09 for 2 years during LA (P < 0.0001). Similarly, Jaeger et al. conducted a longitudinal cohort study of 120 patients to assess whether combined lipid apheresis and lipid-lowering medication can reduce extremely high levels of Lp(a) and thus prevent major adverse coronary events (MACE) more efficaciously than lipid-lowering medication alone [16]. All patients received lipid-lowering medications alone until maximally tolerated doses were no longer effective, followed by combined lipoprotein apheresis and lipid-lowering medication. Median Lp(a) concentration was reduced from 1120 mg/L to 300 mg/L with apheresis treatment (P < 0.0001); the corresponding mean annual MACE rate per patient was 1.056 versus 0.144 (P < 0.0001) [16]. Although both studies are observational cohort studies, they do suggest a treatment effect and provide rationale for a well-designed randomised controlled trial. Bohl et al. explored the effects of a single lipoprotein apheresis session on myocardial perfusion in 20 patients with elevated Lp(a) > 600 mg/L and coronary artery disease using cardiovascular magnetic resonance
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(CMR).[7] The trans-myocardial perfusion gradient (i.e. endo-epi ratio [EER]) was determined and a comprehensive parameter of resting and adenosine-induced stress perfusion was derived (EER-S/R). The EER-S/R at 24 h was lowered by therapy (DEER-S/R 5%; p < 0.03), whereas this effect disappeared at 96 h. In the control group, no corresponding changes were detected. They concluded that CMRI detects subtle treatment related changes in regional myocardial perfusion in patients with elevated Lp(a) and coronary artery disease undergoing lipoprotein apheresis.[7] The study explored the immediate impact of a single treatment, hence the impact on perfusion of sustained regular treatments over a longer period is unknown. Safarova et al. assessed the impact of specific Lp(a) apheresis versus statin therapy on coronary atherosclerosis regression in 30 stable CHD patients with high Lp(a) levels >500 mg/L [17]. Patients were allocated to receive weekly Lp(a) apheresis (n ¼ 15), or atorvastatin only (n ¼ 15). Blinded quantitative coronary angiography analyses of percent diameter stenosis were performed at baseline and after the 18-month treatment period. Median percent diameter stenosis was reduced by 2.0 (95% confidence interval [CI], 5.0e0.0) with apheresis (p < 0.01 in comparison with baseline), and increased by 3.5 (0.0e6.9) with atorvastatin (p < 0.001 between the groups) [17]. This suggests that specific Lp(a) apheresis may produce coronary atherosclerosis regression in stable CHD patients with high Lp(a). 1.6. The need for further research The European Atherosclerosis Society Consensus Panel stated that further international effort is required to assess the athero-thrombotic risk due to Lp(a) and unravelling the mechanisms by which Lp(a) contributes to cardiovascular disease.[4] Good quality lab-based research and welldesigned prospective randomised controlled intervention trials with reduction of plasma Lp(a) are urgently needed to assess the clinical benefit of treating raised Lp(a) and determining the role of Lp(a) treatment in the primary and secondary prevention of coronary disease and its sequelae. In addition, as our case example highlights, further research is needed to explore raised Lp(a) as a risk factor for refractory angina or accelerated coronary artery disease and to determine the clinical and symptomatic benefit of aggressively lowering Lp(a) in such individuals. 2. Hypotheses and aims of the randomised controlled trial 2.1. Main hypothesis That lipoprotein apheresis improves quantitative myocardial perfusion as assessed by Myocardial Perfusion Reserve (MPR) detected by stress/rest Cardiovascular
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Magnetic Resonance imaging (CMRI), in patients with Refractory Angina and raised Lipoprotein (a). The primary aim is to determine the effect of lipoprotein apheresis on myocardial perfusion reserve, as assessed with quantitative perfusion CMR, in patients with refractory angina and raised Lp(a). The secondary aims of the project in such patients are to determine the effect of lipoprotein apheresis on: 1. Carotid atherosclerosis and/or plaque burden as measured by carotid CMR. 2. Functional CMR parameters: LVEF, LVM, LVEDV. 3. Endothelial vascular function as assessed with pulse amplitude tonometry. 4. The severity and frequency of angina as assessed by the Seattle Angina questionnaire. 5. Physical functioning as assessed with a Six Minute Walk test, and on the psychological well-being of patients and quality of life as assessed with a Quality of Life scale questionnaire (SF-36). 6. Rheological parameters (LDL-cholesterol, oxidised LDL and their antibodies, Lp(a), triglycerides, fibrinogen). 7. Thrombotic risk as assessed by markers of thrombogenesis. In addition, to conduct genetic studies on the recruited patients with refractory angina and raised Lp(a) who provide specific consent, to confirm whether these patients are found to genotype positive for the LPA locus variants (rs10455872) and (rs3798220) which are felt to be associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. 3. Methods The study is a prospective, randomised controlled blinded pilot study with a cross-over design involving patients with refractory angina and elevated Lp(a). All patients will provide written informed consent. Eligible patients will be identified from cardiology outpatient clinics and cardiac catheterisation lists of the Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom. 3.1. Inclusion criteria Patients diagnosed with refractory angina for more than three months. Two or more episodes of angina per week. Previous history of myocardial infarction, CABG, PCI or any combination of the above. Prescribed optimal medical therapy with at least two anti-anginal agents. Hypercholesterolaemia with an elevated Lp(a) > 500 mg/L and an LDL-cholesterol less than
4.0 mmol/L, despite optimal lipid lowering drug therapy.
