Michelle L. O’Donoghue, MD, MPH

This transcript has been edited for clarity.

Michelle L. O’Donoghue, MD, MPH: I’m here in Amsterdam at the European Society of Cardiology (ESC) Congress 2023. Joining me for a great discussion is my friend Dr. Pam Taub, who is a cardiologist and a professor of medicine at UC San Diego. She has a particular interest in postural orthostatic tachycardia syndrome (POTS), so that’s what we’ll be talking about today.

Thanks for joining me, Pam. When we think about POTS, for those who are not familiar with the term, what does it actually mean and how do you diagnose it?
 

No tilt table required

Pam R. Taub, MD: As you said, it’s postural orthostatic tachycardia syndrome. What that means is when somebody stands up, they have an elevation in their heart rate that is usually 30 points from when they’re lying down. That’s typically associated with symptoms such as lightheadedness, dizziness, and cognitive difficulties such as brain fog. The diagnosis can be made by tilt-table testing, but it can also be made in the office with simple orthostats.

In my clinic, I have people lie down for 3-5 minutes. At the end of that period, you get a heart rate and blood pressure. Then you have them stand up for 3-5 minutes and then get heart rate and blood pressure, and you look at the differences. If the heart rate goes up by 30 points – so maybe they’re 80 beats/min when they’re lying down and when they stand up, it goes to 110 beats/min  – that’s POTS, so very objective criteria. Typically, these people don’t have what we call orthostatic hypotension, where there is a significant decrease in the blood pressure. It’s more a heart rate issue.

Dr. O’Donoghue: How symptomatically do they usually present?

Dr. Taub: It’s a spectrum. Some people have mild symptoms. After they’re in the upright position for maybe 10 minutes, they get symptoms. There are some people who, when they go from a lying to standing position, they’re extremely symptomatic and can’t really do any activities. There are some people that are even wheelchair-bound because the symptoms are so debilitating. There’s a wide spectrum.

Dr. O’Donoghue: There has been more discussion, I feel like, about the rising prevalence of POTS as a diagnosis, and in particular since the COVID pandemic. What’s our understanding of the relationship between COVID and POTS and what the mechanism might be?

Dr. Taub: We’ve known that POTS can be triggered by a viral infection. Before COVID, we knew that in certain individuals that we think have an underlying genetic predisposition, usually some autoimmune substrate, when they get certain types of infections, whether it’s influenza or mononucleosis, they get POTS.

Typically, when they get an infection, they start getting deconditioned. They don’t feel well, so they’re on bed rest. When they get long periods of bed rest, when they start to become active, they start to have overactivation of their sympathetic nervous system, and they have a large amount of cardiovascular deconditioning. It’s a cycle that is often triggered after an infection.

A huge increase of POTS has been seen after COVID-19 because we had so many people exposed to this virus. With COVID-19, there is a period where people don’t feel great and they are getting bed rest, so they’re getting deconditioned. We’ve seen so many patients referred for post-COVID POTS and also long COVID or the post-acute sequelae of COVID-19, where POTS is a part of that presentation.

Female sex and autoimmune conditions

Dr. O’Donoghue: We know that POTS seems to disproportionately affect women. Is that understood? Is it thought that that’s related to the perhaps the autoimmune component of that illness?

Dr. Taub: Yes. The theory is because women tend to have more autoimmune conditions, that’s why they’re more predisposed. There’s a large amount of genetic susceptibility. For instance, we know that there’s an association between POTS and conditions like Ehlers-Danlos syndrome and between POTS and mast cell activation. Some of those conditions are more prevalent in women as well.

Dr. O’Donoghue: I feel like many physicians don’t know how to manage POTS, and they’re actually a little fearful perhaps to take it on. Fortunately, there have been a growing number of POTS clinics with specialists that focus on that area. For the average practitioner who maybe can’t refer to a POTS clinic, how should they approach that?

Dr. Taub: The first thing is its diagnosis. When someone tells you that they have symptoms of orthostatic intolerance – so, activities that involve standing – you need to first have that on your differential diagnosis. You can make the diagnosis in the office with orthostats. You don’t need a tilt table. It’s sometimes helpful if you’re unsure about the diagnosis, but you can make the diagnosis.

Many times, you’re finding people that have very mild symptoms. You can treat that with some good lifestyle recommendations, such as increased hydration, increasing salt in their diet, and compression. And the exercise component is really important.

Many people with POTS are told to go exercise, go for a run, or go for a walk. That’s incorrect, because these people have symptoms when they’re in the upright position. The type of exercise they need to do initially is exercise in the lying or seated position – so exercises like rowing or a seated bike, and strength training. As they start to feel better, then they can do upright exercise.

You should never tell a person that has POTS to just initially start with upright exercise, because they’re going to feel so much worse and then they’re never going to want to exercise. It’s really important to give them the right exercise recommendations. I find that for many of these mild cases, if they do the right exercise and engage in the right lifestyle strategies, they get better.

Compression wear and drug therapy

Dr. O’Donoghue: When it comes to compression stockings, do you usually start with a particular length?

Dr. Taub: It’s interesting. There are many different compression stockings, medical grade. Through patients with POTS, I’ve gotten feedback on certain types of athletic wear that have built-in compression, and that’s a little bit easier for people to wear every day because they can do their errands and it doesn’t look like they’re wearing medical-grade compression stockings.

Basically, I’ve collected all the different recommendations that patients say help, and I give them a list. The medical-grade compression stockings sometimes are very challenging to put on, and sometimes people just need light compression or even just socks. Any kind of compression is going to help.

Dr. O’Donoghue: That’s a great tip, because I know there are many patients who refuse to wear the compression stockings. If there’s a fashionable alternative, that’s always good to reach for.

Dr. Taub: Another thing that patients have told me is that abdominal compression is also very helpful. There are many commercially available abdominal compression options, like shapewear. Many patients with POTS use that and that helps, too.

Dr. O’Donoghue: Good. For those patients with POTS that is refractory to the measures you’ve already discussed, what are the next steps after that?

Dr. Taub: Pharmacotherapy is very synergistic with lifestyle, and there are many different pharmacotherapy options. One of the first things that you want to think about is lowering that heart rate. The reason people feel horrible is because their heart rate is usually very high when they’re upright. If they’re upright for long periods of time and they’re having very high heart rates, they’re going to get really tired because it’s like they’re exercising for hours when they’re upright.

Heart rate lowering is the cornerstone of therapy. Traditionally, we’ve used beta-blockers for heart rate lowering. The problem is they also lower blood pressure. They can also cause fatigue, so not the ideal agent for patients with POTS.

One of the clinical trials that I led was with a drug called ivabradine, which selectively works on the SA node and decreases heart rate without affecting blood pressure. What’s really elegant about ivabradine is it has a more potent effect when the heart rate is higher. When the patient is standing, it’s going to have a more potent effect on heart rate lowering. It’s really well tolerated in patients with POTS. In our study, we showed an improvement in quality of life metrics. That’s one of the first-line drugs that I use for patients with POTS.

The other thing is some of them will also have a concomitant lowering of blood pressure. You can think about medications that increase blood pressure, like midodrine, fludrocortisone, and droxidopa. Sometimes that combination of a heart rate-lowering medication and a medication that increases blood pressure really works well.

Dr. O’Donoghue: That’s very helpful. I think that those kinds of practical tips are the ones that practitioners really want to reach for, because they need to have that algorithm in their mind to take on this condition. Thanks again for walking us through that.

I think it’s a very interesting space, and there’s more that we’re going to be learning over the next few years as we further flesh out these post-COVID cases and what we learn from that as well.

Dr. Taub: There are many clinical trials now starting in POTS, so it’s exciting.

Dr. O’Donoghue: Absolutely. Thank you again for joining me today. Signing off, this is Dr Michelle O’Donoghue.
 

Dr. O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Dr. O’Donoghue loves spending time outdoors with her family but admits with shame that she’s never strapped on hockey skates. She disclosed ties with Amgen, AstraZeneca Pharmaceuticals LP, CVS Minute Clinic, Eisai, GlaxoSmithKline, Janssen Pharmaceuticals, Merck, Novartis, and The Medicines Company. Dr. Taub is professor of Medicine, University of California San Diego Health, La Jolla. She disclosed ties with Amgen, Bayer, Boehringer Ingelheim, Medtronic, Merck, Novartis, Novo Nordisk, and Sanofi.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Michelle L. O’Donoghue, MD, MPH: I’m here in Amsterdam at the European Society of Cardiology (ESC) Congress 2023. Joining me for a great discussion is my friend Dr. Pam Taub, who is a cardiologist and a professor of medicine at UC San Diego. She has a particular interest in postural orthostatic tachycardia syndrome (POTS), so that’s what we’ll be talking about today.

Thanks for joining me, Pam. When we think about POTS, for those who are not familiar with the term, what does it actually mean and how do you diagnose it?
 

No tilt table required

Pam R. Taub, MD: As you said, it’s postural orthostatic tachycardia syndrome. What that means is when somebody stands up, they have an elevation in their heart rate that is usually 30 points from when they’re lying down. That’s typically associated with symptoms such as lightheadedness, dizziness, and cognitive difficulties such as brain fog. The diagnosis can be made by tilt-table testing, but it can also be made in the office with simple orthostats.

In my clinic, I have people lie down for 3-5 minutes. At the end of that period, you get a heart rate and blood pressure. Then you have them stand up for 3-5 minutes and then get heart rate and blood pressure, and you look at the differences. If the heart rate goes up by 30 points – so maybe they’re 80 beats/min when they’re lying down and when they stand up, it goes to 110 beats/min  – that’s POTS, so very objective criteria. Typically, these people don’t have what we call orthostatic hypotension, where there is a significant decrease in the blood pressure. It’s more a heart rate issue.

