Wolfgang Ramlow

Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events.

Background We investigated in a longitudinal, multicenter, cohort study whether combined lipid apheresis and lipid-lowering medication can reduce extremely high levels of lipoprotein(a) (Lp[a]) and thus prevent major adverse coronary events (MACE) more efficaciously than lipid-lowering medication alone.Methods Eligible patients had coronary artery disease and Lp(a) levels ≥2.14 µmol/l (95th percentile). All patients received lipid-lowering medications alone until maximally tolerated doses were no longer effective, followed by combined lipid apheresis and lipid-lowering medication. The rates of the primary outcome, MACE, were recorded for both periods.Results A total of 120 patients were included. The mean duration of lipid-lowering therapy alone was 5.6±5.8 years, and that of apheresis was 5.0±3.6 years. Median Lp(a) concentration was reduced from 4.00 µmol/l to 1.07 µmol/l with apheresis treatment (P<0.0001); the corresponding mean annual MACE rate per patient was 1.056 versus 0.144 (P<0.0001).Conclusions Lowering of Lp(a) levels by apheresis was efficacious and safe, and we recommend this therapy for patients in whom maximally tolerated doses of medication alone have failed to control coronary artery disease-associated events.

Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial

Aim To evaluate the effect of alirocumab on frequency of standard apheresis treatments [weekly or every 2 weeks (Q2W)] in heterozygous familial hypercholesterolaemia (HeFH). Methods and results ODYSSEY ESCAPE (NCT02326220) was a double-blind study in 62 HeFH patients undergoing regular weekly or Q2W lipoprotein apheresis. Patients were randomly assigned (2:1, respectively) to receive alirocumab 150u2009mg (nu2009=u200941) or placebo (nu2009=u200921) Q2W subcutaneously for 18 weeks. From day 1 to week 6, apheresis rate was fixed according to the patient’s established schedule; from weeks 7 to 18, apheresis rate was adjusted based on the patient’s low-density lipoprotein cholesterol (LDL-C) response in a blinded fashion. Apheresis was not performed when the LDL-C value wasu2009≥30% lower than the baseline (pre-apheresis) value. The primary efficacy endpoint was the rate of apheresis treatments over 12 weeks (weeks 7–18), standardized to number of planned treatments. In the alirocumab group the least square (LS) meanu2009±u2009SE (95% confidence interval [CI]) per cent change in pre-apheresis LDL-C from baseline at week 6 was −53.7u2009±u20092.3 (−58.2 tou2009−u200949.2) compared with 1.6u2009±u20093.1 (–4.7 to 7.9) in the placebo group. The primary efficacy endpoint showed statistically significant benefit in favour of alirocumab (Hodges–Lehmann median estimate of treatment difference: 0.75; 95% CI 0.67–0.83; Pu2009<u20090.0001). Therefore, alirocumab-treated patients had a 0.75 (75%) additional reduction in the standardized rate of apheresis treatments vs. placebo-treated patients. During this period, 63.4% of patients on alirocumab avoided all and 92.7% avoided at least half of the apheresis treatments. Adverse event rates were similar (75.6% of patients on alirocumab vs. 76.2% on placebo). Conclusions Lipoprotein apheresis was discontinued in 63.4% of patients on alirocumab who were previously undergoing regular apheresis, and the rate was at least halved in 92.7% of patients. Alirocumab was generally safe and well tolerated.

