Guidelines for the initiation of LA therapy vary throughout the world. Before initiating therapy, patients need to have exhausted their usage of LMT. In the United States, approved patients are separated into two major groups: (1) Preexisting coronary heart disease (CHD) and LDL-C >200 mg/dL and (2) without CAD and LDL-C >300 mg/dL. In Japan, LA may be initiated if the total cholesterol is above 250 mg/dL with pre-existing CHD. Germany allows LA if the patient has existing CHD and an LDL-C above 130 mg/dL, and as of 2010, the German Government has approved treatment of elevated Lp(a) with LA for patients with progressive CHD and an Lp(a) above 60 mg/dL. The rest of Europe, Russia, Israel, Lebanon, and Canada have variations of the German and American guidelines with some only allowing LA therapy for homozygote FH patients. For most of the world, simple plasma exchange is the method of choice for LA.

Lp(a) is an independent cardiovascular risk factor for CAD, stroke, myocardial infarctions, restenosis, venous thromboembolism and the progression of diabetic nephropathy [14–18]. Lp(a) elevations are more common in FH patients than in the general population [19]. This patient population has limited treatment options with LA currently as the only therapy capable of consistently lowering Lp(a) by at least 50 % [20]. The European Atherosclerosis Society has recommended the use of LA for patients with ongoing symptomatic CHD and elevated Lp(a) levels [21], but presently only Germany is allowed to treat this particular patient population. In the United States, a handful of patients (<20) receive regular LA therapy for an elevated Lp(a). Since initiating LA for elevated Lp(a), German apheresis centers have published three retrospective/prospective studies demonstrating the therapy’s ability in reducing cardiovascular events (Table 12.2). Due to ethical reasons, the studies have used the individual patient’s preapheresis data as the control group.

As previously mentioned, Pokrovsky introduced Lp(a) apheresis (POCARD Ltd., Moscow, Russia), which reduces Lp(a) by greater than 70 % without altering LDL-C levels [7]. In a recent trial, patients with stable CHD and elevated Lp(a) levels (103 ± 23 mg/dL) with near-normal LDL-C (77 ± 23 mg/dL), despite taking atorvastatin, were randomized to apheresis and statin or statin alone. Following 18 months, the apheresis group demonstrated a significant regression of coronary atherosclerosis when compared to the control group [25].

The use of statins and LA has been shown to be a safe and effective manner of cholesterol reduction [26]. Following a treatment of LA, there is an acute rebound of plasma cholesterol through an increase of cholesterol biosynthesis and influx of extravascular cholesterol [27, 28]. The mechanism of influx of extravascular cholesterol may explain the reduction of arterial wall inflammation seen shortly after one treatment of LA [29]. Statins, when used with LA, markedly decrease cholesterol synthesis following a single treatment [30]. In a group of 14 FH patients receiving weekly LA, LDL-C was reduced another 39 % after adding a daily dose of atorvastatin 80 mg/qd [31].

The use of statins with LA has provided a significant regression of coronary calcium and plaque volume [31–34]. The Low-Density Lipoprotein Apheresis Coronary Morphology and Reserve Trial (LACMART), a 1-year study involving 18 FH patients, 7 receiving atorvastatin and 11 receiving atorvastatin plus LA, found no significant change of LDL-C from baseline in the statin-treated group, while the LA and statin group reduced LDL-C by 34 %. Using coronary angiography and intravascular ultrasound (IVUS), the authors found a significant increase in the minimal lumen diameter (p = 0.004) and plaque area (p = 0.008) between the medication group compared to the LA and statin group [33].

Hemorheology is the study of flow dynamics for blood and its components. Alteration of these properties can impair vascular hemodynamics resulting in atherosclerosis and CVD [35]. Since blood is a non-Newtonian fluid, its resistance to flow or viscosity is altered by shear stress/rate, erythrocyte deformability/aggregation, temperature, and plasma viscosity [36]. In regard to FH patients, studies have demonstrated the abnormal coronary blood flow reserve seen with hyperlipidemia due to increased blood viscosity [37]. LA, following a single treatment, reduces blood viscosity by more than 20 % [38], which persists for at least 7 days [39]. Statins, such as atorvastatin, have demonstrated improvement in blood viscosity [40]. To determine the effects of atorvastatin on blood viscosity for FH patients receiving regular LA therapy, Banyai et al. found, following an 8 week period of adding the maximum dose of atorvastatin (80 mg/qd), a significant reduction of low–shear rate blood viscosity (p = 0.03, >10 %) when compared to baseline [41].

