Cardiology

Patients reporting moderate or extreme pain a year after a myocardial infarction (MI) – even pain due to other health conditions – are more likely to die within the next 8 years than those without post-MI pain, new research suggests.

In the analysis of post-MI health data for more than 18,300 Swedish adults, those with moderate pain were 35% more likely to die from any cause during follow-up, compared with those with no pain, and those with extreme pain were more than twice as likely to die.

Furthermore, pain was a stronger predictor of mortality than smoking.

“For a long time, pain has been regarded as merely a symptom of disease rather than a disease” in its own right, Linda Vixner, PT, PhD, of Dalarna University in Falun, Sweden, said in an interview.

Updated definitions of chronic pain in the ICD-11, as well as a recent study using data from the UK Biobank showing that chronic pain is associated with an increased risk of cardiovascular disease, prompted the current study, which looks at the effect of pain on long-term survival after an MI.

“We did not expect that pain would have such a strong impact on the risk of death, and it also surprised us that the risk was more pronounced than that of smoking,” Dr. Vixner said. “Clinicians should consider pain an important cardiovascular risk factor.”

The study was published online in the Journal of the American Heart Association.
 

‘Experienced pain’ prognostic

The investigators analyzed data from the SWEDEHEART registry of 18,376 patients who had an MI in 2004-2013. The mean age of patients was 62 years and 75% were men. Follow-up time was 8.5 years (median, 3.37).

Self-reported levels of experienced pain according to the EuroQol five-dimension instrument were recorded 12 months after hospital discharge.

Moderate pain was reported by 38.2% of patients and extreme pain by 4.5%.

In the extreme pain category, women were overrepresented (7.5% vs. 3.6% of men), as were current smokers, and patients with diabetes, previous MI, previous stroke, previous percutaneous coronary intervention, non-ST-segment–elevation MI, and any kind of chest pain. Patients classified as physically inactive also were overrepresented in this category.

In addition, those with extreme pain had a higher body mass index and waist circumference 12 months after hospital discharge.

Most (73%) of the 7,889 patients who reported no pain at the 2-month follow-up after MI were also pain-free at the 12-month follow-up, and 65% of those experiencing pain at 2 months were also experiencing pain at 12 months.

There were 1,067 deaths. The adjusted hazard ratio was 1.35 for moderate pain and 2.06 for extreme pain.

As noted, pain was a stronger mortality predictor than smoking: C-statistics for pain were 0.60, and for smoking, 0.55.

“Clinicians managing patients after MI should recognize the need to consider experienced pain as a prognostic factor comparable to persistent smoking and to address this when designing individually adjusted [cardiac rehabilitation] and secondary prevention treatments,” the authors write.

Pain should be assessed at follow-up after MI, they add, and, as Dr. Vixner suggested, it should be “acknowledged as an important risk factor.”
 

Managing risks

“These findings parallel prior studies and my own clinical experience,” American Heart Association volunteer expert Gregg C. Fonarow, MD, interim chief of the division of cardiology at the University of California, Los Angeles, and director, Ahmanson-UCLA Cardiomyopathy Center, told this news organization.

“There are many potential causes for patient-reported pain in the year after a heart attack,” he said, including a greater cardiovascular risk burden, more comorbid conditions, less physical activity, and chronic use of nonsteroidal anti-inflammatory medications or opioids for pain control – all of which can contribute to the increased risk of mortality.

Factors beyond those evaluated and adjusted for in the observational study may contribute to the observed associations, he added. “Socioeconomic factors were not accounted for [and] there was no information on the types, doses, and frequency of pain medication use.”

“Clinicians managing patients with prior MI should carefully assess experienced pain and utilize this information to optimize risk factor control recommendations, inform treatment decisions, and consider in terms of prognosis,” he advised.

Further studies should evaluate whether the associations hold true for other patient populations, Dr. Fonarow said. “In addition, intervention trials could evaluate if enhanced management strategies in these higher-risk patients with self-reported pain can successfully lower the mortality risk.”