First data from the German Lipoprotein Apheresis Registry (GLAR)

OBJECTIVEnIn recent years the Federal Joint Committee (G-BA), a paramount decision-making body of the German health care system challenged the approval of diagnostic and therapeutic procedures for regular reimbursement, including lipoprotein apheresis therapy. Years before an interdisciplinary German apheresis working group, established by members of both German Societies of Nephrology (Verband Deutsche Nierenzentren (VDN), Deutsche Gesellschaft für Nephrologie (DGfN)), initiated a revision of the indication of lipoprotein apheresis therapy according to current guidelines and recommendations for the treatment of lipid disorders. This working group was convinced, that data derived from a registry would support lipoprotein apheresis as a therapy for severe hyperlipidemic patients suffering from progressive cardiovascular diseases.nnnMETHODS AND RESULTSnIn 2009 the working group established the indication for lipoprotein apheresis with respect to current cardiovascular guidelines and scientific knowledge for the registry, which are in line with the reimbursement guidelines. In 2011 financing by sponsors was secured and an internet-based registry was created. A pilot project with 5 apheresis centers finished in 2012 - since then the registry is available to all German apheresis centers.nnnCONCLUSIONSnThere has been consensus between the medical societies and health care carriers regarding the need for a German Lipoprotein Apheresis Registry (GLAR). The launch of this registry complies with requirements of the Federal Joint Committee (G-BA). Complementing the Pro(a)LiFe-Study, first data from GLAR support the safety of the different apheresis treatment procedures. In addition these first data suggest, with respect to the results of Pro(a)LiFe-Study, effectiveness in preventing cardiovascular progression as well. Here, further data are needed to statistically substantiate these early findings.

Alirocumab in patients with heterozygous familial hypercholesterolemia undergoing lipoprotein apheresis: Rationale and design of the ODYSSEY ESCAPE trial

BACKGROUNDnMany patients with heterozygous familial hypercholesterolemia (HeFH) fail to reach optimal low-density lipoprotein cholesterol (LDL-C) levels with available lipid-lowering medications, including statins, and require treatment using alternative methods such as lipoprotein apheresis.nnnOBJECTIVEnTo evaluate the efficacy of alirocumab 150xa0mg every 2xa0weeks (Q2W) compared with placebo in reducing the frequency of lipoprotein apheresis treatments in patients with HeFH.nnnMETHODSnODYSSEY ESCAPE is a randomized, double-blind, placebo-controlled, parallel-group, 18-week, phase 3 study being conducted in the United States and Germany. ODYSSEY ESCAPE will evaluate the efficacy and safety of alirocumab in approximately 63 adults with HeFH undergoing regular weekly (QW; for ≥4xa0weeks) or Q2W (for ≥8xa0weeks) lipoprotein apheresis. Patients will be randomly assigned (2:1, respectively) to receive alirocumab 150xa0mg subcutaneously Q2W or placebo subcutaneously Q2W (both in 1-mL injections) for 18xa0weeks. From day 1 to week 6, the apheresis frequency will be fixed to the individual patients established schedule (QW or Q2W); thereafter, apheresis will be performed according to the LDL-C value at that visit: apheresis will not be performed when the LDL-C value isxa0≥30% lower than the baseline pre-apheresis LDL-C value. The primary end point is the frequency of apheresis treatments over a 12-week period starting at weekxa07.nnnDISCUSSIONnThe ODYSSEY ESCAPE trial will determine whether alirocumab reduces the frequency of lipoprotein apheresis in patients with HeFH.

Rationale and design of MultiSELECt: A European Multicenter Study on the Effect of Lipoprotein(a) Elimination by lipoprotein apheresis on Cardiovascular outcomes

