Should a patient with high lipoprotein a, or Lp(a), be started on low-dose aspirin?
This is the conundrum facing many physicians and patients, but even getting to that point will require more availability and coverage of tests and a greater appreciation of the risk associated with Lp(a), said cardiologists.
Lp(a): The Silent Risk
On Lp(a) Awareness Day, C. Michael Gibson, MD, MA, CEO of the Baim Institute for Clinical Research, Boston, and PERFUSE took the opportunity to talk about his experiences with testing on X.
The professor of medicine at Harvard Medical School, Boston, told Medscape Medical News he was surprised to find that he had a very high calcium score, despite a low-density lipoprotein (LDL) cholesterol level of just 70 mg/dL. Eventually, he found out that he had a “very, very high Lp(a),” which was particularly concerning because his grandfather died of a heart attack at 45 years of age.
But how much risk does that represent?
A 2022 consensus statement from the European Atherosclerosis Society (EAS) highlighted that epidemiologic and genetic studies “strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes,” even at very low LDL cholesterol levels.
This is because Lp(a) has pro-inflammatory and pro-atherosclerotic properties, and high levels are associated with both micro- and macrocalcification of the aortic valve. Findings from a US registry study also suggest the threshold related to increased cardiovascular risk may differ for primary and secondary prevention populations.
Lp(a) is, however, genetically determined, and there are no drugs available that directly lower levels, although some are on the horizon. In the meantime, the experts behind the consensus statement recommend that all adults be tested at least once in their lifetime.
Testing Cost and Availability
This recommendation has been translated into guidelines in “many, many” countries, said lead author Florian Kronenberg, MD, MAE, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria, but “we are far away from reaching that goal.”
“We’ve got a real problem,” added Stephen Nicholls, MD, PhD, director of the Victorian Heart Institute and a professor of cardiology at Monash University, Melbourne, Victoria, Australia, as there is “not a country in the world where there’s good access to Lp(a) testing.”
Kronenberg said that the consensus statement “created a kind of momentum” toward universal testing.
Ulrich Laufs, MD, PhD, professor and chair, Department of Cardiology, University Hospital Leipzig, Leipzig, Germany, agreed, saying that, overall, Lp(a) testing has “increased dramatically,” albeit from “extremely low levels.”
Kronenberg believes that “we have to be really patient.” He cited a lack of knowledge among physicians as one of the biggest barriers to greater uptake of testing.
“There is still no appreciation of the role of Lp(a),” agreed Alberico L. Catapano, MD, PhD, director of Cardiovascular Research and of the Lipoproteins and Atherosclerosis Laboratory of IRCCS Multimedica, Milan, Italy, and past president of the EAS.
“That’s why it’s not mentioned” to patients, he said. “What is really needed is to inform physician colleagues that Lp(a) is not only a risk factor but is the cause” of atherosclerotic cardiovascular disease (ASCVD).
Kronenberg said that the pressure for testing can often come from the patient themselves.
Physicians then question why the patient wants to be tested when there are no medications to treat it, he added. “We really tried very hard when we did the consensus paper to say that we should perform the test and give people advice on what to do.”
Catapano believes that another major obstacle is the cost of the test, which remains high “because very few people do it,” and there is some debate over which test to use.
Taken together, these issues have meant that “payers are really struggling with the idea of funding Lp(a),” said Nicholls, adding: “There seems to be this fixation on: ‘Well, if you can’t lower Lp(a), why measure it?'”
Rather than blame the payers, he says there is a need to educate about the science behind testing and underline that Lp(a) is an “important risk enhancer” for cardiovascular disease.
“Because if we’re going to make people pay out of pocket, then you’re creating a massive equity issue in that only those who can afford the test have it.”
High Lp(a) Now What?
But once the test has been performed, there then comes the question as to what to do about the result.
“Before we get anywhere near an agent that effectively lowers Lp(a) and get it into the clinic, there are lots of things that we can do today,” said Nicholls.
If someone has an intermediate or high background cardiovascular risk and they have got a high Lp(a) level, they “should be treated more intensively, as we know that high Lp(a) patients do better if their LDL cholesterol and their blood pressure is lower.”
For Catapano, this means having the “same mindset as you do with [a patient with] high blood pressure, high LDL cholesterol, and so on, because it’s exactly the same thing: It’s interacting with your other risk factors to increase your overall risk.”
