Cascade plasma filtration during the first year after CABG in patients with hyperlipidemia refractory to statins

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1 Atherosclerosis Supplements 14 (2013) 101e105 Cascade plasma filtration during the first year after CABG in patients with hyperlipidemia refractory to statins Marat V. Ezhov a, Larisa N. Il ina a, Maya S. Safarova a, Olga I. Afanasieva a, Irina Yu. Adamova a, Ruslan V. Atanesyan a, Gennadiy A. Konovalov b, Renat S. Akchurin a, Sergei N. Pokrovsky a, * a Cardiology Research Center, 15a, 3rd Cherepkovskaya Street, Moscow, Russia b MEDSI Clinic, 3A, Georgian Lane, Moscow, Russia Abstract Objective: To evaluate the effect of a 12-month course of weekly lipid apheresis on vein graft patency after coronary artery bypass grafting (CABG) in patients with hyperlipidemia refractory to statins. Methods: In a 12-month prospective controlled clinical trial we enrolled 34 male patients (mean age 57 8 years) who passed through successful CABG and low-density lipoprotein cholesterol (LDL-C) level >2.6 mmol/l prior to the operation despite statin treatment. Patients were allocated into 2 groups: active (n ¼ 17, weekly apheresis by cascade plasma filtration (CPF) plus atorvastatin), and control (n ¼ 17, atorvastatin alone). Graft patency was evaluated by multislice computed tomography at 3 months and by angiography at 12 months after an operation. Results: Both groups were comparable in clinical and biochemical characteristics. During each CPF procedure, LDL-C level decreased by 64 9%, apob e by 65 8%, Lp(a) e by 52 15%,; these changes were significant compared to baseline and the control group. Mean net difference in LDL-C level between apheresis and control groups was mmol/l. Vein graft patency at study end was 88.2% (45 of 51) in the apheresis group versus 72.7% (40 of 55) in the control group (p ¼ 0.05). Use of apheresis was associated with decreased vein graft occlusions by 46%: relative risk 0.54; 95% confidence interval 0.27 to 1.02; p ¼ Conclusion: Our data suggest that the use of lipoprotein apheresis with CPF results in a better vein graft patency during the first year after CABG in patients with hyperlipidemia refractory to statins. Ó 2012 Elsevier Ireland Ltd. All rights reserved. Keywords: Lipoprotein apheresis; Cascade plasma filtration; DFPP; Vein graft patency; CABG 1. Introduction Coronary artery bypass grafting (CABG) is a leading choice of myocardial revascularization in the management of multivessel and left main stem coronary heart disease. * Corresponding author. Laboratory of Atherosclerosis, Institute of Experimental Cardiology, Cardiology Research Center, 15a, 3rd Cherepkovskaya Street, Moscow, Russia. Tel.: þ , þ (mobile); fax: þ address: Dr.Pokrovsky@mail.ru (S.N. Pokrovsky). However, about 20e30% of vein grafts become stenosed within the first year of surgery [1e3]. The pathophysiology of vein graft failure is complex, involving disparate factors that include adhesion of platelets and leukocytes, rheological forces, metalloproteinase expression, proliferation and migration of vascular smooth muscle cells, neointima formation, oxidative stress, hypoxia and neural reorganization [le4]. To date, no therapeutic intervention has proved successful in treating vein graft failure [5]. After CABG, statins limit the progression of atherosclerosis in native coronary arteries, inhibit the process of saphenous /$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved.