Dr. O’Donoghue: How symptomatically do they usually present?

Dr. Taub: It’s a spectrum. Some people have mild symptoms. After they’re in the upright position for maybe 10 minutes, they get symptoms. There are some people who, when they go from a lying to standing position, they’re extremely symptomatic and can’t really do any activities. There are some people that are even wheelchair-bound because the symptoms are so debilitating. There’s a wide spectrum.

Dr. O’Donoghue: There has been more discussion, I feel like, about the rising prevalence of POTS as a diagnosis, and in particular since the COVID pandemic. What’s our understanding of the relationship between COVID and POTS and what the mechanism might be?

Dr. Taub: We’ve known that POTS can be triggered by a viral infection. Before COVID, we knew that in certain individuals that we think have an underlying genetic predisposition, usually some autoimmune substrate, when they get certain types of infections, whether it’s influenza or mononucleosis, they get POTS.

Typically, when they get an infection, they start getting deconditioned. They don’t feel well, so they’re on bed rest. When they get long periods of bed rest, when they start to become active, they start to have overactivation of their sympathetic nervous system, and they have a large amount of cardiovascular deconditioning. It’s a cycle that is often triggered after an infection.

A huge increase of POTS has been seen after COVID-19 because we had so many people exposed to this virus. With COVID-19, there is a period where people don’t feel great and they are getting bed rest, so they’re getting deconditioned. We’ve seen so many patients referred for post-COVID POTS and also long COVID or the post-acute sequelae of COVID-19, where POTS is a part of that presentation.

Female sex and autoimmune conditions

Dr. O’Donoghue: We know that POTS seems to disproportionately affect women. Is that understood? Is it thought that that’s related to the perhaps the autoimmune component of that illness?

Dr. Taub: Yes. The theory is because women tend to have more autoimmune conditions, that’s why they’re more predisposed. There’s a large amount of genetic susceptibility. For instance, we know that there’s an association between POTS and conditions like Ehlers-Danlos syndrome and between POTS and mast cell activation. Some of those conditions are more prevalent in women as well.

Dr. O’Donoghue: I feel like many physicians don’t know how to manage POTS, and they’re actually a little fearful perhaps to take it on. Fortunately, there have been a growing number of POTS clinics with specialists that focus on that area. For the average practitioner who maybe can’t refer to a POTS clinic, how should they approach that?

Dr. Taub: The first thing is its diagnosis. When someone tells you that they have symptoms of orthostatic intolerance – so, activities that involve standing – you need to first have that on your differential diagnosis. You can make the diagnosis in the office with orthostats. You don’t need a tilt table. It’s sometimes helpful if you’re unsure about the diagnosis, but you can make the diagnosis.

Many times, you’re finding people that have very mild symptoms. You can treat that with some good lifestyle recommendations, such as increased hydration, increasing salt in their diet, and compression. And the exercise component is really important.

Many people with POTS are told to go exercise, go for a run, or go for a walk. That’s incorrect, because these people have symptoms when they’re in the upright position. The type of exercise they need to do initially is exercise in the lying or seated position – so exercises like rowing or a seated bike, and strength training. As they start to feel better, then they can do upright exercise.

You should never tell a person that has POTS to just initially start with upright exercise, because they’re going to feel so much worse and then they’re never going to want to exercise. It’s really important to give them the right exercise recommendations. I find that for many of these mild cases, if they do the right exercise and engage in the right lifestyle strategies, they get better.

Compression wear and drug therapy

Dr. O’Donoghue: When it comes to compression stockings, do you usually start with a particular length?

Dr. Taub: It’s interesting. There are many different compression stockings, medical grade. Through patients with POTS, I’ve gotten feedback on certain types of athletic wear that have built-in compression, and that’s a little bit easier for people to wear every day because they can do their errands and it doesn’t look like they’re wearing medical-grade compression stockings.

Basically, I’ve collected all the different recommendations that patients say help, and I give them a list. The medical-grade compression stockings sometimes are very challenging to put on, and sometimes people just need light compression or even just socks. Any kind of compression is going to help.

Dr. O’Donoghue: That’s a great tip, because I know there are many patients who refuse to wear the compression stockings. If there’s a fashionable alternative, that’s always good to reach for.

Dr. Taub: Another thing that patients have told me is that abdominal compression is also very helpful. There are many commercially available abdominal compression options, like shapewear. Many patients with POTS use that and that helps, too.

Dr. O’Donoghue: Good. For those patients with POTS that is refractory to the measures you’ve already discussed, what are the next steps after that?

Dr. Taub: Pharmacotherapy is very synergistic with lifestyle, and there are many different pharmacotherapy options. One of the first things that you want to think about is lowering that heart rate. The reason people feel horrible is because their heart rate is usually very high when they’re upright. If they’re upright for long periods of time and they’re having very high heart rates, they’re going to get really tired because it’s like they’re exercising for hours when they’re upright.

Heart rate lowering is the cornerstone of therapy. Traditionally, we’ve used beta-blockers for heart rate lowering. The problem is they also lower blood pressure. They can also cause fatigue, so not the ideal agent for patients with POTS.

One of the clinical trials that I led was with a drug called ivabradine, which selectively works on the SA node and decreases heart rate without affecting blood pressure. What’s really elegant about ivabradine is it has a more potent effect when the heart rate is higher. When the patient is standing, it’s going to have a more potent effect on heart rate lowering. It’s really well tolerated in patients with POTS. In our study, we showed an improvement in quality of life metrics. That’s one of the first-line drugs that I use for patients with POTS.

The other thing is some of them will also have a concomitant lowering of blood pressure. You can think about medications that increase blood pressure, like midodrine, fludrocortisone, and droxidopa. Sometimes that combination of a heart rate-lowering medication and a medication that increases blood pressure really works well.

Dr. O’Donoghue: That’s very helpful. I think that those kinds of practical tips are the ones that practitioners really want to reach for, because they need to have that algorithm in their mind to take on this condition. Thanks again for walking us through that.

I think it’s a very interesting space, and there’s more that we’re going to be learning over the next few years as we further flesh out these post-COVID cases and what we learn from that as well.

Dr. Taub: There are many clinical trials now starting in POTS, so it’s exciting.

Dr. O’Donoghue: Absolutely. Thank you again for joining me today. Signing off, this is Dr Michelle O’Donoghue.
 

Dr. O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Dr. O’Donoghue loves spending time outdoors with her family but admits with shame that she’s never strapped on hockey skates. She disclosed ties with Amgen, AstraZeneca Pharmaceuticals LP, CVS Minute Clinic, Eisai, GlaxoSmithKline, Janssen Pharmaceuticals, Merck, Novartis, and The Medicines Company. Dr. Taub is professor of Medicine, University of California San Diego Health, La Jolla. She disclosed ties with Amgen, Bayer, Boehringer Ingelheim, Medtronic, Merck, Novartis, Novo Nordisk, and Sanofi.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Michelle L. O’Donoghue, MD, MPH: I’m here in Amsterdam at the European Society of Cardiology (ESC) Congress 2023. Joining me for a great discussion is my friend Dr. Pam Taub, who is a cardiologist and a professor of medicine at UC San Diego. She has a particular interest in postural orthostatic tachycardia syndrome (POTS), so that’s what we’ll be talking about today.

Thanks for joining me, Pam. When we think about POTS, for those who are not familiar with the term, what does it actually mean and how do you diagnose it?
 

No tilt table required

Pam R. Taub, MD: As you said, it’s postural orthostatic tachycardia syndrome. What that means is when somebody stands up, they have an elevation in their heart rate that is usually 30 points from when they’re lying down. That’s typically associated with symptoms such as lightheadedness, dizziness, and cognitive difficulties such as brain fog. The diagnosis can be made by tilt-table testing, but it can also be made in the office with simple orthostats.

In my clinic, I have people lie down for 3-5 minutes. At the end of that period, you get a heart rate and blood pressure. Then you have them stand up for 3-5 minutes and then get heart rate and blood pressure, and you look at the differences. If the heart rate goes up by 30 points – so maybe they’re 80 beats/min when they’re lying down and when they stand up, it goes to 110 beats/min  – that’s POTS, so very objective criteria. Typically, these people don’t have what we call orthostatic hypotension, where there is a significant decrease in the blood pressure. It’s more a heart rate issue.

Dr. O’Donoghue: How symptomatically do they usually present?

Dr. Taub: It’s a spectrum. Some people have mild symptoms. After they’re in the upright position for maybe 10 minutes, they get symptoms. There are some people who, when they go from a lying to standing position, they’re extremely symptomatic and can’t really do any activities. There are some people that are even wheelchair-bound because the symptoms are so debilitating. There’s a wide spectrum.

Dr. O’Donoghue: There has been more discussion, I feel like, about the rising prevalence of POTS as a diagnosis, and in particular since the COVID pandemic. What’s our understanding of the relationship between COVID and POTS and what the mechanism might be?

Dr. Taub: We’ve known that POTS can be triggered by a viral infection. Before COVID, we knew that in certain individuals that we think have an underlying genetic predisposition, usually some autoimmune substrate, when they get certain types of infections, whether it’s influenza or mononucleosis, they get POTS.

Typically, when they get an infection, they start getting deconditioned. They don’t feel well, so they’re on bed rest. When they get long periods of bed rest, when they start to become active, they start to have overactivation of their sympathetic nervous system, and they have a large amount of cardiovascular deconditioning. It’s a cycle that is often triggered after an infection.