Gibson agrees. Through a range of measures, including weight loss and statin therapy, he was able to reduce his overall cardiovascular risk, and his LDL cholesterol level dropped to just 20 mg/dL.
A Role for Aspirin?
However, one debate that has been rolling on in recent months is whether to start patients with elevated Lp(a) on low-dose aspirin.
It gained added momentum when Pablo Corral, MD, a lipidologist and a professor in the School of Medicine, Pharmacology Department, FASTA University, Mar del Plata, Buenos Aires, Argentina, highlighted the issue on X.
He pointed to a recent study, which showed that regular aspirin use was associated with a significantly lower rate of ASCVD mortality in adults without clinical ASCVD but who had elevated Lp(a).
Nicholls said that, when you “peel away the layers” of the current evidence, there is some suggestion thatLp(a)may be prothrombotic. “So in theory, perhaps aspirin might be maybe more intuitively useful there.”
He noted that the ASPREE primary prevention study found that low-dose aspirin in older adults resulted in a significantly higher risk for major hemorrhage over placebo and did not significantly reduce the risk for cardiovascular disease.
But an analysis he and his colleagues did suggest that aspirin may indeed benefit older individuals if they have elevated Lp(a) genotypes.
An Individual Decision
For Kronenberg and Laufs, there is currently a lack of appropriate data to make a recommendation either way, particularly for primary prevention.
They warned that the risk for thrombosis in patients with mildly elevated Lp(a) cannot be discounted, and in most cases either “the existing risk of bleeding exceeds the beneficial effects [of aspirin], or it’s not indicated,” said Laufs.
“When we make a recommendation, we should have evidence-based data,” Kronenberg said, but, at the moment, people “somehow put their finger in the air and see” which way the wind is blowing.
Catapano urged patients to talk to their physician, as even low-dose aspirin is “very potent” at inhibiting platelets.
Gibson agreed, saying that he is in two minds, as the potential benefit has to be weighed against the bleeding risk.
He personally takes low-dose aspirin but that is because “I know I have a low bleeding risk,” but it is a decision “that has to be taken individually between a patient and their physician.”
Gibson declared relationships with Amgen, Angel/Avertix Medical Corporation, AstraZeneca, Bayer Corporation, Beren Therapeutics, Boehringer Ingelheim, Boston Clinical Research Institute, Boston Scientific, Bristol Myers Squibb, Cadrenal Therapeutics, Cardiovascular Research Foundation, CeleCor Therapeutics, CSL Behring, DCRI, Esperion, EXCITE International ($0 received), Faraday Pharmaceuticals, Fortress Biotech, HeartFlow, Gilead Sciences, Inc., Intellia Therapeutics, Janssen, Pharmaceuticals, Johnson & Johnson Corporation, Lumanity, MashupMD, MD Magazine, MJHealth, Novo Nordisk, Pfizer, PLx Pharma, Inc., SCAI, Solstice Health/New Amsterdam Pharma, Somahlution/Marizyme, Synergia Medical, Vectura, WebMD, Women as One, Absolutys, Dyad Medical, Inc., Gererable, Flow Therapy Fortress Biotech, HeartBeam, nference, and UpToDate in Cardiovascular Medicine.
Kronenberg declared relationships with Novartis, Amgen, Silence Therapeutics, and Roche.
Nicholls declared relationships with AstraZeneca, Amgen, Anthera Pharmaceuticals, CSL Behring, Cerenis, Eli Lilly, Esperion, Resverlogix Corp., Novartis, Infraredx, and Sanofi-Regeneron and is a consultant for Amgen, Akcea Therapeutics, Inc., AstraZeneca, Boehringer Ingelheim, CSL Behring, Daiichi Sankyo, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi-Regeneron, Novo Nordisk, CSL Seqirus, and Vaxxinity, Inc.
Catapano declared relationships with Amryt Pharma, Menarini, Ultragenyx, Viatris, Amarin, Amgen, AstraZeneca, Daiichi Sankyo, Esperion, Ionis Pharmaceutical, Medscape, Merck, Novartis, PeerVoice, Pfizer, Recordati, Regeneron, Sandoz, Sanofi, and The Corpus.
Laufs declared relationships with Daiichi Sankyo, Novartis, Amgen, Sanofi, Boehringer Ingelheim, MSD, Pfizer, Lilly, and AstraZeneca.
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