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Does colchicine have a role in treating excess ASCVD risk in patients with chronic inflammatory conditions?
The recent Food and Drug Administration approval of colchicine 0.5 mg (Lodoco) for use in atherosclerotic cardiovascular disease (ASCVD) prevention will possibly create opportunities to use the drug to treat residual risk for ASCVD in some patients with immune-mediated inflammatory diseases, particularly in rheumatology.
Potential in rheumatology
The 0.5-mg dose is just a shade under the 0.6-mg, twice daily dosing rheumatologists typically prescribe for gout, Christie Bartels, MD, MS, chief of rheumatology at the University of Wisconsin–Madison, said in an interview. Clinicians also use the 0.6-mg dose off-label for pseudogout or calcium pyrophosphate deposition disease (CPPD), Dr. Bartels noted.
The new formulation opens the consideration for using colchicine more in patients with psoriatic arthritis, lupus, and rheumatoid arthritis, she said. “I think we could certainly discuss it, particularly, in secondary prevention patients who already had an event or who are at the highest risk and already on optimal traditional agents,” she said.
She cited previous comments by Paul Ridker, MD, director of the center for cardiovascular disease prevention at Brigham and Women’s Hospital in Boston, and developer of the high-sensitivity C-reactive protein (hsCRP) test for measuring inflammatory markers. “We might not know the answer because Dr. Ridker pointed out he used colchicine 0.5 mg in patients that had a high-sensitivity CRP that was high; we need patients who have had inflammation of unknown origin, so those patients presumably weren’t already on another anti-inflammatory,” she said, noting that hydroxychloroquine, methotrexate, and some biologics provide some protection from cardiovascular risks.
However, a potential role for long-term colchicine 0.5 mg in ASCVD prevention may cause consideration for changing the drug’s role in gout treatment, Dr. Bartels said. “In gout, where we do have an FDA-approved indication for colchicine, we used to use it only for the first 6 months while we were getting patients to goal on allopurinol, which was usually then monotherapy after the first 6 months,” she said. “I think this will likely change how I treat gout patients in that I may also offer to continue both medications [colchicine and allopurinol] if they are tolerating them well.
“And then in patients where I’m using it off-label in CPPD, I might again share with them that in addition to possibly helping their CPPD, there may be this added benefit to reduce inflammation just in discussing the risks and benefits of the medicine.”
However, rheumatologists must be careful in using colchicine beyond the typical 6-month cycle, Dr. Bartels said. “One of the tricky things with colchicine, and part of the reason we did not traditionally continue it specifically past the first 6 months, was that it can cause myopathies or cytopenias, so we still have to counsel patients regarding these risks and monitor that,” she said.
Additionally, colchicine can have drug interactions with statins or calcium channel blockers that can change colchicine levels. “I think the dose here is so low, the 0.5 mg, that it’s probably still safe, but again, it’s something that we have to take a look at in the patient’s whole picture and the rest of their burden of their meds in order to make a decision with them,” Dr. Bartels said.
Possibilities in dermatology
The LoDoCo2 trial one of two major randomized trials that supported approval of colchicine 0.5 mg, reported that treated patients had a 60% lower rate of gout than the placebo group (1.4% vs. 3.4%). Joel Gelfand, MD, MSCE, the James J. Leyden professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, pointed to this in evaluating the dermatologic implications of the drug’s approval. “This may be of particular interest as people with psoriasis have an increased risk of gout,” he said in emailed comments.
Colchicine’s mechanism of action to reduce inflammation parallels that of tumor necrosis factor (TNF) inhibitors used for dermatologic indications, namely by inhibiting leukocyte adhesion to disrupt the downregulation of TNF receptors, Dr. Gelfand said.
“Interestingly, observational data suggests biologics that target TNF such as adalimumab, etanercept, etc., are associated with a reduction in CV events, and in placebo-controlled trials we conducted in psoriasis patients, it reduced key inflammatory mediators of cardiovascular disease, including IL [interleukin]-6,” he said. “Randomized clinical trials to evaluate the ability of TNF inhibitors, which are now available as biosimilars, to prevent cardiovascular events in high-risk patients, should be conducted, and more work is needed to identify which additional immune-targeted treatments may lower CV risk with an acceptable safety profile.”
Colchicine currently has few indications for rare conditions in dermatology, Dr. Gelfand said, including Sweets syndrome, subcorneal pustular dermatosis, and cutaneous vasculitis. “There are some reports to suggest it may help psoriatic disease, but current data are limited and insufficient to recommend its use for psoriasis and/or psoriatic arthritis,” he said.
The approval of colchicine 0.5 mg for ASCVD could be meaningful for people with psoriasis who are also being treated for CV risk factors, Dr. Gelfand said. “Additional considerations such as signs of residual inflammation (elevated hsCRP) and CV imaging findings may be used to further guide shared decision-making for optimal use,” he said.
Another consideration he noted: “This is also a novel 0.5-mg formulation, and thus cost may be an issue.”
Would side effects bar use in gastroenterology?
Colchicine 0.5 mg may not move the needle much for expanding treatment of ASCVD in patients with inflammatory bowel disease (IBD) and potentially other gastrointestinal conditions, Edward Loftus Jr., MD, the Maxine and Jack Zarrow Family professor of gastroenterology specifically for IBD at the Mayo Clinic in Rochester, Minn., told MDEdge in emailed comments. “Given the GI side effect profile [of colchicine], I am not sure I would go there,” he said.
“Hopefully, the prescribers of this low-dose formulation are aware of the gastrointestinal side effects, such as diarrhea and nausea, and educate patients about these side effects so that a proper risk-benefit discussion can ensue,” he said.
Dr. Bartels reporting a previous financial relationship with Pfizer. Dr. Gelfand said he has financial relationships with AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celldex, GlaxoSmithKline, Twill, Lilly, Leo, Moonlake, Janssen Biologics, Novartis, Pfizer, UCB, Neuroderm, and Veolia North America. Dr. Loftus disclosed relationships with AbbVie, Alvotech, Amgen, Arena, Avalo, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene/Receptos, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iterative Health, Janssen, KSL Diagnostics, Morphic, Ono, Pfizer, Sun, Surrozen, Takeda, Theravance, and UCB.
The recent Food and Drug Administration approval of colchicine 0.5 mg (Lodoco) for use in atherosclerotic cardiovascular disease (ASCVD) prevention will possibly create opportunities to use the drug to treat residual risk for ASCVD in some patients with immune-mediated inflammatory diseases, particularly in rheumatology.
Potential in rheumatology
The 0.5-mg dose is just a shade under the 0.6-mg, twice daily dosing rheumatologists typically prescribe for gout, Christie Bartels, MD, MS, chief of rheumatology at the University of Wisconsin–Madison, said in an interview. Clinicians also use the 0.6-mg dose off-label for pseudogout or calcium pyrophosphate deposition disease (CPPD), Dr. Bartels noted.
The new formulation opens the consideration for using colchicine more in patients with psoriatic arthritis, lupus, and rheumatoid arthritis, she said. “I think we could certainly discuss it, particularly, in secondary prevention patients who already had an event or who are at the highest risk and already on optimal traditional agents,” she said.
She cited previous comments by Paul Ridker, MD, director of the center for cardiovascular disease prevention at Brigham and Women’s Hospital in Boston, and developer of the high-sensitivity C-reactive protein (hsCRP) test for measuring inflammatory markers. “We might not know the answer because Dr. Ridker pointed out he used colchicine 0.5 mg in patients that had a high-sensitivity CRP that was high; we need patients who have had inflammation of unknown origin, so those patients presumably weren’t already on another anti-inflammatory,” she said, noting that hydroxychloroquine, methotrexate, and some biologics provide some protection from cardiovascular risks.
However, a potential role for long-term colchicine 0.5 mg in ASCVD prevention may cause consideration for changing the drug’s role in gout treatment, Dr. Bartels said. “In gout, where we do have an FDA-approved indication for colchicine, we used to use it only for the first 6 months while we were getting patients to goal on allopurinol, which was usually then monotherapy after the first 6 months,” she said. “I think this will likely change how I treat gout patients in that I may also offer to continue both medications [colchicine and allopurinol] if they are tolerating them well.
“And then in patients where I’m using it off-label in CPPD, I might again share with them that in addition to possibly helping their CPPD, there may be this added benefit to reduce inflammation just in discussing the risks and benefits of the medicine.”
However, rheumatologists must be careful in using colchicine beyond the typical 6-month cycle, Dr. Bartels said. “One of the tricky things with colchicine, and part of the reason we did not traditionally continue it specifically past the first 6 months, was that it can cause myopathies or cytopenias, so we still have to counsel patients regarding these risks and monitor that,” she said.
Additionally, colchicine can have drug interactions with statins or calcium channel blockers that can change colchicine levels. “I think the dose here is so low, the 0.5 mg, that it’s probably still safe, but again, it’s something that we have to take a look at in the patient’s whole picture and the rest of their burden of their meds in order to make a decision with them,” Dr. Bartels said.
Possibilities in dermatology
The LoDoCo2 trial one of two major randomized trials that supported approval of colchicine 0.5 mg, reported that treated patients had a 60% lower rate of gout than the placebo group (1.4% vs. 3.4%). Joel Gelfand, MD, MSCE, the James J. Leyden professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, pointed to this in evaluating the dermatologic implications of the drug’s approval. “This may be of particular interest as people with psoriasis have an increased risk of gout,” he said in emailed comments.
Colchicine’s mechanism of action to reduce inflammation parallels that of tumor necrosis factor (TNF) inhibitors used for dermatologic indications, namely by inhibiting leukocyte adhesion to disrupt the downregulation of TNF receptors, Dr. Gelfand said.
“Interestingly, observational data suggests biologics that target TNF such as adalimumab, etanercept, etc., are associated with a reduction in CV events, and in placebo-controlled trials we conducted in psoriasis patients, it reduced key inflammatory mediators of cardiovascular disease, including IL [interleukin]-6,” he said. “Randomized clinical trials to evaluate the ability of TNF inhibitors, which are now available as biosimilars, to prevent cardiovascular events in high-risk patients, should be conducted, and more work is needed to identify which additional immune-targeted treatments may lower CV risk with an acceptable safety profile.”
Colchicine currently has few indications for rare conditions in dermatology, Dr. Gelfand said, including Sweets syndrome, subcorneal pustular dermatosis, and cutaneous vasculitis. “There are some reports to suggest it may help psoriatic disease, but current data are limited and insufficient to recommend its use for psoriasis and/or psoriatic arthritis,” he said.
The approval of colchicine 0.5 mg for ASCVD could be meaningful for people with psoriasis who are also being treated for CV risk factors, Dr. Gelfand said. “Additional considerations such as signs of residual inflammation (elevated hsCRP) and CV imaging findings may be used to further guide shared decision-making for optimal use,” he said.
Another consideration he noted: “This is also a novel 0.5-mg formulation, and thus cost may be an issue.”
Would side effects bar use in gastroenterology?
Colchicine 0.5 mg may not move the needle much for expanding treatment of ASCVD in patients with inflammatory bowel disease (IBD) and potentially other gastrointestinal conditions, Edward Loftus Jr., MD, the Maxine and Jack Zarrow Family professor of gastroenterology specifically for IBD at the Mayo Clinic in Rochester, Minn., told MDEdge in emailed comments. “Given the GI side effect profile [of colchicine], I am not sure I would go there,” he said.
“Hopefully, the prescribers of this low-dose formulation are aware of the gastrointestinal side effects, such as diarrhea and nausea, and educate patients about these side effects so that a proper risk-benefit discussion can ensue,” he said.
Dr. Bartels reporting a previous financial relationship with Pfizer. Dr. Gelfand said he has financial relationships with AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celldex, GlaxoSmithKline, Twill, Lilly, Leo, Moonlake, Janssen Biologics, Novartis, Pfizer, UCB, Neuroderm, and Veolia North America. Dr. Loftus disclosed relationships with AbbVie, Alvotech, Amgen, Arena, Avalo, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene/Receptos, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iterative Health, Janssen, KSL Diagnostics, Morphic, Ono, Pfizer, Sun, Surrozen, Takeda, Theravance, and UCB.
The recent Food and Drug Administration approval of colchicine 0.5 mg (Lodoco) for use in atherosclerotic cardiovascular disease (ASCVD) prevention will possibly create opportunities to use the drug to treat residual risk for ASCVD in some patients with immune-mediated inflammatory diseases, particularly in rheumatology.
Potential in rheumatology
The 0.5-mg dose is just a shade under the 0.6-mg, twice daily dosing rheumatologists typically prescribe for gout, Christie Bartels, MD, MS, chief of rheumatology at the University of Wisconsin–Madison, said in an interview. Clinicians also use the 0.6-mg dose off-label for pseudogout or calcium pyrophosphate deposition disease (CPPD), Dr. Bartels noted.
The new formulation opens the consideration for using colchicine more in patients with psoriatic arthritis, lupus, and rheumatoid arthritis, she said. “I think we could certainly discuss it, particularly, in secondary prevention patients who already had an event or who are at the highest risk and already on optimal traditional agents,” she said.
She cited previous comments by Paul Ridker, MD, director of the center for cardiovascular disease prevention at Brigham and Women’s Hospital in Boston, and developer of the high-sensitivity C-reactive protein (hsCRP) test for measuring inflammatory markers. “We might not know the answer because Dr. Ridker pointed out he used colchicine 0.5 mg in patients that had a high-sensitivity CRP that was high; we need patients who have had inflammation of unknown origin, so those patients presumably weren’t already on another anti-inflammatory,” she said, noting that hydroxychloroquine, methotrexate, and some biologics provide some protection from cardiovascular risks.
However, a potential role for long-term colchicine 0.5 mg in ASCVD prevention may cause consideration for changing the drug’s role in gout treatment, Dr. Bartels said. “In gout, where we do have an FDA-approved indication for colchicine, we used to use it only for the first 6 months while we were getting patients to goal on allopurinol, which was usually then monotherapy after the first 6 months,” she said. “I think this will likely change how I treat gout patients in that I may also offer to continue both medications [colchicine and allopurinol] if they are tolerating them well.
“And then in patients where I’m using it off-label in CPPD, I might again share with them that in addition to possibly helping their CPPD, there may be this added benefit to reduce inflammation just in discussing the risks and benefits of the medicine.”
However, rheumatologists must be careful in using colchicine beyond the typical 6-month cycle, Dr. Bartels said. “One of the tricky things with colchicine, and part of the reason we did not traditionally continue it specifically past the first 6 months, was that it can cause myopathies or cytopenias, so we still have to counsel patients regarding these risks and monitor that,” she said.
Additionally, colchicine can have drug interactions with statins or calcium channel blockers that can change colchicine levels. “I think the dose here is so low, the 0.5 mg, that it’s probably still safe, but again, it’s something that we have to take a look at in the patient’s whole picture and the rest of their burden of their meds in order to make a decision with them,” Dr. Bartels said.
Possibilities in dermatology
The LoDoCo2 trial one of two major randomized trials that supported approval of colchicine 0.5 mg, reported that treated patients had a 60% lower rate of gout than the placebo group (1.4% vs. 3.4%). Joel Gelfand, MD, MSCE, the James J. Leyden professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, pointed to this in evaluating the dermatologic implications of the drug’s approval. “This may be of particular interest as people with psoriasis have an increased risk of gout,” he said in emailed comments.
Colchicine’s mechanism of action to reduce inflammation parallels that of tumor necrosis factor (TNF) inhibitors used for dermatologic indications, namely by inhibiting leukocyte adhesion to disrupt the downregulation of TNF receptors, Dr. Gelfand said.
“Interestingly, observational data suggests biologics that target TNF such as adalimumab, etanercept, etc., are associated with a reduction in CV events, and in placebo-controlled trials we conducted in psoriasis patients, it reduced key inflammatory mediators of cardiovascular disease, including IL [interleukin]-6,” he said. “Randomized clinical trials to evaluate the ability of TNF inhibitors, which are now available as biosimilars, to prevent cardiovascular events in high-risk patients, should be conducted, and more work is needed to identify which additional immune-targeted treatments may lower CV risk with an acceptable safety profile.”
Colchicine currently has few indications for rare conditions in dermatology, Dr. Gelfand said, including Sweets syndrome, subcorneal pustular dermatosis, and cutaneous vasculitis. “There are some reports to suggest it may help psoriatic disease, but current data are limited and insufficient to recommend its use for psoriasis and/or psoriatic arthritis,” he said.
The approval of colchicine 0.5 mg for ASCVD could be meaningful for people with psoriasis who are also being treated for CV risk factors, Dr. Gelfand said. “Additional considerations such as signs of residual inflammation (elevated hsCRP) and CV imaging findings may be used to further guide shared decision-making for optimal use,” he said.
Another consideration he noted: “This is also a novel 0.5-mg formulation, and thus cost may be an issue.”
Would side effects bar use in gastroenterology?
Colchicine 0.5 mg may not move the needle much for expanding treatment of ASCVD in patients with inflammatory bowel disease (IBD) and potentially other gastrointestinal conditions, Edward Loftus Jr., MD, the Maxine and Jack Zarrow Family professor of gastroenterology specifically for IBD at the Mayo Clinic in Rochester, Minn., told MDEdge in emailed comments. “Given the GI side effect profile [of colchicine], I am not sure I would go there,” he said.
“Hopefully, the prescribers of this low-dose formulation are aware of the gastrointestinal side effects, such as diarrhea and nausea, and educate patients about these side effects so that a proper risk-benefit discussion can ensue,” he said.
Dr. Bartels reporting a previous financial relationship with Pfizer. Dr. Gelfand said he has financial relationships with AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celldex, GlaxoSmithKline, Twill, Lilly, Leo, Moonlake, Janssen Biologics, Novartis, Pfizer, UCB, Neuroderm, and Veolia North America. Dr. Loftus disclosed relationships with AbbVie, Alvotech, Amgen, Arena, Avalo, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene/Receptos, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iterative Health, Janssen, KSL Diagnostics, Morphic, Ono, Pfizer, Sun, Surrozen, Takeda, Theravance, and UCB.
Low-dose colchicine approved for CVD: Now what?
The recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco; Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD) represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.
The Food and Drug Administration granted colchicine a very broad label: to reduce the risk for cardiovascular events in adult patients with established ASCVD or with multiple risk factors for cardiovascular disease. But how will the drug be used in clinical practice?
“The idea of inflammation as a driver of atherosclerosis and cardiovascular risk has been around for decades, and it is very well known that atherosclerosis is an inflammatory process. However, treating inflammation is new as we haven’t had a specific agent targeting inflammation before, noted Michael Joseph Blaha, MD, director of clinical research, Ciccarone Center for the Prevention of Cardiovascular Disease at Johns Hopkins Hospital, Baltimore.
Dr. Blaha, who has been an unpaid scientific adviser to Agepha, added that the approval of low-dose colchicine “will open the door toward having a routine conversation about residual inflammatory risk in our patients; and we need to work out exactly how we do that.”
Dr. Blaha is not surprised by the FDA-approved indication for colchicine, pointing out that the main large-scale trial supporting its use in ASCVD, the LoDoCo-2 trial, included a similar broad population.
“I think the approval was appropriate as the indication should always follow the data. But I think how the drug will actually be used will depend on the context for different individual patients,” he said.
“The paradigm coming forward is the idea of residual risk that patients have after they been treated with the standard of care – which in most cases is a statin and blood pressure control – and what is driving that residual risk,” he noted. “If we think patients are still at high risk of recurrent cardiovascular events, we have to think what we will do next. This is where this drug will come in.”
Dr. Blaha pointed out that there are now multiple options for reducing residual risk; he believes that it will depend on the profile of the patient as to which of those options is chosen first.
“If after high-dose statin treatment they still have raised LDL, then we can add another LDL lowering drug; or it might be diabetes and obesity that we want to address first; or elevated triglycerides. But now, we can also consider residual inflammatory risk if we think the patient has residual plaque inflammation,” he said. “So, colchicine will be one of several choices beyond a statin that we can think about as the next step for treating residual risk.”
Is CRP measurement necessary?
Though elevated levels of high-sensitivity C-reactive protein (hsCRP) is a marker of inflammation in ASCVD, the two main trials of colchicine in ASCVD, both of which showed large benefits of the drug, did not measure hsCRP, leading to questions as to whether measurement of this biomarker is necessary to select patients for colchicine treatment.
“Some clinicians will favor testing hsCRP and treating those with levels above 2 mg/L. I think that’s very reasonable,” Dr. Blaha said. “However, because hsCRP was not measured in the trials, I don’t think testing for this biomarker is mandatory to establish that there is inflammation,” he added.
“The label does not stipulate that CRP has to be measured. It is giving physicians latitude; they can measure CRP, or they don’t have to.”
Dr. Blaha added that clinicians need to think about what is driving residual risk in each individual patient: “If you think their other risk factors are well controlled but they are still having recurrent events, then we can consider colchicine as a way of reducing their residual risk which is likely being caused by inflammation.
