The recent US 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 US Food and Drug Administration (FDA) 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, notes Michael Joseph Blaha, MD, Director of Clinical Research, Ciccarone Center for the Prevention of Cardiovascular Disease at Johns Hopkins Hospital, Baltimore.
Blaha, who has been an unpaid scientific advisor to Agepha, adds 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.”
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 comments.
“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 notes. “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.”
Blaha points 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 says. “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,” Blaha says. “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 adds.
“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.”
Blaha also adds 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,” Blaha explains.
‘An Entire Other Axis Driving Atherosclerosis’
Paul Ridker, 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 says.
“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.”
Ridker stresses 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.”
Ridker says he already uses low-dose colchicine for patients who he refers to as “frequent flyers”; those who keep coming back despite aggressive lipid lowering. “They have multiple angioplasties, bypass surgery, etc.”
Like Blaha, 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] who 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 believes 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 says, 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 believes that colchicine should become the “second pillar” of ASCVD treatment, along with statins, for almost all patients.
Tardif refers to the recent study (led by 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 says.
“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 notes.
“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,” Tardif says.
“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 adds.
Tardif says 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.”
Tardif believes 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 adds. “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, Ohio, who was not involved in the colchicine trials, is also enthusiastic about use of colchicine. But like Ridker and 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,” Nissen comments.
“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 says.
“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 notes.
“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 adds.
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,” Nissen says. “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.”
Ridker adds 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.”
Blaha agrees 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, Blaha says 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 suggests.
“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.”
Tardif holds patents on methods for using low-dose colchicine after myocardial infarction, licensed to Montreal Heart Institute. Ridker is a co-inventor on patents held by the Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes. Blaha reports being an unpaid scientific advisor to Agepha Pharma.
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