2 102 M.V. Ezhov et al. / Atherosclerosis Supplements 14 (2013) 101e105 vein graft disease, and improve vein graft patency. Furthermore, postoperative statins reduce the recurrence of cardiovascular events and improve all-cause mortality [6]. There is a category of patients, however, with dyslipidemia resistant to statin therapy and one of the possible ways in this clinical setting could be extracorporeal lipid elimination [7]. Additionally, elevated lipoprotein(a) [Lp(a)] level, which is insensitive to the statin, has a direct association with the vein graft failure [8]. Besides drastic removing of atherogenic lipoproteins, lipoprotein apheresis possesses pleiotropic mechanisms including reducing the concentrations of pro-inflammatory and pro-coagulation markers, improving whole blood viscosity and endotheliummediated vasodilation, and perfusion in the microcirculation [9]. Considering these effects and the different mechanisms of early vein graft failure it is reasonable to use lipoprotein apheresis techniques during the first year after CABG. We suggest that more active treatment with the use of extracorporeal lipoproteins elimination in addition to statin therapy could be more effective to prevent vein graft disease. The purpose of our study was to evaluate the effect of a 12-month course of lipoprotein apheresis with cascade plasma filtration (CPF) on vein graft patency in CABG patients with hyperlipidemia resistant to statin therapy. tests, and coronary angiography. All patients took standard medical therapy including aspirin, beta-blockers, ACE inhibitors, nitrates and calcium antagonists Operation and angiography techniques The coronary angiograms were obtained at baseline and after 52 weeks of treatment, no later than 4 weeks after the last CPF procedure in accordance with a standard protocol. After administration of intracoronary nitroglycerin (250 mg), standard angiographic images were obtained with the Philips AlluraX per FD10 cardiovascular X-ray system and were recorded on a DICOM-formatted CD. All films were read in one angiographic laboratory by two independent observers who were unaware of the treatment assignments. Most of patients at baseline had triple-vessel disease and/or left main stem lesion >50% stenosis (Table 1). All patients were subjected to on-pump CABG and received left internal mammary artery to the left anterior descending artery. Total number of distal vein anastomoses was 51 in apheresis group and 55 in controls that in average 3.0 and 3.2 per patient in corresponding groups (Table 1). At one year follow-up angiography was performed in all patients to assess graft patency. 2. Material and methods 2.1. Study design and population In this 52-week, prospective, open, controlled clinical trial we recruited 34 men (age 40e68 years, mean years) after successful CABG for stable angina pectoris IIIeIV class due to multivessel coronary disease and allocated them with 1 to 1 ratio to either the apheresis group which received therapeutic apheresis plus atorvastatin treatment, or to the control group which received standard treatment with atorvastatin alone. The initial dose of statin after an operation depended on serum transaminases level but was at least 20 mg per day. At 3-month follow-up all patients passed through multislice computed tomography (MSCT) and at one-year coronary angiography was intended for all participants. The protocol was approved by the Institutional Ethics Committee, and written informed consent was obtained from all patients. Patients with LDL cholesterol >2.6 mmol/l before the operation despite optimal lipid lowering drug therapy and clinical indication for CABG due to severe coronary atherosclerosis as shown by the angiogram were included. The study exclusion criteria were: left ventricle ejection fraction <35%; triglycerides >4.5 mmol/l; history of acute coronary syndrome or surgical intervention, infectious and inflammatory disease within previous 3 months; secondary dyslipidemia due to diabetes mellitus, dysfunction of thyroid gland, and liver or kidney failure; statin intolerance; and poor vein access. The initial preoperative examination of all patients included medical history, routine clinical Table 1 Baseline characteristics of study patients. Variable Apheresis (N ¼ 17) Mean age (range), years (40e68) Control (N ¼ 17) (47e68) Obesity, n (%) 4 (24) 5 (29) Hypertension, n (%) 13 (76) 12 (71) Smoking, n (%) 8 (47) 8 (47) CHD family history, n (%) 7 (42) 3 (18) Myocardial infarction, n (%) 9 (53) 9 (53) Left ventricle ejection fraction, % Three-vessel disease, n (%) 16 (94) 16 (94) Left main lesion > 50%, n (%) 7 (42) 6 (35) LIMA graft, n (%) 17 (100) 17 (100) Sole vein graft Sequential vein graft 4 4 Y-vein graft 3 5 Number of distal vein 51/3.0 55/3.2 anastomoses e total/per patient Mean atorvastatin dose, mg Total cholesterol, mmol/l Triglycerides, mmol/l HDL cholesterol, mmol/l LDL cholesterol, mmol/l Lipoprotein(a), mg/dl (range 2e114) (range 4e111) Lipoprotein(a) > 30 mg/dl, n (%) 4 (24) 5 (29) ApoB, mg/dl C-reactive protein, mg/l Pluseminus values are means standard deviation. CHD e coronary heart disease, LIMA e left internal mammary artery, LDL e low-density lipoprotein, HDL e high-density lipoprotein. For all above variables p value >0.1 between groups.

