Recently in the United States, a new low-dose Colchicine Widely indicated for use at 0.5 mg (Lodoco; Agepha Pharma) atherosclerotic cardiovascular disease (ASCVD) is an entirely new approach to treatment, specifically targeting those that promote inflammation. atherosclerosis.
The U.S. Food and Drug Administration (FDA) has given colchicine the very broad label of reducing the risk of cardiovascular events in adult patients with established ASCVD or multiple risk factors for cardiovascular disease. . But how will this drug be used in the clinical setting?
“The idea that inflammation is a driver of atherosclerosis and cardiovascular risk has been around for decades and it is well known that atherosclerosis is an inflammatory process. But Michael Joseph Blaha, M.D., Ph.D., director of clinical research at the Ciccalon Center for Cardiovascular Disease Prevention at Johns Hopkins Hospital in Baltimore, points out that treating inflammation is new because until now there have been no specific drugs to target it. .
Blaha, an unpaid scientific adviser to Agefa, said the approval of low-dose colchicine “will open the door for a routine conversation about residual inflammation risk in patients. And how do we do that?” should be carefully considered,” he added. . ”
Professor Blaha said he was not surprised by the FDA’s approval of the indication for colchicine, noting that a similar broad population was enrolled in the LoDoCo-2 trial, the main large trial supporting the use of colchicine in ASCVD. It pointed out.
“I think the approval was appropriate because the indication should always follow the data. But I think how the drug is actually used depends on different individual patient circumstances.” he commented.
“The paradigm going forward is how we think about the residual risk a patient has after treatment with standard therapy (mostly statins and blood pressure control) and what causes that residual risk,” he said. “If a patient is still considered to be at high risk of recurring cardiovascular events, then we have to think about what to do next. This is where this drug comes into play.”
Blaha points out that there are now multiple options for mitigating residual risk. He believes which of these options to choose first depends on the patient’s profile.
“If your LDL is still elevated after a high-dose statin treatment, you can add another LDL-lowering drug, or you may be diabetic, obesity What we want to work on first.or higher Neutral fat. However, it is now possible to consider the risk of residual inflammation if the patient is considered to have residual plaque inflammation. “So colchicine will be one of several non-statin options he could consider as the next step in treating residual risk,” he says. . ”
Do you need a CRP measurement?
Elevated high-sensitivity C-reactive protein (hsCRP) levels are a marker of inflammation in ASCVD, but two major trials of colchicine in ASCVD both showed a large effect of colchicine, although hsCRP was not measured. However, the following questions arise: Whether measurement of this biomarker is necessary to select patients for colchicine treatment.
“Some clinicians would prefer to test for hsCRP and treat patients with levels above 2 mg/L. I think that makes a lot of sense,” Blaha said. “But hsCRP was not measured in the study, so I don’t think testing for this biomarker is necessary to prove inflammation,” he added.
“The label does not specify that CRP must be measured. This gives physicians the freedom to measure CRP or not. ”
Professor Blaha also added that clinicians need to think about the factors driving residual risk for individual patients. “Colchicine can be considered as a way to reduce residual risk when other risk factors are well controlled, but recurrent events are still suspected.” A risk likely caused by inflammation. ”
“We are in a great position in cardiovascular medicine because we have several different options available after statin administration and now also have this new treatment for inflammation. They can be used in combination, but most clinicians will want to do that,” says Braha, “prioritizing treatments using those treatments that we believe will most reduce residual risk for individual patients.” explains Mr.
“Whole different axes that cause atherosclerosis”
Paul Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, is one of the leading figures in the field of cardiovascular inflammation and has contributed to the development of the hsCRP test. He has similar views.
“This FDA approval is very important because it draws attention to the role of inflammation in atherosclerosis and the need for its treatment,” he says.
“Physicians need to recognize that they certainly need to actively lower cholesterol, but they also need to know that there is an entirely different axis that drives atherosclerosis: inflammation. And until now, there hasn’t been an FDA-approved drug to treat inflammation.”
Ricker stresses that it has no intention of compromising ride height Lipid: “Therapies aimed at inflammation do not compete with those aimed at lipid-lowering. We know that they work for lipid-lowering. is to educate physicians about this new approach.”
Lidker said he was already using low doses of colchicine in patients he called “frequent flyers.” People who continue to relapse despite active lipid lowering. “They’ve had multiple angioplasties, bypass surgeries, etc.”
Like Blaha, Lidker believes doctors should start using the drug in high-risk patients who are already taking statins and have residual inflammation risk. ”[The] Patients whose underlying biological problem is inflammation [is] People who really want to be treated with this drug. That’s where it’s likely to work best and where comfort levels are maximized. ”
He believes that measuring hsCRP is the right way to select these patients.
“We believe this will be a great impetus to start more extensive CRP measurements, so that this anti-inflammatory drug can actually be used in patients with residual inflammation risk, i.e. hsCRP levels greater than 2 mg/L. ,” he said, which may apply to about 30% to 40% of ASCVD patients who are already taking statins.
