Jeffrey Frist was getting desperate. Diagnosed with familial hypercholesterolemia (FH) in 2012 after his first heart attack the year before, he had experienced a cardiovascular event every 11 months on average over 8 years and he’d had enough.

Frist, a former cardiology nurse who now lives in Seattle, had high levels of lipoprotein(a), or Lp(a), a documented risk factor for cardiovascular disease for which no drug treatment exists. When he did his own research, he learned the condition has no approved drug treatments. But he learned something else: Some clinics, including one a few miles from his home in Seattle, offer a procedure that can lower the levels of Lp(a): lipoprotein apheresis.

But getting that procedure, which involves a regimen similar to dialysis for kidney disease with repeat treatments every other week, was not easy. He had been encountering cardiologists who were skeptical about the role Lp(a) plays in atherosclerotic cardiovascular disease (ASCVD) and who were unaware a treatment for it was available in the area.

“My frustration was with the medical community,” Frist said. “I asked to have my Lp(a) checked, and I was told that it doesn’t play a role in heart disease, and there’s nothing we can do about it anyway.”

But it does and there is, P. Barton Duell, MD, who runs the apheresis center at Oregon Health & Science University in Portland, Oregon, told Medscape Medical News. “Lp(a) was first identified in 1963 and has been known to be associated with cardiovascular risk since the 1970s,” Duell said. “What’s new is that people are now paying more attention to it.”

A Seldom-Used Option

As Frist was to find out, lipoprotein apheresis is little used in the US. Reasons experts gave for its low usage are the paucity of centers, the cost and treatment burden of the biweekly sessions, and a lack of data from randomized controlled trials documenting its effectiveness for improving cardiovascular risk.

Once he found out about lipoprotein apheresis and where he could undergo the intervention, it took him 11 months to get an evaluation and then start treatment. Two months after his initial evaluation and while still awaiting to begin apheresis, a stent he had in the peripheral descending artery revascularized for the third time, requiring balloon catheterization to revascularize the vessel.

In 2021 he started apheresis, eventually getting weekly treatments, which are necessary because the effects wane and levels of Lp(a) typically rebound within 2 weeks. 

The regimen proved physically demanding. He was having serious bleeding for 24 hours after each procedure and could not engage in physical activity for 3 days after each session. “It’s a huge commitment in terms of the patient,” he said. Eventually, Frist discontinued apheresis and enrolled in a clinical trial of one of the investigative intravenous agents for treating Lp(a).

However, Frist said he still believes in the effectiveness of apheresis and cites it and his participation in the clinical trial as the reason he has not had a cardiovascular event for 2.5 years. When he was on apheresis, he monitored his own Lp(a). Before treatment, it was around 202 mg/dL — nearly three times the 70 mg/dL mark considered high. After treatment, he said, it would drop to as low as 59 mg/ dL before climbing back to about 188 mg/dL within a week, which is why he began undergoing weekly sessions.

Indications for FH

Apheresis is approved for elevated Lp(a) levels only in people with uncontrolled FH. The four indications for people with FH, as Kenneth Feingold, MD, a professor emeritus at the University of California San Francisco and editor of the Endotext endocrinology online research portal, said, are:

1. Homozygous or heterozygous FH and levels of low-density lipoprotein (LDL) cholesterol greater than 300 mg/dL
2. Heterozygous FH and high cardiovascular disease risk characteristics with an LDL cholesterol greater than 200 mg/dL
3. Heterozygous FH and cardiovascular disease or diabetes with an LDL cholesterol greater than 160 mg/dL
4. Progressive cardiovascular disease and Lp(a) concentrations greater than 60 mg/dL

High Lp(a) alone is not an indication for the treatment, Feingold told Medscape Medical News.“A patient with a high Lp(a) and recurrent cardiovascular events despite optimal medical therapy would be a candidate for lipoprotein apheresis,” he said. That is, until a host of drugs currently in clinical trials are commercially available, he added.

The FDA approved apheresis for Lp(a) in 1996. In a 2024 Scientific Statement on the topic, the American Heart Association (AHA) described the procedure as an FDA-approved adjunctive treatment for high levels of Lp(a) in patients with FH and LDL cholesterol greater than 100 mg/dL despite taking standard therapy to reduce LDL cholesterol.

According to Kaneka, which makes and distributes the LIPOSORBER apheresis system for Lp(a), about 60 apheresis centers exist in the US. Some regions, such as Seattle, Dallas, and Los Angeles, have multiple facilities offering the procedure, while in other regions, centers may be more than 1000 miles apart. The 2024 AHA Scientific Statement estimates the annual cost of apheresis in the US can range from $50,000 to $150,000 when performed every other week. Medicare and private insurance typically cover the treatment, Duell said.

Duell estimated that around 400 patients are undergoing the therapy in the US at a given time. The procedure “remains underused for high-risk patients with suboptimal lipoprotein control,” according to the 2024 AHA Scientific Statement.