“We are at a great place in cardiovascular medicine as we have several different options to use after a statin, and now we have this new therapy targeted at inflammation as well. While we can use all these options together, I think most clinicians will want to prioritize therapies by using the ones that they believe will reduce the residual risk the most in each individual patient,” Dr. Blaha explained.
‘An entire other axis driving atherosclerosis’
Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, is one of the major players in the cardiovascular inflammation field and has helped develop hsCRP testing. He has similar views.
“This FDA approval is extremely important, as it will draw attention to the role of inflammation in atherosclerosis and the need to treat it,” he said.
“Physicians need to be aware that, yes, we need to lower cholesterol aggressively, but they also need to know that there is an entire other axis driving atherosclerosis – and that is inflammation. And until now, we haven’t had an FDA-approved drug to treat inflammation.”
Dr. Ridker stressed that he doesn’t want to undermine lowering lipids: “Therapies aimed at inflammation are not in competition with those aimed at lipid lowering. We know lipid lowering works. But now we have another approach as well. The challenge here is educating physicians on this new approach.”
Dr. Ridker said he already uses low-dose colchicine for patients whom he refers to as “frequent flyers”; those who keep coming back despite aggressive lipid lowering. “They have multiple angioplasties, bypass surgery, etc.”
Like Dr. Blaha, Dr. Ridker thinks that doctors should start using this drug in high-risk patients who are already on a statin and who have residual inflammatory risk: “[The] patient whose underlying biologic problem is inflammation [is whom] we really want to treat with this drug. That is where it is most likely to be highly effective and where the comfort level will be the greatest.”
He said that measurement of hsCRP is an appropriate way to select these patients.
“I think this is a great impetus to start having much wider CRP measurement so we can actually target this anti-inflammatory drug to the patients with residual inflammatory risk – those with hsCRP level above 2 mg/L,” he said, estimating that this could apply to around 30%-40% of patients with ASCVD who are already taking a statin.
A second pillar of ASCVD treatment?
A somewhat different view is held by Jean-Claude Tardif, MD, director of the Research Centre at the Montréal Heart Institute, Canada, who was the lead investigator of the other randomized controlled trial of colchicine in heart disease, the COLCOT trial.
He said that colchicine should become the “second pillar” of ASCVD treatment, along with statins, for almost all patients.
Tardif referred to the recent study (led by Dr. Ridker) in The Lancet, which showed that among patients who are already on a statin, those with high inflammation levels had the highest risk for future events.
“So, the next step after a statin has to be to consider inflammation reduction,” he said.
“Despite all the drugs we have, ASCVD remains the leading cause of death in the Western world. What drives these events is largely inflammation, so it makes sense to directly tackle reduction of inflammation in the vessel, with a drug like colchicine,” he noted.
“I would say all patients with coronary atherosclerosis are potential candidates for low-dose colchicine as long as they do not have severe kidney disease, which is a contraindication,” Dr. Tardif said.
“If you want to fine tune this a bit more, those that are at particular risk are those that have recurrent events, those with multiple risk factors, and those with a recent [myocardial infarction]. In these patients, it would make a lot of sense to add low-dose colchicine to high-dose statins,” he added.
Dr. Tardif said he is not going to use CRP measurements to select patients for colchicine treatment: “Although measuring CRP may make sense intuitively, both large, randomized trials of colchicine did not select patients based on raised CRP, and they showed a benefit across the board.
If I consider a patient with ASCVD to be at high risk of future events and they are already on a statin I’m going to consider colchicine in all these patients, as long as they don’t have severe kidney disease.”
Dr. Tardif said that ASCVD needs to follow the model of heart failure which has several pillars of treatment directed at different targets that are all used together.
“I think we should apply the same approach to patients with ASCVD,” he added. “Yes, we need to hit the cholesterol with a statin, but we can now also hit the inflammation with colchicine.”
Polypharmacy concerns
Steve Nissen, MD, professor of medicine at the Cleveland Clinic, who was not involved in the colchicine trials, is also enthusiastic about use of colchicine. But like Dr. Ridker and Dr. Blaha, he favors selecting patients who are likely to benefit the most.
“I have been an advocate of the inflammatory hypothesis for many years, and we have been on a quest for a pure anti-inflammatory therapy that we can add to the standard treatment of patients with coronary disease. And colchicine has the safety and efficacy to do this,” Dr. Nissen said.
“What colchicine offers here is an inexpensive drug with pretty good data on reduction in morbidity from coronary disease. It has a completely different mechanism, so its benefit is likely to be additive to statins. I think we could probably do a lot of good at very little expense by just using these two therapies,” he said.
“But at present my preference will be to use colchicine selectively in those with raised CRP. I think that’s logical. I’m just worried about polypharmacy. Some of my patients are already on five, six, or seven meds. I need to have a reason to add an additional drug, and I’m not sure if we really analyze this carefully that patients with a low CRP would derive the same benefit. They might do, but I doubt it,” he noted.
“There may be further research and analyses that help us understand the relationship between CRP and efficacy of colchicine, and that may help us figure this out,” he added.
Safety is reassuring
In terms of safety and tolerability of the 0.5-mg colchicine dose, the experts seem to think that this is very manageable.
“When used for gout or pericarditis, colchicine is generally given at a dose of 0.6 mg twice a day and this can cause a lot of gastrointestinal [GI] side effects,” Dr. Nissen said. “But the low dose approved for ASCVD – 0.5 mg once a day – appears to be much better tolerated. There are some GI side effects, but these are not intolerable, and they generally go away with time.”
Dr. Ridker added that in the randomized trials, the adverse effects were “quite minimal,” but, “that being said, this drug is not to be used in severe kidney or liver disease, and there are some drug interactions that we need to be aware of. But in general, side effects are rare with the low dose. There may be some GI effects but they are mainly mild and you can generally treat through them.”
Dr. Blaha agreed that this is not a drug for patients with advanced kidney disease, “and there are some drug interactions that we have to be mindful of, but the list is not so long. There is a signal of modest gastrointestinal and muscle side effects, but most patients will be able to take it without issues. Because it’s already used in gout, physicians are already quite comfortable with its use.”
Part of the backbone of CV treatment?
Concluding, Dr. Blaha said he believes that prescribing of colchicine will start with cardiologists who will use it in their highest-risk patients first.
“But as we become comfortable with it, I think we will start using it in a broader range of patients and eventually primary care doctors will start prescribing it – much like what has happened with the statins,” he suggested.
“Where it sits along with statins in the future will be very interesting to see, but I think some people can envision it being up there with statins as part of the backbone of cardiovascular treatment in future.”
Dr. Tardif holds patents on methods for using low-dose colchicine after myocardial infarction, licensed to Montreal Heart Institute. Dr. Ridker is a consultant to Agepha and has research grants from Novo Nordisk related to the development of alternative anti-inflammatory therapies for atherosclerotic disease. Dr. Blaha reports being an unpaid scientific adviser to Agepha Pharma.
A version of this article first appeared on Medscape.com.
The recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco; Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD) represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.
The Food and Drug Administration granted colchicine a very broad label: to reduce the risk for cardiovascular events in adult patients with established ASCVD or with multiple risk factors for cardiovascular disease. But how will the drug be used in clinical practice?
“The idea of inflammation as a driver of atherosclerosis and cardiovascular risk has been around for decades, and it is very well known that atherosclerosis is an inflammatory process. However, treating inflammation is new as we haven’t had a specific agent targeting inflammation before, noted Michael Joseph Blaha, MD, director of clinical research, Ciccarone Center for the Prevention of Cardiovascular Disease at Johns Hopkins Hospital, Baltimore.
Dr. Blaha, who has been an unpaid scientific adviser to Agepha, added that the approval of low-dose colchicine “will open the door toward having a routine conversation about residual inflammatory risk in our patients; and we need to work out exactly how we do that.”
Dr. Blaha is not surprised by the FDA-approved indication for colchicine, pointing out that the main large-scale trial supporting its use in ASCVD, the LoDoCo-2 trial, included a similar broad population.
“I think the approval was appropriate as the indication should always follow the data. But I think how the drug will actually be used will depend on the context for different individual patients,” he said.
“The paradigm coming forward is the idea of residual risk that patients have after they been treated with the standard of care – which in most cases is a statin and blood pressure control – and what is driving that residual risk,” he noted. “If we think patients are still at high risk of recurrent cardiovascular events, we have to think what we will do next. This is where this drug will come in.”
Dr. Blaha pointed out that there are now multiple options for reducing residual risk; he believes that it will depend on the profile of the patient as to which of those options is chosen first.
“If after high-dose statin treatment they still have raised LDL, then we can add another LDL lowering drug; or it might be diabetes and obesity that we want to address first; or elevated triglycerides. But now, we can also consider residual inflammatory risk if we think the patient has residual plaque inflammation,” he said. “So, colchicine will be one of several choices beyond a statin that we can think about as the next step for treating residual risk.”
Is CRP measurement necessary?
Though elevated levels of high-sensitivity C-reactive protein (hsCRP) is a marker of inflammation in ASCVD, the two main trials of colchicine in ASCVD, both of which showed large benefits of the drug, did not measure hsCRP, leading to questions as to whether measurement of this biomarker is necessary to select patients for colchicine treatment.
“Some clinicians will favor testing hsCRP and treating those with levels above 2 mg/L. I think that’s very reasonable,” Dr. Blaha said. “However, because hsCRP was not measured in the trials, I don’t think testing for this biomarker is mandatory to establish that there is inflammation,” he added.
“The label does not stipulate that CRP has to be measured. It is giving physicians latitude; they can measure CRP, or they don’t have to.”
Dr. Blaha added that clinicians need to think about what is driving residual risk in each individual patient: “If you think their other risk factors are well controlled but they are still having recurrent events, then we can consider colchicine as a way of reducing their residual risk which is likely being caused by inflammation.
“We are at a great place in cardiovascular medicine as we have several different options to use after a statin, and now we have this new therapy targeted at inflammation as well. While we can use all these options together, I think most clinicians will want to prioritize therapies by using the ones that they believe will reduce the residual risk the most in each individual patient,” Dr. Blaha explained.
‘An entire other axis driving atherosclerosis’
Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, is one of the major players in the cardiovascular inflammation field and has helped develop hsCRP testing. He has similar views.
“This FDA approval is extremely important, as it will draw attention to the role of inflammation in atherosclerosis and the need to treat it,” he said.
“Physicians need to be aware that, yes, we need to lower cholesterol aggressively, but they also need to know that there is an entire other axis driving atherosclerosis – and that is inflammation. And until now, we haven’t had an FDA-approved drug to treat inflammation.”
Dr. Ridker stressed that he doesn’t want to undermine lowering lipids: “Therapies aimed at inflammation are not in competition with those aimed at lipid lowering. We know lipid lowering works. But now we have another approach as well. The challenge here is educating physicians on this new approach.”
Dr. Ridker said he already uses low-dose colchicine for patients whom he refers to as “frequent flyers”; those who keep coming back despite aggressive lipid lowering. “They have multiple angioplasties, bypass surgery, etc.”
Like Dr. Blaha, Dr. Ridker thinks that doctors should start using this drug in high-risk patients who are already on a statin and who have residual inflammatory risk: “[The] patient whose underlying biologic problem is inflammation [is whom] we really want to treat with this drug. That is where it is most likely to be highly effective and where the comfort level will be the greatest.”
He said that measurement of hsCRP is an appropriate way to select these patients.
“I think this is a great impetus to start having much wider CRP measurement so we can actually target this anti-inflammatory drug to the patients with residual inflammatory risk – those with hsCRP level above 2 mg/L,” he said, estimating that this could apply to around 30%-40% of patients with ASCVD who are already taking a statin.
A second pillar of ASCVD treatment?
A somewhat different view is held by Jean-Claude Tardif, MD, director of the Research Centre at the Montréal Heart Institute, Canada, who was the lead investigator of the other randomized controlled trial of colchicine in heart disease, the COLCOT trial.
He said that colchicine should become the “second pillar” of ASCVD treatment, along with statins, for almost all patients.
Tardif referred to the recent study (led by Dr. Ridker) in The Lancet, which showed that among patients who are already on a statin, those with high inflammation levels had the highest risk for future events.
“So, the next step after a statin has to be to consider inflammation reduction,” he said.
“Despite all the drugs we have, ASCVD remains the leading cause of death in the Western world. What drives these events is largely inflammation, so it makes sense to directly tackle reduction of inflammation in the vessel, with a drug like colchicine,” he noted.
“I would say all patients with coronary atherosclerosis are potential candidates for low-dose colchicine as long as they do not have severe kidney disease, which is a contraindication,” Dr. Tardif said.
“If you want to fine tune this a bit more, those that are at particular risk are those that have recurrent events, those with multiple risk factors, and those with a recent [myocardial infarction]. In these patients, it would make a lot of sense to add low-dose colchicine to high-dose statins,” he added.
Dr. Tardif said he is not going to use CRP measurements to select patients for colchicine treatment: “Although measuring CRP may make sense intuitively, both large, randomized trials of colchicine did not select patients based on raised CRP, and they showed a benefit across the board.
If I consider a patient with ASCVD to be at high risk of future events and they are already on a statin I’m going to consider colchicine in all these patients, as long as they don’t have severe kidney disease.”
Dr. Tardif said that ASCVD needs to follow the model of heart failure which has several pillars of treatment directed at different targets that are all used together.
“I think we should apply the same approach to patients with ASCVD,” he added. “Yes, we need to hit the cholesterol with a statin, but we can now also hit the inflammation with colchicine.”
Polypharmacy concerns
Steve Nissen, MD, professor of medicine at the Cleveland Clinic, who was not involved in the colchicine trials, is also enthusiastic about use of colchicine. But like Dr. Ridker and Dr. Blaha, he favors selecting patients who are likely to benefit the most.
“I have been an advocate of the inflammatory hypothesis for many years, and we have been on a quest for a pure anti-inflammatory therapy that we can add to the standard treatment of patients with coronary disease. And colchicine has the safety and efficacy to do this,” Dr. Nissen said.
“What colchicine offers here is an inexpensive drug with pretty good data on reduction in morbidity from coronary disease. It has a completely different mechanism, so its benefit is likely to be additive to statins. I think we could probably do a lot of good at very little expense by just using these two therapies,” he said.
“But at present my preference will be to use colchicine selectively in those with raised CRP. I think that’s logical. I’m just worried about polypharmacy. Some of my patients are already on five, six, or seven meds. I need to have a reason to add an additional drug, and I’m not sure if we really analyze this carefully that patients with a low CRP would derive the same benefit. They might do, but I doubt it,” he noted.
“There may be further research and analyses that help us understand the relationship between CRP and efficacy of colchicine, and that may help us figure this out,” he added.
Safety is reassuring
In terms of safety and tolerability of the 0.5-mg colchicine dose, the experts seem to think that this is very manageable.
“When used for gout or pericarditis, colchicine is generally given at a dose of 0.6 mg twice a day and this can cause a lot of gastrointestinal [GI] side effects,” Dr. Nissen said. “But the low dose approved for ASCVD – 0.5 mg once a day – appears to be much better tolerated. There are some GI side effects, but these are not intolerable, and they generally go away with time.”
Dr. Ridker added that in the randomized trials, the adverse effects were “quite minimal,” but, “that being said, this drug is not to be used in severe kidney or liver disease, and there are some drug interactions that we need to be aware of. But in general, side effects are rare with the low dose. There may be some GI effects but they are mainly mild and you can generally treat through them.”
Dr. Blaha agreed that this is not a drug for patients with advanced kidney disease, “and there are some drug interactions that we have to be mindful of, but the list is not so long. There is a signal of modest gastrointestinal and muscle side effects, but most patients will be able to take it without issues. Because it’s already used in gout, physicians are already quite comfortable with its use.”
Part of the backbone of CV treatment?
Concluding, Dr. Blaha said he believes that prescribing of colchicine will start with cardiologists who will use it in their highest-risk patients first.
“But as we become comfortable with it, I think we will start using it in a broader range of patients and eventually primary care doctors will start prescribing it – much like what has happened with the statins,” he suggested.
“Where it sits along with statins in the future will be very interesting to see, but I think some people can envision it being up there with statins as part of the backbone of cardiovascular treatment in future.”
Dr. Tardif holds patents on methods for using low-dose colchicine after myocardial infarction, licensed to Montreal Heart Institute. Dr. Ridker is a consultant to Agepha and has research grants from Novo Nordisk related to the development of alternative anti-inflammatory therapies for atherosclerotic disease. Dr. Blaha reports being an unpaid scientific adviser to Agepha Pharma.
A version of this article first appeared on Medscape.com.
The recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco; Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD) represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.
The Food and Drug Administration granted colchicine a very broad label: to reduce the risk for cardiovascular events in adult patients with established ASCVD or with multiple risk factors for cardiovascular disease. But how will the drug be used in clinical practice?
“The idea of inflammation as a driver of atherosclerosis and cardiovascular risk has been around for decades, and it is very well known that atherosclerosis is an inflammatory process. However, treating inflammation is new as we haven’t had a specific agent targeting inflammation before, noted Michael Joseph Blaha, MD, director of clinical research, Ciccarone Center for the Prevention of Cardiovascular Disease at Johns Hopkins Hospital, Baltimore.
Dr. Blaha, who has been an unpaid scientific adviser to Agepha, added that the approval of low-dose colchicine “will open the door toward having a routine conversation about residual inflammatory risk in our patients; and we need to work out exactly how we do that.”
Dr. Blaha is not surprised by the FDA-approved indication for colchicine, pointing out that the main large-scale trial supporting its use in ASCVD, the LoDoCo-2 trial, included a similar broad population.
“I think the approval was appropriate as the indication should always follow the data. But I think how the drug will actually be used will depend on the context for different individual patients,” he said.
“The paradigm coming forward is the idea of residual risk that patients have after they been treated with the standard of care – which in most cases is a statin and blood pressure control – and what is driving that residual risk,” he noted. “If we think patients are still at high risk of recurrent cardiovascular events, we have to think what we will do next. This is where this drug will come in.”
Dr. Blaha pointed out that there are now multiple options for reducing residual risk; he believes that it will depend on the profile of the patient as to which of those options is chosen first.
“If after high-dose statin treatment they still have raised LDL, then we can add another LDL lowering drug; or it might be diabetes and obesity that we want to address first; or elevated triglycerides. But now, we can also consider residual inflammatory risk if we think the patient has residual plaque inflammation,” he said. “So, colchicine will be one of several choices beyond a statin that we can think about as the next step for treating residual risk.”
Is CRP measurement necessary?
Though elevated levels of high-sensitivity C-reactive protein (hsCRP) is a marker of inflammation in ASCVD, the two main trials of colchicine in ASCVD, both of which showed large benefits of the drug, did not measure hsCRP, leading to questions as to whether measurement of this biomarker is necessary to select patients for colchicine treatment.
“Some clinicians will favor testing hsCRP and treating those with levels above 2 mg/L. I think that’s very reasonable,” Dr. Blaha said. “However, because hsCRP was not measured in the trials, I don’t think testing for this biomarker is mandatory to establish that there is inflammation,” he added.
“The label does not stipulate that CRP has to be measured. It is giving physicians latitude; they can measure CRP, or they don’t have to.”
Dr. Blaha added that clinicians need to think about what is driving residual risk in each individual patient: “If you think their other risk factors are well controlled but they are still having recurrent events, then we can consider colchicine as a way of reducing their residual risk which is likely being caused by inflammation.
“We are at a great place in cardiovascular medicine as we have several different options to use after a statin, and now we have this new therapy targeted at inflammation as well. While we can use all these options together, I think most clinicians will want to prioritize therapies by using the ones that they believe will reduce the residual risk the most in each individual patient,” Dr. Blaha explained.
‘An entire other axis driving atherosclerosis’
Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, is one of the major players in the cardiovascular inflammation field and has helped develop hsCRP testing. He has similar views.
“This FDA approval is extremely important, as it will draw attention to the role of inflammation in atherosclerosis and the need to treat it,” he said.
“Physicians need to be aware that, yes, we need to lower cholesterol aggressively, but they also need to know that there is an entire other axis driving atherosclerosis – and that is inflammation. And until now, we haven’t had an FDA-approved drug to treat inflammation.”
Dr. Ridker stressed that he doesn’t want to undermine lowering lipids: “Therapies aimed at inflammation are not in competition with those aimed at lipid lowering. We know lipid lowering works. But now we have another approach as well. The challenge here is educating physicians on this new approach.”
Dr. Ridker said he already uses low-dose colchicine for patients whom he refers to as “frequent flyers”; those who keep coming back despite aggressive lipid lowering. “They have multiple angioplasties, bypass surgery, etc.”
Like Dr. Blaha, Dr. Ridker thinks that doctors should start using this drug in high-risk patients who are already on a statin and who have residual inflammatory risk: “[The] patient whose underlying biologic problem is inflammation [is whom] we really want to treat with this drug. That is where it is most likely to be highly effective and where the comfort level will be the greatest.”
He said that measurement of hsCRP is an appropriate way to select these patients.