A huge increase of POTS has been seen after COVID-19 because we had so many people exposed to this virus. With COVID-19, there is a period where people don’t feel great and they are getting bed rest, so they’re getting deconditioned. We’ve seen so many patients referred for post-COVID POTS and also long COVID or the post-acute sequelae of COVID-19, where POTS is a part of that presentation.

Female sex and autoimmune conditions

Dr. O’Donoghue: We know that POTS seems to disproportionately affect women. Is that understood? Is it thought that that’s related to the perhaps the autoimmune component of that illness?

Dr. Taub: Yes. The theory is because women tend to have more autoimmune conditions, that’s why they’re more predisposed. There’s a large amount of genetic susceptibility. For instance, we know that there’s an association between POTS and conditions like Ehlers-Danlos syndrome and between POTS and mast cell activation. Some of those conditions are more prevalent in women as well.

Dr. O’Donoghue: I feel like many physicians don’t know how to manage POTS, and they’re actually a little fearful perhaps to take it on. Fortunately, there have been a growing number of POTS clinics with specialists that focus on that area. For the average practitioner who maybe can’t refer to a POTS clinic, how should they approach that?

Dr. Taub: The first thing is its diagnosis. When someone tells you that they have symptoms of orthostatic intolerance – so, activities that involve standing – you need to first have that on your differential diagnosis. You can make the diagnosis in the office with orthostats. You don’t need a tilt table. It’s sometimes helpful if you’re unsure about the diagnosis, but you can make the diagnosis.

Many times, you’re finding people that have very mild symptoms. You can treat that with some good lifestyle recommendations, such as increased hydration, increasing salt in their diet, and compression. And the exercise component is really important.

Many people with POTS are told to go exercise, go for a run, or go for a walk. That’s incorrect, because these people have symptoms when they’re in the upright position. The type of exercise they need to do initially is exercise in the lying or seated position – so exercises like rowing or a seated bike, and strength training. As they start to feel better, then they can do upright exercise.

You should never tell a person that has POTS to just initially start with upright exercise, because they’re going to feel so much worse and then they’re never going to want to exercise. It’s really important to give them the right exercise recommendations. I find that for many of these mild cases, if they do the right exercise and engage in the right lifestyle strategies, they get better.

Compression wear and drug therapy

Dr. O’Donoghue: When it comes to compression stockings, do you usually start with a particular length?

Dr. Taub: It’s interesting. There are many different compression stockings, medical grade. Through patients with POTS, I’ve gotten feedback on certain types of athletic wear that have built-in compression, and that’s a little bit easier for people to wear every day because they can do their errands and it doesn’t look like they’re wearing medical-grade compression stockings.

Basically, I’ve collected all the different recommendations that patients say help, and I give them a list. The medical-grade compression stockings sometimes are very challenging to put on, and sometimes people just need light compression or even just socks. Any kind of compression is going to help.

Dr. O’Donoghue: That’s a great tip, because I know there are many patients who refuse to wear the compression stockings. If there’s a fashionable alternative, that’s always good to reach for.

Dr. Taub: Another thing that patients have told me is that abdominal compression is also very helpful. There are many commercially available abdominal compression options, like shapewear. Many patients with POTS use that and that helps, too.

Dr. O’Donoghue: Good. For those patients with POTS that is refractory to the measures you’ve already discussed, what are the next steps after that?

Dr. Taub: Pharmacotherapy is very synergistic with lifestyle, and there are many different pharmacotherapy options. One of the first things that you want to think about is lowering that heart rate. The reason people feel horrible is because their heart rate is usually very high when they’re upright. If they’re upright for long periods of time and they’re having very high heart rates, they’re going to get really tired because it’s like they’re exercising for hours when they’re upright.

Heart rate lowering is the cornerstone of therapy. Traditionally, we’ve used beta-blockers for heart rate lowering. The problem is they also lower blood pressure. They can also cause fatigue, so not the ideal agent for patients with POTS.

One of the clinical trials that I led was with a drug called ivabradine, which selectively works on the SA node and decreases heart rate without affecting blood pressure. What’s really elegant about ivabradine is it has a more potent effect when the heart rate is higher. When the patient is standing, it’s going to have a more potent effect on heart rate lowering. It’s really well tolerated in patients with POTS. In our study, we showed an improvement in quality of life metrics. That’s one of the first-line drugs that I use for patients with POTS.

The other thing is some of them will also have a concomitant lowering of blood pressure. You can think about medications that increase blood pressure, like midodrine, fludrocortisone, and droxidopa. Sometimes that combination of a heart rate-lowering medication and a medication that increases blood pressure really works well.

Dr. O’Donoghue: That’s very helpful. I think that those kinds of practical tips are the ones that practitioners really want to reach for, because they need to have that algorithm in their mind to take on this condition. Thanks again for walking us through that.

I think it’s a very interesting space, and there’s more that we’re going to be learning over the next few years as we further flesh out these post-COVID cases and what we learn from that as well.

Dr. Taub: There are many clinical trials now starting in POTS, so it’s exciting.

Dr. O’Donoghue: Absolutely. Thank you again for joining me today. Signing off, this is Dr Michelle O’Donoghue.
 

Dr. O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Dr. O’Donoghue loves spending time outdoors with her family but admits with shame that she’s never strapped on hockey skates. She disclosed ties with Amgen, AstraZeneca Pharmaceuticals LP, CVS Minute Clinic, Eisai, GlaxoSmithKline, Janssen Pharmaceuticals, Merck, Novartis, and The Medicines Company. Dr. Taub is professor of Medicine, University of California San Diego Health, La Jolla. She disclosed ties with Amgen, Bayer, Boehringer Ingelheim, Medtronic, Merck, Novartis, Novo Nordisk, and Sanofi.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Michelle L. O’Donoghue, MD, MPH: Hi. This is Dr. Michelle O’Donoghue reporting for Medscape. Joining me today is Dr. Sahil Parikh, who’s a cardiologist and an interventionalist at Columbia University. He’s an associate professor of medicine.

We’ll be discussing two interesting trials that were presented at the ESC Congress here in Amsterdam. They do have the potential to be very practice-changing, so I think it’s worth talking about.
 

The FIRE trial

The first trial we’ll be talking about is the FIRE trial. Perhaps setting the stage, Sahil, I’d love to get your thoughts. We’ve had data in this space to suggest that, for patients with STEMI [ST-segment elevation myocardial infarction], a strategy of complete revascularization – and not only treating the culprit lesion but also treating additional lesions – may be of benefit. Where does that lead us in terms of what we didn’t know?

Sahil A. Parikh, MD: I think that the practice has moved, at least in the United States, over the past two decades, from staging percutaneous coronary interventions over 30 days from index to intervention to now trying to do patients in the same hospitalization whenever possible to achieve complete revascularization.

I think these data support not only that complete revascularization is compulsory now in these patients, but also doing it sooner rather than later, and that the benefit applies to most of the patients that we see in clinical practice. In the earlier data, the patients were relatively youthful – under Medicare age, less than 65 – and now this dataset has a median age of 80. This is more like the real-world clinical practice that most of us are encountering, and it extends the benefit, perhaps, greater than we’ve ever seen before.

O’Donoghue: The FIRE trial is interesting. As you say, it enrolled patients who were over the age of 75, where I think that some proceduralists are probably a little bit hesitant to think about complete revascularization due to concerns about any additional contrast load on their kidneys and other types of comorbidities. Of course, for any trial, there’s going to be some patient selection.

I think it’s very reassuring that even in this older patient group, a strategy of treating all the lesions – and not only in STEMI but also in non-STEMI patients – reduced cardiovascular events and mortality. I was really quite impressed by the mortality benefit.

Parikh: The mortality curve is almost surprising to me. On the other hand, it emboldens us now that we can treat these patients more completely and earlier in their clinical presentation. Certainly, we worried about contrast exposure and the duration of procedures in this older population, but it seems that the benefit that’s derived, which we saw in younger patients where we had a natural inclination to be more aggressive, extends also to this older population.
 

MULTISTARS AMI

O’Donoghue: To the question of timing, as you mentioned, prior to this, we had a study presented earlier this year, the BIOVASC trial, which also was suggestive that maybe earlier complete revascularization was better. But it wasn’t a significant difference, at least for the primary outcome. Now we have MULTISTARS AMI, which is very supportive of what we saw earlier this year, suggesting that complete revascularization really at the time that you’re treating the culprit may be the way to go.

Parikh: All of us, as interventionalists, are circumspect about what we might do in the middle of the night versus what we would do in the light of day. Certainly it seems clear, particularly if it’s straightforward anatomy, that taking care of it in the index procedure is not only saving contrast and fluoroscopy time, but it’s also providing a clinical benefit to the patients. That’s something that will also impact how clinicians interpret these data. Previously, there was always a question about whether we should just do it in the same hospitalization or do it at the same time. I think now, increasingly, we’re emboldened to do more in the index procedure.

O’Donoghue: When you’re thinking about nonculprit lesions and which ones to treat, do you always make that determination based on physiologic guidance of some kind? Are you using instantaneous wave-free ratio? What’s your practice?

Parikh: In the acute setting, imaging is superior for at least the assessment of which is a culprit. If you see a ruptured atherothrombotic situation on optical coherence tomography, for example, that’s fairly convincing and definitive. In the absence of that physiology, we are taught to avoid in the infarct-related artery because of potential spuriously false-negative findings.

In this situation, certainly, an imaging subgroup probably would be helpful because some of the benefit is almost certainly derived from identifying the infarct-related artery by accident – in other words, doing what you thought was the nonculprit artery, which is, in fact, the culprit. I think that probably is part of this. As somebody who uses imaging in the overwhelming number of my cases, I think that imaging would be an important surrogate to this.
 