3.2. Exclusion criteria Patients with poor calibre veins for cannulation. Patients with any other chronic systemic illness such as liver or renal failure, neoplastic disease, overt cardiac failure, unstable coronary artery disease, coronary revascularisation or a myocardial infarction within the previous eight weeks. Pregnancy, untreated diabetes mellitus, untreated arterial hypertension, and those with general contraindications to undergoing CMR or contraindications to adenosine. A total of at least 20 patients with refractory angina and elevated Lp(a) levels will be included in the study. Half of the patients will be randomly assigned to either a treatment arm who will undergo lipoprotein apheresis treatment sessions every week for a total period of three months (12 sessions in total), or to a control group who will receive a placebo ‘sham’ apheresis treatment session also every week for a three month period. All enrolled patients will attend a baseline study visit which is detailed below. Subsequently, all participants will undergo 12 sessions of lipoprotein apheresis or ‘sham’ apheresis depending on randomisation. At the end of the three-month period, both groups will undergo a repeat of the tests and assessments performed at baseline for comparison. After a wash-out period of at least 1 month, the patients who started with the treatment arm will cross-over to three months of weekly ‘sham’ apheresis; and the patients who started with ‘sham’ apheresis will undergo lipoprotein apheresis. Baseline and post-intervention investigations will again be conducted before and after the second threemonth treatment period. Baseline visit: Study introduction, followed by informed consent and randomisation. Physiological measurements including resting ECG, blood pressure and heart rate, weight, BMI, waist and hip circumference. Fasting blood samples will be taken to measure a full fasting lipid profile including total cholesterol, Lp(a), LDL cholesterol, HDL cholesterol, total cholesterol to HDL ratio, TG; Apolipoprotein(A) (Apo(A)) and Apolipoprotein(B) (Apo(B)), fasting glucose, urea and electrolytes, liver function tests, thyroid function tests, B-natriuretic peptide (BNP), coagulation screen, ferritin, haematocrit, bone profile and CReactive protein (CRP). At baseline all patients recruited will also have genetic testing for the LPA locus variants (rs10455872) and (rs3798220). In order to specifically assess the impact of lipoprotein apheresis on thrombotic risk, we will also check a thrombotic screen and tissue factor pathway inhibitor(TFPI), plasminogen activator inhibitor-1(PAI-1), D-dimer, plasmin/antiplasmin, thrombin/antithrombin, thrombin
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generation assay and vWF ELISAs on plasma and thrombomodulin levels. We will also conduct a GlobalThrombosis-Thrombolysis test (GTT), which is a validated bedside test performed on the patient’s native blood which assesses endogenous thrombotic and thrombolytic status and has been used successfully to identify patients at risk of future cardiac events following acute coronary syndromes [18]. We will also measure plasma levels of oxidised phospholipids which are believed to be increased in the presence of elevated Lp(a), which is the preferential carrier. We hope to demonstrate that levels of oxidised phospholipids will be reduced by apheresis. All patients will have CMR at baseline assessing functional MR parameters, first-pass quantitative perfusion at stress and rest and late gadolinium enhancement (LGE), as well as quantitative assessment of carotid atherosclerosis burden. All patients will undergo testing of endothelial vascular function using pulse amplitude tonometry (PAT), an assessment of exercise capacity using a Six Minute Walk test and an objective assessment of their anginal symptoms using a validated angina scoring system (the Seattle Angina Scoring Questionnaire). Quality of life assessments at baseline will be assessed with a Quality of Life scale questionnaire (SF-36). Participants will also be given a symptom-monitoring diary to be filled in during the course of the study. Post intervention visit: All patients will undergo a postintervention CMR study and an endothelial function test (PAT) to assess changes in the parameters measured at baseline. We will repeat all of the biochemical and haematological tests and serum markers of thrombogenesis described above. They will be asked to complete identical physiological, symptomatic and psychological measurements as at the baseline visit. 3.3. Lipoprotein apheresis Lipoprotein apheresis will be performed on the treatment group. The control group will receive placebo ‘sham’ apheresis sessions where the lipoprotein absorber column will be omitted from the apparatus and the patient will not be connected to the machine. Patients will be blinded to their treatment allocation and screens and drapes will be used so that patients will not be able to determine their treatment allocation. The sessions for both groups will be carried out in the Apheresis Unit in Harefield Hospital, Middlesex which is the largest Apheresis unit in the UK. The DX21 DHP (Direct Hemo Perfusion) Lipoprotein Apheresis machine will be used, with the Liposorber DL-75 column which utilises dextran sulphate to covalently bind Apo-B containing lipoproteins to remove them directly from whole blood. 3.4. Cardiovascular magnetic resonance All CMR studies will be performed at Royal Brompton Hospital CMR unit and will involve assessment of