Dr. Vixner sees a role for physical activity in lowering the mortality risk.

“One of the core treatments for chronic pain is physical activity,” she said. “It positively influences quality of life, activities of daily living, pain intensity, and overall physical function, and reduces the risk of social isolation” and cardiovascular diseases.

Her team recently developed the “eVISualisation of physical activity and pain” (eVIS) intervention, which aims to promote healthy physical activity levels in persons living with chronic pain. The intervention is currently being evaluated in an ongoing registry-based, randomized controlled trial.

The study was supported by Svenska Försäkringsföreningen, Dalarna University, Region Dalarna. Dr. Vixner and coauthors have reported no relevant financial relationships. Dr. Fonarow has disclosed consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Eli Lilly, Johnson & Johnson, Medtronic, Merck, Novartis, and Pfizer.

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

Patients reporting moderate or extreme pain a year after a myocardial infarction (MI) – even pain due to other health conditions – are more likely to die within the next 8 years than those without post-MI pain, new research suggests.

In the analysis of post-MI health data for more than 18,300 Swedish adults, those with moderate pain were 35% more likely to die from any cause during follow-up, compared with those with no pain, and those with extreme pain were more than twice as likely to die.

Furthermore, pain was a stronger predictor of mortality than smoking.

“For a long time, pain has been regarded as merely a symptom of disease rather than a disease” in its own right, Linda Vixner, PT, PhD, of Dalarna University in Falun, Sweden, said in an interview.

Updated definitions of chronic pain in the ICD-11, as well as a recent study using data from the UK Biobank showing that chronic pain is associated with an increased risk of cardiovascular disease, prompted the current study, which looks at the effect of pain on long-term survival after an MI.

“We did not expect that pain would have such a strong impact on the risk of death, and it also surprised us that the risk was more pronounced than that of smoking,” Dr. Vixner said. “Clinicians should consider pain an important cardiovascular risk factor.”

The study was published online in the Journal of the American Heart Association.
 

‘Experienced pain’ prognostic

The investigators analyzed data from the SWEDEHEART registry of 18,376 patients who had an MI in 2004-2013. The mean age of patients was 62 years and 75% were men. Follow-up time was 8.5 years (median, 3.37).

Self-reported levels of experienced pain according to the EuroQol five-dimension instrument were recorded 12 months after hospital discharge.

Moderate pain was reported by 38.2% of patients and extreme pain by 4.5%.

In the extreme pain category, women were overrepresented (7.5% vs. 3.6% of men), as were current smokers, and patients with diabetes, previous MI, previous stroke, previous percutaneous coronary intervention, non-ST-segment–elevation MI, and any kind of chest pain. Patients classified as physically inactive also were overrepresented in this category.

In addition, those with extreme pain had a higher body mass index and waist circumference 12 months after hospital discharge.

Most (73%) of the 7,889 patients who reported no pain at the 2-month follow-up after MI were also pain-free at the 12-month follow-up, and 65% of those experiencing pain at 2 months were also experiencing pain at 12 months.

There were 1,067 deaths. The adjusted hazard ratio was 1.35 for moderate pain and 2.06 for extreme pain.

As noted, pain was a stronger mortality predictor than smoking: C-statistics for pain were 0.60, and for smoking, 0.55.

“Clinicians managing patients after MI should recognize the need to consider experienced pain as a prognostic factor comparable to persistent smoking and to address this when designing individually adjusted [cardiac rehabilitation] and secondary prevention treatments,” the authors write.

Pain should be assessed at follow-up after MI, they add, and, as Dr. Vixner suggested, it should be “acknowledged as an important risk factor.”
 

Managing risks

“These findings parallel prior studies and my own clinical experience,” American Heart Association volunteer expert Gregg C. Fonarow, MD, interim chief of the division of cardiology at the University of California, Los Angeles, and director, Ahmanson-UCLA Cardiomyopathy Center, told this news organization.

