High Lp(a) May Predict Risk of CV and Limb Events in PAD

Patients with PAD who have elevated lipoprotein(a) levels and who undergo peripheral endovascular procedures are at increased risk for adverse CV and limb events in the ensuing years, a Japanese study shows.

The cumulative 5-year incidence of MACE was 48.1% in those with elevated Lp(a) versus 27.3% in those without elevated Lp(a), while the cumulative 5-year incidence of major adverse limb events (MALE) was 67.9% versus 27.2% (P < 0.001 for both).

The findings suggest that in addition to more-intensive medical therapy, these patients should be considered for emerging Lp(a)-lowering therapies, the researchers conclude.  “International multicenter RCT are warranted to prove whether Lp(a)-lowering therapy can improve clinical outcomes in patients undergoing peripheral [endovascular procedures],” Yusuke Tomoi, MD (Kokura Memorial Hospital, Kitakyushu, Japan), the study’s lead investigator, told TCTMD in an email.

Tomoi further said he believes the value of novel therapies to lower Lp(a) will be born out in several ongoing trials, including HORIZON, OCEAN(a)-DOSE, and the European MultiSELECT study. Recent topline data from OCEAN(a)-DOSE showed a reduction from baseline in Lp(a) levels of 90% or more with subcutaneous olpasiran (Amgen), a small interfering RNA. Prior to that, the APOLLO study of another small interfering RNA given subcutaneously, SLN360 (Silence Therapeutics), showed reduced production of Lp(a) by as much as 98% in those treated with the highest dose. Tomoi’s study is one of the first to look at the impact of Lp(a) in PAD patients who have undergone interventions.

In an editorial accompanying the study in JACC: Cardiovascular Interventions, Mark D. Benson, MD, PhD (Beth Israel Deaconess Medical Center, Boston, MA), notes that the enthusiasm for reducing Lp(a) has been spurred by growing evidence of the role it plays in atherosclerotic cardiovascular disease (ASCVD). At high enough levels, Lp(a) “carries the same estimated lifetime burden of ASCVD risk to that of a clinical diagnosis of heterozygous familial hypercholesterolemia,” Benson writes. For the PAD patients in the study, lifetime exposure to ASCVD risk from elevated Lp(a) “may have contributed to their higher rates of preexisting PAD before [endovascular therapy] and ‘primed’ them for higher MACE and MALE following their procedure,” he hypothesizes.

[The study is] probably going to get people excited that this might potentially be a new target to treat patients with peripheral artery disease. Beau Hawkins

Commenting for TCTMD, Beau M. Hawkins, MD (University of Oklahoma Health Sciences Center, Oklahoma City), called the study findings “compelling” and said they give vascular specialists much to think about.

“In taking care of patients with peripheral artery disease, Lp(a) is not something we really pay much attention to, but I think this study highlights that it is a potent marker of risk,” he said. “When you put the findings in conjunction with the other exciting news that's come out lately about Lp(a), it’s probably going to get people excited that this might potentially be a new target to treat patients with peripheral artery disease.”

Still, Hawkins said it is early days and caution is warranted. “Newer therapies might actually be more effective in treating these patients and reducing their risk long term, but we don't know that yet,” he added. However, the research offers the possibility at least, that elevated Lp(a) could be the missing link that explains why some PAD patients do worse than others after endovascular therapies despite having similar disease and risk factors.

Findings Consistent Across Subgroups

For the single-center study, Tomoi and colleagues evaluated 1,169 symptomatic PAD patients (mean age 75 years; 70% male) who underwent successful peripheral endovascular procedures with balloon angioplasty, bare-metal or interwoven nitinol stents, drug-coated balloons, or drug-eluting stents. High Lp(a) was defined as > 30 mg/dL, which accounted for 31.6% of the study population.

Patients with high Lp(a) were less likely to be male and had lower body mass index than those with low Lp(a), but they were more likely to have heart failure, critical limb-threatening ischemia, multivessel disease, and elevated LDL cholesterol. Approximately 62% of patients in both the high and low Lp(a) groups were on statins at the time of the endovascular procedure.

In addition to the higher rates of overall MACE and MALE, patients with high Lp(a) had higher rates of all individual components of those endpoints. Multivariable analysis confirmed the independent association between high Lp(a) levels and incident MACE (HR 1.93; 95% CI 1.44-2.59) and MALE (HR 4.15; 95% CI 3.14-5.50). Further analysis by categories of Lp(a) levels found that measurements of 31 to 50 mg/dl and > 50 mg/dL, compared with lower Lp(a) levels, were significantly associated with increased risk of adverse events at 5 years.

The risks of MACE and MALE associated with high Lp(a) were consisted across multiple patient subgroups, including older age, sex, presence of diabetes, need for hemodialysis, presentation of PAD, multivessel lesions, LDL ≥ 70 mg/dL, and use of statins (interaction P > 0.05 for all).

Future Considerations for Patients and Family Members

Tomoi and colleagues say measuring Lp(a) in PAD patients at extremely high risk could provide important additional information regardless of whether they are already on LDL cholesterol-lowering therapy.

“Elevated Lp(a) levels might be clinically useful for identifying high-risk patients who require careful management in clinical practice and who will benefit the most from intensive medical treatment against the progression and evolution of atherothrombosis,” they write.

Knowing about the potential risk is important, but until more data emerge about the impact of novel therapies, Hawkins said it’s still a bit premature to conclude that adding stronger cholesterol-lowering medications like PCSK9 inhibitors will lower Lp(a) and mitigate risk.

“Do I check Lp(a) now? No. Will I start to do that more often in select patients? I think so,” he added. “This is exciting, and I think it all makes logical sense. We just need a little bit more data to prove that we can make a difference by intervening in high Lp(a).”

Because elevated Lp(a) is hereditary, Benson notes that a case could be made that the nearly one-third of patients in this study with elevated levels are “probands” for elevated LPA gene-mediated ASCVD risk. This, he adds, “raises the intriguing hypothesis that Lp(a) testing at the time of [endovascular therapy] may have valuable downstream consequences in regard to informing primary ASCVD risk prevention strategies for patient family members.”