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quantitative perfusion (stress/rest) with calculation of Myocardial Perfusion Reserve (MPR), systolic function, volumes, viability and assessment of carotid atherosclerosis. All studies will be performed at 3T, which has higher spatial resolution, superior signal to noise and superior results for perfusion quantification. Analysis of quantitative perfusion and carotid atherosclerosis will be performed fully blinded to treatment allocation to avoid observer bias. 3.5. Endothelial function studies Measurement of endothelial vascular function will be performed using pulse amplitude tonometry (PAT) [EndoPAT device, Itamar Medical, Israel], a validated device which tests endothelial vasomotor function after reactive hyperaemia by PAT as measured in the fingertips via probes. 3.6. Power calculations The primary endpoint is a change in Myocardial Perfusion Reserve (MPR). A power calculation was performed by the trial statistician prior to commencing the study. With the cross-over design, assuming the inter-study reproducibility for MPR to have a standard deviation (SD) of 0.15 to detect a change in MPR of 0.2 between the groups, following treatment versus control, a sample size of 20 patients is required to achieve 99% power at a p-value of 0.05. The cross-over design helps to improve statistical power and eliminates potential randomisation issues, since all the same patients undergo treatment and sham apheresis. 4. Study outcome measures The study primary outcome measure or endpoint is a change in the Myocardial Perfusion Reserve (MPR) from baseline to the value after three months of lipoprotein apheresis treatment. The secondary outcome measures will be the changes in the following parameters after three months of lipoprotein apheresis: Carotid atherosclerosis and/or plaque burden as measured by CMR. LV functional parameters as measured by CMR. Endothelial vascular function. Markers of thrombogenesis. Rheological parameters (LDL-cholesterol, oxidised LDL and their antibodies, Lp(a), triglycerides, fibrinogen). Symptoms of angina as assessed with the Seattle Angina Scoring Questionnaire. Quality of life as assessed by SF-36 Questionnaire. Exercise capacity as assessed by the Six Minute Walk test. We will also examine whether we can determine a correlation in the genotypic presence of LPA locus
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variants (rs10455872) and (rs3798220) in our study patients with raised Lp(a) and refractory angina.
[4]
5. Conclusions [5]
This is a novel area of research, as previous studies have not assessed the role of lipoprotein apheresis in patients with refractory angina with raised Lp(a) in a prospective randomised controlled manner. We will also be comparing lipoprotein apheresis against sham apheresis in order to try and ascertain the true effect of this treatment against any potential placebo effect. If our hypotheses are verified, lipoprotein apheresis may potentially be applied as a treatment modality in the management of patients with Refractory Angina and raised Lp(a). In addition, our study will assess the impact of lipoprotein apheresis on a wide spectrum of parameters including symptoms, myocardial perfusion, atherosclerosis, endothelial vascular function, thrombogenesis and platelet function, exercise capacity and quality of life. Hence we will provide valuable insights into the role of Lp(a) and the mechanisms of action by which it contributes to the atherosclerotic process and how it increases the risk of ischaemic heart disease and adverse cardiovascular events. Results are expected to be available by the end of 2015. Conflicts of interest None.
[6]
[7]
[8]
[9] [10]
[11]
[12] [13]
Acknowledgements [14]
This project is supported by the NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London. Apheresis equipment being used has been provided by Kaneka Pharma, Osaka, Japan.
[15]
References
[16]
[1] Cremer P, Nagel D, Labrot B, Mann H, Muche R, Elster H, et al. Lipoprotein(a) as predictor of myocardial infarction in comparison to fibrinogen, LDL cholesterol and other risk factors: results from the prospective Gottingen Risk Incidence and Prevalence Study (GRIPS). Eur J Clin Invest 1994;24:444e53. [2] Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation 2000; 102(10):1082e5. [3] Erqou S, Kaptoge S, Perry PL, Angelantonio ED, Thompson A, White IR, et al. Lipoprotein(a) concentration and the risk of coronary
[17]
[18]