“There are many potential causes for patient-reported pain in the year after a heart attack,” he said, including a greater cardiovascular risk burden, more comorbid conditions, less physical activity, and chronic use of nonsteroidal anti-inflammatory medications or opioids for pain control – all of which can contribute to the increased risk of mortality.

Factors beyond those evaluated and adjusted for in the observational study may contribute to the observed associations, he added. “Socioeconomic factors were not accounted for [and] there was no information on the types, doses, and frequency of pain medication use.”

“Clinicians managing patients with prior MI should carefully assess experienced pain and utilize this information to optimize risk factor control recommendations, inform treatment decisions, and consider in terms of prognosis,” he advised.

Further studies should evaluate whether the associations hold true for other patient populations, Dr. Fonarow said. “In addition, intervention trials could evaluate if enhanced management strategies in these higher-risk patients with self-reported pain can successfully lower the mortality risk.”

Dr. Vixner sees a role for physical activity in lowering the mortality risk.

“One of the core treatments for chronic pain is physical activity,” she said. “It positively influences quality of life, activities of daily living, pain intensity, and overall physical function, and reduces the risk of social isolation” and cardiovascular diseases.

Her team recently developed the “eVISualisation of physical activity and pain” (eVIS) intervention, which aims to promote healthy physical activity levels in persons living with chronic pain. The intervention is currently being evaluated in an ongoing registry-based, randomized controlled trial.

The study was supported by Svenska Försäkringsföreningen, Dalarna University, Region Dalarna. Dr. Vixner and coauthors have reported no relevant financial relationships. Dr. Fonarow has disclosed consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Eli Lilly, Johnson & Johnson, Medtronic, Merck, Novartis, and Pfizer.

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

Patients reporting moderate or extreme pain a year after a myocardial infarction (MI) – even pain due to other health conditions – are more likely to die within the next 8 years than those without post-MI pain, new research suggests.

In the analysis of post-MI health data for more than 18,300 Swedish adults, those with moderate pain were 35% more likely to die from any cause during follow-up, compared with those with no pain, and those with extreme pain were more than twice as likely to die.

Furthermore, pain was a stronger predictor of mortality than smoking.

“For a long time, pain has been regarded as merely a symptom of disease rather than a disease” in its own right, Linda Vixner, PT, PhD, of Dalarna University in Falun, Sweden, said in an interview.

Updated definitions of chronic pain in the ICD-11, as well as a recent study using data from the UK Biobank showing that chronic pain is associated with an increased risk of cardiovascular disease, prompted the current study, which looks at the effect of pain on long-term survival after an MI.

“We did not expect that pain would have such a strong impact on the risk of death, and it also surprised us that the risk was more pronounced than that of smoking,” Dr. Vixner said. “Clinicians should consider pain an important cardiovascular risk factor.”

The study was published online in the Journal of the American Heart Association.
 

‘Experienced pain’ prognostic

The investigators analyzed data from the SWEDEHEART registry of 18,376 patients who had an MI in 2004-2013. The mean age of patients was 62 years and 75% were men. Follow-up time was 8.5 years (median, 3.37).

Self-reported levels of experienced pain according to the EuroQol five-dimension instrument were recorded 12 months after hospital discharge.

Moderate pain was reported by 38.2% of patients and extreme pain by 4.5%.

In the extreme pain category, women were overrepresented (7.5% vs. 3.6% of men), as were current smokers, and patients with diabetes, previous MI, previous stroke, previous percutaneous coronary intervention, non-ST-segment–elevation MI, and any kind of chest pain. Patients classified as physically inactive also were overrepresented in this category.

In addition, those with extreme pain had a higher body mass index and waist circumference 12 months after hospital discharge.

Most (73%) of the 7,889 patients who reported no pain at the 2-month follow-up after MI were also pain-free at the 12-month follow-up, and 65% of those experiencing pain at 2 months were also experiencing pain at 12 months.

There were 1,067 deaths. The adjusted hazard ratio was 1.35 for moderate pain and 2.06 for extreme pain.

As noted, pain was a stronger mortality predictor than smoking: C-statistics for pain were 0.60, and for smoking, 0.55.