A large percentage of patients receiving LA have a history of statin intolerance [42]. Other therapeutic options including ezetimibe, niacin, bile acid sequestrants, phytosterols, fibrate, and omega-3-fatty acids should be considered with or without statins. The recent Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) involving more than 18,000 individuals with acute coronary disease who had ezetimibe added to a statin (simvastatin) over a period of ~6 years demonstrated the drug’s ability to safely reduce LDL-C by 24 % and reduce CVD by 8–9 % [43]. Geiss et al. in 2005 found when ezetimibe was added to LA and statins, the LDL-C was further reduced by 16 % [44]. The Low-Density Lipoprotein Apheresis Coronary Atherosclerosis Prospective Study (L-CAPS) in 1999 by Nichimura et al. investigated the use of multiple lipid-lowering therapies along with or without LA in 36 FH patients. Pravastatin, probucol (not available in the United States), and a resin (cholestyramine) were used for each patient. When compared to the medication-only group, minimal lumen diameter regression was significantly improved (P < 0.0001) in the medication-and-LA group [34]. More importantly, this study demonstrated the safety and benefits of using multiple LMT along with LA.

In the past few years, lomitapide and mipomersen have been approved as therapy for the HoFH population. Lomitapide, an inhibitor of the microsomal triglyceride transport protein (MTP), was tested on a group of 29 HoFH patients in which 18 were receiving periodic apheresis treatments. After 26 weeks, lomitapide (40 mg a day) reduced LDL-C by 50 %, and three patients had permanently discontinued LA therapy based on their LDL-C response [45]. Mipomersen, an antisense oglionucleotide that inhibits ApoB and lowers LDL-C by 28 %, has not been studied in combination with LA. Of note, unlike lomitapide, mipomersen does consistently lower Lp(a) levels by 26 %.

Understanding the outcomes and benefits of other alternative medications to statins for patients receiving LA is vital for those with statin intolerance and other high-risk populations (Table 12.3). Unfortunately, there is a severe lack of research on the efficacy and safety of using these alternative drug therapies along with LA.

As previously discussed, LA is mostly indicated for those with FH and/or elevated Lp(a) but has also been applied, when standard therapy has failed, for other vascular diseases such as idiopathic sudden hearing loss (ISHL), age-related macular degeneration (MD), nonarteritic acute ischemic anterior optic neuropathy (NAION), primary focal segmental glomerulosclerosis (FSGS), diabetic nephrotic syndrome, preeclampsia, cardiac transplantation, acute coronary syndrome, and peripheral and cerebral vascular disease [53–59]. Microcirculation disturbances may be a potential etiology for these diseases, and the possible improvement of symptoms following LA therapy may be based on its complex modification of vascular physiology [60, 61].

Proprotein convertase subtilisin kexin type 9 (PCSK9) is an enzyme which induces LDL receptor degradation resulting in hypercholesterolemia. Since the discovery of this protein, pharmaceutical companies have been developing antibodies, peptide mimics, and gene silencing techniques to inhibit PCSK9’s activity. The PCSK9 inhibitor companies are leading in attaining their drug first to market. Recent studies with PCSK9 inhibitor drugs have shown LDL-C reductions by 53–57 % and have provided evidence that the drug is safe, effective, and more tolerable than statin drugs [62–64]. FH patients receiving LA therapy would be the population to benefit the most from this class of lipid-lowering therapy. As of March 2015, the REGN727/SAR236553 ODYSSEY ESCAPE study is underway to evaluate the effect of an PCSK9 inhibitor (Alirocumab), compared to placebo, on the frequency of LA treatments in patients with HeFH [65].