heart disease, stroke and non-vascular mortality. JAMA 2009;302: 412e23. Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts GF, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844e53. Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 2009;361(26):2518e28. Bambauer R, Olbricht CJ, Schoeppe E. Low-density lipoprotein apheresis for prevention and regression of atherosclerosis: clinical results. Ther Dial 1997;1:242e8. Bohl S, Kassner U, Eckardt R, Utz W, Mueller-Nordhorn J, Busjahn A, et al. Single lipoprotein apheresis session improves cardiac microvascular function in patients with elevated lipoprotein(a): detection by Stress/Rest perfusion magnetic resonance imaging. Ther Dial 2009;13:129e37. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/ laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013;34(17): 1279e91. Borberg H. Comparison of different Lp(a) elimination techniques: a retrospective evaluation. TransApheresSci 2009;41:61e5. Merki E, Graham M, Taleb A, Leibundgut G, Yang X, Miller ER, et al. Antisense oligonucleotide lowers plasma levels of apolipoprotein(a) and lipoprotein (a) in transgenic mice. J Am Coll Cardiol 2011;57:1611e21. Thompson GR, Catapano A, Saheb S, Atassi-Dumont M, Barbir M, Eriksson M, et al. Severe hypercholesterolaemia; therapeutic goals and eligibility criteria for LDL apheresis in Europe. Curr Opin Lipidol 2010;21:492e8. Kim MC, Kini A, Sharma SK. Refractory angina pectoris. Mechanism and therapeutic options. J Am Coll Cardiol 2002;39:923e34. Mannheimer C, Camici P, Chester MR, Collins A, DeJongste M, Eliasson T, et al. The problem of chronic refractory angina; report from the ESC Joint Study Group on the Treatment of Refractory Angina. Eur Heart J 2002;23(5):355e70. Ibrahim M, Ussen B, Pottle A, Barbir M. 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. J Clin Lipidol 2012;6(2):192e4. Leebmann J, Roseler E, Julius U, Heigl F, Spitthoever R, Heutling D, et al. Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease. Prospective observational multicenter study. Circulation 2013;128:2567e76. Jaeger BR, Richter Y, Nagel D, Heigl F, Vogt A, Roeseler E, et al. Longitudinal cohort study on the effectiveness of apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events. Nat Clin Pract Cardiovasc Med 2009;6:229e39. Safarova MS, Ezhov MV, Afanasieva OI, Matchin YG, Atanesyan RV, Adamova IY, et al. Effect of specific lipoprotein(a) apheresis on coronary atherosclerosis regression assessed by quantitative coronary angiography. Atheroscler Suppl 2013;14:93e9. Saraf S, Christopoulos C, Salha I, Gorog D. Impaired endogenous thrombolysis in acute coronary syndrome patients predicts cardiovascular death and nonfatal myocardial infarction. JACC 2010;55: 2107e15.
The impact of lipoprotein apheresis in patients with refractory angina and raised lipoprotein(a): Objectives and methods of a randomised controlled trial Tina Z. Khan a,*, Alison Pottle a, Dudley J. Pennell b, Mahmoud S. Barbir a b
a Harefield Hospital, Hill End Road, Uxbridge UB9 6JH, UK Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
Abstract 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. Ó 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Lipoprotein(a); Lipoprotein apheresis; Ischaemic heart disease; Refractory angina
1. Introduction 1.1. Lipoprotein(a) * Corresponding author. Tel.: þ44 (0)1895 82 37 37; fax: þ44 (0)1895 82 88 96. E-mail addresses: [email protected] (T.Z. Khan), A.Pottle@rbht. nhs.uk (A. Pottle), [email protected] (D.J. Pennell), M.Barbir@ rbht.nhs.uk (M.S. Barbir). http://dx.doi.org/10.1016/j.atherosclerosissup.2015.02.019 1567-5688/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
Lipoprotein(a) [Lp(a)] is a plasma lipoprotein consisting of a cholesterol-rich LDL particle with one molecule of apolipoprotein B100 and a protein, apolipoprotein(a), attached via a disulphide bond. [See Fig. 1]. An elevated Lp(a) level (>500 mg/L) is established as an important
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Fig. 1. The structure of lipoprotein(a).
independent cardiovascular risk factor and predictor of adverse outcome in atherosclerotic disease [1,2]. A large epidemiological study demonstrated that the relative risk of CHD per 3.5-fold higher Lp(a) level adjusted for age and sex only was 1.16 and 1.13 (95% CI: 1.09e1.18) following further adjustment for systolic blood pressure, smoking, history of diabetes and total cholesterol [3]. Elevated Lp(a) is believed to promote atherosclerosis via Lp(a)-derived cholesterol entrapment in the intima, inflammatory cell recruitment and/or via the binding of proinflammatory-oxidised phospholipids, such as oxidised LDL.[4] In addition, elevated Lp(a) is felt to be prothrombotic via the inhibition of fibrinolysis with enhancement of clot stabilisation as well as via enhanced coagulation via the inhibition of tissue factor pathway inhibitor [4]. An increased level of Lp(a) is highly heritable. Two variants of the LPA locus on 6q26-27 encoding Lp(a) lipoprotein (rs10455872) and (rs3798220) were strongly associated with both an increased level of Lp(a) and risk of coronary disease [5]. Most patients with raised LDL-cholesterol can be adequately treated with appropriate dietary measures and lipid lowering drug therapy [6]. However, the conservative therapy of elevated Lp(a) is unsatisfactory [7]. Data assessing the impact of statins on Lp(a) are limited and highly variable [4] and overall, statins are ineffective at significantly lowering Lp(a). Nicotinic acid based treatment (eg. Tredaptive) was previously felt to be modestly effective at lowering Lp(a), however the European Medicines Agency have withdrawn it based on preliminary findings from the HPS2-THRIVE trial showing that this drug does not reduce major adverse cardiac events and causes a higher incidence of serious non-fatal side effects [8]. 1.2. Lipoprotein apheresis Lipoprotein apheresis is a selective lipid-lowering extracorporeal treatment by which excess atherogenic