“I think this is a great impetus to start having much wider CRP measurement so we can actually target this anti-inflammatory drug to the patients with residual inflammatory risk – those with hsCRP level above 2 mg/L,” he said, estimating that this could apply to around 30%-40% of patients with ASCVD who are already taking a statin.
A second pillar of ASCVD treatment?
A somewhat different view is held by Jean-Claude Tardif, MD, director of the Research Centre at the Montréal Heart Institute, Canada, who was the lead investigator of the other randomized controlled trial of colchicine in heart disease, the COLCOT trial.
He said that colchicine should become the “second pillar” of ASCVD treatment, along with statins, for almost all patients.
Tardif referred to the recent study (led by Dr. Ridker) in The Lancet, which showed that among patients who are already on a statin, those with high inflammation levels had the highest risk for future events.
“So, the next step after a statin has to be to consider inflammation reduction,” he said.
“Despite all the drugs we have, ASCVD remains the leading cause of death in the Western world. What drives these events is largely inflammation, so it makes sense to directly tackle reduction of inflammation in the vessel, with a drug like colchicine,” he noted.
“I would say all patients with coronary atherosclerosis are potential candidates for low-dose colchicine as long as they do not have severe kidney disease, which is a contraindication,” Dr. Tardif said.
“If you want to fine tune this a bit more, those that are at particular risk are those that have recurrent events, those with multiple risk factors, and those with a recent [myocardial infarction]. In these patients, it would make a lot of sense to add low-dose colchicine to high-dose statins,” he added.
Dr. Tardif said he is not going to use CRP measurements to select patients for colchicine treatment: “Although measuring CRP may make sense intuitively, both large, randomized trials of colchicine did not select patients based on raised CRP, and they showed a benefit across the board.
If I consider a patient with ASCVD to be at high risk of future events and they are already on a statin I’m going to consider colchicine in all these patients, as long as they don’t have severe kidney disease.”
Dr. Tardif said that ASCVD needs to follow the model of heart failure which has several pillars of treatment directed at different targets that are all used together.
“I think we should apply the same approach to patients with ASCVD,” he added. “Yes, we need to hit the cholesterol with a statin, but we can now also hit the inflammation with colchicine.”
Polypharmacy concerns
Steve Nissen, MD, professor of medicine at the Cleveland Clinic, who was not involved in the colchicine trials, is also enthusiastic about use of colchicine. But like Dr. Ridker and Dr. Blaha, he favors selecting patients who are likely to benefit the most.
“I have been an advocate of the inflammatory hypothesis for many years, and we have been on a quest for a pure anti-inflammatory therapy that we can add to the standard treatment of patients with coronary disease. And colchicine has the safety and efficacy to do this,” Dr. Nissen said.
“What colchicine offers here is an inexpensive drug with pretty good data on reduction in morbidity from coronary disease. It has a completely different mechanism, so its benefit is likely to be additive to statins. I think we could probably do a lot of good at very little expense by just using these two therapies,” he said.
“But at present my preference will be to use colchicine selectively in those with raised CRP. I think that’s logical. I’m just worried about polypharmacy. Some of my patients are already on five, six, or seven meds. I need to have a reason to add an additional drug, and I’m not sure if we really analyze this carefully that patients with a low CRP would derive the same benefit. They might do, but I doubt it,” he noted.
“There may be further research and analyses that help us understand the relationship between CRP and efficacy of colchicine, and that may help us figure this out,” he added.
Safety is reassuring
In terms of safety and tolerability of the 0.5-mg colchicine dose, the experts seem to think that this is very manageable.
“When used for gout or pericarditis, colchicine is generally given at a dose of 0.6 mg twice a day and this can cause a lot of gastrointestinal [GI] side effects,” Dr. Nissen said. “But the low dose approved for ASCVD – 0.5 mg once a day – appears to be much better tolerated. There are some GI side effects, but these are not intolerable, and they generally go away with time.”
Dr. Ridker added that in the randomized trials, the adverse effects were “quite minimal,” but, “that being said, this drug is not to be used in severe kidney or liver disease, and there are some drug interactions that we need to be aware of. But in general, side effects are rare with the low dose. There may be some GI effects but they are mainly mild and you can generally treat through them.”
Dr. Blaha agreed that this is not a drug for patients with advanced kidney disease, “and there are some drug interactions that we have to be mindful of, but the list is not so long. There is a signal of modest gastrointestinal and muscle side effects, but most patients will be able to take it without issues. Because it’s already used in gout, physicians are already quite comfortable with its use.”
Part of the backbone of CV treatment?
Concluding, Dr. Blaha said he believes that prescribing of colchicine will start with cardiologists who will use it in their highest-risk patients first.
“But as we become comfortable with it, I think we will start using it in a broader range of patients and eventually primary care doctors will start prescribing it – much like what has happened with the statins,” he suggested.
“Where it sits along with statins in the future will be very interesting to see, but I think some people can envision it being up there with statins as part of the backbone of cardiovascular treatment in future.”
Dr. Tardif holds patents on methods for using low-dose colchicine after myocardial infarction, licensed to Montreal Heart Institute. Dr. Ridker is a consultant to Agepha and has research grants from Novo Nordisk related to the development of alternative anti-inflammatory therapies for atherosclerotic disease. Dr. Blaha reports being an unpaid scientific adviser to Agepha Pharma.
A version of this article first appeared on Medscape.com.
FDA OKs low-dose colchicine for broad CV indication
The Food and Drug Administration has approved the anti-inflammatory drug colchicine 0.5 mg tablets (Lodoco) as the first specific anti-inflammatory drug demonstrated to reduce the risk for myocardial infarction, stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.
The drug, which targets residual inflammation as an underlying cause of atherosclerotic cardiovascular disease, has a dosage of 0.5 mg once daily, and can be used alone or in combination with cholesterol-lowering medications. 
The drug’s manufacturer, Agepha Pharma, said it anticipates that Lodoco will be available for prescription in the second half of 2023.
Colchicine has been available for many years and used at higher doses for the acute treatment of gout and pericarditis, but the current formulation is a much lower dose for long-term use in patients with atherosclerotic heart disease.
Data supporting the approval has come from two major randomized trials, LoDoCo-2 and COLCOT.
In the LoDoCo-2 trial, the anti-inflammatory drug cut the risk of cardiovascular events by one third when added to standard prevention therapies in patients with chronic coronary disease. And in the COLCOT study, use of colchicine reduced cardiovascular events by 23% compared with placebo in patients with a recent MI.
Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, who has been a pioneer in establishing inflammation as an underlying cause of atherosclerotic cardiovascular disease, welcomed the Lodoco approval.
‘A very big day for cardiology’
“This is a very big day for cardiology,” Dr. Ridker said in an interview.
“The FDA approval of colchicine for patients with atherosclerotic disease is a huge signal that physicians need to be aware of inflammation as a key player in cardiovascular disease,” he said.
Dr. Ridker was the lead author of a recent study showing that among patients receiving contemporary statins, inflammation assessed by high-sensitivity C-reactive protein (hsCRP) was a stronger predictor for risk of future cardiovascular events and death than LDL cholesterol.
He pointed out that
“That is virtually identical to the indication approved for statin therapy. That shows just how important the FDA thinks this is,” he commented.
But Dr. Ridker added that, while the label does not specify that Lodoco has to be used in addition to statin therapy, he believes that it will be used as additional therapy to statins in the vast majority of patients.
“This is not an alternative to statin therapy. In the randomized trials, the benefits were seen on top of statins,” he stressed.
Dr. Ridker believes that physicians will need time to feel comfortable with this new approach.
“Initially, I think, it will be used mainly by cardiologists who know about inflammation, but I believe over time it will be widely prescribed by internists, in much the same way as statins are used today,” he commented.
Dr. Ridker said he already uses low dose colchicine in his high-risk patients who have high levels of inflammation as seen on hsCRP testing. He believes this is where the drug will mostly be used initially, as this is where it is likely to be most effective.
The prescribing information states that Lodoco is contraindicated in patients who are taking strong CYP3A4 inhibitors or P-glycoprotein inhibitors, such as ketoconazole, fluconazole, and clarithromycin, and in patients with preexisting blood dyscrasias, renal failure, and severe hepatic impairment.
Common side effects reported in published clinical studies and literature with the use of colchicine are gastrointestinal symptoms (diarrhea, vomiting, abdominal cramping) and myalgia.
More serious adverse effects are listed as blood dyscrasias such as myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia; and neuromuscular toxicity in the form of myotoxicity including rhabdomyolysis, which may occur, especially in combination with other drugs known to cause this effect. If these adverse effects occur, it is recommended that the drug be stopped.
The prescribing information also notes that Lodoco may rarely and transiently impair fertility in males; and that patients with renal or hepatic impairment should be monitored closely for adverse effects of colchicine.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved the anti-inflammatory drug colchicine 0.5 mg tablets (Lodoco) as the first specific anti-inflammatory drug demonstrated to reduce the risk for myocardial infarction, stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.
The drug, which targets residual inflammation as an underlying cause of atherosclerotic cardiovascular disease, has a dosage of 0.5 mg once daily, and can be used alone or in combination with cholesterol-lowering medications.
The drug’s manufacturer, Agepha Pharma, said it anticipates that Lodoco will be available for prescription in the second half of 2023.
Colchicine has been available for many years and used at higher doses for the acute treatment of gout and pericarditis, but the current formulation is a much lower dose for long-term use in patients with atherosclerotic heart disease.
Data supporting the approval has come from two major randomized trials, LoDoCo-2 and COLCOT.
In the LoDoCo-2 trial, the anti-inflammatory drug cut the risk of cardiovascular events by one third when added to standard prevention therapies in patients with chronic coronary disease. And in the COLCOT study, use of colchicine reduced cardiovascular events by 23% compared with placebo in patients with a recent MI.
Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, who has been a pioneer in establishing inflammation as an underlying cause of atherosclerotic cardiovascular disease, welcomed the Lodoco approval.
‘A very big day for cardiology’
“This is a very big day for cardiology,” Dr. Ridker said in an interview.
“The FDA approval of colchicine for patients with atherosclerotic disease is a huge signal that physicians need to be aware of inflammation as a key player in cardiovascular disease,” he said.
Dr. Ridker was the lead author of a recent study showing that among patients receiving contemporary statins, inflammation assessed by high-sensitivity C-reactive protein (hsCRP) was a stronger predictor for risk of future cardiovascular events and death than LDL cholesterol.
He pointed out that
“That is virtually identical to the indication approved for statin therapy. That shows just how important the FDA thinks this is,” he commented.
But Dr. Ridker added that, while the label does not specify that Lodoco has to be used in addition to statin therapy, he believes that it will be used as additional therapy to statins in the vast majority of patients.
“This is not an alternative to statin therapy. In the randomized trials, the benefits were seen on top of statins,” he stressed.
Dr. Ridker believes that physicians will need time to feel comfortable with this new approach.
“Initially, I think, it will be used mainly by cardiologists who know about inflammation, but I believe over time it will be widely prescribed by internists, in much the same way as statins are used today,” he commented.
Dr. Ridker said he already uses low dose colchicine in his high-risk patients who have high levels of inflammation as seen on hsCRP testing. He believes this is where the drug will mostly be used initially, as this is where it is likely to be most effective.
The prescribing information states that Lodoco is contraindicated in patients who are taking strong CYP3A4 inhibitors or P-glycoprotein inhibitors, such as ketoconazole, fluconazole, and clarithromycin, and in patients with preexisting blood dyscrasias, renal failure, and severe hepatic impairment.
Common side effects reported in published clinical studies and literature with the use of colchicine are gastrointestinal symptoms (diarrhea, vomiting, abdominal cramping) and myalgia.
More serious adverse effects are listed as blood dyscrasias such as myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia; and neuromuscular toxicity in the form of myotoxicity including rhabdomyolysis, which may occur, especially in combination with other drugs known to cause this effect. If these adverse effects occur, it is recommended that the drug be stopped.
The prescribing information also notes that Lodoco may rarely and transiently impair fertility in males; and that patients with renal or hepatic impairment should be monitored closely for adverse effects of colchicine.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved the anti-inflammatory drug colchicine 0.5 mg tablets (Lodoco) as the first specific anti-inflammatory drug demonstrated to reduce the risk for myocardial infarction, stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.
The drug, which targets residual inflammation as an underlying cause of atherosclerotic cardiovascular disease, has a dosage of 0.5 mg once daily, and can be used alone or in combination with cholesterol-lowering medications.
The drug’s manufacturer, Agepha Pharma, said it anticipates that Lodoco will be available for prescription in the second half of 2023.
Colchicine has been available for many years and used at higher doses for the acute treatment of gout and pericarditis, but the current formulation is a much lower dose for long-term use in patients with atherosclerotic heart disease.
Data supporting the approval has come from two major randomized trials, LoDoCo-2 and COLCOT.
In the LoDoCo-2 trial, the anti-inflammatory drug cut the risk of cardiovascular events by one third when added to standard prevention therapies in patients with chronic coronary disease. And in the COLCOT study, use of colchicine reduced cardiovascular events by 23% compared with placebo in patients with a recent MI.
Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, who has been a pioneer in establishing inflammation as an underlying cause of atherosclerotic cardiovascular disease, welcomed the Lodoco approval.
‘A very big day for cardiology’
“This is a very big day for cardiology,” Dr. Ridker said in an interview.
“The FDA approval of colchicine for patients with atherosclerotic disease is a huge signal that physicians need to be aware of inflammation as a key player in cardiovascular disease,” he said.
Dr. Ridker was the lead author of a recent study showing that among patients receiving contemporary statins, inflammation assessed by high-sensitivity C-reactive protein (hsCRP) was a stronger predictor for risk of future cardiovascular events and death than LDL cholesterol.
He pointed out that
“That is virtually identical to the indication approved for statin therapy. That shows just how important the FDA thinks this is,” he commented.
But Dr. Ridker added that, while the label does not specify that Lodoco has to be used in addition to statin therapy, he believes that it will be used as additional therapy to statins in the vast majority of patients.
“This is not an alternative to statin therapy. In the randomized trials, the benefits were seen on top of statins,” he stressed.
Dr. Ridker believes that physicians will need time to feel comfortable with this new approach.
“Initially, I think, it will be used mainly by cardiologists who know about inflammation, but I believe over time it will be widely prescribed by internists, in much the same way as statins are used today,” he commented.
Dr. Ridker said he already uses low dose colchicine in his high-risk patients who have high levels of inflammation as seen on hsCRP testing. He believes this is where the drug will mostly be used initially, as this is where it is likely to be most effective.
The prescribing information states that Lodoco is contraindicated in patients who are taking strong CYP3A4 inhibitors or P-glycoprotein inhibitors, such as ketoconazole, fluconazole, and clarithromycin, and in patients with preexisting blood dyscrasias, renal failure, and severe hepatic impairment.
Common side effects reported in published clinical studies and literature with the use of colchicine are gastrointestinal symptoms (diarrhea, vomiting, abdominal cramping) and myalgia.
More serious adverse effects are listed as blood dyscrasias such as myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia; and neuromuscular toxicity in the form of myotoxicity including rhabdomyolysis, which may occur, especially in combination with other drugs known to cause this effect. If these adverse effects occur, it is recommended that the drug be stopped.
The prescribing information also notes that Lodoco may rarely and transiently impair fertility in males; and that patients with renal or hepatic impairment should be monitored closely for adverse effects of colchicine.
A version of this article first appeared on Medscape.com.
AHA flags CV risk with lead, cadmium, and arsenic exposure
in a new scientific statement.
“In reality, identifying a new type of cardiovascular risk factor leads to more questions than answers,” Gervasio A. Lamas, MD, chair of the statement writing group, said in an interview.
“For the most part, as cardiologists, we are used to risk factors we can manage with antihypertensives, statins, weight loss, exercise, and avoidance of smoking. Unfortunately, the ubiquity of toxic metals and their multiple sources increases the complexity of potential treatment,” said Dr. Lamas, chairman of medicine and chief of the Columbia University division of cardiology at Mount Sinai Medical Center in Miami Beach, Fla.
The statement addressing contaminant metals as CV risk factors was published online in the Journal of the American Heart Association.
Involuntary exposure harms the heart
Exposure to contaminant metals most often happens involuntarily through air, water, soil, and food, and extensive industrial and public use, the writing group notes.
These contaminant metals interfere with critical intracellular reactions and functions, leading to oxidative stress and chronic inflammation; this in turn leads to endothelial dysfunction, hypertension, epigenetic dysregulation, dyslipidemia, and changes in myocardial excitation and contractile function, the authors point out.
Lead, cadmium, and arsenic have been linked to subclinical atherosclerosis, coronary artery stenosis and calcification, as well as to an increased risk for ischemic heart disease and stroke, left ventricular hypertrophy, and heart failure and peripheral artery disease.
Epidemiologic studies show that exposure to lead, cadmium, or arsenic is associated with cardiovascular death mostly attributable to ischemic heart disease. In the United States alone, one study suggested that more than 450,000 deaths annually could be attributed to lead exposure.
“This is a global issue in which lower-income communities are disproportionately exposed to toxic metals through contaminated air, water, and soil,” Ana Navas-Acien, MD, PhD, vice chair of the statement writing group, said in a news release.
“Addressing metal exposure in these populations may provide a strategy to reduce cardiovascular disease disparities and advance environmental justice,” adds Dr. Navas-Acien, professor of environmental health sciences at Columbia University, New York.
Dr. Lamas said in an interview that the writing group is “hopeful that there will be a multilevel response” to publication of the scientific statement.
“On the societal level, we believe more effort can be made to measure these pollutants and protect the public. On the physician level, knowledge of metal levels could become part of the routine risk evaluation of the cardiac patient. On the individual level, patients can try to avoid these pollutants, by knowing arsenic levels of well-water, lead and cadmium levels of drinking water, avoiding tobacco and vaping, and using filters when available or necessary,” Dr. Lamas said.
“On the scientific level, identifying ubiquitous pollutants should spur scientists and pharmaceutical companies to develop preventive and therapeutic approaches.”
Finally, clinical trials should be encouraged to assess existing drugs that can remove these atherogenic toxins from the body or treat their ill effects. One such trial is expected to be completed within a year, Dr. Lamas added.
This scientific statement was prepared by the volunteer writing group on behalf of the AHA Council on Epidemiology and Prevention; the Council on Cardiovascular and Stroke Nursing; the Council on Lifestyle and Cardiometabolic Health; the Council on Peripheral Vascular Disease; and the Council on the Kidney in Cardiovascular Disease.
A version of this article originally appeared on Medscape.com.
in a new scientific statement.
“In reality, identifying a new type of cardiovascular risk factor leads to more questions than answers,” Gervasio A. Lamas, MD, chair of the statement writing group, said in an interview.
“For the most part, as cardiologists, we are used to risk factors we can manage with antihypertensives, statins, weight loss, exercise, and avoidance of smoking. Unfortunately, the ubiquity of toxic metals and their multiple sources increases the complexity of potential treatment,” said Dr. Lamas, chairman of medicine and chief of the Columbia University division of cardiology at Mount Sinai Medical Center in Miami Beach, Fla.
The statement addressing contaminant metals as CV risk factors was published online in the Journal of the American Heart Association.
Involuntary exposure harms the heart
Exposure to contaminant metals most often happens involuntarily through air, water, soil, and food, and extensive industrial and public use, the writing group notes.
These contaminant metals interfere with critical intracellular reactions and functions, leading to oxidative stress and chronic inflammation; this in turn leads to endothelial dysfunction, hypertension, epigenetic dysregulation, dyslipidemia, and changes in myocardial excitation and contractile function, the authors point out.
Lead, cadmium, and arsenic have been linked to subclinical atherosclerosis, coronary artery stenosis and calcification, as well as to an increased risk for ischemic heart disease and stroke, left ventricular hypertrophy, and heart failure and peripheral artery disease.
Epidemiologic studies show that exposure to lead, cadmium, or arsenic is associated with cardiovascular death mostly attributable to ischemic heart disease. In the United States alone, one study suggested that more than 450,000 deaths annually could be attributed to lead exposure.
“This is a global issue in which lower-income communities are disproportionately exposed to toxic metals through contaminated air, water, and soil,” Ana Navas-Acien, MD, PhD, vice chair of the statement writing group, said in a news release.
“Addressing metal exposure in these populations may provide a strategy to reduce cardiovascular disease disparities and advance environmental justice,” adds Dr. Navas-Acien, professor of environmental health sciences at Columbia University, New York.
Dr. Lamas said in an interview that the writing group is “hopeful that there will be a multilevel response” to publication of the scientific statement.
“On the societal level, we believe more effort can be made to measure these pollutants and protect the public. On the physician level, knowledge of metal levels could become part of the routine risk evaluation of the cardiac patient. On the individual level, patients can try to avoid these pollutants, by knowing arsenic levels of well-water, lead and cadmium levels of drinking water, avoiding tobacco and vaping, and using filters when available or necessary,” Dr. Lamas said.
“On the scientific level, identifying ubiquitous pollutants should spur scientists and pharmaceutical companies to develop preventive and therapeutic approaches.”