In Germany, by comparison, where lipoprotein apheresis is far more common, the procedure is available in more than 390 centers in a country with one fourth the population and roughly one thirtieth the land mass of the US. DIAMED Medical Technology, the company that manufactures the apheresis systems in Germany, estimated more than 2 million lipoprotein apheresis procedures have been performed in Germany over the past three decades — an average of about 1300 treatments a week. According to DIAMED, German health insurance reimburses for the procedure.

Small studies of lipoprotein apheresis have been conducted in Japan, Australia, Canada, and other countries, but data on its use outside Germany are limited. A 2019 study from Austria estimated that 12 patients in 1 million patients there were receiving treatments and that 5000 had been treated worldwide, about half of them in Germany.

Barriers to Adoption

The lack of large randomized cardiovascular outcome studies evaluating apheresis for high Lp(a) is a considerable barrier to wider use in the US, Feingold said.

“Relatively small studies” have consistently shown a reduction in ASCVD events in patients while on lipoprotein apheresis compared to when they were not undergoing the therapy, he said. “However, these studies do not have a randomized matched control group, and the decrease in ASCVD events could be related to ‘regression to the mean’ or other confounding variables,” Feingold said. He added that apheresis may also improve other measures, such as LDL cholesterol and thrombotic biomarkers, that can also contribute to lowering ASCVD risks.

Other studies assigned patients to lipoprotein apheresis or a control group and examined markers such as carotid intima-media thickness or quantitative coronary angiography, he said. “These studies had a small number of patients and some, but not all, demonstrated a decrease or slower progression of atherosclerosis with lipoprotein apheresis compared to the control group,” Feingold added.

Cost is another hurdle. As a 2016 systematic review stated, “While apheresis reduces LDL-C, high per-session costs and the frequency of guideline-recommended treatment result in substantial annual costs, which are barriers to optimal treatment of FH.” That study was funded by Amgen, which is currently sponsoring a phase 3 clinical trial of olpasiran, an injectable small interfering RNA to treat high Lp(a).

The Evidence, Such As It Is

Duell said the effectiveness of apheresis to reduce Lp(a) has been “well documented, no question about it. The thing that’s unknown is whether that impacts health.”

No study has yet linked lower Lp(a) levels after apheresis to a reduction in cardiovascular events, Duell said. “It should be true that lower Lp(a) will lower cardiovascular events, but we’re still waiting to have the evidence,” he said.

The data that do exist tend to involve small sample sizes. A 1995 UK study of 39 patients found apheresis did not improve coronary atherosclerosis and should be used only in patients who do not respond to drug therapy and that decreasing Lp(a) may be unnecessary if LDL cholesterol is reduced to 131.5 mg/dL or less. A 2013 Russian study of 30 patients with elevated Lp(a) and stable coronary heart disease achieved regression of coronary atherosclerosis and LDL cholesterol goals after 18 months of apheresis.

A 2016 German review noted two previous randomized controlled trials — “each with significant limitations” — came to conflicting conclusions about the ability of apheresis to induce positive angiographic changes.

A small 2020 University of Kansas study that evaluated 14 of 60 patients on biweekly apheresis reported a 94% reduction in cardiovascular events compared with the patients’ previous history over an average of 4 years and a greater than 70% reduction in average corrected LDL cholesterol and Lp(a) levels.

More recently, a 2024 report of the German Lipoprotein Apheresis Registry, which included 2301 patients at 92 apheresis centers from 2012 to 2022, found treatment was associated with a 73% reduction in major adverse cardiovascular events after 2 years and that the rate of those events continued to be low for up to 11 years.

But the ongoing trials of Lp(a)-lowering drugs may obviate the need for more definitive evidence about the effectiveness of lipoprotein apheresis to reduce cardiovascular events, Feingold said, noting that more than 28,000 patients are already enrolled in those studies.

“It is hard to imagine that one could carry out a randomized controlled outcome trial using lipoprotein apheresis,” Feingold said. “It would be a very expensive study, and I do not think that there would be a funding source for such a study. Also, given the current drug trials, there is no need for such a study.”

With new therapies on the horizon, the cardiology community needs to do more to advance treatment for elevated Lp(a), Frist said. “People need to get off their butt and be more proactive because we know that 20% of the population has high Lp(a),” he said.

He called on the American College of Cardiology (ACC) and the AHA to recommend testing for Lp(a) at least once in a person’s lifetime. (The 2018 ACC/AHA Guideline on the Management of Blood Cholesterol does not recommend routine testing of Lp(a) but acknowledges its utility in select high-risk patients.)

“Everybody should know what their Lp(a) is and then start looking at treatment options,” Frist said. “We’ve been doing this thing for a while, and the medical community is just dragging their feet.”

Frist and Feingold reported having no relevant financial conflicts of interest. Duell reported serving as a consultant for Amryt, Ionis, Kaneka, Mirum, New Amsterdam, and Regeneron.

Richard Mark Kirkner is a medical journalist based in Philadelphia.