ApoB100-containing lipoproteins, including Lp(a) and LDL are removed from blood or plasma.[9] Currently it remains the most effective means of lowering Lp(a) levels [9]. The European Atherosclerosis Society Consensus Panel recommended that Lp(a) levels should be reduced below 500 mg/L, in extreme cases, by lipoprotein apheresis [4]. The HEART UK guidelines recommend lipoprotein apheresis for patients with Lp(a) levels >600 mg/L with progressive coronary heart disease and LDL levels >3.2 mmol/L despite treatment with maximally tolerated combined drug therapy. However, objective prospective evidence to support these recommendations is limited. A potential pharmacological treatment that holds promise for the future are antisense oligonucleotides (ASO) directed to apolipoprotein (a) [apo(a)], thereby reducing apo(a) and Lp(a) levels. So far, animal studies have shown that this may provide an effective approach to lower elevated Lp(a) levels [10]. However, phase 1 and 2 human studies are needed to determine safety and efficacy of this treatment before it can be established for widespread use. 1.3. Refractory angina Cardiovascular disease remains a leading cause of death in the western world [11]. Most patients with angina are successfully treated with conventional medical therapy and revascularisation techniques such as coronary artery bypass graft (CABG) surgery or percutaneous coronary interventions (PCI) [12]. However, there is a group of patients who are particularly challenging to manage, who have severe disabling angina from coronary artery disease which is refractory to conventional therapy [13]. There is a real need for effective treatment options for patients with refractory angina. Estimates suggest that between 30,000 and 50,000 patients per year develop the condition [13]. 1.4. The impact of lipoprotein apheresis on refractory angina with raised lipoprotein(a): A case history In our centre, we have experience of treating a patient with refractory angina and raised Lp(a) with lipoprotein apheresis and demonstrated that aggressive reduction of Lp(a) successfully ameliorated the progression of coronary stenosis and provided effective and durable relief of angina [14]. Aged 42, this gentleman presented with unstable angina and diffuse multi-vessel coronary disease. Subsequently, he was treated with quadruple CABG and a total of 12 stents over a three year period. Despite these multiple coronary interventions and optimal medical therapy, he continued to experience angina which was adversely affecting his quality of life. His Lp(a) was screened and was found to be significantly elevated at 1200 mg/L (normal range: 0e300 mg/L). The remainder of his fasting lipid profile revealed normal total cholesterol (TC) 3.2 mmol/L, LDL-C (1.5 mmol/L) and plasma triglycerides (TG)
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(1.4 mmol/L). He was started on a fortnightly regimen of lipoprotein apheresis which reduced the plasma levels of Lp(a) by an average of 70%. He has since experienced significant improvement of his angina and quality of life. Lipoprotein apheresis has slowed the rate of progression of his coronary disease, with a reduction in the rate of revascularisation procedures. During the five year period the patient has undergone lipoprotein apheresis, he has had four prophylactic stents in an in-stent stenosis; in contrast to the multiple frequent interventions he was requiring prior to apheresis. Our case study, in combination with the existing evidence described below provide rationale for our study, specifically to assess the impact of lipoprotein apheresis on patients with isolated raised Lipoprotein(a) in the context of refractory angina, a condition which affects a substantial population and which is challenging to manage. Our study aims to confirm a positive treatment effect in these individuals on a larger scale. 1.5. Existing evidence Although it is confirmed that raised Lp(a) is an important independent cardiovascular risk factor and predictor of adverse cardiovascular events, more research is required to demonstrate that vigorously treating it can objectively improve clinical outcomes. Recently, Leebmann et al. performed a prospective observational multi-center study [15] in which 170 patients were investigated who commenced lipoprotein apheresis (LA) because of Lp(a)-hyperlipoproteinemia and progressive cardiovascular disease. The incidence rates of cardiovascular events 2 years before (y-2 and y-1) and prospectively 2 years during LA treatment (yþ1, yþ2) were compared. Mean annual rates for major adverse coronary events declined from 0.41 for 2 years before LA to 0.09 for 2 years during LA (P < 0.0001). Similarly, Jaeger et al. conducted a longitudinal cohort study of 120 patients to assess whether combined lipid apheresis and lipid-lowering medication can reduce extremely high levels of Lp(a) and thus prevent major adverse coronary events (MACE) more efficaciously than lipid-lowering medication alone [16]. All patients received lipid-lowering medications alone until maximally tolerated doses were no longer effective, followed by combined lipoprotein apheresis and lipid-lowering medication. Median Lp(a) concentration was reduced from 1120 mg/L to 300 mg/L with apheresis treatment (P < 0.0001); the corresponding mean annual MACE rate per patient was 1.056 versus 0.144 (P < 0.0001) [16]. Although both studies are observational cohort studies, they do suggest a treatment effect and provide rationale for a well-designed randomised controlled trial. Bohl et al. explored the effects of a single lipoprotein apheresis session on myocardial perfusion in 20 patients with elevated Lp(a) > 600 mg/L and coronary artery disease using cardiovascular magnetic resonance