Finally, clinical trials should be encouraged to assess existing drugs that can remove these atherogenic toxins from the body or treat their ill effects. One such trial is expected to be completed within a year, Dr. Lamas added.
This scientific statement was prepared by the volunteer writing group on behalf of the AHA Council on Epidemiology and Prevention; the Council on Cardiovascular and Stroke Nursing; the Council on Lifestyle and Cardiometabolic Health; the Council on Peripheral Vascular Disease; and the Council on the Kidney in Cardiovascular Disease.
A version of this article originally appeared on Medscape.com.
in a new scientific statement.
“In reality, identifying a new type of cardiovascular risk factor leads to more questions than answers,” Gervasio A. Lamas, MD, chair of the statement writing group, said in an interview.
“For the most part, as cardiologists, we are used to risk factors we can manage with antihypertensives, statins, weight loss, exercise, and avoidance of smoking. Unfortunately, the ubiquity of toxic metals and their multiple sources increases the complexity of potential treatment,” said Dr. Lamas, chairman of medicine and chief of the Columbia University division of cardiology at Mount Sinai Medical Center in Miami Beach, Fla.
The statement addressing contaminant metals as CV risk factors was published online in the Journal of the American Heart Association.
Involuntary exposure harms the heart
Exposure to contaminant metals most often happens involuntarily through air, water, soil, and food, and extensive industrial and public use, the writing group notes.
These contaminant metals interfere with critical intracellular reactions and functions, leading to oxidative stress and chronic inflammation; this in turn leads to endothelial dysfunction, hypertension, epigenetic dysregulation, dyslipidemia, and changes in myocardial excitation and contractile function, the authors point out.
Lead, cadmium, and arsenic have been linked to subclinical atherosclerosis, coronary artery stenosis and calcification, as well as to an increased risk for ischemic heart disease and stroke, left ventricular hypertrophy, and heart failure and peripheral artery disease.
Epidemiologic studies show that exposure to lead, cadmium, or arsenic is associated with cardiovascular death mostly attributable to ischemic heart disease. In the United States alone, one study suggested that more than 450,000 deaths annually could be attributed to lead exposure.
“This is a global issue in which lower-income communities are disproportionately exposed to toxic metals through contaminated air, water, and soil,” Ana Navas-Acien, MD, PhD, vice chair of the statement writing group, said in a news release.
“Addressing metal exposure in these populations may provide a strategy to reduce cardiovascular disease disparities and advance environmental justice,” adds Dr. Navas-Acien, professor of environmental health sciences at Columbia University, New York.
Dr. Lamas said in an interview that the writing group is “hopeful that there will be a multilevel response” to publication of the scientific statement.
“On the societal level, we believe more effort can be made to measure these pollutants and protect the public. On the physician level, knowledge of metal levels could become part of the routine risk evaluation of the cardiac patient. On the individual level, patients can try to avoid these pollutants, by knowing arsenic levels of well-water, lead and cadmium levels of drinking water, avoiding tobacco and vaping, and using filters when available or necessary,” Dr. Lamas said.
“On the scientific level, identifying ubiquitous pollutants should spur scientists and pharmaceutical companies to develop preventive and therapeutic approaches.”
Finally, clinical trials should be encouraged to assess existing drugs that can remove these atherogenic toxins from the body or treat their ill effects. One such trial is expected to be completed within a year, Dr. Lamas added.
This scientific statement was prepared by the volunteer writing group on behalf of the AHA Council on Epidemiology and Prevention; the Council on Cardiovascular and Stroke Nursing; the Council on Lifestyle and Cardiometabolic Health; the Council on Peripheral Vascular Disease; and the Council on the Kidney in Cardiovascular Disease.
A version of this article originally appeared on Medscape.com.
FROM THE JOURNAL OF THE AMERICAN HEART ASSOCIATION
High Lp(a) tied to higher coronary plaque volume, progression
MANNHEIM, GERMANY – , an observational imaging study shows.
This could explain the greater risk for major adverse cardiovascular events seen in patients with high Lp(a) levels, suggests the research, presented during the annual European Atherosclerosis Society Congress.
The team performed follow-up coronary CT angiography (CCTA) on almost 275 patients who had undergone imaging approximately 10 years earlier, finding that almost one-third had high Lp(a) levels.
At baseline, per cent plaque volumes were 1.8 times greater in high Lp(a) patients versus those with low levels of the protein. After 10 years, plaque volumes were 3.3 times larger in patients with high Lp(a) levels.
Over this period, the rate of increase of plaque volume was 1.9 times greater in patients with high Lp(a) levels.
Study presenter Nick S. Nurmohamed, MD, PhD candidate, department of vascular medicine, Amsterdam University Medical Centers, also showed that high Lp(a) levels were associated with a 2.1-fold increase in rates of MACE.
He said in an interview that this finding could be related to Lp(a) increasing inflammatory signaling in the plaque, “making it more prone to rupture, and we saw that on the CCTA scans,” where high Lp(a) levels were associated with the presence of more high-risk plaques.
He added that in the absence of drugs that target Lp(a) levels directly, the results underline the need to focus on other means of lipid-lowering, as well as “creating awareness that Lp(a) is associated with plaque formation.”
Dr. Nurmohamed said that “for the moment, we have to treat patients with high Lp(a) with other risk-lowering therapies, such as low-density lipoprotein [LDL] cholesterol–lowering drugs, and the management of other risk factors.”
However, he noted that “there are a couple of Lp(a)-lowering medications in trials,” with results expected in the next 2-3 years.
“Then we will have the means to treat those patients, and with CCTA we can identify the patients with the biggest risk,” Dr. Nurmohamed added.
Plaque burden
Philippe Moulin, MD, PhD, head of endocrinology and professor of human nutrition at Faculté Lyon Est, Claude Bernard Lyon (France) 1 University, said that the association between Lp(a) and plaque burden has been seen previously in the literature in a very similar study but with only 1-year follow-up.
Similarly, registry data have suggested that Lp(a) is associated with worsening plaque progression over time.
“Here, with 10-year follow-up, [the study] is much more interesting,” due to its greater statistical power, he said in an interview. It is also “well-documented” and uses an “appropriate” methodology.
But Dr. Moulin underlined that the number of patients with high Lp(a) levels included in the study is relatively small.
Consequently, the researchers were not able to look at the level and rate of progression of atherosclerosis between different quartiles of Lp(a), “so you have no dose-response analysis.”
It also does not “establish causality,” as it remains an observational study, despite being longitudinal, “well done, and so on.”
Dr. Moulin added that the study nevertheless adds “one more stone” to the construct of the idea of high risk around high Lp(a) levels, and “prepares the ground” for the availability of two drugs to decrease Lp(a) levels, expected in 2026 and 2027.
These are expected to substantially reduce Lp(a) levels and achieve a reduction in cardiovascular risk of around 20%-40%, “which would be interesting,” especially as “we have patients who have Lp(a) levels four times above the upper normal value.”
Crucially, they may already have normal LDL cholesterol levels, meaning that, for some patients, “there is clearly a need for such treatment, as long as it is proven that it will decrease cardiovascular risk.”
For the moment, however, the strategy for managing patients with high Lp(a) remains to increase the dose of statin and to have more stringent targets, although Dr. Moulin pointed out that, “when you give statins, you raise slightly Lp(a) levels.”
Dr. Nurmohamed said in an interview that “we know from largely genetic and observational studies that Lp(a) is causally associated with atherosclerotic cardiovascular disease.”
What is less clear is the exact underlying mechanism, he said, noting that there have been several imaging studies in high and low Lp(a) patients that have yielded conflicting results in terms of the relationship with plaque burden.
To investigate the impact of Lp(a) levels on long-term coronary plaque progression, the team invited patients who had taken part in a previous CCTA study to undergo repeat CCTA, regardless of their underlying symptoms.
In all, 299 patients underwent follow-up imaging a median of 10.2 years after their original scan. Plaque volumes were quantified and adjusted for vessel volumes, and the patients were classified as having high (≥ 70 nmol/L) or low (< 70 nmol/L) Lp(a) levels.
After excluding patients who had undergone coronary artery bypass grafting, the team analyzed 274 patients with a mean age at baseline of 57 years. Of these, 159 (58%) were men. High Lp(a) levels were identified in 87 (32%) patients.
The team found that at baseline, patients with high Lp(a) levels had significantly larger percent atheroma volumes than those with low levels, at 3.92% versus 2.17%, or an absolute difference of 1.75% (P = .013).
The difference between the two groups was even greater at the follow-up, when percent atheroma volumes reached 8.75% in patients with high Lp(a) levels versus 3.90% for those with low levels, or an absolute difference of 4.85% (P = .005).
Similar findings were seen when looking separately at percentage of noncalcified and calcified plaque volumes as well as when analyzing for the presence of low-density plaques.
Multivariate analysis taking into account clinical risk factors, statin use, and CT tube voltage found that high Lp(a) levels were associated with a greater percent atheroma volume at baseline, at an odds ratio versus low Lp(a) of 1.83 (95% confidence interval, 0.12-3.54; P = .037).
High Lp(a) levels were also linked to a larger percent atheroma volume on follow-up imaging, at an odds ratio of 3.25 (95% CI, 0.80-5.71; P = .010), and a significantly greater change in atheroma volume from baseline to follow-up imaging, at an odds ratio of 1.86 (95% CI, 0.59-3.14; P = .005)
Finally, the team showed that, after adjusting for clinical risk factors, high baseline Lp(a) levels were associated with an increased risk of MACE during the follow-up period, at a hazard ratio versus low Lp(a) levels of 2.10 (95% CI, 1.01-4.29, P = .048).
No funding was declared. Dr. Nurmohamed is cofounder of Lipid Tools. Other authors declare relationships with Amgen, Novartis, Esperion, Sanofi-Regeneron, Ackee, Cleerly, GW Heart and Vascular Institute, Siemens Healthineers, and HeartFlow.
A version of this article first appeared on Medscape.com.
MANNHEIM, GERMANY – , an observational imaging study shows.
This could explain the greater risk for major adverse cardiovascular events seen in patients with high Lp(a) levels, suggests the research, presented during the annual European Atherosclerosis Society Congress.
The team performed follow-up coronary CT angiography (CCTA) on almost 275 patients who had undergone imaging approximately 10 years earlier, finding that almost one-third had high Lp(a) levels.
At baseline, per cent plaque volumes were 1.8 times greater in high Lp(a) patients versus those with low levels of the protein. After 10 years, plaque volumes were 3.3 times larger in patients with high Lp(a) levels.
Over this period, the rate of increase of plaque volume was 1.9 times greater in patients with high Lp(a) levels.
Study presenter Nick S. Nurmohamed, MD, PhD candidate, department of vascular medicine, Amsterdam University Medical Centers, also showed that high Lp(a) levels were associated with a 2.1-fold increase in rates of MACE.
He said in an interview that this finding could be related to Lp(a) increasing inflammatory signaling in the plaque, “making it more prone to rupture, and we saw that on the CCTA scans,” where high Lp(a) levels were associated with the presence of more high-risk plaques.
He added that in the absence of drugs that target Lp(a) levels directly, the results underline the need to focus on other means of lipid-lowering, as well as “creating awareness that Lp(a) is associated with plaque formation.”
Dr. Nurmohamed said that “for the moment, we have to treat patients with high Lp(a) with other risk-lowering therapies, such as low-density lipoprotein [LDL] cholesterol–lowering drugs, and the management of other risk factors.”
However, he noted that “there are a couple of Lp(a)-lowering medications in trials,” with results expected in the next 2-3 years.
“Then we will have the means to treat those patients, and with CCTA we can identify the patients with the biggest risk,” Dr. Nurmohamed added.
Plaque burden
Philippe Moulin, MD, PhD, head of endocrinology and professor of human nutrition at Faculté Lyon Est, Claude Bernard Lyon (France) 1 University, said that the association between Lp(a) and plaque burden has been seen previously in the literature in a very similar study but with only 1-year follow-up.
Similarly, registry data have suggested that Lp(a) is associated with worsening plaque progression over time.
“Here, with 10-year follow-up, [the study] is much more interesting,” due to its greater statistical power, he said in an interview. It is also “well-documented” and uses an “appropriate” methodology.
But Dr. Moulin underlined that the number of patients with high Lp(a) levels included in the study is relatively small.
Consequently, the researchers were not able to look at the level and rate of progression of atherosclerosis between different quartiles of Lp(a), “so you have no dose-response analysis.”
It also does not “establish causality,” as it remains an observational study, despite being longitudinal, “well done, and so on.”
Dr. Moulin added that the study nevertheless adds “one more stone” to the construct of the idea of high risk around high Lp(a) levels, and “prepares the ground” for the availability of two drugs to decrease Lp(a) levels, expected in 2026 and 2027.
These are expected to substantially reduce Lp(a) levels and achieve a reduction in cardiovascular risk of around 20%-40%, “which would be interesting,” especially as “we have patients who have Lp(a) levels four times above the upper normal value.”
Crucially, they may already have normal LDL cholesterol levels, meaning that, for some patients, “there is clearly a need for such treatment, as long as it is proven that it will decrease cardiovascular risk.”
For the moment, however, the strategy for managing patients with high Lp(a) remains to increase the dose of statin and to have more stringent targets, although Dr. Moulin pointed out that, “when you give statins, you raise slightly Lp(a) levels.”
Dr. Nurmohamed said in an interview that “we know from largely genetic and observational studies that Lp(a) is causally associated with atherosclerotic cardiovascular disease.”
What is less clear is the exact underlying mechanism, he said, noting that there have been several imaging studies in high and low Lp(a) patients that have yielded conflicting results in terms of the relationship with plaque burden.
To investigate the impact of Lp(a) levels on long-term coronary plaque progression, the team invited patients who had taken part in a previous CCTA study to undergo repeat CCTA, regardless of their underlying symptoms.
In all, 299 patients underwent follow-up imaging a median of 10.2 years after their original scan. Plaque volumes were quantified and adjusted for vessel volumes, and the patients were classified as having high (≥ 70 nmol/L) or low (< 70 nmol/L) Lp(a) levels.
After excluding patients who had undergone coronary artery bypass grafting, the team analyzed 274 patients with a mean age at baseline of 57 years. Of these, 159 (58%) were men. High Lp(a) levels were identified in 87 (32%) patients.
The team found that at baseline, patients with high Lp(a) levels had significantly larger percent atheroma volumes than those with low levels, at 3.92% versus 2.17%, or an absolute difference of 1.75% (P = .013).
The difference between the two groups was even greater at the follow-up, when percent atheroma volumes reached 8.75% in patients with high Lp(a) levels versus 3.90% for those with low levels, or an absolute difference of 4.85% (P = .005).
Similar findings were seen when looking separately at percentage of noncalcified and calcified plaque volumes as well as when analyzing for the presence of low-density plaques.
Multivariate analysis taking into account clinical risk factors, statin use, and CT tube voltage found that high Lp(a) levels were associated with a greater percent atheroma volume at baseline, at an odds ratio versus low Lp(a) of 1.83 (95% confidence interval, 0.12-3.54; P = .037).
High Lp(a) levels were also linked to a larger percent atheroma volume on follow-up imaging, at an odds ratio of 3.25 (95% CI, 0.80-5.71; P = .010), and a significantly greater change in atheroma volume from baseline to follow-up imaging, at an odds ratio of 1.86 (95% CI, 0.59-3.14; P = .005)
Finally, the team showed that, after adjusting for clinical risk factors, high baseline Lp(a) levels were associated with an increased risk of MACE during the follow-up period, at a hazard ratio versus low Lp(a) levels of 2.10 (95% CI, 1.01-4.29, P = .048).
No funding was declared. Dr. Nurmohamed is cofounder of Lipid Tools. Other authors declare relationships with Amgen, Novartis, Esperion, Sanofi-Regeneron, Ackee, Cleerly, GW Heart and Vascular Institute, Siemens Healthineers, and HeartFlow.
A version of this article first appeared on Medscape.com.
MANNHEIM, GERMANY – , an observational imaging study shows.
This could explain the greater risk for major adverse cardiovascular events seen in patients with high Lp(a) levels, suggests the research, presented during the annual European Atherosclerosis Society Congress.
The team performed follow-up coronary CT angiography (CCTA) on almost 275 patients who had undergone imaging approximately 10 years earlier, finding that almost one-third had high Lp(a) levels.
At baseline, per cent plaque volumes were 1.8 times greater in high Lp(a) patients versus those with low levels of the protein. After 10 years, plaque volumes were 3.3 times larger in patients with high Lp(a) levels.
Over this period, the rate of increase of plaque volume was 1.9 times greater in patients with high Lp(a) levels.
Study presenter Nick S. Nurmohamed, MD, PhD candidate, department of vascular medicine, Amsterdam University Medical Centers, also showed that high Lp(a) levels were associated with a 2.1-fold increase in rates of MACE.
He said in an interview that this finding could be related to Lp(a) increasing inflammatory signaling in the plaque, “making it more prone to rupture, and we saw that on the CCTA scans,” where high Lp(a) levels were associated with the presence of more high-risk plaques.
He added that in the absence of drugs that target Lp(a) levels directly, the results underline the need to focus on other means of lipid-lowering, as well as “creating awareness that Lp(a) is associated with plaque formation.”
Dr. Nurmohamed said that “for the moment, we have to treat patients with high Lp(a) with other risk-lowering therapies, such as low-density lipoprotein [LDL] cholesterol–lowering drugs, and the management of other risk factors.”
However, he noted that “there are a couple of Lp(a)-lowering medications in trials,” with results expected in the next 2-3 years.
“Then we will have the means to treat those patients, and with CCTA we can identify the patients with the biggest risk,” Dr. Nurmohamed added.
Plaque burden
Philippe Moulin, MD, PhD, head of endocrinology and professor of human nutrition at Faculté Lyon Est, Claude Bernard Lyon (France) 1 University, said that the association between Lp(a) and plaque burden has been seen previously in the literature in a very similar study but with only 1-year follow-up.
Similarly, registry data have suggested that Lp(a) is associated with worsening plaque progression over time.
“Here, with 10-year follow-up, [the study] is much more interesting,” due to its greater statistical power, he said in an interview. It is also “well-documented” and uses an “appropriate” methodology.
But Dr. Moulin underlined that the number of patients with high Lp(a) levels included in the study is relatively small.
Consequently, the researchers were not able to look at the level and rate of progression of atherosclerosis between different quartiles of Lp(a), “so you have no dose-response analysis.”
It also does not “establish causality,” as it remains an observational study, despite being longitudinal, “well done, and so on.”
Dr. Moulin added that the study nevertheless adds “one more stone” to the construct of the idea of high risk around high Lp(a) levels, and “prepares the ground” for the availability of two drugs to decrease Lp(a) levels, expected in 2026 and 2027.
These are expected to substantially reduce Lp(a) levels and achieve a reduction in cardiovascular risk of around 20%-40%, “which would be interesting,” especially as “we have patients who have Lp(a) levels four times above the upper normal value.”
Crucially, they may already have normal LDL cholesterol levels, meaning that, for some patients, “there is clearly a need for such treatment, as long as it is proven that it will decrease cardiovascular risk.”
For the moment, however, the strategy for managing patients with high Lp(a) remains to increase the dose of statin and to have more stringent targets, although Dr. Moulin pointed out that, “when you give statins, you raise slightly Lp(a) levels.”
Dr. Nurmohamed said in an interview that “we know from largely genetic and observational studies that Lp(a) is causally associated with atherosclerotic cardiovascular disease.”
What is less clear is the exact underlying mechanism, he said, noting that there have been several imaging studies in high and low Lp(a) patients that have yielded conflicting results in terms of the relationship with plaque burden.
To investigate the impact of Lp(a) levels on long-term coronary plaque progression, the team invited patients who had taken part in a previous CCTA study to undergo repeat CCTA, regardless of their underlying symptoms.
In all, 299 patients underwent follow-up imaging a median of 10.2 years after their original scan. Plaque volumes were quantified and adjusted for vessel volumes, and the patients were classified as having high (≥ 70 nmol/L) or low (< 70 nmol/L) Lp(a) levels.
After excluding patients who had undergone coronary artery bypass grafting, the team analyzed 274 patients with a mean age at baseline of 57 years. Of these, 159 (58%) were men. High Lp(a) levels were identified in 87 (32%) patients.
The team found that at baseline, patients with high Lp(a) levels had significantly larger percent atheroma volumes than those with low levels, at 3.92% versus 2.17%, or an absolute difference of 1.75% (P = .013).
The difference between the two groups was even greater at the follow-up, when percent atheroma volumes reached 8.75% in patients with high Lp(a) levels versus 3.90% for those with low levels, or an absolute difference of 4.85% (P = .005).
Similar findings were seen when looking separately at percentage of noncalcified and calcified plaque volumes as well as when analyzing for the presence of low-density plaques.
Multivariate analysis taking into account clinical risk factors, statin use, and CT tube voltage found that high Lp(a) levels were associated with a greater percent atheroma volume at baseline, at an odds ratio versus low Lp(a) of 1.83 (95% confidence interval, 0.12-3.54; P = .037).