The second pillar of ASCVD treatment?
Jean-Claude Tardiff, M.D., Ph.D., director of the Montreal Heart Institute Research Center in Canada, has a slightly different view, but he was the principal investigator of the COLCOT trial, another randomized controlled trial of colchicine for heart disease. rice field.
Colchicine, he believes, should become the “second pillar” of ASCVD treatment for almost all patients, alongside statins.
What is Tardiff Recent research (led by Lidker) lancetThis indicated that among patients already taking statins, those with high levels of inflammation had the highest risk of future events.
“So the next step after statin administration should be to consider reducing inflammation,” he says.
“Despite all the drugs we have, ASCVD is still the leading cause of death in the Western world. Because inflammation is primarily what causes these events, drugs like colchicine can reduce inflammation in blood vessels. It makes sense to address directly the mitigation of ,” he said. Note.
“All I can say is all of the patients below. coronary artery atherosclerosis Unless you have severe kidney disease, which is a contraindication, you are a potential candidate for low-dose colchicine,” says Tardiff.
“If you want to fine-tune this a bit more, at particular risk are people who have recurrent events, people who have multiple risk factors, and people who have recently been infected. [myocardial infarction]. In such patients, adding low-dose colchicine to high-dose statins would make a lot of sense,” he added.
Dr. Tardiff says he does not intend to use CRP measurements to select patients for colchicine treatment: “While CRP measurements may make intuitive sense, the large-scale None of the randomized trials selected patients on the basis of elevated CRP and showed an overall benefit.”
If patients with ASCVD are at high risk of developing future disease and are already taking statins, we would consider colchicine in all these patients, unless they have severe renal disease. ”
Tardif believes ASCVD should follow this model: heart failure It has several pillars of treatment aimed at different targets, all used together.
“I think the same approach should be applied to ASCVD patients,” he added. “Yes, you need statins to keep your cholesterol down, but now you can also get colchicine to keep your inflammation down.”
Polypharmacy concerns
Steve Nissen, M.D., professor of medicine at the Cleveland Clinic in Ohio, is also enthusiastic about using colchicine, although he has not been involved in clinical trials of colchicine. But like Lidker and Blaha, he prefers to select patients who are most likely to benefit.
“I have long been a proponent of the inflammatory hypothesis and have been searching for a purely anti-inflammatory therapy that could be added to the standard of care for patients with coronary artery disease. And colchicine is safe and effective. Do it.” Nissen commented.
“What colchicine offers here is a cheap drug with pretty good data on reducing morbidity from coronary artery disease. I think we could probably do a lot of good things,” he says, “just using these two treatments will cost you very little.”
“But my preference at the moment is to use colchicine selectively in patients with elevated CRP. I think that’s logical. The only thing I’m worried about is polypharmacy.” “Some of my patients are already on 5, 6 or 7 medications.” I don’t know if patients with low CRP would get the same benefit, they might, but I doubt it,” he points out.
“Further studies and analyzes may be conducted to help understand the relationship between CRP and colchicine efficacy, which may help elucidate,” he added.
Safety is Reliable
From a colchicine 0.5 mg dose safety and tolerability standpoint, experts seem to think this is very manageable.
“Used for gout, pericarditiscolchicine is usually given at 0.6 mg twice daily, which can cause gastroenteritis. [GI] “There are side effects,” says Nissen. “However, the lower dose approved for ASCVD (0.5 mg once daily) appears to be much better tolerated. rather, it usually disappears over time.”
Professor Ridker added that the side effects were “extremely minor” in the randomized trial, “although the drug cannot be used for severe kidney or liver disease and there are some drug interactions to be aware of. There is,” he added. “But in general, there are few side effects at low doses. There may be gastrointestinal effects, but they are mostly mild and usually treatable.”
Braha also agreed that this is not a drug for patients with advanced kidney disease, saying, “There are some drug interactions that you should be aware of, but the list is not long. There may be side effects,” he said. “But most patients take it just fine. It’s already been used for gout, so doctors are already very familiar with its use.”
Part of the foundation of CV treatment?
Blaha concluded that colchicine prescribing would begin with cardiologists, using colchicine first in the highest-risk patients.
“But as we get used to it, I think we’ll start using it in a wider range of patients and eventually primary care doctors will start prescribing it. It’s the same thing that happened with statins,” he said. suggests.
“It will be very interesting to see where it stands alongside statins in the future, but I think it’s going to be there where it sits alongside statins as part of the backbone of cardiovascular therapy in the future. I think some people can imagine that.”
Tardiff has a patent on how to use low-dose colchicine post-surgery. myocardial infarction, licensed to the Montreal Heart Institute. Mr. Lidker is a co-inventor of patents owned by Brigham and Women’s Hospital relating to the use of inflammatory biomarkers in cardiovascular disease and diabetes. Braha reportedly serves as an unpaid scientific advisor to Agepha Pharma.
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