Index procedure versus staged

O’Donoghue: For the operator who is coming in to do their STEMI case at 2:00 in the morning, would these data now push you toward doing complete revascularization at that time of night, or do you think that there is wiggle room in terms of interpreting these results regarding timing, where as long as you were doing it before hospital discharge and not, let’s say, 30 days out, that you may be able to derive the same benefit? What are some of the pros and cons?

Parikh: There’s definitely a fatigue factor in the middle of the night if it’s a particularly arduous intervention for the index infarct-related artery. I think there’s a human element where it may make sense just to stop and then bring the patient back in the same hospitalization. It’s clear, though, that doing complete revascularization is better and doing it sooner is better. How soon one actually does it is a judgment call, as ever.

In our practice, we’ve been pushing ourselves to get most of the patients done in their index hospitalization. If you have a left-sided culprit, the left anterior descending artery, for example, and there’s a high-grade stenosis in the circumflex, it may make sense to take care of that in the same index procedure. If, on the other hand, it’s in the right coronary artery where you have to put a new guide in and spend more time, that may be a patient whom you stage. I think those nuances will come up as interventionalists look at the subgroup analysis data more carefully.

O’Donoghue: Those are great points, and I think they also underscore that we always need to think about what type of patient was enrolled in these studies. Certainly, if you have somebody with renal dysfunction, there might be more concern about giving them a large contrast load all in one sitting, albeit hard to know whether they do or not. But spacing that out by just a couple of days would really have a big impact.

Parikh: Very often in the STEMI patient, you don’t have the benefit of knowing the creatinine. The patient will come in immediately, if not directly from the ambulance to the cath lab, and there are no laboratories at all to work with. If the patient has never been seen in the system before, you won’t know. Again, in those situations, one may have pause, particularly if it’s an older patient. I think what’s reassuring, though, is that the data are supportive of being more aggressive earlier, and certainly this is the dataset that we were looking for.

O’Donoghue: To summarize, the two key takeaways are that, one, we now have more data to support a complete revascularization strategy and even extending that now to non-STEMI patients. Two, sooner appears to be better, so ideally, all done at the time of the index procedure. I think this is very interesting science and we’ll see how it changes practice.

Thanks for joining me today. Signing off for Medscape, this is Dr. Michelle O’Donoghue.

Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Michelle L. O’Donoghue, MD, MPH: Hi. This is Dr. Michelle O’Donoghue reporting for Medscape. Joining me today is Dr. Sahil Parikh, who’s a cardiologist and an interventionalist at Columbia University. He’s an associate professor of medicine.

We’ll be discussing two interesting trials that were presented at the ESC Congress here in Amsterdam. They do have the potential to be very practice-changing, so I think it’s worth talking about.
 

The FIRE trial

The first trial we’ll be talking about is the FIRE trial. Perhaps setting the stage, Sahil, I’d love to get your thoughts. We’ve had data in this space to suggest that, for patients with STEMI [ST-segment elevation myocardial infarction], a strategy of complete revascularization – and not only treating the culprit lesion but also treating additional lesions – may be of benefit. Where does that lead us in terms of what we didn’t know?

Sahil A. Parikh, MD: I think that the practice has moved, at least in the United States, over the past two decades, from staging percutaneous coronary interventions over 30 days from index to intervention to now trying to do patients in the same hospitalization whenever possible to achieve complete revascularization.

I think these data support not only that complete revascularization is compulsory now in these patients, but also doing it sooner rather than later, and that the benefit applies to most of the patients that we see in clinical practice. In the earlier data, the patients were relatively youthful – under Medicare age, less than 65 – and now this dataset has a median age of 80. This is more like the real-world clinical practice that most of us are encountering, and it extends the benefit, perhaps, greater than we’ve ever seen before.

O’Donoghue: The FIRE trial is interesting. As you say, it enrolled patients who were over the age of 75, where I think that some proceduralists are probably a little bit hesitant to think about complete revascularization due to concerns about any additional contrast load on their kidneys and other types of comorbidities. Of course, for any trial, there’s going to be some patient selection.

I think it’s very reassuring that even in this older patient group, a strategy of treating all the lesions – and not only in STEMI but also in non-STEMI patients – reduced cardiovascular events and mortality. I was really quite impressed by the mortality benefit.

Parikh: The mortality curve is almost surprising to me. On the other hand, it emboldens us now that we can treat these patients more completely and earlier in their clinical presentation. Certainly, we worried about contrast exposure and the duration of procedures in this older population, but it seems that the benefit that’s derived, which we saw in younger patients where we had a natural inclination to be more aggressive, extends also to this older population.
 

MULTISTARS AMI

O’Donoghue: To the question of timing, as you mentioned, prior to this, we had a study presented earlier this year, the BIOVASC trial, which also was suggestive that maybe earlier complete revascularization was better. But it wasn’t a significant difference, at least for the primary outcome. Now we have MULTISTARS AMI, which is very supportive of what we saw earlier this year, suggesting that complete revascularization really at the time that you’re treating the culprit may be the way to go.

Parikh: All of us, as interventionalists, are circumspect about what we might do in the middle of the night versus what we would do in the light of day. Certainly it seems clear, particularly if it’s straightforward anatomy, that taking care of it in the index procedure is not only saving contrast and fluoroscopy time, but it’s also providing a clinical benefit to the patients. That’s something that will also impact how clinicians interpret these data. Previously, there was always a question about whether we should just do it in the same hospitalization or do it at the same time. I think now, increasingly, we’re emboldened to do more in the index procedure.

O’Donoghue: When you’re thinking about nonculprit lesions and which ones to treat, do you always make that determination based on physiologic guidance of some kind? Are you using instantaneous wave-free ratio? What’s your practice?

Parikh: In the acute setting, imaging is superior for at least the assessment of which is a culprit. If you see a ruptured atherothrombotic situation on optical coherence tomography, for example, that’s fairly convincing and definitive. In the absence of that physiology, we are taught to avoid in the infarct-related artery because of potential spuriously false-negative findings.

In this situation, certainly, an imaging subgroup probably would be helpful because some of the benefit is almost certainly derived from identifying the infarct-related artery by accident – in other words, doing what you thought was the nonculprit artery, which is, in fact, the culprit. I think that probably is part of this. As somebody who uses imaging in the overwhelming number of my cases, I think that imaging would be an important surrogate to this.
 

Index procedure versus staged

O’Donoghue: For the operator who is coming in to do their STEMI case at 2:00 in the morning, would these data now push you toward doing complete revascularization at that time of night, or do you think that there is wiggle room in terms of interpreting these results regarding timing, where as long as you were doing it before hospital discharge and not, let’s say, 30 days out, that you may be able to derive the same benefit? What are some of the pros and cons?

Parikh: There’s definitely a fatigue factor in the middle of the night if it’s a particularly arduous intervention for the index infarct-related artery. I think there’s a human element where it may make sense just to stop and then bring the patient back in the same hospitalization. It’s clear, though, that doing complete revascularization is better and doing it sooner is better. How soon one actually does it is a judgment call, as ever.

In our practice, we’ve been pushing ourselves to get most of the patients done in their index hospitalization. If you have a left-sided culprit, the left anterior descending artery, for example, and there’s a high-grade stenosis in the circumflex, it may make sense to take care of that in the same index procedure. If, on the other hand, it’s in the right coronary artery where you have to put a new guide in and spend more time, that may be a patient whom you stage. I think those nuances will come up as interventionalists look at the subgroup analysis data more carefully.

O’Donoghue: Those are great points, and I think they also underscore that we always need to think about what type of patient was enrolled in these studies. Certainly, if you have somebody with renal dysfunction, there might be more concern about giving them a large contrast load all in one sitting, albeit hard to know whether they do or not. But spacing that out by just a couple of days would really have a big impact.

Parikh: Very often in the STEMI patient, you don’t have the benefit of knowing the creatinine. The patient will come in immediately, if not directly from the ambulance to the cath lab, and there are no laboratories at all to work with. If the patient has never been seen in the system before, you won’t know. Again, in those situations, one may have pause, particularly if it’s an older patient. I think what’s reassuring, though, is that the data are supportive of being more aggressive earlier, and certainly this is the dataset that we were looking for.

O’Donoghue: To summarize, the two key takeaways are that, one, we now have more data to support a complete revascularization strategy and even extending that now to non-STEMI patients. Two, sooner appears to be better, so ideally, all done at the time of the index procedure. I think this is very interesting science and we’ll see how it changes practice.

Thanks for joining me today. Signing off for Medscape, this is Dr. Michelle O’Donoghue.

Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Michelle L. O’Donoghue, MD, MPH: Hi. This is Dr. Michelle O’Donoghue reporting for Medscape. Joining me today is Dr. Sahil Parikh, who’s a cardiologist and an interventionalist at Columbia University. He’s an associate professor of medicine.

We’ll be discussing two interesting trials that were presented at the ESC Congress here in Amsterdam. They do have the potential to be very practice-changing, so I think it’s worth talking about.
 

The FIRE trial

The first trial we’ll be talking about is the FIRE trial. Perhaps setting the stage, Sahil, I’d love to get your thoughts. We’ve had data in this space to suggest that, for patients with STEMI [ST-segment elevation myocardial infarction], a strategy of complete revascularization – and not only treating the culprit lesion but also treating additional lesions – may be of benefit. Where does that lead us in terms of what we didn’t know?

Sahil A. Parikh, MD: I think that the practice has moved, at least in the United States, over the past two decades, from staging percutaneous coronary interventions over 30 days from index to intervention to now trying to do patients in the same hospitalization whenever possible to achieve complete revascularization.