BACKGROUNDnDyslipidemia is a well-known risk factor for atherosclerosis and subsequent cardiovascular disease (CVD). While low density lipoprotein cholesterol (LDL-C) is well-established and taken into consideration for risk management and therapy, lipoprotein(a) is another established CVD risk factor frequently not undergoing screening due to a lack of medical treatment options. For patients suffering from CVD due to massive elevation of Lp(a) in presence of normal LDL-C levels, lipoprotein apheresis is the only available treatment option. While this constellation is an accepted indication for lipoprotein apheresis (LA) in Germany, prospective studies including a control group are still lacking.nnnOBJECTIVEnPrimary objective of this trial is to evaluate the clinical benefit of lipoprotein apheresis on myocardial infarction, PCI, CABG and death from cardiovascular disease in subjects with elevated Lp(a). This study evaluates the clinical benefit of weekly LA inxa0subjects with progressive cardiovascular disease, as accepted by the German Federal Joint Committee (treatment group). Comparator will be well-matched subjects under maximum tolerated lipid lowering therapy without access to LA treatment (control group).nnnMETHODSnMultiSELECt, is a prospective, multicenter, multinational, two-arm matched-pair cohort study designed to directly compare subjects with significantly elevated Lp(a) approved for LA subsequently undergoing weekly apheresis treatment versus a continuation of maximal medical therapy. The follow-up period will be 2 years after the baseline visit and until at least 60 events of the primary end-point occurred in the control group. A central trial expert committee will review all subjects with respect to their potential indication for LA according to established German guidelines in a blinded fashion. All control subjects will be contacted monthly via telephone visits to compensate for the more frequent visits during apheresis. Approximately 150 matched pairs will be necessary to detect an event reduction of at least 10% in subjects under LA treatment.nnnCONCLUSIONnThe MultiSELECt trial provides the unique opportunity to demonstrate the efficiency of LA on CVD in patients with elevated Lp(a) under strongly controlled conditions.

Safety aspects of lipidapheresis using DALI and MONET – Multicenter observational study

BACKGROUNDnLipidapheresis was introduced for intractable hyperlipidemia as a more selective therapy than plasma exchange aiming to enhance efficacy and limit side-effects. Although this therapy is regarded safe, multicenter data from routine application are limited. We investigated direct adsorption of lipoproteins (DALI) and lipofiltration (MONET) regarding the short and the long-term safety aspects.nnnMETHODSnThis multicenter observational study prospectively evaluated 2154 DALI and 1297 MONET sessions of 122 patients during a period of 2 years. Safety parameters included clinical side-effects (adverse device effects, ADEs), technical complications, blood pressure and pulse rate. Also routinely performed laboratory parameters were documented. Analysis of laboratory parameters was not corrected for blood dilution.nnnRESULTSnOverall 0.4% DALI and 0.5% MONET treatments were affected by ADE. Technical complications occurred in 2.1% and in 0.8% DALI and MONET sessions, respectively. The most frequent ADE was hypotension, and the majority of technical problems were related to vascular access. Both types of treatments led to a drop of thrombocytes in the range of 7-8%. Hematocrit and erythrocytes decreased only during the DALI treatments by about 6%. Leucocytes decreased during the DALI therapy (∼15%), whereas they increased during the MONET application (∼11%). MONET treatment was associated with a higher reduction of proteins (fibrinogen: 58% vs. 23%, albumin: 12% vs. 7%, CRP: 33% vs. 19% for MONET and DALI, respectively). Apart from severe thrombocytopenia in two DALI patients, changes of other parameters were typically transient.nnnCONCLUSIONSnUnder routine use the frequency of side-effects was low. Still, monitoring of blood count and proteins in chronic apheresis patients is recommended.