“Clinicians managing patients after MI should recognize the need to consider experienced pain as a prognostic factor comparable to persistent smoking and to address this when designing individually adjusted [cardiac rehabilitation] and secondary prevention treatments,” the authors write.

Pain should be assessed at follow-up after MI, they add, and, as Dr. Vixner suggested, it should be “acknowledged as an important risk factor.”
 

Managing risks

“These findings parallel prior studies and my own clinical experience,” American Heart Association volunteer expert Gregg C. Fonarow, MD, interim chief of the division of cardiology at the University of California, Los Angeles, and director, Ahmanson-UCLA Cardiomyopathy Center, told this news organization.

“There are many potential causes for patient-reported pain in the year after a heart attack,” he said, including a greater cardiovascular risk burden, more comorbid conditions, less physical activity, and chronic use of nonsteroidal anti-inflammatory medications or opioids for pain control – all of which can contribute to the increased risk of mortality.

Factors beyond those evaluated and adjusted for in the observational study may contribute to the observed associations, he added. “Socioeconomic factors were not accounted for [and] there was no information on the types, doses, and frequency of pain medication use.”

“Clinicians managing patients with prior MI should carefully assess experienced pain and utilize this information to optimize risk factor control recommendations, inform treatment decisions, and consider in terms of prognosis,” he advised.

Further studies should evaluate whether the associations hold true for other patient populations, Dr. Fonarow said. “In addition, intervention trials could evaluate if enhanced management strategies in these higher-risk patients with self-reported pain can successfully lower the mortality risk.”

Dr. Vixner sees a role for physical activity in lowering the mortality risk.

“One of the core treatments for chronic pain is physical activity,” she said. “It positively influences quality of life, activities of daily living, pain intensity, and overall physical function, and reduces the risk of social isolation” and cardiovascular diseases.

Her team recently developed the “eVISualisation of physical activity and pain” (eVIS) intervention, which aims to promote healthy physical activity levels in persons living with chronic pain. The intervention is currently being evaluated in an ongoing registry-based, randomized controlled trial.

The study was supported by Svenska Försäkringsföreningen, Dalarna University, Region Dalarna. Dr. Vixner and coauthors have reported no relevant financial relationships. Dr. Fonarow has disclosed consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Eli Lilly, Johnson & Johnson, Medtronic, Merck, Novartis, and Pfizer.

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

Sudden cardiac arrest is the term given to death that results from a cardiac cause and occurs within an hour of symptoms being observed. If no witnesses are present, sudden cardiac arrest is present if the person had been in apparently good health 24 hours before cardiac death. Fatality is usually a result of sustained ventricular fibrillation or sustained ventricular tachycardia that leads to cardiac arrest.

What should primary care practitioners consider in order to detect at-risk patients in time?
 

Recognizing warning signs

Warning signs that should prompt physicians to consider an increased risk of sudden cardiac arrest include the following:

• Unexplained, brief fainting episodes that above all occur with stress, physical activity, or loud noises (for example, alarm ringing)
• Seizures without a clear pathologic EEG result (for example, epilepsy)
• Unexplained accidents or car crashes
• Heart failure or pacemaker dependency before age 50 years

“These are all indications that could point to an underlying heart disease that should be investigated by a medical professional,” explained Silke Kauferstein, PhD, head of the Center for Sudden Cardiac Arrest and Familial Arrhythmia Syndrome at the Institute of Forensic Medicine of the University Frankfurt am Main (Germany), in a podcast by the German Heart Foundation.
 

Sports rarely responsible

Sudden cardiac arrest has numerous causes. Sudden cardiac arrests in a professional sports environment always attract attention. Yet sports play a less important role in sudden cardiac arrest than is often assumed, even in young individuals.

“The incidence of sudden cardiac arrest is on average 0.7-3 per 100,000 sports players from all age groups,” said Thomas Voigtländer, MD, chair of the German Heart Foundation, in an interview. Men make up 95% of those affected, and 90% of these events occur during recreational sports.
 