I think these data support not only that complete revascularization is compulsory now in these patients, but also doing it sooner rather than later, and that the benefit applies to most of the patients that we see in clinical practice. In the earlier data, the patients were relatively youthful – under Medicare age, less than 65 – and now this dataset has a median age of 80. This is more like the real-world clinical practice that most of us are encountering, and it extends the benefit, perhaps, greater than we’ve ever seen before.

O’Donoghue: The FIRE trial is interesting. As you say, it enrolled patients who were over the age of 75, where I think that some proceduralists are probably a little bit hesitant to think about complete revascularization due to concerns about any additional contrast load on their kidneys and other types of comorbidities. Of course, for any trial, there’s going to be some patient selection.

I think it’s very reassuring that even in this older patient group, a strategy of treating all the lesions – and not only in STEMI but also in non-STEMI patients – reduced cardiovascular events and mortality. I was really quite impressed by the mortality benefit.

Parikh: The mortality curve is almost surprising to me. On the other hand, it emboldens us now that we can treat these patients more completely and earlier in their clinical presentation. Certainly, we worried about contrast exposure and the duration of procedures in this older population, but it seems that the benefit that’s derived, which we saw in younger patients where we had a natural inclination to be more aggressive, extends also to this older population.
 

MULTISTARS AMI

O’Donoghue: To the question of timing, as you mentioned, prior to this, we had a study presented earlier this year, the BIOVASC trial, which also was suggestive that maybe earlier complete revascularization was better. But it wasn’t a significant difference, at least for the primary outcome. Now we have MULTISTARS AMI, which is very supportive of what we saw earlier this year, suggesting that complete revascularization really at the time that you’re treating the culprit may be the way to go.

Parikh: All of us, as interventionalists, are circumspect about what we might do in the middle of the night versus what we would do in the light of day. Certainly it seems clear, particularly if it’s straightforward anatomy, that taking care of it in the index procedure is not only saving contrast and fluoroscopy time, but it’s also providing a clinical benefit to the patients. That’s something that will also impact how clinicians interpret these data. Previously, there was always a question about whether we should just do it in the same hospitalization or do it at the same time. I think now, increasingly, we’re emboldened to do more in the index procedure.

O’Donoghue: When you’re thinking about nonculprit lesions and which ones to treat, do you always make that determination based on physiologic guidance of some kind? Are you using instantaneous wave-free ratio? What’s your practice?

Parikh: In the acute setting, imaging is superior for at least the assessment of which is a culprit. If you see a ruptured atherothrombotic situation on optical coherence tomography, for example, that’s fairly convincing and definitive. In the absence of that physiology, we are taught to avoid in the infarct-related artery because of potential spuriously false-negative findings.

In this situation, certainly, an imaging subgroup probably would be helpful because some of the benefit is almost certainly derived from identifying the infarct-related artery by accident – in other words, doing what you thought was the nonculprit artery, which is, in fact, the culprit. I think that probably is part of this. As somebody who uses imaging in the overwhelming number of my cases, I think that imaging would be an important surrogate to this.
 

Index procedure versus staged

O’Donoghue: For the operator who is coming in to do their STEMI case at 2:00 in the morning, would these data now push you toward doing complete revascularization at that time of night, or do you think that there is wiggle room in terms of interpreting these results regarding timing, where as long as you were doing it before hospital discharge and not, let’s say, 30 days out, that you may be able to derive the same benefit? What are some of the pros and cons?

Parikh: There’s definitely a fatigue factor in the middle of the night if it’s a particularly arduous intervention for the index infarct-related artery. I think there’s a human element where it may make sense just to stop and then bring the patient back in the same hospitalization. It’s clear, though, that doing complete revascularization is better and doing it sooner is better. How soon one actually does it is a judgment call, as ever.

In our practice, we’ve been pushing ourselves to get most of the patients done in their index hospitalization. If you have a left-sided culprit, the left anterior descending artery, for example, and there’s a high-grade stenosis in the circumflex, it may make sense to take care of that in the same index procedure. If, on the other hand, it’s in the right coronary artery where you have to put a new guide in and spend more time, that may be a patient whom you stage. I think those nuances will come up as interventionalists look at the subgroup analysis data more carefully.

O’Donoghue: Those are great points, and I think they also underscore that we always need to think about what type of patient was enrolled in these studies. Certainly, if you have somebody with renal dysfunction, there might be more concern about giving them a large contrast load all in one sitting, albeit hard to know whether they do or not. But spacing that out by just a couple of days would really have a big impact.

Parikh: Very often in the STEMI patient, you don’t have the benefit of knowing the creatinine. The patient will come in immediately, if not directly from the ambulance to the cath lab, and there are no laboratories at all to work with. If the patient has never been seen in the system before, you won’t know. Again, in those situations, one may have pause, particularly if it’s an older patient. I think what’s reassuring, though, is that the data are supportive of being more aggressive earlier, and certainly this is the dataset that we were looking for.

O’Donoghue: To summarize, the two key takeaways are that, one, we now have more data to support a complete revascularization strategy and even extending that now to non-STEMI patients. Two, sooner appears to be better, so ideally, all done at the time of the index procedure. I think this is very interesting science and we’ll see how it changes practice.

Thanks for joining me today. Signing off for Medscape, this is Dr. Michelle O’Donoghue.

Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Dr. O’Donoghue: We’re going to discuss a very important and emerging topic, which is the use of low-dose colchicine. I think there’s much interest in the use of this drug, which now has a Food and Drug Administration indication, which we’ll talk about further, and it’s also been written into both European and American guidelines that have been recently released.

Many people are talking about where this fits into our current armamentarium, and I think there probably is no better person to discuss this than Paul Ridker, who’s been at the forefront of research into anti-inflammatory therapeutics.
 

Lifestyle lipid-lowering paramount

Dr. O’Donoghue: As we think about the concept behind the use of colchicine, we’ve obviously done a large amount of research into lipid-lowering drugs, but where does colchicine now fit in?

Dr. Ridker: Let’s make sure we get the basics down. Anti-inflammatory therapy is going to be added on top of quality other care. This is not a replacement for lipids; it’s not a change in diet, exercise, and smoking cessation. The new data are really telling us that a patient who’s aggressively treated to guideline-recommended levels can still do much better in terms of preventing heart attack, stroke, cardiovascular death, and revascularization by adding low-dose colchicine as the first proven anti-inflammatory therapy for atherosclerotic disease.

I have to say, Michelle, for me, it’s been a wonderful end of a journey in many ways. This story starts almost 30 years ago for quite a few of us, thinking about inflammation and atherosclerosis. The whole C-reactive protein (CRP) story is still an ongoing one. We recently showed, for example, that residual inflammatory risk in some 30,000 patients, all taking a statin, was a far better predictor of the likelihood of more cardiovascular events, in particular cardiovascular death, than was residual cholesterol risk.

Think about that. We’re all aggressively giving second lipid-lowering drugs in our very sick patients, but that means inflammation is really the untapped piece of this.

The two clinical trials we have in front of us, the COLCOT trial and the LoDoCo2 trial – both New England Journal of Medicine papers, both with roughly 5,000 patients – provide very clear evidence that following a relatively recent myocardial infarction (that’s COLCOT) in chronic stable atherosclerosis (that’s LoDoCo2), we’re getting 25%-30% relative risk reductions in major adverse cardiovascular events (MACEs) on top of aggressive statin therapy. That’s a big deal. It’s safe, it works, and it’s fully consistent with all the information we have about inflammation being part and parcel of atherosclerosis. It’s a pretty exciting time.
 

Inflammatory pathway

Dr. O’Donoghue: It beautifully proves the inflammatory hypothesis in many ways. You led CANTOS, and that was a much more specific target. Here, in terms of the effects of colchicine, what do we know about how it may work on the inflammatory cascade?

Dr. Ridker: Our CANTOS trial was proof of principle that you could directly target, with a very specific monoclonal antibody, a specific piece of this innate immune cascade and lower cardiovascular event rates.

Colchicine is a more broad-spectrum drug. It does have a number of antineutrophil effects – that’s important, by the way. Neutrophils are really becoming very important in atherosclerotic disease progression. It’s an indirect inhibitor of the so-called NLRP3 inflammasome, which is where both interleukin-1 (that’s the target for canakinumab) and IL-6 are up-regulated. As you know, it’s been used to treat gout and pericarditis in high doses in short, little bursts.

The change here is this use of low-dose colchicine, that’s 0.5 mg once a day for years to treat chronic, stable atherosclerosis. It is very much like using a statin. The idea here is to prevent the progression of the disease by slowing down and maybe stabilizing the plaque so we have fewer heart attacks and strokes down the road.

It’s entering the armamentarium – at least my armamentarium – as chronic, stable secondary prevention. That’s where the new American College of Cardiology/American Heart Association guidelines also put it. It’s really in as a treatment for chronic, stable atherosclerosis. I think that’s where it belongs.
 

When to start colchicine, and in whom?

Dr. O’Donoghue: To that point, as we think about the efficacy, I think it’s nice, as you outlined, that we have two complementary trials that are both showing a consistent reduction in MACEs, one in the post–acute coronary syndrome (ACS) state and one for more chronic patients.

At what point do you think would be the appropriate time to start therapy, and who would you be starting it for?

Dr. Ridker: Michelle, that’s a great question. There’s a very interesting analysis that just came out from the LoDoCo2 investigators. It’s kind of a landmark analysis. What they show is that 1 year, 2 years, 3 years, and 4 years since the initiating myocardial infarction, the drug is very effective.

In fact, you could think about starting this drug at your clinic in patients with chronic, stable atherosclerotic disease. That’s just like we would start a statin in people who had a heart attack some time ago, and that’s absolutely fine.