High Lp(a) levels were also linked to a larger percent atheroma volume on follow-up imaging, at an odds ratio of 3.25 (95% CI, 0.80-5.71; P = .010), and a significantly greater change in atheroma volume from baseline to follow-up imaging, at an odds ratio of 1.86 (95% CI, 0.59-3.14; P = .005)
Finally, the team showed that, after adjusting for clinical risk factors, high baseline Lp(a) levels were associated with an increased risk of MACE during the follow-up period, at a hazard ratio versus low Lp(a) levels of 2.10 (95% CI, 1.01-4.29, P = .048).
No funding was declared. Dr. Nurmohamed is cofounder of Lipid Tools. Other authors declare relationships with Amgen, Novartis, Esperion, Sanofi-Regeneron, Ackee, Cleerly, GW Heart and Vascular Institute, Siemens Healthineers, and HeartFlow.
A version of this article first appeared on Medscape.com.
AT EAS 2023
Troponin to ID diabetes patients with silent heart disease?
– based on data from a representative sample of more than 10,000 U.S. adults.
The finding suggests hs-cTnT maybe a useful marker for adults with diabetes who could benefit from more aggressive CVD risk reduction despite having no clinical indications of CVD.
The results “highlight the substantial burden of subclinical CVD in persons with diabetes and emphasize the importance of early detection and treatment of CVD for this high-risk population,” say the authors of the research, published in the Journal of the American Heart Association.
“This is the first study to examine subclinical CVD, defined by elevated cardiac biomarkers, in a nationally representative population of adults with or without diabetes. It provides novel information on the high burden of subclinical CVD [in American adults with diabetes] and the potential utility of hs-cTnT for monitoring this risk in people with diabetes,” said Elizabeth Selvin, PhD, senior author and a professor of epidemiology at Johns Hopkins University, Baltimore.
“What we are seeing is that many people with type 2 diabetes who have not had a heart attack or a history of cardiovascular disease are at high risk for cardiovascular complications,” added Dr. Selvin in an AHA press release. “When we look at the whole population of people diagnosed with type 2 diabetes, about 27 million adults in the U.S., according to the [Centers for Disease Control and Prevention], some are at low risk and some are at high risk for cardiovascular disease, so the open question is: ‘Who is most at risk?’ These cardiac biomarkers give us a window into cardiovascular risk in people who otherwise might not be recognized as highest risk.”
“Our results provide evidence to support use of cardiac biomarkers for routine risk monitoring in high-risk populations such as people with diabetes,” Dr. Selvin noted in an interview.
Need for aggressive CVD risk reduction
The findings also indicate that people with diabetes and an elevated hs-cTnT “should be targeted for aggressive cardiovascular risk reduction, including lifestyle interventions, weight loss, and treatment with statins, blood pressure medications, and cardioprotective therapies such as sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagonlike peptide-1 (GLP-1) receptor agonists,” Dr. Selvin added.
“Cholesterol is often the factor that we target to reduce the risk of cardiovascular disease in people with type 2 diabetes,” she observed. “However, type 2 diabetes may have a direct effect on the heart not related to cholesterol levels. If type 2 diabetes is directly causing damage to the small vessels in the heart unrelated to cholesterol plaque buildup, then cholesterol-lowering medications are not going to prevent cardiac damage,” Dr. Selvin explained. “Our research suggests that additional non–statin-related therapies are needed to lower the cardiovascular disease risk in people with type 2 diabetes.”
However, she noted that a necessary step prior to formally recommending such a strategy is to run clinical trials to assess the efficacy of specific treatments, such as SGLT-2 inhibitors and GLP-1 agonists, in people with diabetes and elevated hs-cTnT.
“Randomized controlled trials would be best to test the relevance of measuring these biomarkers to assess risk in asymptomatic people with diabetes,” as well as prospective study of the value of hs-cTnT to guide treatment, commented Robert H. Eckel, MD, an endocrinologist affiliated with the University of Colorado at Denver, Aurora.
“I doubt measurements [of hs-cTnT] would be reimbursed [by third-party payers] if carried out without such outcome data,” he added.
Dr. Eckel also highlights the need to further validate in additional cohorts the link between elevations in hs-cTnT and CVD events in adults with diabetes, and to confirm that elevated levels of another cardiac biomarker – N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) – do not work as well as troponin as a risk marker for people with diabetes, another finding of the study.
ADA report already recommends testing these biomarkers for HF
However, a consensus report published in 2022 by the American Diabetes Association laid out the case for routinely and regularly measuring levels of both high sensitivity cardiac troponin and natriuretic peptides in people with diabetes for early identification of incident heart failure.
“Among individuals with diabetes, measurement of a natriuretic peptide or high-sensitivity cardiac troponin is recommended on at least a yearly basis to identify the earliest heart failure stages and implement strategies to prevent transition to symptomatic heart failure,” noted the ADA consensus report on heart failure.
The new study run by Dr. Selvin and coauthors used data collected by the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004 from U.S. adults who were at least 20 years old and had no history of CVD: myocardial infarction, stroke, coronary heart disease, or heart failure. This included 9,273 people without diabetes and 1,031 with diabetes, defined as a prior diagnosis or hemoglobin A1c of at least 6.5%.
“Cardiovascular risk varies substantially in adults with type 2 diabetes, highlighting the need for accurate risk stratification,” the authors observed.
All study participants had recorded measures of hs-cTnT and NT-proBNP.
The researchers considered an hs-cTnT level of greater than 14 ng/L and an NT-proBNP level of greater than 125 pg/mL as indicators of subclinical CVD.
The crude prevalence of elevated NT-proBNP was 33.4% among those with diabetes and 16.1% in those without diabetes. Elevated hs-cTnT occurred in 19% of those with diabetes and in 5% of those without diabetes. Elevated levels of both markers existed in 9% of those with diabetes and in 3% of those without diabetes.
“Approximately one in three adults with diabetes had subclinical CVD, with 19% having elevated levels of hs-cTnT, 23% having elevated NT-proBNP, and 9% having elevations in both cardiac biomarkers,” the researchers noted.
Diabetes linked with a doubled prevalence of elevated hs-cTnT
After adjustment for several demographic variables as well as traditional CVD risk factors, people with diabetes had a significant 98% higher rate of elevated hs-cTnT, compared with those without diabetes. But after similar adjustments, the rate of elevated NT-proBNP was significantly lower among people with diabetes, compared with controls, by a relative reduction of 24%.
“Our findings suggest that, in people with diabetes, hs-cTnT may be more useful [than NT-proBNP] for general risk monitoring, as its interpretation is less complicated,” said Dr. Selvin, who explained that “NT-proBNP is affected by overweight and obesity.”
In people with diabetes, the age-adjusted prevalence of elevated hs-cTnT ran higher in those with longer duration diabetes, and in those with less well-controlled diabetes based on a higher level of A1c. Neither of these factors showed any significant relationship with measured levels of NT-proBNP.
Further analysis linked the NHANES findings during 1999-2004 with U.S. national death records through the end of 2019. This showed that elevated levels of both hs-cTnT and NT-proBNP significantly linked with subsequently higher rates of all-cause mortality among people with diabetes. Elevated hs-cTnT linked with a 77% increased mortality and NT-proBNP linked with a 78% increased rate, compared with people with diabetes and no elevations in these markers, after adjustment for demographic variables and CVD risk factors.
However, for the outcome of cardiovascular death, elevated hs-cTnT linked with a nonsignificant 54% relative increase, while elevated NT-proBNP linked with a significant 2.46-fold relative increase.
The study “adds new data on biomarkers that are not routinely measured in asymptomatic people with or without diabetes” and the relationships of these markers to CVD mortality and all-cause mortality, Dr. Eckel concluded.
The study received no commercial funding, but used reagents donated by Abbott Laboratories, Ortho Clinical Diagnostics, Roche Diagnostics, and Siemens Healthcare Diagnostics. Dr. Selvin and Dr. Eckel had no disclosures.
A version of this article first appeared on Medscape.com.
– based on data from a representative sample of more than 10,000 U.S. adults.
The finding suggests hs-cTnT maybe a useful marker for adults with diabetes who could benefit from more aggressive CVD risk reduction despite having no clinical indications of CVD.
The results “highlight the substantial burden of subclinical CVD in persons with diabetes and emphasize the importance of early detection and treatment of CVD for this high-risk population,” say the authors of the research, published in the Journal of the American Heart Association.
“This is the first study to examine subclinical CVD, defined by elevated cardiac biomarkers, in a nationally representative population of adults with or without diabetes. It provides novel information on the high burden of subclinical CVD [in American adults with diabetes] and the potential utility of hs-cTnT for monitoring this risk in people with diabetes,” said Elizabeth Selvin, PhD, senior author and a professor of epidemiology at Johns Hopkins University, Baltimore.
“What we are seeing is that many people with type 2 diabetes who have not had a heart attack or a history of cardiovascular disease are at high risk for cardiovascular complications,” added Dr. Selvin in an AHA press release. “When we look at the whole population of people diagnosed with type 2 diabetes, about 27 million adults in the U.S., according to the [Centers for Disease Control and Prevention], some are at low risk and some are at high risk for cardiovascular disease, so the open question is: ‘Who is most at risk?’ These cardiac biomarkers give us a window into cardiovascular risk in people who otherwise might not be recognized as highest risk.”
“Our results provide evidence to support use of cardiac biomarkers for routine risk monitoring in high-risk populations such as people with diabetes,” Dr. Selvin noted in an interview.
Need for aggressive CVD risk reduction
The findings also indicate that people with diabetes and an elevated hs-cTnT “should be targeted for aggressive cardiovascular risk reduction, including lifestyle interventions, weight loss, and treatment with statins, blood pressure medications, and cardioprotective therapies such as sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagonlike peptide-1 (GLP-1) receptor agonists,” Dr. Selvin added.
“Cholesterol is often the factor that we target to reduce the risk of cardiovascular disease in people with type 2 diabetes,” she observed. “However, type 2 diabetes may have a direct effect on the heart not related to cholesterol levels. If type 2 diabetes is directly causing damage to the small vessels in the heart unrelated to cholesterol plaque buildup, then cholesterol-lowering medications are not going to prevent cardiac damage,” Dr. Selvin explained. “Our research suggests that additional non–statin-related therapies are needed to lower the cardiovascular disease risk in people with type 2 diabetes.”
However, she noted that a necessary step prior to formally recommending such a strategy is to run clinical trials to assess the efficacy of specific treatments, such as SGLT-2 inhibitors and GLP-1 agonists, in people with diabetes and elevated hs-cTnT.
“Randomized controlled trials would be best to test the relevance of measuring these biomarkers to assess risk in asymptomatic people with diabetes,” as well as prospective study of the value of hs-cTnT to guide treatment, commented Robert H. Eckel, MD, an endocrinologist affiliated with the University of Colorado at Denver, Aurora.
“I doubt measurements [of hs-cTnT] would be reimbursed [by third-party payers] if carried out without such outcome data,” he added.
Dr. Eckel also highlights the need to further validate in additional cohorts the link between elevations in hs-cTnT and CVD events in adults with diabetes, and to confirm that elevated levels of another cardiac biomarker – N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) – do not work as well as troponin as a risk marker for people with diabetes, another finding of the study.
ADA report already recommends testing these biomarkers for HF
However, a consensus report published in 2022 by the American Diabetes Association laid out the case for routinely and regularly measuring levels of both high sensitivity cardiac troponin and natriuretic peptides in people with diabetes for early identification of incident heart failure.
“Among individuals with diabetes, measurement of a natriuretic peptide or high-sensitivity cardiac troponin is recommended on at least a yearly basis to identify the earliest heart failure stages and implement strategies to prevent transition to symptomatic heart failure,” noted the ADA consensus report on heart failure.
The new study run by Dr. Selvin and coauthors used data collected by the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004 from U.S. adults who were at least 20 years old and had no history of CVD: myocardial infarction, stroke, coronary heart disease, or heart failure. This included 9,273 people without diabetes and 1,031 with diabetes, defined as a prior diagnosis or hemoglobin A1c of at least 6.5%.
“Cardiovascular risk varies substantially in adults with type 2 diabetes, highlighting the need for accurate risk stratification,” the authors observed.
All study participants had recorded measures of hs-cTnT and NT-proBNP.
The researchers considered an hs-cTnT level of greater than 14 ng/L and an NT-proBNP level of greater than 125 pg/mL as indicators of subclinical CVD.
The crude prevalence of elevated NT-proBNP was 33.4% among those with diabetes and 16.1% in those without diabetes. Elevated hs-cTnT occurred in 19% of those with diabetes and in 5% of those without diabetes. Elevated levels of both markers existed in 9% of those with diabetes and in 3% of those without diabetes.
“Approximately one in three adults with diabetes had subclinical CVD, with 19% having elevated levels of hs-cTnT, 23% having elevated NT-proBNP, and 9% having elevations in both cardiac biomarkers,” the researchers noted.
Diabetes linked with a doubled prevalence of elevated hs-cTnT
After adjustment for several demographic variables as well as traditional CVD risk factors, people with diabetes had a significant 98% higher rate of elevated hs-cTnT, compared with those without diabetes. But after similar adjustments, the rate of elevated NT-proBNP was significantly lower among people with diabetes, compared with controls, by a relative reduction of 24%.
“Our findings suggest that, in people with diabetes, hs-cTnT may be more useful [than NT-proBNP] for general risk monitoring, as its interpretation is less complicated,” said Dr. Selvin, who explained that “NT-proBNP is affected by overweight and obesity.”
In people with diabetes, the age-adjusted prevalence of elevated hs-cTnT ran higher in those with longer duration diabetes, and in those with less well-controlled diabetes based on a higher level of A1c. Neither of these factors showed any significant relationship with measured levels of NT-proBNP.
Further analysis linked the NHANES findings during 1999-2004 with U.S. national death records through the end of 2019. This showed that elevated levels of both hs-cTnT and NT-proBNP significantly linked with subsequently higher rates of all-cause mortality among people with diabetes. Elevated hs-cTnT linked with a 77% increased mortality and NT-proBNP linked with a 78% increased rate, compared with people with diabetes and no elevations in these markers, after adjustment for demographic variables and CVD risk factors.
However, for the outcome of cardiovascular death, elevated hs-cTnT linked with a nonsignificant 54% relative increase, while elevated NT-proBNP linked with a significant 2.46-fold relative increase.
The study “adds new data on biomarkers that are not routinely measured in asymptomatic people with or without diabetes” and the relationships of these markers to CVD mortality and all-cause mortality, Dr. Eckel concluded.
The study received no commercial funding, but used reagents donated by Abbott Laboratories, Ortho Clinical Diagnostics, Roche Diagnostics, and Siemens Healthcare Diagnostics. Dr. Selvin and Dr. Eckel had no disclosures.
A version of this article first appeared on Medscape.com.
– based on data from a representative sample of more than 10,000 U.S. adults.
The finding suggests hs-cTnT maybe a useful marker for adults with diabetes who could benefit from more aggressive CVD risk reduction despite having no clinical indications of CVD.
The results “highlight the substantial burden of subclinical CVD in persons with diabetes and emphasize the importance of early detection and treatment of CVD for this high-risk population,” say the authors of the research, published in the Journal of the American Heart Association.
“This is the first study to examine subclinical CVD, defined by elevated cardiac biomarkers, in a nationally representative population of adults with or without diabetes. It provides novel information on the high burden of subclinical CVD [in American adults with diabetes] and the potential utility of hs-cTnT for monitoring this risk in people with diabetes,” said Elizabeth Selvin, PhD, senior author and a professor of epidemiology at Johns Hopkins University, Baltimore.
“What we are seeing is that many people with type 2 diabetes who have not had a heart attack or a history of cardiovascular disease are at high risk for cardiovascular complications,” added Dr. Selvin in an AHA press release. “When we look at the whole population of people diagnosed with type 2 diabetes, about 27 million adults in the U.S., according to the [Centers for Disease Control and Prevention], some are at low risk and some are at high risk for cardiovascular disease, so the open question is: ‘Who is most at risk?’ These cardiac biomarkers give us a window into cardiovascular risk in people who otherwise might not be recognized as highest risk.”
“Our results provide evidence to support use of cardiac biomarkers for routine risk monitoring in high-risk populations such as people with diabetes,” Dr. Selvin noted in an interview.
Need for aggressive CVD risk reduction
The findings also indicate that people with diabetes and an elevated hs-cTnT “should be targeted for aggressive cardiovascular risk reduction, including lifestyle interventions, weight loss, and treatment with statins, blood pressure medications, and cardioprotective therapies such as sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagonlike peptide-1 (GLP-1) receptor agonists,” Dr. Selvin added.
“Cholesterol is often the factor that we target to reduce the risk of cardiovascular disease in people with type 2 diabetes,” she observed. “However, type 2 diabetes may have a direct effect on the heart not related to cholesterol levels. If type 2 diabetes is directly causing damage to the small vessels in the heart unrelated to cholesterol plaque buildup, then cholesterol-lowering medications are not going to prevent cardiac damage,” Dr. Selvin explained. “Our research suggests that additional non–statin-related therapies are needed to lower the cardiovascular disease risk in people with type 2 diabetes.”
However, she noted that a necessary step prior to formally recommending such a strategy is to run clinical trials to assess the efficacy of specific treatments, such as SGLT-2 inhibitors and GLP-1 agonists, in people with diabetes and elevated hs-cTnT.
“Randomized controlled trials would be best to test the relevance of measuring these biomarkers to assess risk in asymptomatic people with diabetes,” as well as prospective study of the value of hs-cTnT to guide treatment, commented Robert H. Eckel, MD, an endocrinologist affiliated with the University of Colorado at Denver, Aurora.
“I doubt measurements [of hs-cTnT] would be reimbursed [by third-party payers] if carried out without such outcome data,” he added.
Dr. Eckel also highlights the need to further validate in additional cohorts the link between elevations in hs-cTnT and CVD events in adults with diabetes, and to confirm that elevated levels of another cardiac biomarker – N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) – do not work as well as troponin as a risk marker for people with diabetes, another finding of the study.
ADA report already recommends testing these biomarkers for HF
However, a consensus report published in 2022 by the American Diabetes Association laid out the case for routinely and regularly measuring levels of both high sensitivity cardiac troponin and natriuretic peptides in people with diabetes for early identification of incident heart failure.
“Among individuals with diabetes, measurement of a natriuretic peptide or high-sensitivity cardiac troponin is recommended on at least a yearly basis to identify the earliest heart failure stages and implement strategies to prevent transition to symptomatic heart failure,” noted the ADA consensus report on heart failure.
The new study run by Dr. Selvin and coauthors used data collected by the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004 from U.S. adults who were at least 20 years old and had no history of CVD: myocardial infarction, stroke, coronary heart disease, or heart failure. This included 9,273 people without diabetes and 1,031 with diabetes, defined as a prior diagnosis or hemoglobin A1c of at least 6.5%.
“Cardiovascular risk varies substantially in adults with type 2 diabetes, highlighting the need for accurate risk stratification,” the authors observed.
All study participants had recorded measures of hs-cTnT and NT-proBNP.
The researchers considered an hs-cTnT level of greater than 14 ng/L and an NT-proBNP level of greater than 125 pg/mL as indicators of subclinical CVD.
The crude prevalence of elevated NT-proBNP was 33.4% among those with diabetes and 16.1% in those without diabetes. Elevated hs-cTnT occurred in 19% of those with diabetes and in 5% of those without diabetes. Elevated levels of both markers existed in 9% of those with diabetes and in 3% of those without diabetes.
“Approximately one in three adults with diabetes had subclinical CVD, with 19% having elevated levels of hs-cTnT, 23% having elevated NT-proBNP, and 9% having elevations in both cardiac biomarkers,” the researchers noted.
Diabetes linked with a doubled prevalence of elevated hs-cTnT
After adjustment for several demographic variables as well as traditional CVD risk factors, people with diabetes had a significant 98% higher rate of elevated hs-cTnT, compared with those without diabetes. But after similar adjustments, the rate of elevated NT-proBNP was significantly lower among people with diabetes, compared with controls, by a relative reduction of 24%.
“Our findings suggest that, in people with diabetes, hs-cTnT may be more useful [than NT-proBNP] for general risk monitoring, as its interpretation is less complicated,” said Dr. Selvin, who explained that “NT-proBNP is affected by overweight and obesity.”
In people with diabetes, the age-adjusted prevalence of elevated hs-cTnT ran higher in those with longer duration diabetes, and in those with less well-controlled diabetes based on a higher level of A1c. Neither of these factors showed any significant relationship with measured levels of NT-proBNP.
Further analysis linked the NHANES findings during 1999-2004 with U.S. national death records through the end of 2019. This showed that elevated levels of both hs-cTnT and NT-proBNP significantly linked with subsequently higher rates of all-cause mortality among people with diabetes. Elevated hs-cTnT linked with a 77% increased mortality and NT-proBNP linked with a 78% increased rate, compared with people with diabetes and no elevations in these markers, after adjustment for demographic variables and CVD risk factors.