Inherited disorders

The most significant risk factor for sudden cardiac arrest is age; it is often associated with coronary heart disease. This factor can be significant from as early as age 35 years. Among young individuals, sudden cardiac arrest is often a result of congenital heart diseases, such as hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy. Diseases such as long QT syndrome and Brugada syndrome can also lead to sudden cardiac arrest.

Among young sports players who experience sudden cardiac arrest, the cause is often an overlooked hereditary factor. “Cardiac screening is recommended in particular for young, high-performance athletes from around 14 years old,” said Dr. Voigtländer, who is also a cardiologist and medical director of the Agaplesion Bethanien Hospital in Frankfurt.
 

Testing of family

“If sudden cardiac arrest or an unexplained sudden death occurs at a young age in the family, the primary care practitioner must be aware that this could be due to heart diseases that could affect the rest of the family,” said Dr. Voigtländer.

In these cases, primary care practitioners must connect the other family members to specialist outpatient departments that can test for genetic factors, he added. “Many of these genetic diseases can be treated successfully if they are diagnosed promptly.”
 

Lack of knowledge

Dr. Kauferstein, who runs such a specialist outpatient department, said, “unfortunately, many affected families do not know that they should be tested as well. This lack of knowledge can also lead to fatal consequences for relatives.”

For this reason, she believes that it is crucial to provide more information to the general population. Sudden cardiac arrest is often the first sign of an underlying heart disease in young, healthy individuals. “We do see warning signals in our in-depth testing of sudden cardiac arrest cases that have often been overlooked,” said Dr. Kauferstein.

This article was translated from the Medscape German Edition. A version appeared on Medscape.com.

Sudden cardiac arrest is the term given to death that results from a cardiac cause and occurs within an hour of symptoms being observed. If no witnesses are present, sudden cardiac arrest is present if the person had been in apparently good health 24 hours before cardiac death. Fatality is usually a result of sustained ventricular fibrillation or sustained ventricular tachycardia that leads to cardiac arrest.

What should primary care practitioners consider in order to detect at-risk patients in time?
 

Recognizing warning signs

Warning signs that should prompt physicians to consider an increased risk of sudden cardiac arrest include the following:

• Unexplained, brief fainting episodes that above all occur with stress, physical activity, or loud noises (for example, alarm ringing)
• Seizures without a clear pathologic EEG result (for example, epilepsy)
• Unexplained accidents or car crashes
• Heart failure or pacemaker dependency before age 50 years

“These are all indications that could point to an underlying heart disease that should be investigated by a medical professional,” explained Silke Kauferstein, PhD, head of the Center for Sudden Cardiac Arrest and Familial Arrhythmia Syndrome at the Institute of Forensic Medicine of the University Frankfurt am Main (Germany), in a podcast by the German Heart Foundation.
 

Sports rarely responsible

Sudden cardiac arrest has numerous causes. Sudden cardiac arrests in a professional sports environment always attract attention. Yet sports play a less important role in sudden cardiac arrest than is often assumed, even in young individuals.

“The incidence of sudden cardiac arrest is on average 0.7-3 per 100,000 sports players from all age groups,” said Thomas Voigtländer, MD, chair of the German Heart Foundation, in an interview. Men make up 95% of those affected, and 90% of these events occur during recreational sports.
 

Inherited disorders

The most significant risk factor for sudden cardiac arrest is age; it is often associated with coronary heart disease. This factor can be significant from as early as age 35 years. Among young individuals, sudden cardiac arrest is often a result of congenital heart diseases, such as hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy. Diseases such as long QT syndrome and Brugada syndrome can also lead to sudden cardiac arrest.

Among young sports players who experience sudden cardiac arrest, the cause is often an overlooked hereditary factor. “Cardiac screening is recommended in particular for young, high-performance athletes from around 14 years old,” said Dr. Voigtländer, who is also a cardiologist and medical director of the Agaplesion Bethanien Hospital in Frankfurt.
 