I’m using it for what I call my frequent fliers, those patients who just keep coming back. They’re already on aggressive lipid-lowering therapy. I have them on beta-blockers, aspirin, and all the usual things. I say, look, I can get a large risk reduction by starting them on this drug.

There are a few caveats, Michelle. Like all drugs, colchicine comes with some adverse effects. Most of them are pretty rare, but there are some patients I would not give this drug to, just to be very clear. Colchicine is cleared by the kidney and by the liver. Patients who have severe chronic kidney disease and severe liver disease – this is a no-go for those patients. We should talk about where patients in that realm might want to go.

Then there are some unusual drugs. Colchicine is metabolized by the CYP3A4 and the P-glycoprotein pathway. There are a few drugs, such as ketoconazole, fluconazole, and cyclosporine, that if your primary care doctor or internist is going to start for a short term, you probably want to stop your colchicine for a week or two.

In people with familial Mediterranean fever, for whom colchicine is lifesaving and life-changing and who take it for 20, 30, or 40 years, there’s been no increase in risk for cancer. There have been very few adverse effects. I think it’s interesting that we, who practice in North America, basically never see familial Mediterranean fever. If we were practicing in Lebanon, Israel, or North Africa, this would be a very common therapy that we’d all be extremely familiar with.

Dr. O’Donoghue: To that point, it’s interesting to hear that colchicine was even used by the ancient Greeks and ancient Egyptians. It’s a drug that’s been around for a long time.

In terms of its safety, some people have been talking about the fact that an increase in noncardiovascular death was seen in LoDoCo2. What are your thoughts on that? Is that anything that we should be concerned about?

Colchicine safety and contraindications

Dr. Ridker: First, to set the record straight, a meta-analysis has been done of all-cause mortality in the various colchicine trials, and the hazard ratio is 1.04. I’ll remind you, and all of us know, that the hazard ratios for all-cause mortality in the PCSK9 trials, the bempedoic acid trials, and the ezetimibe trials are also essentially neutral. We’re in a state where we don’t let these trials roll long enough to see benefits necessarily on all-cause mortality. Some of us think we probably should, but that’s just the reality of trials.

One of most interesting things that was part of the FDA review, I suspect, was that there was no specific cause of any of this. It was not like there was a set of particular issues. I suspect that most people think this is probably the play of chance and with time, things will get better.

Again, I do want to emphasize this is not a drug for severe chronic kidney disease and severe liver disease, because those patients will get in trouble with this. The other thing that’s worth knowing is when you start a patient on low-dose colchicine – that’s 0.5 mg/d – there will be some patients who get some short-term gastrointestinal upset. That’s very common when you start colchicine at the much higher doses you might use to treat acute gout or pericarditis. In these trials, the vast majority of patients treated through that, and there were very few episodes long-term. I think it’s generally safe. That’s where we’re at.

Dr. O’Donoghue: Paul, you’ve been a leader, certainly, at looking at CRP as a marker of inflammation. Do you, in your practice, consider CRP levels when making a decision about who is appropriate for this therapy?

Dr. Ridker: That’s another terrific question. I do, because I’m trying to distinguish in my own mind patients who have residual inflammatory risk, in whom the high-sensitivity CRP (hsCRP) level remains high despite being on statins versus those with residual cholesterol risk, in whom I’m really predominantly worried about LDL cholesterol, that I haven’t brought it down far enough.

I do measure it, and if the CRP remains high and the LDL cholesterol is low, to me, that’s residual inflammatory risk and that’s the patient I would target this to. Conversely, if the LDL cholesterol was still, say, above some threshold of 75-100 and I’m worried about that, even if the CRP is low, I’ll probably add a second lipid-lowering drug.

The complexity of this, however, is that CRP was not measured in either LoDoCo2 or COLCOT. That’s mostly because they didn’t have much funding. These trials were done really on a shoestring. They were not sponsored by major pharma at all. We know that the median hsCRP in these trials was probably around 3.5-4 mg/L so I’m pretty comfortable doing that. Others have just advocated giving it to many patients. I must say I like to use biomarkers to think through the biology and who might have the best benefit-to-risk ratio. In my practice, I am doing it that way.
 

Inpatient vs. outpatient initiation

Dr. O’Donoghue: This is perhaps my last question for you before we wrap up. I know you talked about use of low-dose colchicine for patients with more chronic, stable coronary disease. Now obviously, COLCOT studied patients who were early post ACS, and there we certainly think about the anti-inflammatory effects as potentially having more benefit. What are your thoughts about early initiation of colchicine in that setting, the acute hospitalized setting? Do you think it’s more appropriate for an outpatient start?

Dr. Ridker: Today, I think this is all about chronic, stable atherosclerosis. Yes, COLCOT enrolled their patients within 30 days of a recent myocardial infarction, but as we all know, that’s a pretty stable phase. The vast majority were enrolled after 15 days. There were a small number enrolled within 3 days or something like that, but the benefit is about the same in all these patients.

Conversely, there’s been a small number of trials looking at colchicine in acute coronary ischemia and they’ve not been terribly promising. That makes some sense, though, right? We want to get an artery open. In acute ischemia, that’s about revascularization. It’s about oxygenation. It’s about reperfusion injury. My guess is that 3, 4, 5, or 6 days later, when it becomes a stable situation, is when the drug is probably effective.

Again, there will be some ongoing true intervention trials with large sample sizes for acute coronary ischemia. We don’t have those yet. Right now, I think it’s a therapy for chronic, stable angina. That’s many of our patients.

I would say that if you compare the relative benefit in these trials of adding ezetimibe to a statin, that’s a 5% or 6% benefit. For PCSK9 inhibitors – we all use them – it’s about a 15% benefit. These are 25%-30% risk reductions. If we’re going to think about what’s the next drug to give on top of the statin, serious consideration should be given to low-dose colchicine.

Let me also emphasize that this is not an either/or situation. This is about the fact that we now understand atherosclerosis to be a disorder both of lipid accumulation and a proinflammatory systemic response. We can give these drugs together. I suspect that the best patient care is going to be very aggressive lipid-lowering combined with pretty aggressive inflammation inhibition. I suspect that, down the road, that’s where all of us are going to be.

Dr. O’Donoghue: Thank you so much, Paul, for walking us through that today. I think it was a very nice, succinct review of the evidence, and then also just getting our minds more accustomed to the concept that we can now start to target more orthogonal axes that really get at the pathobiology of what’s going on in the atherosclerotic plaque. I think it’s an important topic.

Dr. O’Donoghue is an associate professor of medicine at Harvard Medical School and an associate physician at Brigham and Women’s Hospital, both in Boston. Dr. Ridker is director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital. Both Dr. O’Donoghue and Dr. Ridker reported numerous conflicts of interest.

This transcript has been edited for clarity.

Dr. O’Donoghue: We’re going to discuss a very important and emerging topic, which is the use of low-dose colchicine. I think there’s much interest in the use of this drug, which now has a Food and Drug Administration indication, which we’ll talk about further, and it’s also been written into both European and American guidelines that have been recently released.

Many people are talking about where this fits into our current armamentarium, and I think there probably is no better person to discuss this than Paul Ridker, who’s been at the forefront of research into anti-inflammatory therapeutics.
 

Lifestyle lipid-lowering paramount

Dr. O’Donoghue: As we think about the concept behind the use of colchicine, we’ve obviously done a large amount of research into lipid-lowering drugs, but where does colchicine now fit in?

Dr. Ridker: Let’s make sure we get the basics down. Anti-inflammatory therapy is going to be added on top of quality other care. This is not a replacement for lipids; it’s not a change in diet, exercise, and smoking cessation. The new data are really telling us that a patient who’s aggressively treated to guideline-recommended levels can still do much better in terms of preventing heart attack, stroke, cardiovascular death, and revascularization by adding low-dose colchicine as the first proven anti-inflammatory therapy for atherosclerotic disease.

I have to say, Michelle, for me, it’s been a wonderful end of a journey in many ways. This story starts almost 30 years ago for quite a few of us, thinking about inflammation and atherosclerosis. The whole C-reactive protein (CRP) story is still an ongoing one. We recently showed, for example, that residual inflammatory risk in some 30,000 patients, all taking a statin, was a far better predictor of the likelihood of more cardiovascular events, in particular cardiovascular death, than was residual cholesterol risk.

Think about that. We’re all aggressively giving second lipid-lowering drugs in our very sick patients, but that means inflammation is really the untapped piece of this.

The two clinical trials we have in front of us, the COLCOT trial and the LoDoCo2 trial – both New England Journal of Medicine papers, both with roughly 5,000 patients – provide very clear evidence that following a relatively recent myocardial infarction (that’s COLCOT) in chronic stable atherosclerosis (that’s LoDoCo2), we’re getting 25%-30% relative risk reductions in major adverse cardiovascular events (MACEs) on top of aggressive statin therapy. That’s a big deal. It’s safe, it works, and it’s fully consistent with all the information we have about inflammation being part and parcel of atherosclerosis. It’s a pretty exciting time.
 

Inflammatory pathway

Dr. O’Donoghue: It beautifully proves the inflammatory hypothesis in many ways. You led CANTOS, and that was a much more specific target. Here, in terms of the effects of colchicine, what do we know about how it may work on the inflammatory cascade?

Dr. Ridker: Our CANTOS trial was proof of principle that you could directly target, with a very specific monoclonal antibody, a specific piece of this innate immune cascade and lower cardiovascular event rates.

Colchicine is a more broad-spectrum drug. It does have a number of antineutrophil effects – that’s important, by the way. Neutrophils are really becoming very important in atherosclerotic disease progression. It’s an indirect inhibitor of the so-called NLRP3 inflammasome, which is where both interleukin-1 (that’s the target for canakinumab) and IL-6 are up-regulated. As you know, it’s been used to treat gout and pericarditis in high doses in short, little bursts.