However, for the outcome of cardiovascular death, elevated hs-cTnT linked with a nonsignificant 54% relative increase, while elevated NT-proBNP linked with a significant 2.46-fold relative increase.
The study “adds new data on biomarkers that are not routinely measured in asymptomatic people with or without diabetes” and the relationships of these markers to CVD mortality and all-cause mortality, Dr. Eckel concluded.
The study received no commercial funding, but used reagents donated by Abbott Laboratories, Ortho Clinical Diagnostics, Roche Diagnostics, and Siemens Healthcare Diagnostics. Dr. Selvin and Dr. Eckel had no disclosures.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF THE AMERICAN HEART ASSOCIATION
Overweight in heterozygous FH tied to even higher CAD risk
MANNHEIM, GERMANY – – rates that appear to have a substantial impact on these patients’ already increased risk of coronary artery disease, a registry analysis suggests.
Data on almost 36,000 individuals with FH were collated from an international registry, revealing that 55% of adults and 25% of children and adolescents with the homozygous form of FH had overweight or obesity. The figures for heterozygous FH were 52% and 27%, respectively.
Crucially, overweight or obesity was associated with substantially increased rates of coronary artery disease, particularly in persons with heterozygous FH, among whom adults with obesity faced a twofold increased risk, rising to more than sixfold in children and adolescents.
Moreover, “obesity is associated with a worse lipid profile, even from childhood, regardless of whether a patient is on medication,” said study presenter Amany Elshorbagy, DPhil, Cardiovascular Epidemiologist, department of primary care and public health, Imperial College London.
She added that, with the increased risk of coronary artery disease associated with heterozygous FH, the results showed that “together with lipid-lowering medication, weight management is needed.”
The research was presented at the annual meeting of the European Atherosclerosis Society.
Tended to be thin
Alberico L. Catapano, MD, PhD, director of cardiovascular research and of the Lipoproteins and Atherosclerosis Laboratory of IRCCS Multimedica, Milan, and past president of the EAS, said in an interview that, historically, few FH patients were overweight or obese; rather, they tended to be thin.
However, there is now “a trend for people with FH to show more diabetes and obesity,” with the “bottom line” being that, as they are already at increased risk of coronary artery disease, it pushes their risk up even further.
In other words, if a risk factor such as obesity is added “on top of the strongest risk factor, that is LDL cholesterol, it is not one plus one makes two, it is one plus one makes three,” he said.
As such, Dr. Catapano believes that the study is “very interesting,” because it further underlines the importance of weight management for individuals with increased LDL cholesterol, “especially when you have genetic forms, like FH.”
Dr. Catapano’s comments were echoed by session co-chair Ulrike Schatz, MD, leader of the lipidology specialty department at the University Hospital Carl Gustav Carus, Technical University of Dresden (Germany).
Indeed, she told Dr. Elshorbagy before her presentation that she finds “a lot of my FH patients have a tendency towards anorexia.”
In an interview, Dr. Elshorbagy said that that reaction was typical of “most of the clinicians” she had spoken to. Upon seeing her data, especially for homozygous FH patients, they say, “They are on the lean side.”
Consequently, the research team went into the study “with the expectation that they might have a lower prevalence of obesity and overweight than the general population,” but “that’s not what we’re seeing.”
Dr. Elshorbagy noted that it would be helpful to have longitudinal data to determine whether, 50 years ago, patients with HF “were leaner, along with the rest of the population.”
The registry data are cross-sectional, and the team is now reaching out to the respective national lead investigators to submit follow-up data on their patients, with the aim of looking at changes in body weight and the impact on outcomes over time.
Another key question for the researchers is in regard to fat distribution, as body mass index “is not the best predictor of heart disease,” Dr. Elshorbagy said, but is rather central obesity.
Although they have also asked investigators to share waist circumference data, she conceded that it is a measurement that “is a lot harder to standardize across centers and countries; it’s not like putting patients on a scale.”
Overall, Dr. Elshorbagy believes that her findings indicate that clinicians should take a broader, more holistic approach toward their patients – in other words, an approach in which lipid lowering medication is “key but is just one of several things we need to do to make sure the coronary event rate goes down.”
More with than without
Dr. Elshorbagy began her presentation by highlighting that the prevalence of overweight and obesity ranges from 50% to 70% and that it is “the only health condition where you’ve got more people worldwide with the condition than without.”
Crucially, overweight increases the risk of coronary artery disease by approximately 20%. Among patients with obesity, the risk rises to 50%.
Given that FH patients “already have a very high risk of cardiovascular disease from their high cholesterol levels,” the team set out to determine rates of obesity and overweight in this population and their impact on coronary artery disease risk.
They used cross-sectional data from the EAS FH Studies Collaboration Global Registry, which involves 29,262 adults aged greater than or equal to 18 years and 6,275 children and adolescents aged 5 to 17 years with heterozygous FH, and 325 adults and 57 children with homozygous FH.
Dividing the adults into standard BMI categories, they found that 16% of heterozygous and 23% of homozygous FH patients had obesity, while 52% and 55%, respectively, had overweight or obesity.
For children, the team used World Health Organization z score cutoffs, which indicated that 9% of patients with heterozygous FH and 7% of patients with homozygous FH had obesity. Rates of overweight or obesity were 27% and 25%, respectively.
Among patients with heterozygous FH, rates of overweight or obesity among adults were 50% in high-income countries and 63% in other countries; among children, the rates were and 27% and 29%, respectively.
Stratified by region, the team found that the lowest rate of overweight or obesity among adult patients with heterozygous FH was in Eastern Asia, at 27%, while the highest was in Northern Africa/Western Asia (the Middle East), at 82%.
In North America, 56% of adult patients had overweight or obesity. The prevalence of coronary artery disease rose with increasing BMI.
Among adult patients with heterozygous FH, 11.3% of those with normal weight had coronary artery disease; the percentage rose to 22.9% among those with overweight, and 30.9% among those with obesity. Among children, the corresponding figures were 0.1%, 0.2%, and 0.7%.
Putting adults and children with homozygous FH together, the researchers found that 29.0% of patients with normal weight had coronary artery disease, compared with 31.3% of those with overweight and 49.3% of those with obesity.
Moreover, the results showed that levels of LDL and remnant cholesterol were significantly associated with BMI in adults and children with heterozygous FH, even after adjusting for age, sex, and lipid-lowering medication (P < .001 for all).
Multivariate analysis that took into account age, sex, lipid-lowering medication, and LDL cholesterol revealed that having obesity, compared with not having obesity, was associated with a substantial increase in the risk of coronary artery disease among patients with heterozygous FH.
Among adults with the condition, the odds ratio was 2.16 (95% confidence interval, 1.97-2.36), while among children and adolescents, it was 6.87 (95% CI, 1.55-30.46).
The results remained similar after further adjustment for the presence of diabetes and when considering peripheral artery disease and stroke.
No funding for the study was declared. Dr. Elshorbagy has relationships with Amgen, Daiichi Sankyo, and Regeneron.
A version of this article first appeared on Medscape.com.
MANNHEIM, GERMANY – – rates that appear to have a substantial impact on these patients’ already increased risk of coronary artery disease, a registry analysis suggests.
Data on almost 36,000 individuals with FH were collated from an international registry, revealing that 55% of adults and 25% of children and adolescents with the homozygous form of FH had overweight or obesity. The figures for heterozygous FH were 52% and 27%, respectively.
Crucially, overweight or obesity was associated with substantially increased rates of coronary artery disease, particularly in persons with heterozygous FH, among whom adults with obesity faced a twofold increased risk, rising to more than sixfold in children and adolescents.
Moreover, “obesity is associated with a worse lipid profile, even from childhood, regardless of whether a patient is on medication,” said study presenter Amany Elshorbagy, DPhil, Cardiovascular Epidemiologist, department of primary care and public health, Imperial College London.
She added that, with the increased risk of coronary artery disease associated with heterozygous FH, the results showed that “together with lipid-lowering medication, weight management is needed.”
The research was presented at the annual meeting of the European Atherosclerosis Society.
Tended to be thin
Alberico L. Catapano, MD, PhD, director of cardiovascular research and of the Lipoproteins and Atherosclerosis Laboratory of IRCCS Multimedica, Milan, and past president of the EAS, said in an interview that, historically, few FH patients were overweight or obese; rather, they tended to be thin.
However, there is now “a trend for people with FH to show more diabetes and obesity,” with the “bottom line” being that, as they are already at increased risk of coronary artery disease, it pushes their risk up even further.
In other words, if a risk factor such as obesity is added “on top of the strongest risk factor, that is LDL cholesterol, it is not one plus one makes two, it is one plus one makes three,” he said.
As such, Dr. Catapano believes that the study is “very interesting,” because it further underlines the importance of weight management for individuals with increased LDL cholesterol, “especially when you have genetic forms, like FH.”
Dr. Catapano’s comments were echoed by session co-chair Ulrike Schatz, MD, leader of the lipidology specialty department at the University Hospital Carl Gustav Carus, Technical University of Dresden (Germany).
Indeed, she told Dr. Elshorbagy before her presentation that she finds “a lot of my FH patients have a tendency towards anorexia.”
In an interview, Dr. Elshorbagy said that that reaction was typical of “most of the clinicians” she had spoken to. Upon seeing her data, especially for homozygous FH patients, they say, “They are on the lean side.”
Consequently, the research team went into the study “with the expectation that they might have a lower prevalence of obesity and overweight than the general population,” but “that’s not what we’re seeing.”
Dr. Elshorbagy noted that it would be helpful to have longitudinal data to determine whether, 50 years ago, patients with HF “were leaner, along with the rest of the population.”
The registry data are cross-sectional, and the team is now reaching out to the respective national lead investigators to submit follow-up data on their patients, with the aim of looking at changes in body weight and the impact on outcomes over time.
Another key question for the researchers is in regard to fat distribution, as body mass index “is not the best predictor of heart disease,” Dr. Elshorbagy said, but is rather central obesity.
Although they have also asked investigators to share waist circumference data, she conceded that it is a measurement that “is a lot harder to standardize across centers and countries; it’s not like putting patients on a scale.”
Overall, Dr. Elshorbagy believes that her findings indicate that clinicians should take a broader, more holistic approach toward their patients – in other words, an approach in which lipid lowering medication is “key but is just one of several things we need to do to make sure the coronary event rate goes down.”
More with than without
Dr. Elshorbagy began her presentation by highlighting that the prevalence of overweight and obesity ranges from 50% to 70% and that it is “the only health condition where you’ve got more people worldwide with the condition than without.”
Crucially, overweight increases the risk of coronary artery disease by approximately 20%. Among patients with obesity, the risk rises to 50%.
Given that FH patients “already have a very high risk of cardiovascular disease from their high cholesterol levels,” the team set out to determine rates of obesity and overweight in this population and their impact on coronary artery disease risk.
They used cross-sectional data from the EAS FH Studies Collaboration Global Registry, which involves 29,262 adults aged greater than or equal to 18 years and 6,275 children and adolescents aged 5 to 17 years with heterozygous FH, and 325 adults and 57 children with homozygous FH.
Dividing the adults into standard BMI categories, they found that 16% of heterozygous and 23% of homozygous FH patients had obesity, while 52% and 55%, respectively, had overweight or obesity.
For children, the team used World Health Organization z score cutoffs, which indicated that 9% of patients with heterozygous FH and 7% of patients with homozygous FH had obesity. Rates of overweight or obesity were 27% and 25%, respectively.
Among patients with heterozygous FH, rates of overweight or obesity among adults were 50% in high-income countries and 63% in other countries; among children, the rates were and 27% and 29%, respectively.
Stratified by region, the team found that the lowest rate of overweight or obesity among adult patients with heterozygous FH was in Eastern Asia, at 27%, while the highest was in Northern Africa/Western Asia (the Middle East), at 82%.
In North America, 56% of adult patients had overweight or obesity. The prevalence of coronary artery disease rose with increasing BMI.
Among adult patients with heterozygous FH, 11.3% of those with normal weight had coronary artery disease; the percentage rose to 22.9% among those with overweight, and 30.9% among those with obesity. Among children, the corresponding figures were 0.1%, 0.2%, and 0.7%.
Putting adults and children with homozygous FH together, the researchers found that 29.0% of patients with normal weight had coronary artery disease, compared with 31.3% of those with overweight and 49.3% of those with obesity.
Moreover, the results showed that levels of LDL and remnant cholesterol were significantly associated with BMI in adults and children with heterozygous FH, even after adjusting for age, sex, and lipid-lowering medication (P < .001 for all).
Multivariate analysis that took into account age, sex, lipid-lowering medication, and LDL cholesterol revealed that having obesity, compared with not having obesity, was associated with a substantial increase in the risk of coronary artery disease among patients with heterozygous FH.
Among adults with the condition, the odds ratio was 2.16 (95% confidence interval, 1.97-2.36), while among children and adolescents, it was 6.87 (95% CI, 1.55-30.46).
The results remained similar after further adjustment for the presence of diabetes and when considering peripheral artery disease and stroke.
No funding for the study was declared. Dr. Elshorbagy has relationships with Amgen, Daiichi Sankyo, and Regeneron.
A version of this article first appeared on Medscape.com.
MANNHEIM, GERMANY – – rates that appear to have a substantial impact on these patients’ already increased risk of coronary artery disease, a registry analysis suggests.
Data on almost 36,000 individuals with FH were collated from an international registry, revealing that 55% of adults and 25% of children and adolescents with the homozygous form of FH had overweight or obesity. The figures for heterozygous FH were 52% and 27%, respectively.
Crucially, overweight or obesity was associated with substantially increased rates of coronary artery disease, particularly in persons with heterozygous FH, among whom adults with obesity faced a twofold increased risk, rising to more than sixfold in children and adolescents.
Moreover, “obesity is associated with a worse lipid profile, even from childhood, regardless of whether a patient is on medication,” said study presenter Amany Elshorbagy, DPhil, Cardiovascular Epidemiologist, department of primary care and public health, Imperial College London.
She added that, with the increased risk of coronary artery disease associated with heterozygous FH, the results showed that “together with lipid-lowering medication, weight management is needed.”
The research was presented at the annual meeting of the European Atherosclerosis Society.
Tended to be thin
Alberico L. Catapano, MD, PhD, director of cardiovascular research and of the Lipoproteins and Atherosclerosis Laboratory of IRCCS Multimedica, Milan, and past president of the EAS, said in an interview that, historically, few FH patients were overweight or obese; rather, they tended to be thin.
However, there is now “a trend for people with FH to show more diabetes and obesity,” with the “bottom line” being that, as they are already at increased risk of coronary artery disease, it pushes their risk up even further.
In other words, if a risk factor such as obesity is added “on top of the strongest risk factor, that is LDL cholesterol, it is not one plus one makes two, it is one plus one makes three,” he said.
As such, Dr. Catapano believes that the study is “very interesting,” because it further underlines the importance of weight management for individuals with increased LDL cholesterol, “especially when you have genetic forms, like FH.”
Dr. Catapano’s comments were echoed by session co-chair Ulrike Schatz, MD, leader of the lipidology specialty department at the University Hospital Carl Gustav Carus, Technical University of Dresden (Germany).
Indeed, she told Dr. Elshorbagy before her presentation that she finds “a lot of my FH patients have a tendency towards anorexia.”
In an interview, Dr. Elshorbagy said that that reaction was typical of “most of the clinicians” she had spoken to. Upon seeing her data, especially for homozygous FH patients, they say, “They are on the lean side.”
Consequently, the research team went into the study “with the expectation that they might have a lower prevalence of obesity and overweight than the general population,” but “that’s not what we’re seeing.”
Dr. Elshorbagy noted that it would be helpful to have longitudinal data to determine whether, 50 years ago, patients with HF “were leaner, along with the rest of the population.”
The registry data are cross-sectional, and the team is now reaching out to the respective national lead investigators to submit follow-up data on their patients, with the aim of looking at changes in body weight and the impact on outcomes over time.
Another key question for the researchers is in regard to fat distribution, as body mass index “is not the best predictor of heart disease,” Dr. Elshorbagy said, but is rather central obesity.
Although they have also asked investigators to share waist circumference data, she conceded that it is a measurement that “is a lot harder to standardize across centers and countries; it’s not like putting patients on a scale.”
Overall, Dr. Elshorbagy believes that her findings indicate that clinicians should take a broader, more holistic approach toward their patients – in other words, an approach in which lipid lowering medication is “key but is just one of several things we need to do to make sure the coronary event rate goes down.”
More with than without
Dr. Elshorbagy began her presentation by highlighting that the prevalence of overweight and obesity ranges from 50% to 70% and that it is “the only health condition where you’ve got more people worldwide with the condition than without.”
Crucially, overweight increases the risk of coronary artery disease by approximately 20%. Among patients with obesity, the risk rises to 50%.
Given that FH patients “already have a very high risk of cardiovascular disease from their high cholesterol levels,” the team set out to determine rates of obesity and overweight in this population and their impact on coronary artery disease risk.
They used cross-sectional data from the EAS FH Studies Collaboration Global Registry, which involves 29,262 adults aged greater than or equal to 18 years and 6,275 children and adolescents aged 5 to 17 years with heterozygous FH, and 325 adults and 57 children with homozygous FH.
Dividing the adults into standard BMI categories, they found that 16% of heterozygous and 23% of homozygous FH patients had obesity, while 52% and 55%, respectively, had overweight or obesity.
For children, the team used World Health Organization z score cutoffs, which indicated that 9% of patients with heterozygous FH and 7% of patients with homozygous FH had obesity. Rates of overweight or obesity were 27% and 25%, respectively.
Among patients with heterozygous FH, rates of overweight or obesity among adults were 50% in high-income countries and 63% in other countries; among children, the rates were and 27% and 29%, respectively.
Stratified by region, the team found that the lowest rate of overweight or obesity among adult patients with heterozygous FH was in Eastern Asia, at 27%, while the highest was in Northern Africa/Western Asia (the Middle East), at 82%.
In North America, 56% of adult patients had overweight or obesity. The prevalence of coronary artery disease rose with increasing BMI.
Among adult patients with heterozygous FH, 11.3% of those with normal weight had coronary artery disease; the percentage rose to 22.9% among those with overweight, and 30.9% among those with obesity. Among children, the corresponding figures were 0.1%, 0.2%, and 0.7%.
Putting adults and children with homozygous FH together, the researchers found that 29.0% of patients with normal weight had coronary artery disease, compared with 31.3% of those with overweight and 49.3% of those with obesity.
Moreover, the results showed that levels of LDL and remnant cholesterol were significantly associated with BMI in adults and children with heterozygous FH, even after adjusting for age, sex, and lipid-lowering medication (P < .001 for all).
Multivariate analysis that took into account age, sex, lipid-lowering medication, and LDL cholesterol revealed that having obesity, compared with not having obesity, was associated with a substantial increase in the risk of coronary artery disease among patients with heterozygous FH.
Among adults with the condition, the odds ratio was 2.16 (95% confidence interval, 1.97-2.36), while among children and adolescents, it was 6.87 (95% CI, 1.55-30.46).
The results remained similar after further adjustment for the presence of diabetes and when considering peripheral artery disease and stroke.
No funding for the study was declared. Dr. Elshorbagy has relationships with Amgen, Daiichi Sankyo, and Regeneron.
A version of this article first appeared on Medscape.com.
AT EAS 2023
Coronary artery calcium score bests polygenic risk score in CHD prediction
As a predictor of coronary heart disease (CHD) events, the coronary artery calcium (CAC) score on computed tomography had better risk discrimination than the polygenic risk score, a binational study found. And when added to classic cardiovascular risk factors, the CAC score significantly improved risk classification while the polygenic risk factor score did not.
These findings emerged from two large cohorts of middle-aged and older White adults from the United States and the Netherlands in the first head-to-head comparison of these two approaches. Led by Sadiya S. Kahn, MD, MSc, an assistant professor of medicine (cardiology) and preventive medicine (epidemiology) at Northwestern University, Chicago, the study was published online in JAMA.
There has been much interest in using both genetic factors and CT imaging to better identify individuals at risk for heart disease. “Each approach has advantages and disadvantages, and we wanted to better understand the comparative predictive utility to provide support for what the preferred approach should be,” Dr. Kahn said in an interview. “We focused on middle-aged to older adults for whom current risk prediction equations are relevant in estimating risk with the Pooled Cohort Equation, or PCE.”
The superiority of the CT-imaged coronary artery risk score may be because of its direct visualization of calcification in the arteries and the subclinical disease burden rather than a focus on common genetic variants, Dr. Kahn explained. “In addition, prior studies have demonstrated that genetics, or inherited risk, is not destiny, so this score may not perform as well for risk discrimination as the traditional risk factors themselves along with CT.”
The study
Study participants came from the U.S. Multi-Ethnic Study of Atherosclerosis (MESA, n = 1,991) and the Dutch Rotterdam Study (RS, n = 1,217). Ages ranged from 45 to 79, with the medians in the two cohorts 61 and 68 years, respectively. Slightly more than half of participants in both groups were female.