Testing of family

“If sudden cardiac arrest or an unexplained sudden death occurs at a young age in the family, the primary care practitioner must be aware that this could be due to heart diseases that could affect the rest of the family,” said Dr. Voigtländer.

In these cases, primary care practitioners must connect the other family members to specialist outpatient departments that can test for genetic factors, he added. “Many of these genetic diseases can be treated successfully if they are diagnosed promptly.”
 

Lack of knowledge

Dr. Kauferstein, who runs such a specialist outpatient department, said, “unfortunately, many affected families do not know that they should be tested as well. This lack of knowledge can also lead to fatal consequences for relatives.”

For this reason, she believes that it is crucial to provide more information to the general population. Sudden cardiac arrest is often the first sign of an underlying heart disease in young, healthy individuals. “We do see warning signals in our in-depth testing of sudden cardiac arrest cases that have often been overlooked,” said Dr. Kauferstein.

This article was translated from the Medscape German Edition. A version appeared on Medscape.com.

Sudden cardiac arrest is the term given to death that results from a cardiac cause and occurs within an hour of symptoms being observed. If no witnesses are present, sudden cardiac arrest is present if the person had been in apparently good health 24 hours before cardiac death. Fatality is usually a result of sustained ventricular fibrillation or sustained ventricular tachycardia that leads to cardiac arrest.

What should primary care practitioners consider in order to detect at-risk patients in time?
 

Recognizing warning signs

Warning signs that should prompt physicians to consider an increased risk of sudden cardiac arrest include the following:

• Unexplained, brief fainting episodes that above all occur with stress, physical activity, or loud noises (for example, alarm ringing)
• Seizures without a clear pathologic EEG result (for example, epilepsy)
• Unexplained accidents or car crashes
• Heart failure or pacemaker dependency before age 50 years

“These are all indications that could point to an underlying heart disease that should be investigated by a medical professional,” explained Silke Kauferstein, PhD, head of the Center for Sudden Cardiac Arrest and Familial Arrhythmia Syndrome at the Institute of Forensic Medicine of the University Frankfurt am Main (Germany), in a podcast by the German Heart Foundation.
 

Sports rarely responsible

Sudden cardiac arrest has numerous causes. Sudden cardiac arrests in a professional sports environment always attract attention. Yet sports play a less important role in sudden cardiac arrest than is often assumed, even in young individuals.

“The incidence of sudden cardiac arrest is on average 0.7-3 per 100,000 sports players from all age groups,” said Thomas Voigtländer, MD, chair of the German Heart Foundation, in an interview. Men make up 95% of those affected, and 90% of these events occur during recreational sports.
 

Inherited disorders

The most significant risk factor for sudden cardiac arrest is age; it is often associated with coronary heart disease. This factor can be significant from as early as age 35 years. Among young individuals, sudden cardiac arrest is often a result of congenital heart diseases, such as hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy. Diseases such as long QT syndrome and Brugada syndrome can also lead to sudden cardiac arrest.

Among young sports players who experience sudden cardiac arrest, the cause is often an overlooked hereditary factor. “Cardiac screening is recommended in particular for young, high-performance athletes from around 14 years old,” said Dr. Voigtländer, who is also a cardiologist and medical director of the Agaplesion Bethanien Hospital in Frankfurt.
 

Testing of family

“If sudden cardiac arrest or an unexplained sudden death occurs at a young age in the family, the primary care practitioner must be aware that this could be due to heart diseases that could affect the rest of the family,” said Dr. Voigtländer.

In these cases, primary care practitioners must connect the other family members to specialist outpatient departments that can test for genetic factors, he added. “Many of these genetic diseases can be treated successfully if they are diagnosed promptly.”
 

Lack of knowledge

Dr. Kauferstein, who runs such a specialist outpatient department, said, “unfortunately, many affected families do not know that they should be tested as well. This lack of knowledge can also lead to fatal consequences for relatives.”