3 M.V. Ezhov et al. / Atherosclerosis Supplements 14 (2013) 101e Multislice computed tomography (MSCT) All patients were scheduled for MSCT at 3 months after an operation with the 64-slice MSCT (Toshiba Aquilion 64, Toshiba Corporation, Japan) according to standard protocol. Each section was made during a 0.1 s interval with a breath-hold and with ECG-gating to minimize motion artifacts. The analysis of 106 vein and 34 arterial grafts was performed by 2 radiologists in a blinded manner for patient treatment arms but in accordance with operation history. Each graft was classified as patent (flow visible) or occluded (if it did not fill with contrast at all). Nine of 106 vein grafts were not visualized and considered as nonpatent or occluded. As we have previously shown, sensitivity and specificity of computed tomography for graft occlusions detection was 100% [8] Apheresis techniques All patients from the active group were managed weekly with therapeutic LDL apheresis by CPF. Patients were connected via cubical vein with centrifuge plasmaseparator Cobe Spectra (Caridian BCT, USA). Patients plasma passed through the single use filters EvafluxÔ 5A (Kawasumi Laboratories, Inc., Japan). The total throughput of plasma in each CPF was 50 ml/kg. All procedures were performed in the MEDSI Clinic. Patients did not have any major side effects or events during the course of extracorporeal treatment Lipids, lipoproteins, and laboratory safety measures Prior to surgery, blood samples were collected from all patients, and concentration of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and lipoprotein(a) [Lp(a)], C-reactive protein (CRP) were tested enzymatically on a Architect (Abbott, USA) analyzer. LDL-C was calculated by Friedewald formula. In both groups lipids, lipoproteins, blood chemistry, hematology, apolipoprotein B [apob] were measured monthly at scheduled visits. In the apheresis group, lipids, lipoproteins and apob were measured before and immediately after each apheresis procedure Statistical analysis Statistical analysis was performed using SPSS (version 16.0). Data are expressed as mean standard deviation. Continuous variables at baseline and follow-up in each group were compared by paired t-test or Wilcoxon test. Continuous variables between the groups were compared by t-tests or ManneWhitney test. Fourfold tables were analyzed by two-sided Fisher exact test or Yates corrected c2 test. Relative risk of vein graft patency was calculated by 2 2 table. The differences were considered significant at p < Results Apheresis and control groups were comparable by baseline clinical characteristics including age, conventional risk factors, and left ventricular ejection fraction (Table 1) and concomitant medication (data not shown). More than half the subjects in both groups had past myocardial infarction. There were no valuable differences in all parameters between the groups. During the CPF procedure, LDL-C level decreased by 64 9%, apob e by 65 8%, Lp(a) e by 52 15%. Mean net difference in LDL-C level between apheresis and control groups was mmol/l. TG and HDL-C decreased after the each procedure but at scheduled visits there were no differences between the groups by these variables. Assessment of vein grafts patency by MSCT after 3 months of treatment did not reveal a difference in number of occluded anastomoses between the groups but after 12 months lipoprotein apheresis demonstrated a net benefit for active treatment (Fig. 1). Vein graft patency at study end was 88.2% (45 of 51) in apheresis group versus 72.7% (40 of 55) in the control group, p ¼ Use of apheresis is associated with decreased vein graft occlusions by 46%: relative risk 0.54; 95% confidence interval 0.27 to 1.02; p ¼ All other confounding factors did not differ between the subgroups with patent and occluded vein grafts. 