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(CMR).[7] The trans-myocardial perfusion gradient (i.e. endo-epi ratio [EER]) was determined and a comprehensive parameter of resting and adenosine-induced stress perfusion was derived (EER-S/R). The EER-S/R at 24 h was lowered by therapy (DEER-S/R 5%; p < 0.03), whereas this effect disappeared at 96 h. In the control group, no corresponding changes were detected. They concluded that CMRI detects subtle treatment related changes in regional myocardial perfusion in patients with elevated Lp(a) and coronary artery disease undergoing lipoprotein apheresis.[7] The study explored the immediate impact of a single treatment, hence the impact on perfusion of sustained regular treatments over a longer period is unknown. Safarova et al. assessed the impact of specific Lp(a) apheresis versus statin therapy on coronary atherosclerosis regression in 30 stable CHD patients with high Lp(a) levels >500 mg/L [17]. Patients were allocated to receive weekly Lp(a) apheresis (n ¼ 15), or atorvastatin only (n ¼ 15). Blinded quantitative coronary angiography analyses of percent diameter stenosis were performed at baseline and after the 18-month treatment period. Median percent diameter stenosis was reduced by 2.0 (95% confidence interval [CI], 5.0e0.0) with apheresis (p < 0.01 in comparison with baseline), and increased by 3.5 (0.0e6.9) with atorvastatin (p < 0.001 between the groups) [17]. This suggests that specific Lp(a) apheresis may produce coronary atherosclerosis regression in stable CHD patients with high Lp(a). 1.6. The need for further research The European Atherosclerosis Society Consensus Panel stated that further international effort is required to assess the athero-thrombotic risk due to Lp(a) and unravelling the mechanisms by which Lp(a) contributes to cardiovascular disease.[4] Good quality lab-based research and welldesigned prospective randomised controlled intervention trials with reduction of plasma Lp(a) are urgently needed to assess the clinical benefit of treating raised Lp(a) and determining the role of Lp(a) treatment in the primary and secondary prevention of coronary disease and its sequelae. In addition, as our case example highlights, further research is needed to explore raised Lp(a) as a risk factor for refractory angina or accelerated coronary artery disease and to determine the clinical and symptomatic benefit of aggressively lowering Lp(a) in such individuals. 2. Hypotheses and aims of the randomised controlled trial 2.1. Main hypothesis That lipoprotein apheresis improves quantitative myocardial perfusion as assessed by Myocardial Perfusion Reserve (MPR) detected by stress/rest Cardiovascular
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Magnetic Resonance imaging (CMRI), in patients with Refractory Angina and raised Lipoprotein (a). The primary aim is to determine the effect of lipoprotein apheresis on myocardial perfusion reserve, as assessed with quantitative perfusion CMR, in patients with refractory angina and raised Lp(a). The secondary aims of the project in such patients are to determine the effect of lipoprotein apheresis on: 1. Carotid atherosclerosis and/or plaque burden as measured by carotid CMR. 2. Functional CMR parameters: LVEF, LVM, LVEDV. 3. Endothelial vascular function as assessed with pulse amplitude tonometry. 4. The severity and frequency of angina as assessed by the Seattle Angina questionnaire. 5. Physical functioning as assessed with a Six Minute Walk test, and on the psychological well-being of patients and quality of life as assessed with a Quality of Life scale questionnaire (SF-36). 6. Rheological parameters (LDL-cholesterol, oxidised LDL and their antibodies, Lp(a), triglycerides, fibrinogen). 7. Thrombotic risk as assessed by markers of thrombogenesis. In addition, to conduct genetic studies on the recruited patients with refractory angina and raised Lp(a) who provide specific consent, to confirm whether these patients are found to genotype positive for the LPA locus variants (rs10455872) and (rs3798220) which are felt to be associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. 3. Methods The study is a prospective, randomised controlled blinded pilot study with a cross-over design involving patients with refractory angina and elevated Lp(a). All patients will provide written informed consent. Eligible patients will be identified from cardiology outpatient clinics and cardiac catheterisation lists of the Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom. 3.1. Inclusion criteria Patients diagnosed with refractory angina for more than three months. Two or more episodes of angina per week. Previous history of myocardial infarction, CABG, PCI or any combination of the above. Prescribed optimal medical therapy with at least two anti-anginal agents. Hypercholesterolaemia with an elevated Lp(a) > 500 mg/L and an LDL-cholesterol less than
4.0 mmol/L, despite optimal lipid lowering drug therapy.