The change here is this use of low-dose colchicine, that’s 0.5 mg once a day for years to treat chronic, stable atherosclerosis. It is very much like using a statin. The idea here is to prevent the progression of the disease by slowing down and maybe stabilizing the plaque so we have fewer heart attacks and strokes down the road.

It’s entering the armamentarium – at least my armamentarium – as chronic, stable secondary prevention. That’s where the new American College of Cardiology/American Heart Association guidelines also put it. It’s really in as a treatment for chronic, stable atherosclerosis. I think that’s where it belongs.
 

When to start colchicine, and in whom?

Dr. O’Donoghue: To that point, as we think about the efficacy, I think it’s nice, as you outlined, that we have two complementary trials that are both showing a consistent reduction in MACEs, one in the post–acute coronary syndrome (ACS) state and one for more chronic patients.

At what point do you think would be the appropriate time to start therapy, and who would you be starting it for?

Dr. Ridker: Michelle, that’s a great question. There’s a very interesting analysis that just came out from the LoDoCo2 investigators. It’s kind of a landmark analysis. What they show is that 1 year, 2 years, 3 years, and 4 years since the initiating myocardial infarction, the drug is very effective.

In fact, you could think about starting this drug at your clinic in patients with chronic, stable atherosclerotic disease. That’s just like we would start a statin in people who had a heart attack some time ago, and that’s absolutely fine.

I’m using it for what I call my frequent fliers, those patients who just keep coming back. They’re already on aggressive lipid-lowering therapy. I have them on beta-blockers, aspirin, and all the usual things. I say, look, I can get a large risk reduction by starting them on this drug.

There are a few caveats, Michelle. Like all drugs, colchicine comes with some adverse effects. Most of them are pretty rare, but there are some patients I would not give this drug to, just to be very clear. Colchicine is cleared by the kidney and by the liver. Patients who have severe chronic kidney disease and severe liver disease – this is a no-go for those patients. We should talk about where patients in that realm might want to go.

Then there are some unusual drugs. Colchicine is metabolized by the CYP3A4 and the P-glycoprotein pathway. There are a few drugs, such as ketoconazole, fluconazole, and cyclosporine, that if your primary care doctor or internist is going to start for a short term, you probably want to stop your colchicine for a week or two.

In people with familial Mediterranean fever, for whom colchicine is lifesaving and life-changing and who take it for 20, 30, or 40 years, there’s been no increase in risk for cancer. There have been very few adverse effects. I think it’s interesting that we, who practice in North America, basically never see familial Mediterranean fever. If we were practicing in Lebanon, Israel, or North Africa, this would be a very common therapy that we’d all be extremely familiar with.

Dr. O’Donoghue: To that point, it’s interesting to hear that colchicine was even used by the ancient Greeks and ancient Egyptians. It’s a drug that’s been around for a long time.

In terms of its safety, some people have been talking about the fact that an increase in noncardiovascular death was seen in LoDoCo2. What are your thoughts on that? Is that anything that we should be concerned about?

Colchicine safety and contraindications

Dr. Ridker: First, to set the record straight, a meta-analysis has been done of all-cause mortality in the various colchicine trials, and the hazard ratio is 1.04. I’ll remind you, and all of us know, that the hazard ratios for all-cause mortality in the PCSK9 trials, the bempedoic acid trials, and the ezetimibe trials are also essentially neutral. We’re in a state where we don’t let these trials roll long enough to see benefits necessarily on all-cause mortality. Some of us think we probably should, but that’s just the reality of trials.

One of most interesting things that was part of the FDA review, I suspect, was that there was no specific cause of any of this. It was not like there was a set of particular issues. I suspect that most people think this is probably the play of chance and with time, things will get better.

Again, I do want to emphasize this is not a drug for severe chronic kidney disease and severe liver disease, because those patients will get in trouble with this. The other thing that’s worth knowing is when you start a patient on low-dose colchicine – that’s 0.5 mg/d – there will be some patients who get some short-term gastrointestinal upset. That’s very common when you start colchicine at the much higher doses you might use to treat acute gout or pericarditis. In these trials, the vast majority of patients treated through that, and there were very few episodes long-term. I think it’s generally safe. That’s where we’re at.

Dr. O’Donoghue: Paul, you’ve been a leader, certainly, at looking at CRP as a marker of inflammation. Do you, in your practice, consider CRP levels when making a decision about who is appropriate for this therapy?

Dr. Ridker: That’s another terrific question. I do, because I’m trying to distinguish in my own mind patients who have residual inflammatory risk, in whom the high-sensitivity CRP (hsCRP) level remains high despite being on statins versus those with residual cholesterol risk, in whom I’m really predominantly worried about LDL cholesterol, that I haven’t brought it down far enough.

I do measure it, and if the CRP remains high and the LDL cholesterol is low, to me, that’s residual inflammatory risk and that’s the patient I would target this to. Conversely, if the LDL cholesterol was still, say, above some threshold of 75-100 and I’m worried about that, even if the CRP is low, I’ll probably add a second lipid-lowering drug.

The complexity of this, however, is that CRP was not measured in either LoDoCo2 or COLCOT. That’s mostly because they didn’t have much funding. These trials were done really on a shoestring. They were not sponsored by major pharma at all. We know that the median hsCRP in these trials was probably around 3.5-4 mg/L so I’m pretty comfortable doing that. Others have just advocated giving it to many patients. I must say I like to use biomarkers to think through the biology and who might have the best benefit-to-risk ratio. In my practice, I am doing it that way.
 

Inpatient vs. outpatient initiation

Dr. O’Donoghue: This is perhaps my last question for you before we wrap up. I know you talked about use of low-dose colchicine for patients with more chronic, stable coronary disease. Now obviously, COLCOT studied patients who were early post ACS, and there we certainly think about the anti-inflammatory effects as potentially having more benefit. What are your thoughts about early initiation of colchicine in that setting, the acute hospitalized setting? Do you think it’s more appropriate for an outpatient start?

Dr. Ridker: Today, I think this is all about chronic, stable atherosclerosis. Yes, COLCOT enrolled their patients within 30 days of a recent myocardial infarction, but as we all know, that’s a pretty stable phase. The vast majority were enrolled after 15 days. There were a small number enrolled within 3 days or something like that, but the benefit is about the same in all these patients.

Conversely, there’s been a small number of trials looking at colchicine in acute coronary ischemia and they’ve not been terribly promising. That makes some sense, though, right? We want to get an artery open. In acute ischemia, that’s about revascularization. It’s about oxygenation. It’s about reperfusion injury. My guess is that 3, 4, 5, or 6 days later, when it becomes a stable situation, is when the drug is probably effective.

Again, there will be some ongoing true intervention trials with large sample sizes for acute coronary ischemia. We don’t have those yet. Right now, I think it’s a therapy for chronic, stable angina. That’s many of our patients.

I would say that if you compare the relative benefit in these trials of adding ezetimibe to a statin, that’s a 5% or 6% benefit. For PCSK9 inhibitors – we all use them – it’s about a 15% benefit. These are 25%-30% risk reductions. If we’re going to think about what’s the next drug to give on top of the statin, serious consideration should be given to low-dose colchicine.

Let me also emphasize that this is not an either/or situation. This is about the fact that we now understand atherosclerosis to be a disorder both of lipid accumulation and a proinflammatory systemic response. We can give these drugs together. I suspect that the best patient care is going to be very aggressive lipid-lowering combined with pretty aggressive inflammation inhibition. I suspect that, down the road, that’s where all of us are going to be.

Dr. O’Donoghue: Thank you so much, Paul, for walking us through that today. I think it was a very nice, succinct review of the evidence, and then also just getting our minds more accustomed to the concept that we can now start to target more orthogonal axes that really get at the pathobiology of what’s going on in the atherosclerotic plaque. I think it’s an important topic.

Dr. O’Donoghue is an associate professor of medicine at Harvard Medical School and an associate physician at Brigham and Women’s Hospital, both in Boston. Dr. Ridker is director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital. Both Dr. O’Donoghue and Dr. Ridker reported numerous conflicts of interest.

This transcript has been edited for clarity.

Dr. O’Donoghue: We’re going to discuss a very important and emerging topic, which is the use of low-dose colchicine. I think there’s much interest in the use of this drug, which now has a Food and Drug Administration indication, which we’ll talk about further, and it’s also been written into both European and American guidelines that have been recently released.

Many people are talking about where this fits into our current armamentarium, and I think there probably is no better person to discuss this than Paul Ridker, who’s been at the forefront of research into anti-inflammatory therapeutics.
 

Lifestyle lipid-lowering paramount

Dr. O’Donoghue: As we think about the concept behind the use of colchicine, we’ve obviously done a large amount of research into lipid-lowering drugs, but where does colchicine now fit in?

Dr. Ridker: Let’s make sure we get the basics down. Anti-inflammatory therapy is going to be added on top of quality other care. This is not a replacement for lipids; it’s not a change in diet, exercise, and smoking cessation. The new data are really telling us that a patient who’s aggressively treated to guideline-recommended levels can still do much better in terms of preventing heart attack, stroke, cardiovascular death, and revascularization by adding low-dose colchicine as the first proven anti-inflammatory therapy for atherosclerotic disease.

I have to say, Michelle, for me, it’s been a wonderful end of a journey in many ways. This story starts almost 30 years ago for quite a few of us, thinking about inflammation and atherosclerosis. The whole C-reactive protein (CRP) story is still an ongoing one. We recently showed, for example, that residual inflammatory risk in some 30,000 patients, all taking a statin, was a far better predictor of the likelihood of more cardiovascular events, in particular cardiovascular death, than was residual cholesterol risk.