Traditional risk factors were used to calculate CHD risk with pooled cohort equations, while computed tomography was used to determine the CAC score and genotyped samples for a validated polygenic risk score.
Both scores were significantly associated with 10-year risk of incident CHD.
The median predicted atherosclerotic disease risk based on traditional risk factors was 6.99% in MESA and 5.93% in RS. During the total available follow-up in MESA (median, 16.0 years) and RS (median, 14.2 years), incident CHD occurred in 187 participants (9.4%) and 98 participants (8.1%), respectively.
C (concordance) statistics for the two scores showed the superiority of the CAC. This statistic measures a model’s ability to rank patients from high to low risk, with a value of 1 being perfect risk fit or concordance and 0.70 or more indicating good concordance and risk discrimination. The CAC score had a C statistic of 0.76 (95% confidence interval, 0.71-0.79) vs. 0.69 for the polygenic risk score (95% CI, 0.63-0.71).
When each score was added to PCEs, the C statistics changed as follows: CAC score, 0.09 (95% CI, 0.06-0.13); polygenic risk score, 0.02 (95% CI, 0.00-0.04); and 0.10 (95% CI, 0.07-0.14) for both.
Net reclassification significantly improved with the CAC plus PCEs by the following values: 0.19 (95% CI, 0.06-0.28). The change was not significant, however, with the polygenic risk score plus PCEs: 0.04 (95% CI, –0.05-0.10).
In the clinical setting, Dr. Kahn said, “The use of CT in patients who are at intermediate risk for heart disease can be helpful in refining risk estimation and guiding recommendations for lipid-lowering therapy. Polygenic risk scores are not helpful in middle-aged to older adults above and beyond traditional risk factors for predicting risk of heart disease.”
This study was supported by the National Heart, Lung, and Blood Institute. MESA is supported by the NHLBI. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Netherlands Genomics Initiative; the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. Dr. Khan reported grants from the NHLBI and the NIH during the study and outside of the submitted work. Several coauthors reported grant support from, variously, the NIH, the NHLBI, and the American Heart Association.
As a predictor of coronary heart disease (CHD) events, the coronary artery calcium (CAC) score on computed tomography had better risk discrimination than the polygenic risk score, a binational study found. And when added to classic cardiovascular risk factors, the CAC score significantly improved risk classification while the polygenic risk factor score did not.
These findings emerged from two large cohorts of middle-aged and older White adults from the United States and the Netherlands in the first head-to-head comparison of these two approaches. Led by Sadiya S. Kahn, MD, MSc, an assistant professor of medicine (cardiology) and preventive medicine (epidemiology) at Northwestern University, Chicago, the study was published online in JAMA.
There has been much interest in using both genetic factors and CT imaging to better identify individuals at risk for heart disease. “Each approach has advantages and disadvantages, and we wanted to better understand the comparative predictive utility to provide support for what the preferred approach should be,” Dr. Kahn said in an interview. “We focused on middle-aged to older adults for whom current risk prediction equations are relevant in estimating risk with the Pooled Cohort Equation, or PCE.”
The superiority of the CT-imaged coronary artery risk score may be because of its direct visualization of calcification in the arteries and the subclinical disease burden rather than a focus on common genetic variants, Dr. Kahn explained. “In addition, prior studies have demonstrated that genetics, or inherited risk, is not destiny, so this score may not perform as well for risk discrimination as the traditional risk factors themselves along with CT.”
The study
Study participants came from the U.S. Multi-Ethnic Study of Atherosclerosis (MESA, n = 1,991) and the Dutch Rotterdam Study (RS, n = 1,217). Ages ranged from 45 to 79, with the medians in the two cohorts 61 and 68 years, respectively. Slightly more than half of participants in both groups were female.
Traditional risk factors were used to calculate CHD risk with pooled cohort equations, while computed tomography was used to determine the CAC score and genotyped samples for a validated polygenic risk score.
Both scores were significantly associated with 10-year risk of incident CHD.
The median predicted atherosclerotic disease risk based on traditional risk factors was 6.99% in MESA and 5.93% in RS. During the total available follow-up in MESA (median, 16.0 years) and RS (median, 14.2 years), incident CHD occurred in 187 participants (9.4%) and 98 participants (8.1%), respectively.
C (concordance) statistics for the two scores showed the superiority of the CAC. This statistic measures a model’s ability to rank patients from high to low risk, with a value of 1 being perfect risk fit or concordance and 0.70 or more indicating good concordance and risk discrimination. The CAC score had a C statistic of 0.76 (95% confidence interval, 0.71-0.79) vs. 0.69 for the polygenic risk score (95% CI, 0.63-0.71).
When each score was added to PCEs, the C statistics changed as follows: CAC score, 0.09 (95% CI, 0.06-0.13); polygenic risk score, 0.02 (95% CI, 0.00-0.04); and 0.10 (95% CI, 0.07-0.14) for both.
Net reclassification significantly improved with the CAC plus PCEs by the following values: 0.19 (95% CI, 0.06-0.28). The change was not significant, however, with the polygenic risk score plus PCEs: 0.04 (95% CI, –0.05-0.10).
In the clinical setting, Dr. Kahn said, “The use of CT in patients who are at intermediate risk for heart disease can be helpful in refining risk estimation and guiding recommendations for lipid-lowering therapy. Polygenic risk scores are not helpful in middle-aged to older adults above and beyond traditional risk factors for predicting risk of heart disease.”
This study was supported by the National Heart, Lung, and Blood Institute. MESA is supported by the NHLBI. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Netherlands Genomics Initiative; the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. Dr. Khan reported grants from the NHLBI and the NIH during the study and outside of the submitted work. Several coauthors reported grant support from, variously, the NIH, the NHLBI, and the American Heart Association.
As a predictor of coronary heart disease (CHD) events, the coronary artery calcium (CAC) score on computed tomography had better risk discrimination than the polygenic risk score, a binational study found. And when added to classic cardiovascular risk factors, the CAC score significantly improved risk classification while the polygenic risk factor score did not.
These findings emerged from two large cohorts of middle-aged and older White adults from the United States and the Netherlands in the first head-to-head comparison of these two approaches. Led by Sadiya S. Kahn, MD, MSc, an assistant professor of medicine (cardiology) and preventive medicine (epidemiology) at Northwestern University, Chicago, the study was published online in JAMA.
There has been much interest in using both genetic factors and CT imaging to better identify individuals at risk for heart disease. “Each approach has advantages and disadvantages, and we wanted to better understand the comparative predictive utility to provide support for what the preferred approach should be,” Dr. Kahn said in an interview. “We focused on middle-aged to older adults for whom current risk prediction equations are relevant in estimating risk with the Pooled Cohort Equation, or PCE.”
The superiority of the CT-imaged coronary artery risk score may be because of its direct visualization of calcification in the arteries and the subclinical disease burden rather than a focus on common genetic variants, Dr. Kahn explained. “In addition, prior studies have demonstrated that genetics, or inherited risk, is not destiny, so this score may not perform as well for risk discrimination as the traditional risk factors themselves along with CT.”
The study
Study participants came from the U.S. Multi-Ethnic Study of Atherosclerosis (MESA, n = 1,991) and the Dutch Rotterdam Study (RS, n = 1,217). Ages ranged from 45 to 79, with the medians in the two cohorts 61 and 68 years, respectively. Slightly more than half of participants in both groups were female.
Traditional risk factors were used to calculate CHD risk with pooled cohort equations, while computed tomography was used to determine the CAC score and genotyped samples for a validated polygenic risk score.
Both scores were significantly associated with 10-year risk of incident CHD.
The median predicted atherosclerotic disease risk based on traditional risk factors was 6.99% in MESA and 5.93% in RS. During the total available follow-up in MESA (median, 16.0 years) and RS (median, 14.2 years), incident CHD occurred in 187 participants (9.4%) and 98 participants (8.1%), respectively.
C (concordance) statistics for the two scores showed the superiority of the CAC. This statistic measures a model’s ability to rank patients from high to low risk, with a value of 1 being perfect risk fit or concordance and 0.70 or more indicating good concordance and risk discrimination. The CAC score had a C statistic of 0.76 (95% confidence interval, 0.71-0.79) vs. 0.69 for the polygenic risk score (95% CI, 0.63-0.71).
When each score was added to PCEs, the C statistics changed as follows: CAC score, 0.09 (95% CI, 0.06-0.13); polygenic risk score, 0.02 (95% CI, 0.00-0.04); and 0.10 (95% CI, 0.07-0.14) for both.
Net reclassification significantly improved with the CAC plus PCEs by the following values: 0.19 (95% CI, 0.06-0.28). The change was not significant, however, with the polygenic risk score plus PCEs: 0.04 (95% CI, –0.05-0.10).
In the clinical setting, Dr. Kahn said, “The use of CT in patients who are at intermediate risk for heart disease can be helpful in refining risk estimation and guiding recommendations for lipid-lowering therapy. Polygenic risk scores are not helpful in middle-aged to older adults above and beyond traditional risk factors for predicting risk of heart disease.”
This study was supported by the National Heart, Lung, and Blood Institute. MESA is supported by the NHLBI. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Netherlands Genomics Initiative; the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. Dr. Khan reported grants from the NHLBI and the NIH during the study and outside of the submitted work. Several coauthors reported grant support from, variously, the NIH, the NHLBI, and the American Heart Association.
FROM JAMA
Endovascular approach best for below-knee limb-threatening ischemia?
in a new randomized trial.
In the Bypass Versus Angioplasty in Severe Ischaemia of the Leg (BASIL-2) trial, patients who received vein bypass as the first approach were more likely to require a major amputation or to die during follow-up than patients who were randomly assigned to the endovascular approach as first strategy.
“Our findings suggest that a best endovascular treatment first revascularization strategy is associated with a better amputation-free survival. This is mainly because the best endovascular treatment first revascularization strategy resulted in fewer deaths. Limb-related outcomes were similar between groups,” the authors stated.
“The BASIL-2 trial has produced a statistically robust and clinically meaningful result that is likely to have an influence on the management of chronic limb-threatening ischemia worldwide,” added the study’s chief investigator, Andrew Bradbury, MD, professor of vascular surgery at the University of Birmingham (England).
However, the results of the BASIL-2 trial conflict with those from two previous studies – BASIL-1 and BEST-CLI, which both suggested that a surgical approach for chronic limb-threatening ischemia may be most appropriate.
The BASIL-2 study was published online in The Lancet.
The authors explained that chronic limb-threatening ischemia, previously known as critical limb ischemia and severe ischemia of the leg, is the most severe form of peripheral arterial disease caused by atherosclerosis. Patients present with ischemic rest pain and tissue loss (ulceration, gangrene, or both) that usually affects the foot.
Mainly because of tobacco smoking and the growing prevalence of type 2 diabetes, chronic limb-threatening ischemia represents a growing burden on health care and social care services around the world.
Unless the blood supply to the affected limb is restored, patients with chronic limb-threatening ischemia are at high risk for amputation or death. Although it is universally agreed that – in addition to best medical therapy – virtually all patients with chronic limb-threatening ischemia should at least be considered for revascularization, there is continuing debate as to whether conducting vein bypass surgery, preferably using a vein taken from the patient’s own leg, or endovascular treatment (balloon angioplasty with or without stents) is preferable.
“BASIL-2 is the only randomized trial to specifically compare a vein bypass first with best endovascular treatment first revascularisation strategy in patients with chronic limb-threatening ischemia who required an infrapopliteal (with or without an additional more proximal infrainguinal) revascularization procedure to restore limb perfusion,” the authors noted.
For the trial, which was conducted at 41 vascular surgery units in the United Kingdom, Sweden, and Denmark, 345 patients with chronic limb-threatening ischemia who required an infrapopliteal revascularization procedure to restore limb perfusion were randomly assigned to receive either vein bypass or best endovascular treatment as their first revascularization procedure.
Most vein bypasses used the great saphenous vein and originated from the common or superficial femoral arteries. Most endovascular interventions comprised plain balloon angioplasty with selective use of plain or drug-eluting stents. Participants were followed up for a minimum of 2 years.
The primary outcome was amputation-free survival, defined as time to first major (above the ankle) amputation or death from any cause measured in the intention-to-treat population.
Results showed that major amputation or death occurred in 63% of patients in the vein bypass group and in 53% of those in the best endovascular treatment group (adjusted hazard ratio, 1.35; P = .037).
The results were driven by a higher death rate in the vein bypass group (53% vs. 45%; aHR, 1.37).
In both groups, the most common causes of morbidity and death, including death occurring within 30 days of first revascularization, were cardiovascular and respiratory events.
The authors noted that outcomes for the patients in the BASIL-2 trial were poor (median amputation-free survival was 3.8 years, and half the patients died within 5 years).
They pointed out that severe, multilevel atherosclerotic disease that causes chronic limb-threatening ischemia develops over many years, but at baseline in this study, around 20% of patients said they were still smoking, and around 70% of patients had diabetes, of whom around 50% required insulin. In addition, around 90% of the participants often had quite extensive tissue loss.
“These baseline data suggest that there might still be missed opportunities in public health and primary care to prevent chronic limb-threatening ischemia through medical therapy and lifestyle interventions and missed opportunities to refer patients to secondary care earlier once chronic limb-threatening ischemia begins to develop,” they suggested.
“Better prevention and timely referral are important: the BASIL-2 trial shows that, by the time patients present to vascular and endovascular surgeons and interventional radiologists with established chronic limb-threatening ischemia, their prognosis is often poor regardless of what form of revascularization they are offered,” they added.
Conflicting results
In an accompanying comment, Ankur Kalra, MD, Franciscan Health, Lafayette, Ind., and Ashish Kumar, MD, Cleveland Clinic Akron (Ohio) General, noted that atherosclerotic lower-extremity peripheral artery disease affects more than 230 million people worldwide, and prevalence is increasing. Chronic limb-threatening ischemia is a severe form of peripheral artery disease that affects 11% of patients with peripheral artery disease and is associated with significant cardiovascular morbidity and death.
Furthermore, amputation rates of 10%-40% during a 6-month follow-up of patients with chronic limb-threatening ischemia who were unable to undergo revascularization have been reported, highlighting the severity of atherosclerotic burden and the need for improved treatment strategies.
Dr. Kalra and Dr. Kumar pointed out that two previous randomized clinical trials compared surgical vein graft bypass with endovascular treatment for patients with chronic limb-threatening ischemia – the BASIL-1 trial, and the BEST-CLI trial.
In the BASIL-1 trial, vein bypass was associated with improved overall survival and amputation-free survival for patients who survived at least 2 years. The BEST-CLI trial also reported a lower risk of a composite of major adverse limb events or death among patients undergoing a surgery-first strategy, compared with endovascular therapy, mostly in patients with suitable single segment of great saphenous vein.
Dr. Kalra and Dr. Kumar said the findings of the BASIL-2 trial should be put in context with these previous studies, which report a positive or equivocal effect of surgery. The results of the BEST-CLI trial were driven by fewer major reinterventions and above-ankle amputations in the surgical group, whereas the results of the BASIL-2 trial were driven by fewer deaths in the best endovascular treatment group, “which potentially points towards a difference in the characteristics of the patients randomly assigned in the two trials.”
They concluded: “Considering the results of the BASIL-2 trial and the BEST-CLI trial, choice of intervention should be based on shared decision making between interventional cardiology, vascular surgery, and the patient, until more evidence is accrued.”
The BASIL-2 trial was funded by the U.K. National Institute of Health Research.
A version of this article first appeared on Medscape.com.
in a new randomized trial.
In the Bypass Versus Angioplasty in Severe Ischaemia of the Leg (BASIL-2) trial, patients who received vein bypass as the first approach were more likely to require a major amputation or to die during follow-up than patients who were randomly assigned to the endovascular approach as first strategy.
“Our findings suggest that a best endovascular treatment first revascularization strategy is associated with a better amputation-free survival. This is mainly because the best endovascular treatment first revascularization strategy resulted in fewer deaths. Limb-related outcomes were similar between groups,” the authors stated.
“The BASIL-2 trial has produced a statistically robust and clinically meaningful result that is likely to have an influence on the management of chronic limb-threatening ischemia worldwide,” added the study’s chief investigator, Andrew Bradbury, MD, professor of vascular surgery at the University of Birmingham (England).
However, the results of the BASIL-2 trial conflict with those from two previous studies – BASIL-1 and BEST-CLI, which both suggested that a surgical approach for chronic limb-threatening ischemia may be most appropriate.
The BASIL-2 study was published online in The Lancet.
The authors explained that chronic limb-threatening ischemia, previously known as critical limb ischemia and severe ischemia of the leg, is the most severe form of peripheral arterial disease caused by atherosclerosis. Patients present with ischemic rest pain and tissue loss (ulceration, gangrene, or both) that usually affects the foot.
Mainly because of tobacco smoking and the growing prevalence of type 2 diabetes, chronic limb-threatening ischemia represents a growing burden on health care and social care services around the world.
Unless the blood supply to the affected limb is restored, patients with chronic limb-threatening ischemia are at high risk for amputation or death. Although it is universally agreed that – in addition to best medical therapy – virtually all patients with chronic limb-threatening ischemia should at least be considered for revascularization, there is continuing debate as to whether conducting vein bypass surgery, preferably using a vein taken from the patient’s own leg, or endovascular treatment (balloon angioplasty with or without stents) is preferable.
“BASIL-2 is the only randomized trial to specifically compare a vein bypass first with best endovascular treatment first revascularisation strategy in patients with chronic limb-threatening ischemia who required an infrapopliteal (with or without an additional more proximal infrainguinal) revascularization procedure to restore limb perfusion,” the authors noted.
For the trial, which was conducted at 41 vascular surgery units in the United Kingdom, Sweden, and Denmark, 345 patients with chronic limb-threatening ischemia who required an infrapopliteal revascularization procedure to restore limb perfusion were randomly assigned to receive either vein bypass or best endovascular treatment as their first revascularization procedure.
Most vein bypasses used the great saphenous vein and originated from the common or superficial femoral arteries. Most endovascular interventions comprised plain balloon angioplasty with selective use of plain or drug-eluting stents. Participants were followed up for a minimum of 2 years.
The primary outcome was amputation-free survival, defined as time to first major (above the ankle) amputation or death from any cause measured in the intention-to-treat population.
Results showed that major amputation or death occurred in 63% of patients in the vein bypass group and in 53% of those in the best endovascular treatment group (adjusted hazard ratio, 1.35; P = .037).
The results were driven by a higher death rate in the vein bypass group (53% vs. 45%; aHR, 1.37).
In both groups, the most common causes of morbidity and death, including death occurring within 30 days of first revascularization, were cardiovascular and respiratory events.
The authors noted that outcomes for the patients in the BASIL-2 trial were poor (median amputation-free survival was 3.8 years, and half the patients died within 5 years).
They pointed out that severe, multilevel atherosclerotic disease that causes chronic limb-threatening ischemia develops over many years, but at baseline in this study, around 20% of patients said they were still smoking, and around 70% of patients had diabetes, of whom around 50% required insulin. In addition, around 90% of the participants often had quite extensive tissue loss.
“These baseline data suggest that there might still be missed opportunities in public health and primary care to prevent chronic limb-threatening ischemia through medical therapy and lifestyle interventions and missed opportunities to refer patients to secondary care earlier once chronic limb-threatening ischemia begins to develop,” they suggested.
“Better prevention and timely referral are important: the BASIL-2 trial shows that, by the time patients present to vascular and endovascular surgeons and interventional radiologists with established chronic limb-threatening ischemia, their prognosis is often poor regardless of what form of revascularization they are offered,” they added.
Conflicting results
In an accompanying comment, Ankur Kalra, MD, Franciscan Health, Lafayette, Ind., and Ashish Kumar, MD, Cleveland Clinic Akron (Ohio) General, noted that atherosclerotic lower-extremity peripheral artery disease affects more than 230 million people worldwide, and prevalence is increasing. Chronic limb-threatening ischemia is a severe form of peripheral artery disease that affects 11% of patients with peripheral artery disease and is associated with significant cardiovascular morbidity and death.
Furthermore, amputation rates of 10%-40% during a 6-month follow-up of patients with chronic limb-threatening ischemia who were unable to undergo revascularization have been reported, highlighting the severity of atherosclerotic burden and the need for improved treatment strategies.
Dr. Kalra and Dr. Kumar pointed out that two previous randomized clinical trials compared surgical vein graft bypass with endovascular treatment for patients with chronic limb-threatening ischemia – the BASIL-1 trial, and the BEST-CLI trial.
In the BASIL-1 trial, vein bypass was associated with improved overall survival and amputation-free survival for patients who survived at least 2 years. The BEST-CLI trial also reported a lower risk of a composite of major adverse limb events or death among patients undergoing a surgery-first strategy, compared with endovascular therapy, mostly in patients with suitable single segment of great saphenous vein.
Dr. Kalra and Dr. Kumar said the findings of the BASIL-2 trial should be put in context with these previous studies, which report a positive or equivocal effect of surgery. The results of the BEST-CLI trial were driven by fewer major reinterventions and above-ankle amputations in the surgical group, whereas the results of the BASIL-2 trial were driven by fewer deaths in the best endovascular treatment group, “which potentially points towards a difference in the characteristics of the patients randomly assigned in the two trials.”