Efficacy of lipid reduction with DALI and MONET

BACKGROUNDnLipidapheresis techniques are increasingly used to treat drug-resistant hyperlipidemia but few efficacy studies under routine application are available. In this multicenter observational study we investigated direct adsorption of lipoproteins (DALI) and lipoprotein filtration (MONET) for the short and the long-term effects on lipid-lowering effects.nnnMETHODSnData of 122 apheresis patients from 11 centers (DALI: nxa0=xa078, MONET: nxa0=xa044) were prospectively collected for a period of 2 years. Routine lipid measurements were evaluated (2154 DALI and 1297 MONET sessions). It was investigated whether the relative reduction of LDL-C during apheresis session achieves at least 60%. Also relative reduction of total cholesterol, HDL, triglyceride, and Lp(a) were analyzed.nnnRESULTSnThe relative reduction of LDL-C was at least 60%: DALI: 70.62%, 95% CIxa0=xa0[69.34; 71.90] and MONET: 64.12%, 95% CIxa0=xa0[60.79; 67.46]. Also triglycerides were reduced with both systems: DALI 38.63%, 95% CIxa0=xa0[33.95; 43.30] vs. MONET 57.68%, 95% CIxa0=xa0[51.91; 63.45]. Relative reductions of total cholesterol were in the range of 50% (DALI 95% CIxa0=xa0[46.49; 49.65] MONET 95% CIxa0=xa0[48.93; 55.26]) and of Lp(a) in the range of 65% (DALI 95% CIxa0=xa0[61.92; 65.83] MONET 95% CIxa0=xa0[63.71; 70.30]. HDL reduction was: DALI 15.01%, 95% CIxa0=xa0[13.22; 16.79] and MONET 22.59%, 95% CIxa0=xa0[19.33; 25.84]. For both devices treated patient plasma/blood volume and in case of DALI the use of the larger adsorber configurations (DALI 1000 and DALI 1250) were independent positive predictors of the relative reduction of LDL-C and of Lp(a).nnnCONCLUSIONSnBoth systems effectively improved lipid profile and reduced atherogenic lipids. The results point to the importance of the individualized application of these valuable therapies to achieve clinical targets.

Prospective crossover study for a standardized comparison of the dextrane sulfate whole blood and plasma apheresis system in patients with cardiovascular disease and severe dyslipidemia

BACKGROUND AND AIMSnThe objective of this study was a standardized comparison of the safety and effectiveness of the Kaneka (Kaneka Corporation, Osaka, Japan) whole blood (Liposorber DL-100) and plasma (Liposorber LA-15) lipoprotein apheresis (LA) system to optimize the individual therapy of patients with cardiovascular disease and severe dyslipidemia.nnnMETHODSnSix chronic LA patients with a pre-treatment LDL-Cxa0<xa06xa0mmol/l in steady state received a total of three treatments with the LA-15 device, followed by three treatments with the DL-100 device or vice versa. To achieve a standardized comparison the treated blood volume for any patient was kept identical for both procedures. Sampling points for total cholesterol, LDL-C, HDL-C, Lp(a), triglyceride, blood count, and bradykinin measurements were adjusted for both techniques.nnnRESULTSnTotal cholesterol, LDL-C, HDL-C, Lp(a), and triglycerides were reduced by 59.2xa0±xa06.5%, 79.3xa0±xa06.9%, 7.1xa0±xa03.9%, 87.3xa0±xa03.1%, 22.5xa0±xa024.2% using the DL-100 system and by 51.4xa0±xa05.2%, 65.2xa0±xa03.7%, 2.2xa0±xa04.9%, 72.7xa0±xa02.2%, 46.5xa0±xa09.4% using the LA-15 system, showing that the DL-100 adsorber was significantly more effective for lowering total cholesterol (pxa0=xa00.044), LDL-C (pxa0=xa00.001), Lp(a) (pxa0=xa00.029), while triglycerides were reduced to a higher extent by the plasma system (pxa0=xa00.046) in this patient group. The regenerable LA-15 adsorber columns showed a higher removal capacity considering the difference between inflow and outflow concentrations. Bradykinin levels significantly increased up to 145 fold in the outflow lines using the plasma system (pxa0=xa00.028), but not systemically. There was no significant bradykinin generation using the whole blood adsorber.nnnCONCLUSIONnIn conclusion, the whole blood system was faster and more effective in this LA patient group with pre apheresis LDL-C<6xa0mmol/l. Whether the regenerable plasma system is more effective in patients with higher LDL-C content should be evaluated in future standardized comparisons.

Selective Immune Apheresis Technologies – Where Do We Stand?

Due to inadequate scientific evidence there are almost no established guidelines for the application of nimmune apheresis therapy in a specific disease condition. Relatively high costs and the require