Think about that. We’re all aggressively giving second lipid-lowering drugs in our very sick patients, but that means inflammation is really the untapped piece of this.

The two clinical trials we have in front of us, the COLCOT trial and the LoDoCo2 trial – both New England Journal of Medicine papers, both with roughly 5,000 patients – provide very clear evidence that following a relatively recent myocardial infarction (that’s COLCOT) in chronic stable atherosclerosis (that’s LoDoCo2), we’re getting 25%-30% relative risk reductions in major adverse cardiovascular events (MACEs) on top of aggressive statin therapy. That’s a big deal. It’s safe, it works, and it’s fully consistent with all the information we have about inflammation being part and parcel of atherosclerosis. It’s a pretty exciting time.
 

Inflammatory pathway

Dr. O’Donoghue: It beautifully proves the inflammatory hypothesis in many ways. You led CANTOS, and that was a much more specific target. Here, in terms of the effects of colchicine, what do we know about how it may work on the inflammatory cascade?

Dr. Ridker: Our CANTOS trial was proof of principle that you could directly target, with a very specific monoclonal antibody, a specific piece of this innate immune cascade and lower cardiovascular event rates.

Colchicine is a more broad-spectrum drug. It does have a number of antineutrophil effects – that’s important, by the way. Neutrophils are really becoming very important in atherosclerotic disease progression. It’s an indirect inhibitor of the so-called NLRP3 inflammasome, which is where both interleukin-1 (that’s the target for canakinumab) and IL-6 are up-regulated. As you know, it’s been used to treat gout and pericarditis in high doses in short, little bursts.

The change here is this use of low-dose colchicine, that’s 0.5 mg once a day for years to treat chronic, stable atherosclerosis. It is very much like using a statin. The idea here is to prevent the progression of the disease by slowing down and maybe stabilizing the plaque so we have fewer heart attacks and strokes down the road.

It’s entering the armamentarium – at least my armamentarium – as chronic, stable secondary prevention. That’s where the new American College of Cardiology/American Heart Association guidelines also put it. It’s really in as a treatment for chronic, stable atherosclerosis. I think that’s where it belongs.
 

When to start colchicine, and in whom?

Dr. O’Donoghue: To that point, as we think about the efficacy, I think it’s nice, as you outlined, that we have two complementary trials that are both showing a consistent reduction in MACEs, one in the post–acute coronary syndrome (ACS) state and one for more chronic patients.

At what point do you think would be the appropriate time to start therapy, and who would you be starting it for?

Dr. Ridker: Michelle, that’s a great question. There’s a very interesting analysis that just came out from the LoDoCo2 investigators. It’s kind of a landmark analysis. What they show is that 1 year, 2 years, 3 years, and 4 years since the initiating myocardial infarction, the drug is very effective.

In fact, you could think about starting this drug at your clinic in patients with chronic, stable atherosclerotic disease. That’s just like we would start a statin in people who had a heart attack some time ago, and that’s absolutely fine.

I’m using it for what I call my frequent fliers, those patients who just keep coming back. They’re already on aggressive lipid-lowering therapy. I have them on beta-blockers, aspirin, and all the usual things. I say, look, I can get a large risk reduction by starting them on this drug.

There are a few caveats, Michelle. Like all drugs, colchicine comes with some adverse effects. Most of them are pretty rare, but there are some patients I would not give this drug to, just to be very clear. Colchicine is cleared by the kidney and by the liver. Patients who have severe chronic kidney disease and severe liver disease – this is a no-go for those patients. We should talk about where patients in that realm might want to go.

Then there are some unusual drugs. Colchicine is metabolized by the CYP3A4 and the P-glycoprotein pathway. There are a few drugs, such as ketoconazole, fluconazole, and cyclosporine, that if your primary care doctor or internist is going to start for a short term, you probably want to stop your colchicine for a week or two.

In people with familial Mediterranean fever, for whom colchicine is lifesaving and life-changing and who take it for 20, 30, or 40 years, there’s been no increase in risk for cancer. There have been very few adverse effects. I think it’s interesting that we, who practice in North America, basically never see familial Mediterranean fever. If we were practicing in Lebanon, Israel, or North Africa, this would be a very common therapy that we’d all be extremely familiar with.

Dr. O’Donoghue: To that point, it’s interesting to hear that colchicine was even used by the ancient Greeks and ancient Egyptians. It’s a drug that’s been around for a long time.

In terms of its safety, some people have been talking about the fact that an increase in noncardiovascular death was seen in LoDoCo2. What are your thoughts on that? Is that anything that we should be concerned about?

Colchicine safety and contraindications

Dr. Ridker: First, to set the record straight, a meta-analysis has been done of all-cause mortality in the various colchicine trials, and the hazard ratio is 1.04. I’ll remind you, and all of us know, that the hazard ratios for all-cause mortality in the PCSK9 trials, the bempedoic acid trials, and the ezetimibe trials are also essentially neutral. We’re in a state where we don’t let these trials roll long enough to see benefits necessarily on all-cause mortality. Some of us think we probably should, but that’s just the reality of trials.

One of most interesting things that was part of the FDA review, I suspect, was that there was no specific cause of any of this. It was not like there was a set of particular issues. I suspect that most people think this is probably the play of chance and with time, things will get better.

Again, I do want to emphasize this is not a drug for severe chronic kidney disease and severe liver disease, because those patients will get in trouble with this. The other thing that’s worth knowing is when you start a patient on low-dose colchicine – that’s 0.5 mg/d – there will be some patients who get some short-term gastrointestinal upset. That’s very common when you start colchicine at the much higher doses you might use to treat acute gout or pericarditis. In these trials, the vast majority of patients treated through that, and there were very few episodes long-term. I think it’s generally safe. That’s where we’re at.

Dr. O’Donoghue: Paul, you’ve been a leader, certainly, at looking at CRP as a marker of inflammation. Do you, in your practice, consider CRP levels when making a decision about who is appropriate for this therapy?

Dr. Ridker: That’s another terrific question. I do, because I’m trying to distinguish in my own mind patients who have residual inflammatory risk, in whom the high-sensitivity CRP (hsCRP) level remains high despite being on statins versus those with residual cholesterol risk, in whom I’m really predominantly worried about LDL cholesterol, that I haven’t brought it down far enough.

I do measure it, and if the CRP remains high and the LDL cholesterol is low, to me, that’s residual inflammatory risk and that’s the patient I would target this to. Conversely, if the LDL cholesterol was still, say, above some threshold of 75-100 and I’m worried about that, even if the CRP is low, I’ll probably add a second lipid-lowering drug.

The complexity of this, however, is that CRP was not measured in either LoDoCo2 or COLCOT. That’s mostly because they didn’t have much funding. These trials were done really on a shoestring. They were not sponsored by major pharma at all. We know that the median hsCRP in these trials was probably around 3.5-4 mg/L so I’m pretty comfortable doing that. Others have just advocated giving it to many patients. I must say I like to use biomarkers to think through the biology and who might have the best benefit-to-risk ratio. In my practice, I am doing it that way.
 

Inpatient vs. outpatient initiation

Dr. O’Donoghue: This is perhaps my last question for you before we wrap up. I know you talked about use of low-dose colchicine for patients with more chronic, stable coronary disease. Now obviously, COLCOT studied patients who were early post ACS, and there we certainly think about the anti-inflammatory effects as potentially having more benefit. What are your thoughts about early initiation of colchicine in that setting, the acute hospitalized setting? Do you think it’s more appropriate for an outpatient start?

Dr. Ridker: Today, I think this is all about chronic, stable atherosclerosis. Yes, COLCOT enrolled their patients within 30 days of a recent myocardial infarction, but as we all know, that’s a pretty stable phase. The vast majority were enrolled after 15 days. There were a small number enrolled within 3 days or something like that, but the benefit is about the same in all these patients.

Conversely, there’s been a small number of trials looking at colchicine in acute coronary ischemia and they’ve not been terribly promising. That makes some sense, though, right? We want to get an artery open. In acute ischemia, that’s about revascularization. It’s about oxygenation. It’s about reperfusion injury. My guess is that 3, 4, 5, or 6 days later, when it becomes a stable situation, is when the drug is probably effective.

Again, there will be some ongoing true intervention trials with large sample sizes for acute coronary ischemia. We don’t have those yet. Right now, I think it’s a therapy for chronic, stable angina. That’s many of our patients.

I would say that if you compare the relative benefit in these trials of adding ezetimibe to a statin, that’s a 5% or 6% benefit. For PCSK9 inhibitors – we all use them – it’s about a 15% benefit. These are 25%-30% risk reductions. If we’re going to think about what’s the next drug to give on top of the statin, serious consideration should be given to low-dose colchicine.

Let me also emphasize that this is not an either/or situation. This is about the fact that we now understand atherosclerosis to be a disorder both of lipid accumulation and a proinflammatory systemic response. We can give these drugs together. I suspect that the best patient care is going to be very aggressive lipid-lowering combined with pretty aggressive inflammation inhibition. I suspect that, down the road, that’s where all of us are going to be.

Dr. O’Donoghue: Thank you so much, Paul, for walking us through that today. I think it was a very nice, succinct review of the evidence, and then also just getting our minds more accustomed to the concept that we can now start to target more orthogonal axes that really get at the pathobiology of what’s going on in the atherosclerotic plaque. I think it’s an important topic.

Dr. O’Donoghue is an associate professor of medicine at Harvard Medical School and an associate physician at Brigham and Women’s Hospital, both in Boston. Dr. Ridker is director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital. Both Dr. O’Donoghue and Dr. Ridker reported numerous conflicts of interest.