3.2. Exclusion criteria Patients with poor calibre veins for cannulation. Patients with any other chronic systemic illness such as liver or renal failure, neoplastic disease, overt cardiac failure, unstable coronary artery disease, coronary revascularisation or a myocardial infarction within the previous eight weeks. Pregnancy, untreated diabetes mellitus, untreated arterial hypertension, and those with general contraindications to undergoing CMR or contraindications to adenosine. A total of at least 20 patients with refractory angina and elevated Lp(a) levels will be included in the study. Half of the patients will be randomly assigned to either a treatment arm who will undergo lipoprotein apheresis treatment sessions every week for a total period of three months (12 sessions in total), or to a control group who will receive a placebo ‘sham’ apheresis treatment session also every week for a three month period. All enrolled patients will attend a baseline study visit which is detailed below. Subsequently, all participants will undergo 12 sessions of lipoprotein apheresis or ‘sham’ apheresis depending on randomisation. At the end of the three-month period, both groups will undergo a repeat of the tests and assessments performed at baseline for comparison. After a wash-out period of at least 1 month, the patients who started with the treatment arm will cross-over to three months of weekly ‘sham’ apheresis; and the patients who started with ‘sham’ apheresis will undergo lipoprotein apheresis. Baseline and post-intervention investigations will again be conducted before and after the second threemonth treatment period. Baseline visit: Study introduction, followed by informed consent and randomisation. Physiological measurements including resting ECG, blood pressure and heart rate, weight, BMI, waist and hip circumference. Fasting blood samples will be taken to measure a full fasting lipid profile including total cholesterol, Lp(a), LDL cholesterol, HDL cholesterol, total cholesterol to HDL ratio, TG; Apolipoprotein(A) (Apo(A)) and Apolipoprotein(B) (Apo(B)), fasting glucose, urea and electrolytes, liver function tests, thyroid function tests, B-natriuretic peptide (BNP), coagulation screen, ferritin, haematocrit, bone profile and CReactive protein (CRP). At baseline all patients recruited will also have genetic testing for the LPA locus variants (rs10455872) and (rs3798220). In order to specifically assess the impact of lipoprotein apheresis on thrombotic risk, we will also check a thrombotic screen and tissue factor pathway inhibitor(TFPI), plasminogen activator inhibitor-1(PAI-1), D-dimer, plasmin/antiplasmin, thrombin/antithrombin, thrombin
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generation assay and vWF ELISAs on plasma and thrombomodulin levels. We will also conduct a GlobalThrombosis-Thrombolysis test (GTT), which is a validated bedside test performed on the patient’s native blood which assesses endogenous thrombotic and thrombolytic status and has been used successfully to identify patients at risk of future cardiac events following acute coronary syndromes [18]. We will also measure plasma levels of oxidised phospholipids which are believed to be increased in the presence of elevated Lp(a), which is the preferential carrier. We hope to demonstrate that levels of oxidised phospholipids will be reduced by apheresis. All patients will have CMR at baseline assessing functional MR parameters, first-pass quantitative perfusion at stress and rest and late gadolinium enhancement (LGE), as well as quantitative assessment of carotid atherosclerosis burden. All patients will undergo testing of endothelial vascular function using pulse amplitude tonometry (PAT), an assessment of exercise capacity using a Six Minute Walk test and an objective assessment of their anginal symptoms using a validated angina scoring system (the Seattle Angina Scoring Questionnaire). Quality of life assessments at baseline will be assessed with a Quality of Life scale questionnaire (SF-36). Participants will also be given a symptom-monitoring diary to be filled in during the course of the study. Post intervention visit: All patients will undergo a postintervention CMR study and an endothelial function test (PAT) to assess changes in the parameters measured at baseline. We will repeat all of the biochemical and haematological tests and serum markers of thrombogenesis described above. They will be asked to complete identical physiological, symptomatic and psychological measurements as at the baseline visit. 3.3. Lipoprotein apheresis Lipoprotein apheresis will be performed on the treatment group. The control group will receive placebo ‘sham’ apheresis sessions where the lipoprotein absorber column will be omitted from the apparatus and the patient will not be connected to the machine. Patients will be blinded to their treatment allocation and screens and drapes will be used so that patients will not be able to determine their treatment allocation. The sessions for both groups will be carried out in the Apheresis Unit in Harefield Hospital, Middlesex which is the largest Apheresis unit in the UK. The DX21 DHP (Direct Hemo Perfusion) Lipoprotein Apheresis machine will be used, with the Liposorber DL-75 column which utilises dextran sulphate to covalently bind Apo-B containing lipoproteins to remove them directly from whole blood. 3.4. Cardiovascular magnetic resonance All CMR studies will be performed at Royal Brompton Hospital CMR unit and will involve assessment of
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quantitative perfusion (stress/rest) with calculation of Myocardial Perfusion Reserve (MPR), systolic function, volumes, viability and assessment of carotid atherosclerosis. All studies will be performed at 3T, which has higher spatial resolution, superior signal to noise and superior results for perfusion quantification. Analysis of quantitative perfusion and carotid atherosclerosis will be performed fully blinded to treatment allocation to avoid observer bias. 3.5. Endothelial function studies Measurement of endothelial vascular function will be performed using pulse amplitude tonometry (PAT) [EndoPAT device, Itamar Medical, Israel], a validated device which tests endothelial vasomotor function after reactive hyperaemia by PAT as measured in the fingertips via probes. 3.6. Power calculations The primary endpoint is a change in Myocardial Perfusion Reserve (MPR). A power calculation was performed by the trial statistician prior to commencing the study. With the cross-over design, assuming the inter-study reproducibility for MPR to have a standard deviation (SD) of 0.15 to detect a change in MPR of 0.2 between the groups, following treatment versus control, a sample size of 20 patients is required to achieve 99% power at a p-value of 0.05. The cross-over design helps to improve statistical power and eliminates potential randomisation issues, since all the same patients undergo treatment and sham apheresis. 4. Study outcome measures The study primary outcome measure or endpoint is a change in the Myocardial Perfusion Reserve (MPR) from baseline to the value after three months of lipoprotein apheresis treatment. The secondary outcome measures will be the changes in the following parameters after three months of lipoprotein apheresis: Carotid atherosclerosis and/or plaque burden as measured by CMR. LV functional parameters as measured by CMR. Endothelial vascular function. Markers of thrombogenesis. Rheological parameters (LDL-cholesterol, oxidised LDL and their antibodies, Lp(a), triglycerides, fibrinogen). Symptoms of angina as assessed with the Seattle Angina Scoring Questionnaire. Quality of life as assessed by SF-36 Questionnaire. Exercise capacity as assessed by the Six Minute Walk test. We will also examine whether we can determine a correlation in the genotypic presence of LPA locus
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variants (rs10455872) and (rs3798220) in our study patients with raised Lp(a) and refractory angina.