4. Discussion Cascade filtration or CPF is an apheresis technique that allows elimination of atherogenic lipoproteins from plasma on the basis of particle size. More than 25 years ago we showed that the use of CPF with EvafluxÔ (Kawasumi Laboratories, Inc., Japan) filters provided considerable decrease the concentration of atherogenic apob containing lipoproteins by 59% with return of 70e75% of the total plasma proteins [10]. The main finding of our new study is the positive effect of CPF on the first year vein graft patency. The problem of early vein grafts occlusion remains unresolved. During the first months after operation the processes of thrombosis and intimal hyperplasia prevail [1]. Thus, despite evaluated apheresis effect in the special category of patients with severe hyperlipidemia, it could be speculated that the benefit of this treatment was also due to decreasing of level pro-inflammatory and pro-thrombotic markers. It has been reported that mean percentage of grafts with progression of atherosclerosis is lower for patients who underwent aggressive statin treatment than for those who underwent standard treatment (27% vs 39% p < 0.001) [11]. The study included 1351 patients who underwent bypass surgery [11]. Some studies have examined the role

4 104 M.V. Ezhov et al. / Atherosclerosis Supplements 14 (2013) 101e105 Fig. 1. Vein graft patency in two treatment groups at 3 months (A) and 12 months (B) of follow-up. Black segments e occluded grafts, white segments e patent grafts. The p values are given for the comparison between the treatment groups. of hemostatic factors in prognosis after CABG. In one of these studies, angiography performed 10 days postoperatively showed graft occlusion in 23% of 82 patients. Patients with graft occlusion had significantly higher preoperative plasminogen activator inhibitor activity than patients without occlusion [12]. The reduction of blood thrombogenicity and endothelial dysfunction, as well as anti-inflammatory effect, may be mechanisms by which apheresis plus statins improve graft function and patency much earlier than the retarding of atherosclerosis through hypolipidemic activity [9]. It is important to note that after single CPF procedure both LDL-C and Lp(a) level dropped up to 60%. As it is well known Lp(a), besides LDL-like properties, due to structural resemblance of apo(a) molecule to plasminogen, may compete for fibrin binding, interacts with plasminogen receptor [13] and in CABG patients accumulates in both native coronary arteries [14] and vein grafts wall [15]. It was also shown that Lp(a) stimulates smooth muscle cell proliferation [16]. About 30 percent of the present study participants had elevated Lp(a). In patients with fast recurrent angina pectoris during the first months after CABG we previously showed that elevated Lp(a) is associated with vein grafts occlusions [8]. Therefore, the positive effect of CPF on vein graft patency could be at least partly attributed due to sustained Lp(a) decreasing during the 12 months after CABG. Moreover, in CABG patients with elevated Lp(a) and optimal LDL-C on statins it could be reasonable to apply a 12 month course of specific Lp(a) apheresis [17]. In this study we performed CPF weekly while in the previous ones with overall negative results on the course of angiographic end-points the investigators used the extracorporeal procedures biweekly [18,19]. Our study has several limitations specific for most apheresis trials: 1) open-label design, non-randomized but controlled; 2) small sample size, but due to choosing number vein grafts as a surrogate end-point we could obtain a clinically significant result. 5. Conclusions In conclusion, we have revealed in this prospective controlled study that use of lipoprotein apheresis in CABG