They concluded: “Considering the results of the BASIL-2 trial and the BEST-CLI trial, choice of intervention should be based on shared decision making between interventional cardiology, vascular surgery, and the patient, until more evidence is accrued.”
The BASIL-2 trial was funded by the U.K. National Institute of Health Research.
A version of this article first appeared on Medscape.com.
in a new randomized trial.
In the Bypass Versus Angioplasty in Severe Ischaemia of the Leg (BASIL-2) trial, patients who received vein bypass as the first approach were more likely to require a major amputation or to die during follow-up than patients who were randomly assigned to the endovascular approach as first strategy.
“Our findings suggest that a best endovascular treatment first revascularization strategy is associated with a better amputation-free survival. This is mainly because the best endovascular treatment first revascularization strategy resulted in fewer deaths. Limb-related outcomes were similar between groups,” the authors stated.
“The BASIL-2 trial has produced a statistically robust and clinically meaningful result that is likely to have an influence on the management of chronic limb-threatening ischemia worldwide,” added the study’s chief investigator, Andrew Bradbury, MD, professor of vascular surgery at the University of Birmingham (England).
However, the results of the BASIL-2 trial conflict with those from two previous studies – BASIL-1 and BEST-CLI, which both suggested that a surgical approach for chronic limb-threatening ischemia may be most appropriate.
The BASIL-2 study was published online in The Lancet.
The authors explained that chronic limb-threatening ischemia, previously known as critical limb ischemia and severe ischemia of the leg, is the most severe form of peripheral arterial disease caused by atherosclerosis. Patients present with ischemic rest pain and tissue loss (ulceration, gangrene, or both) that usually affects the foot.
Mainly because of tobacco smoking and the growing prevalence of type 2 diabetes, chronic limb-threatening ischemia represents a growing burden on health care and social care services around the world.
Unless the blood supply to the affected limb is restored, patients with chronic limb-threatening ischemia are at high risk for amputation or death. Although it is universally agreed that – in addition to best medical therapy – virtually all patients with chronic limb-threatening ischemia should at least be considered for revascularization, there is continuing debate as to whether conducting vein bypass surgery, preferably using a vein taken from the patient’s own leg, or endovascular treatment (balloon angioplasty with or without stents) is preferable.
“BASIL-2 is the only randomized trial to specifically compare a vein bypass first with best endovascular treatment first revascularisation strategy in patients with chronic limb-threatening ischemia who required an infrapopliteal (with or without an additional more proximal infrainguinal) revascularization procedure to restore limb perfusion,” the authors noted.
For the trial, which was conducted at 41 vascular surgery units in the United Kingdom, Sweden, and Denmark, 345 patients with chronic limb-threatening ischemia who required an infrapopliteal revascularization procedure to restore limb perfusion were randomly assigned to receive either vein bypass or best endovascular treatment as their first revascularization procedure.
Most vein bypasses used the great saphenous vein and originated from the common or superficial femoral arteries. Most endovascular interventions comprised plain balloon angioplasty with selective use of plain or drug-eluting stents. Participants were followed up for a minimum of 2 years.
The primary outcome was amputation-free survival, defined as time to first major (above the ankle) amputation or death from any cause measured in the intention-to-treat population.
Results showed that major amputation or death occurred in 63% of patients in the vein bypass group and in 53% of those in the best endovascular treatment group (adjusted hazard ratio, 1.35; P = .037).
The results were driven by a higher death rate in the vein bypass group (53% vs. 45%; aHR, 1.37).
In both groups, the most common causes of morbidity and death, including death occurring within 30 days of first revascularization, were cardiovascular and respiratory events.
The authors noted that outcomes for the patients in the BASIL-2 trial were poor (median amputation-free survival was 3.8 years, and half the patients died within 5 years).
They pointed out that severe, multilevel atherosclerotic disease that causes chronic limb-threatening ischemia develops over many years, but at baseline in this study, around 20% of patients said they were still smoking, and around 70% of patients had diabetes, of whom around 50% required insulin. In addition, around 90% of the participants often had quite extensive tissue loss.
“These baseline data suggest that there might still be missed opportunities in public health and primary care to prevent chronic limb-threatening ischemia through medical therapy and lifestyle interventions and missed opportunities to refer patients to secondary care earlier once chronic limb-threatening ischemia begins to develop,” they suggested.
“Better prevention and timely referral are important: the BASIL-2 trial shows that, by the time patients present to vascular and endovascular surgeons and interventional radiologists with established chronic limb-threatening ischemia, their prognosis is often poor regardless of what form of revascularization they are offered,” they added.
Conflicting results
In an accompanying comment, Ankur Kalra, MD, Franciscan Health, Lafayette, Ind., and Ashish Kumar, MD, Cleveland Clinic Akron (Ohio) General, noted that atherosclerotic lower-extremity peripheral artery disease affects more than 230 million people worldwide, and prevalence is increasing. Chronic limb-threatening ischemia is a severe form of peripheral artery disease that affects 11% of patients with peripheral artery disease and is associated with significant cardiovascular morbidity and death.
Furthermore, amputation rates of 10%-40% during a 6-month follow-up of patients with chronic limb-threatening ischemia who were unable to undergo revascularization have been reported, highlighting the severity of atherosclerotic burden and the need for improved treatment strategies.
Dr. Kalra and Dr. Kumar pointed out that two previous randomized clinical trials compared surgical vein graft bypass with endovascular treatment for patients with chronic limb-threatening ischemia – the BASIL-1 trial, and the BEST-CLI trial.
In the BASIL-1 trial, vein bypass was associated with improved overall survival and amputation-free survival for patients who survived at least 2 years. The BEST-CLI trial also reported a lower risk of a composite of major adverse limb events or death among patients undergoing a surgery-first strategy, compared with endovascular therapy, mostly in patients with suitable single segment of great saphenous vein.
Dr. Kalra and Dr. Kumar said the findings of the BASIL-2 trial should be put in context with these previous studies, which report a positive or equivocal effect of surgery. The results of the BEST-CLI trial were driven by fewer major reinterventions and above-ankle amputations in the surgical group, whereas the results of the BASIL-2 trial were driven by fewer deaths in the best endovascular treatment group, “which potentially points towards a difference in the characteristics of the patients randomly assigned in the two trials.”
They concluded: “Considering the results of the BASIL-2 trial and the BEST-CLI trial, choice of intervention should be based on shared decision making between interventional cardiology, vascular surgery, and the patient, until more evidence is accrued.”
The BASIL-2 trial was funded by the U.K. National Institute of Health Research.
A version of this article first appeared on Medscape.com.
FROM THE LANCET
High cholesterol in seniors: Use statins for primary prevention?
LONG BEACH, CALIF. – For years, clinicians have debated whether prescribing statins to patients older than 75 for the prevention of cardiovascular events is appropriate.
In 2022, the U.S. Preventive Services Task Force concluded that scientific evidence was insufficient to assess the balance between the benefits and harms of the therapy for this older population.
At a session of the annual meeting of the American Geriatrics Society, experts laid out new preliminary recommendations of the AGS and the National Lipid Association on assessing risk and deciding on treatment.
The group concluded that LDL cholesterol levels are associated with incident arteriosclerotic cardiovascular disease (ASCVD), that the coronary artery calcium (CAC) score can be a valuable measure, and that statins may be reasonable to prescribe, even given the risks that have been linked to statins, such as that for muscle pain. Final recommendations are expected by fall 2023.
“This is still a work in progress,” said Daniel E. Forman, MD, professor of medicine and chair of geriatric cardiology at the University of Pittsburgh.
The AGS-NLA panel concluded that, for those aged 75 or older without established ASCVD, LDL cholesterol is associated with incident ASCVD, the only recommendation to be given a class I (strong) rating; others were classed as moderate or weak.
Dr. Forman reviewed the evidence for lowering LDL cholesterol to decrease ASCVD, citing a 2018 study that concluded, “Reverse causation may contribute to the association of lower TC with higher mortality in nonrandomized studies.”
However, research overall shows that, as LDL cholesterol levels increase, patients are more likely to experience a heart event.
Dr. Forman noted that the utility of equations for assessing 5- or 10-year risk of ASCVD is uncertain. However, he said, traditional risk factors, such as family history and ethnicity, still have value.
Assessing risk “has been enriched in the past few years by the introduction of the coronary artery calcium [CAC] score,” he said.
Lower scores predict lower rates of CVD events, Forman said. The AGS-NLA recommends measuring CAC if clinical uncertainty exists about the value of statins.
“It’s reasonable to measure CAC and to withhold statins when the CAC is zero,” Dr. Forman said. “When the CAC score is zero ... the risk of having a cardiovascular event is really next to nil. Patients are happy to know they have a CAC of zero.”
Likewise, patients appreciate knowing whether their score is high, which would indicate increased risk. He said the CAC score is underused by geriatric physicians.
The group also determined, after reviewing the research, that starting treatment is reasonable for patients with an LDL cholesterol level of 70-189 if they have no life-limiting illness and their life expectancy is over 5 years.
Other preliminary recommendations include the use of statins for those aged 75 and older, irrespective of risk for statin-associated muscle symptoms, type 2 diabetes, or impaired cognition. These associations are often weak, Dr. Forman added.
Focusing on person-centered decisions
Ariel Green, MD, MPH, PhD, associate professor of medicine at Johns Hopkins University, Baltimore, said statin therapy “should be individualized” to weigh benefits, noncardiac risks, and other considerations.
Clinicians can incorporate life expectancy into prevention decisions using tools such as ePrognosis, from the University of California, San Francisco, Dr. Green said.
If life expectancy is greater than the time to benefit, statin therapy may help. Dr. Green cited research that showed that 2.5 years of statin therapy was needed to prevent one major adverse cardiovascular event (MACE) per 100 patients in a population aged 50-75. Other data show reductions in MACE for those older than 75, but overall, the data are limited in this population.
The proposed recommendation is to use tools such as life tables that include comorbid conditions and functional status to guide clinical decisions.
“Another aspect of assessing net benefits of statin therapy is to consider competing health risks,” Dr. Green said.
The group recommends considering using competing risk-adjusted CVD models, though these are not widely used.
The group also recommends integrating screenings for frailty (Clinical Frailty Scale), dementia (Mini-Cog), and functional status (Vulnerable Elders Scale–13) into assessments.
“The presence of these syndromes should prompt elicitation of patient values and preferences related to prevention and medication use,” Dr. Green said.
Clinicians can use decision aids, but these are not always practical, owing to obstacles such as patients’ cognitive problems, Dr. Green said.
“Another approach is asking people to prioritize a set of universal health outcomes that apply across health conditions, such as maintaining independence, staying alive, reducing, or eliminating symptoms and focusing on comfort,” Dr. Green said.
She addressed the evidence about deprescribing statins, with a focus on those with a life expectancy of less than a year. Researchers have found an increase in quality of life and no increases in cardiovascular events or death when statins were deprescribed.
A welcome framework
Cory Krueger, MD, an internal medicine and geriatric physician in Cornville, Ariz., who attended the talk, said he welcomed the presentation, in which preliminary recommendations were explained.
“This has been a controversial area in geriatrics,” Dr. Krueger said. “At least this gave me a framework for discussing this with my patients in a reasonable way.”
Dr. Forman and Dr. Krueger disclosed no relevant financial relationships. Dr. Green receives funding from the National Institute of Aging and Impact Collaboratory.
A version of this article first appeared on Medscape.com.
LONG BEACH, CALIF. – For years, clinicians have debated whether prescribing statins to patients older than 75 for the prevention of cardiovascular events is appropriate.
In 2022, the U.S. Preventive Services Task Force concluded that scientific evidence was insufficient to assess the balance between the benefits and harms of the therapy for this older population.
At a session of the annual meeting of the American Geriatrics Society, experts laid out new preliminary recommendations of the AGS and the National Lipid Association on assessing risk and deciding on treatment.
The group concluded that LDL cholesterol levels are associated with incident arteriosclerotic cardiovascular disease (ASCVD), that the coronary artery calcium (CAC) score can be a valuable measure, and that statins may be reasonable to prescribe, even given the risks that have been linked to statins, such as that for muscle pain. Final recommendations are expected by fall 2023.
“This is still a work in progress,” said Daniel E. Forman, MD, professor of medicine and chair of geriatric cardiology at the University of Pittsburgh.
The AGS-NLA panel concluded that, for those aged 75 or older without established ASCVD, LDL cholesterol is associated with incident ASCVD, the only recommendation to be given a class I (strong) rating; others were classed as moderate or weak.
Dr. Forman reviewed the evidence for lowering LDL cholesterol to decrease ASCVD, citing a 2018 study that concluded, “Reverse causation may contribute to the association of lower TC with higher mortality in nonrandomized studies.”
However, research overall shows that, as LDL cholesterol levels increase, patients are more likely to experience a heart event.
Dr. Forman noted that the utility of equations for assessing 5- or 10-year risk of ASCVD is uncertain. However, he said, traditional risk factors, such as family history and ethnicity, still have value.
Assessing risk “has been enriched in the past few years by the introduction of the coronary artery calcium [CAC] score,” he said.
Lower scores predict lower rates of CVD events, Forman said. The AGS-NLA recommends measuring CAC if clinical uncertainty exists about the value of statins.
“It’s reasonable to measure CAC and to withhold statins when the CAC is zero,” Dr. Forman said. “When the CAC score is zero ... the risk of having a cardiovascular event is really next to nil. Patients are happy to know they have a CAC of zero.”
Likewise, patients appreciate knowing whether their score is high, which would indicate increased risk. He said the CAC score is underused by geriatric physicians.
The group also determined, after reviewing the research, that starting treatment is reasonable for patients with an LDL cholesterol level of 70-189 if they have no life-limiting illness and their life expectancy is over 5 years.
Other preliminary recommendations include the use of statins for those aged 75 and older, irrespective of risk for statin-associated muscle symptoms, type 2 diabetes, or impaired cognition. These associations are often weak, Dr. Forman added.
Focusing on person-centered decisions
Ariel Green, MD, MPH, PhD, associate professor of medicine at Johns Hopkins University, Baltimore, said statin therapy “should be individualized” to weigh benefits, noncardiac risks, and other considerations.
Clinicians can incorporate life expectancy into prevention decisions using tools such as ePrognosis, from the University of California, San Francisco, Dr. Green said.
If life expectancy is greater than the time to benefit, statin therapy may help. Dr. Green cited research that showed that 2.5 years of statin therapy was needed to prevent one major adverse cardiovascular event (MACE) per 100 patients in a population aged 50-75. Other data show reductions in MACE for those older than 75, but overall, the data are limited in this population.
The proposed recommendation is to use tools such as life tables that include comorbid conditions and functional status to guide clinical decisions.
“Another aspect of assessing net benefits of statin therapy is to consider competing health risks,” Dr. Green said.
The group recommends considering using competing risk-adjusted CVD models, though these are not widely used.
The group also recommends integrating screenings for frailty (Clinical Frailty Scale), dementia (Mini-Cog), and functional status (Vulnerable Elders Scale–13) into assessments.
“The presence of these syndromes should prompt elicitation of patient values and preferences related to prevention and medication use,” Dr. Green said.
Clinicians can use decision aids, but these are not always practical, owing to obstacles such as patients’ cognitive problems, Dr. Green said.
“Another approach is asking people to prioritize a set of universal health outcomes that apply across health conditions, such as maintaining independence, staying alive, reducing, or eliminating symptoms and focusing on comfort,” Dr. Green said.
She addressed the evidence about deprescribing statins, with a focus on those with a life expectancy of less than a year. Researchers have found an increase in quality of life and no increases in cardiovascular events or death when statins were deprescribed.
A welcome framework
Cory Krueger, MD, an internal medicine and geriatric physician in Cornville, Ariz., who attended the talk, said he welcomed the presentation, in which preliminary recommendations were explained.
“This has been a controversial area in geriatrics,” Dr. Krueger said. “At least this gave me a framework for discussing this with my patients in a reasonable way.”
Dr. Forman and Dr. Krueger disclosed no relevant financial relationships. Dr. Green receives funding from the National Institute of Aging and Impact Collaboratory.
A version of this article first appeared on Medscape.com.
LONG BEACH, CALIF. – For years, clinicians have debated whether prescribing statins to patients older than 75 for the prevention of cardiovascular events is appropriate.
In 2022, the U.S. Preventive Services Task Force concluded that scientific evidence was insufficient to assess the balance between the benefits and harms of the therapy for this older population.
At a session of the annual meeting of the American Geriatrics Society, experts laid out new preliminary recommendations of the AGS and the National Lipid Association on assessing risk and deciding on treatment.
The group concluded that LDL cholesterol levels are associated with incident arteriosclerotic cardiovascular disease (ASCVD), that the coronary artery calcium (CAC) score can be a valuable measure, and that statins may be reasonable to prescribe, even given the risks that have been linked to statins, such as that for muscle pain. Final recommendations are expected by fall 2023.
“This is still a work in progress,” said Daniel E. Forman, MD, professor of medicine and chair of geriatric cardiology at the University of Pittsburgh.
The AGS-NLA panel concluded that, for those aged 75 or older without established ASCVD, LDL cholesterol is associated with incident ASCVD, the only recommendation to be given a class I (strong) rating; others were classed as moderate or weak.
Dr. Forman reviewed the evidence for lowering LDL cholesterol to decrease ASCVD, citing a 2018 study that concluded, “Reverse causation may contribute to the association of lower TC with higher mortality in nonrandomized studies.”
However, research overall shows that, as LDL cholesterol levels increase, patients are more likely to experience a heart event.
Dr. Forman noted that the utility of equations for assessing 5- or 10-year risk of ASCVD is uncertain. However, he said, traditional risk factors, such as family history and ethnicity, still have value.
Assessing risk “has been enriched in the past few years by the introduction of the coronary artery calcium [CAC] score,” he said.
Lower scores predict lower rates of CVD events, Forman said. The AGS-NLA recommends measuring CAC if clinical uncertainty exists about the value of statins.
“It’s reasonable to measure CAC and to withhold statins when the CAC is zero,” Dr. Forman said. “When the CAC score is zero ... the risk of having a cardiovascular event is really next to nil. Patients are happy to know they have a CAC of zero.”
Likewise, patients appreciate knowing whether their score is high, which would indicate increased risk. He said the CAC score is underused by geriatric physicians.
The group also determined, after reviewing the research, that starting treatment is reasonable for patients with an LDL cholesterol level of 70-189 if they have no life-limiting illness and their life expectancy is over 5 years.
Other preliminary recommendations include the use of statins for those aged 75 and older, irrespective of risk for statin-associated muscle symptoms, type 2 diabetes, or impaired cognition. These associations are often weak, Dr. Forman added.
Focusing on person-centered decisions
Ariel Green, MD, MPH, PhD, associate professor of medicine at Johns Hopkins University, Baltimore, said statin therapy “should be individualized” to weigh benefits, noncardiac risks, and other considerations.
Clinicians can incorporate life expectancy into prevention decisions using tools such as ePrognosis, from the University of California, San Francisco, Dr. Green said.
If life expectancy is greater than the time to benefit, statin therapy may help. Dr. Green cited research that showed that 2.5 years of statin therapy was needed to prevent one major adverse cardiovascular event (MACE) per 100 patients in a population aged 50-75. Other data show reductions in MACE for those older than 75, but overall, the data are limited in this population.
The proposed recommendation is to use tools such as life tables that include comorbid conditions and functional status to guide clinical decisions.
“Another aspect of assessing net benefits of statin therapy is to consider competing health risks,” Dr. Green said.
The group recommends considering using competing risk-adjusted CVD models, though these are not widely used.
The group also recommends integrating screenings for frailty (Clinical Frailty Scale), dementia (Mini-Cog), and functional status (Vulnerable Elders Scale–13) into assessments.
“The presence of these syndromes should prompt elicitation of patient values and preferences related to prevention and medication use,” Dr. Green said.
Clinicians can use decision aids, but these are not always practical, owing to obstacles such as patients’ cognitive problems, Dr. Green said.
“Another approach is asking people to prioritize a set of universal health outcomes that apply across health conditions, such as maintaining independence, staying alive, reducing, or eliminating symptoms and focusing on comfort,” Dr. Green said.
She addressed the evidence about deprescribing statins, with a focus on those with a life expectancy of less than a year. Researchers have found an increase in quality of life and no increases in cardiovascular events or death when statins were deprescribed.
A welcome framework
Cory Krueger, MD, an internal medicine and geriatric physician in Cornville, Ariz., who attended the talk, said he welcomed the presentation, in which preliminary recommendations were explained.
“This has been a controversial area in geriatrics,” Dr. Krueger said. “At least this gave me a framework for discussing this with my patients in a reasonable way.”
Dr. Forman and Dr. Krueger disclosed no relevant financial relationships. Dr. Green receives funding from the National Institute of Aging and Impact Collaboratory.
A version of this article first appeared on Medscape.com.
AT AGS 2023