[4]
5. Conclusions [5]
This is a novel area of research, as previous studies have not assessed the role of lipoprotein apheresis in patients with refractory angina with raised Lp(a) in a prospective randomised controlled manner. We will also be comparing lipoprotein apheresis against sham apheresis in order to try and ascertain the true effect of this treatment against any potential placebo effect. If our hypotheses are verified, lipoprotein apheresis may potentially be applied as a treatment modality in the management of patients with Refractory Angina and raised Lp(a). In addition, our study will assess the impact of lipoprotein apheresis on a wide spectrum of parameters including symptoms, myocardial perfusion, atherosclerosis, endothelial vascular function, thrombogenesis and platelet function, exercise capacity and quality of life. Hence we will provide valuable insights into the role of Lp(a) and the mechanisms of action by which it contributes to the atherosclerotic process and how it increases the risk of ischaemic heart disease and adverse cardiovascular events. Results are expected to be available by the end of 2015. Conflicts of interest None.
[6]
[7]
[8]
[9] [10]
[11]
[12] [13]
Acknowledgements [14]
This project is supported by the NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and Imperial College London. Apheresis equipment being used has been provided by Kaneka Pharma, Osaka, Japan.
[15]
References
[16]
[1] Cremer P, Nagel D, Labrot B, Mann H, Muche R, Elster H, et al. Lipoprotein(a) as predictor of myocardial infarction in comparison to fibrinogen, LDL cholesterol and other risk factors: results from the prospective Gottingen Risk Incidence and Prevalence Study (GRIPS). Eur J Clin Invest 1994;24:444e53. [2] Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation 2000; 102(10):1082e5. [3] Erqou S, Kaptoge S, Perry PL, Angelantonio ED, Thompson A, White IR, et al. Lipoprotein(a) concentration and the risk of coronary
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heart disease, stroke and non-vascular mortality. JAMA 2009;302: 412e23. Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts GF, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844e53. Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 2009;361(26):2518e28. Bambauer R, Olbricht CJ, Schoeppe E. Low-density lipoprotein apheresis for prevention and regression of atherosclerosis: clinical results. Ther Dial 1997;1:242e8. Bohl S, Kassner U, Eckardt R, Utz W, Mueller-Nordhorn J, Busjahn A, et al. Single lipoprotein apheresis session improves cardiac microvascular function in patients with elevated lipoprotein(a): detection by Stress/Rest perfusion magnetic resonance imaging. Ther Dial 2009;13:129e37. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/ laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013;34(17): 1279e91. Borberg H. Comparison of different Lp(a) elimination techniques: a retrospective evaluation. TransApheresSci 2009;41:61e5. Merki E, Graham M, Taleb A, Leibundgut G, Yang X, Miller ER, et al. Antisense oligonucleotide lowers plasma levels of apolipoprotein(a) and lipoprotein (a) in transgenic mice. J Am Coll Cardiol 2011;57:1611e21. Thompson GR, Catapano A, Saheb S, Atassi-Dumont M, Barbir M, Eriksson M, et al. Severe hypercholesterolaemia; therapeutic goals and eligibility criteria for LDL apheresis in Europe. Curr Opin Lipidol 2010;21:492e8. Kim MC, Kini A, Sharma SK. Refractory angina pectoris. Mechanism and therapeutic options. J Am Coll Cardiol 2002;39:923e34. Mannheimer C, Camici P, Chester MR, Collins A, DeJongste M, Eliasson T, et al. The problem of chronic refractory angina; report from the ESC Joint Study Group on the Treatment of Refractory Angina. Eur Heart J 2002;23(5):355e70. Ibrahim M, Ussen B, Pottle A, Barbir M. 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. J Clin Lipidol 2012;6(2):192e4. Leebmann J, Roseler E, Julius U, Heigl F, Spitthoever R, Heutling D, et al. Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease. Prospective observational multicenter study. Circulation 2013;128:2567e76. Jaeger BR, Richter Y, Nagel D, Heigl F, Vogt A, Roeseler E, et al. Longitudinal cohort study on the effectiveness of apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events. Nat Clin Pract Cardiovasc Med 2009;6:229e39. Safarova MS, Ezhov MV, Afanasieva OI, Matchin YG, Atanesyan RV, Adamova IY, et al. Effect of specific lipoprotein(a) apheresis on coronary atherosclerosis regression assessed by quantitative coronary angiography. Atheroscler Suppl 2013;14:93e9. Saraf S, Christopoulos C, Salha I, Gorog D. Impaired endogenous thrombolysis in acute coronary syndrome patients predicts cardiovascular death and nonfatal myocardial infarction. JACC 2010;55: 2107e15.