5 M.V. Ezhov et al. / Atherosclerosis Supplements 14 (2013) 101e patients with lipid abnormalities refractory to statin treatment is associated with lower rates of vein graft occlusions at 12 months but not at 3 months after CABG in comparison to atorvastatin monotherapy. This preliminary data provide evidence that in this very high-risk population aggressive lipid-lowering strategy with lipidfiltration should be considered for vein graft disease prevention. Conflict of interest statement All authors report no financial relationships or conflicts of interest regarding the content herein. Acknowledgments Authors thank professor Sergei Ternovoi and Dr. Igor Fedotenkov for MSCT performing and analyzing. We appreciate the colleagues and nurses from the MEDSI clinic. The study was supported by the research grant No 8/3-284n-10 from the Moscow State Government. References [1] Motwani J, Topol E. Aortocoronary saphenous vein graft disease. Circulation 1998;97:916e31. [2] McLean R, Nazarian S, Gluckman T, et al. Relative importance of patient, procedural and anatomic risk factors for early vein graft thrombosis after coronary artery bypass graft surgery. J Cardiovasc Surg (Torino) 2011;52:877e85. [3] Alexander J, Hafley G, Harrington R, et al. Efficacy and safety of edifoligide, an E2F transcription factor decoy, for prevention of vein graft failure following coronary artery bypass graft surgery: PREVENT IV: a randomized controlled trial. JAMA 2005;29: 2446e54. [4] Jeremy J, Shukla N, Angelini G, Wan S. Endothelin-1 (ET-1) and vein graft failure and the therapeutic potential of ET-1 receptor antagonists. Pharmacol Res 2011;63:483e9. [5] Shukla N, Jeremy J. Pathophysiology of saphenous vein graft failure: a brief overview of interventions. Curr Opin Pharmacol 2012;12: 114e20. [6] Kulik A, Ruel M. Lipid-lowering therapy and coronary artery bypass graft surgery: what are the benefits? Curr Opin Cardiol 2011;26: 508e17. [7] Winters J. Lipid apheresis, indications, and principles. J Clin Apher 2011;26:269e75. [8] Pokrovsky S, Ezhov M, Il ina L, et al. Association of lipoprotein(a) excess with early vein graft occlusions in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg 2003;126: 1071e5. [9] Ramunni A, Burzo M, Vernò L, Brescia P. Pleiotropic effects of LDL apheresis. Atheroscler Suppl 2009;10:53e5. [10] Konovalov G, Vedernikov A, Olfer ev A, Kukharchuk V. Comparative analysis of plasmapheresis and cascade plasma filtration in the management of patients with hereditary hypercholesterolemia. Ter- Arkh 1987;59:84e7 [Rus]. [11] Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997;336:153e62. [12] Rifon J, Paramo J, Panizo C, Montes R, Rocha E. The increase of plasminogen activator inhibitor activity is associated with graft occlusion in patients undergoing aorto-coronary bypass surgery. Br J Haematol 1997;99:262e7. [13] Loscalzo J, Weunfeld M, Fless G, Scanu A. Lipoprotein(a), fibrin binding, and plasminogen activation. Arteriosclerosis 1990;10: 240e6. [14] Rath M, Niendorf A, Reblin T, Dietel M, Krebber H, Beisiegel U. Detection and quantification of lipoprotein(a) in arterial wall of 107 coronary bypass patients. Arteriosclerosis 1989;9:579e92. [15] Cushing G, Gaubatz J, Nava M, et al. Quantitation and localization of apolipoproteins(a) and B in coronary artery bypass vein grafts resected at reoperation. Arteriosclerosis 1989;9:593e603. [16] Grainger DJ, Kemp PR, Liu AC, et al. Activation of transforming growth factor-b is inhibited in transgenic apolipoprotein(a) mice. Nature 1994;370:460e2. [17] Pokrovsky S, Sussekov A, Afanasieva O, et al. Extracorporeal immunoadsorbtion for the specific removal of lipoprotein(a) [Lp(a) apheresis]: preliminary clinical data. Chem Phys Lipids 1994;67/68: 323e30. [18] Kroon A, Aengevaeren W, van der Werf T, et al. LDL-Apheresis Atherosclerosis Regression Study (LAARS). Effect of aggressive versus conventional lipid lowering treatment on coronary atherosclerosis. Circulation 1996;93:1826e35. [19] Thompson G, Maher V, Matthews S, et al. Familial Hypercholesterolaemia Regression Study: a randomised trial of lowdensity-lipoprotein apheresis. Lancet 1995;345:811e6.