For this reason, she believes that it is crucial to provide more information to the general population. Sudden cardiac arrest is often the first sign of an underlying heart disease in young, healthy individuals. “We do see warning signals in our in-depth testing of sudden cardiac arrest cases that have often been overlooked,” said Dr. Kauferstein.

This article was translated from the Medscape German Edition. A version 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.

The latest clinical practice guideline for managing patients with chronic coronary disease (CCD) takes an evidence-based and patient-centered approach to care and includes key updates on revascularization, beta-blocker use, and routine functional and anatomic testing.

Developed by the American Heart Association, the American College of Cardiology, and other specialty societies, the 2023 guideline both updates and consolidates ACC/AHA guidelines previously published in 2012 and 2014 for the management of patients with stable ischemic heart disease.

It was published online in Circulation and the Journal of the American College of Cardiology .

Among the key recommendations were the following.

• Long-term beta-blocker therapy is no longer recommended for improving outcomes for patients with CCD in the absence of myocardial infarction within the past year, left ventricular ejection fraction (LVEF) less than or equal to 50%, or another primary indication for beta-blocker therapy. Either a calcium channel blocker or a beta-blocker is recommended as first-line antianginal therapy.
• Sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are recommended for select groups of patients with CCD, including individuals without diabetes, to improve outcomes.
• Statins remain first-line therapy for lipid lowering for patients with CCD. Several adjunctive therapies, such as ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, inclisiran, or bempedoic acid, may be used in select populations, although clinical outcomes data are not yet available for novel agents such as inclisiran and bempedoic acid.
• Shorter durations of dual antiplatelet therapy are safe and effective in many circumstances, particularly when the risk of bleeding is high and the ischemic risk is not high.
• The use of nonprescription or dietary supplements, including fish oil and omega-3 fatty acids or vitamins, is not recommended for patients with CCD, given the lack of benefit in reducing cardiovascular events.
• Revascularization is recommended in two scenarios: (1) for patients with lifestyle-limiting angina despite guideline-directed medical therapy and with coronary stenoses amenable to revascularization, with the goal of improving symptoms; and (2) for patients with significant left main disease or multivessel disease with severe LV dysfunction (LVEF ≤ 35%), for whom coronary artery bypass grafting plus medical therapy is recommended over medical therapy alone, with the goal of improving survival.
• Routine periodic anatomic or ischemic testing in the absence of a change in clinical or functional status is not recommended for risk stratification or to guide therapeutic decision-making for patients with CCD.
• Nondrug therapies, including healthy dietary habits and exercise, are recommended for all patients with CCD. When possible, patients should participate in regular physical activity, including activities to reduce sitting time and to increase aerobic and resistance exercise.
• Cardiac rehabilitation for eligible patients provides significant cardiovascular benefits, including decreased morbidity and mortality.
• Electronic cigarettes increase the odds of successful smoking cessation, but they are not recommended as first-line therapy, owing to the lack of long-term safety data and risks associated with sustained use.

Living document

The co-authors of a related editorial note that “CCD as defined in the 2023 guideline includes patients who may or may not have classic signs and symptoms of CAD.

“The 2023 guideline reflects this heterogeneity by including patients stabilized after acute coronary syndrome hospitalization, those with ischemic cardiomyopathy, stable angina or equivalent with or without a positive imaging test, vasospasm or microvascular disease, and positive noninvasive screening test leading to a clinician diagnosis of CAD,” write Sunil V. Rao, MD, with NYU Langone Health System, and co-authors.

“The focus of the guideline is on extending life and improving quality of life for CCD patients, taking into account patient priorities and the importance of equitable care. There is emphasis on shared decision-making that involves the patient’s preferences and values when considering treatment options,” they point out.

“Importantly, the guidelines exist to provide guidance and are meant to complement, not supplant, clinical judgment. As the evidence for the management of CCD continues to evolve, the guidelines will need to be a ‘living document’ to ensure that clinicians and patients can achieve their shared therapeutic goals of reducing mortality and improving quality of life,” they add.

The 2023 guideline on management of patients with CCD was developed in collaboration with and was endorsed by the American College of Clinical Pharmacy, the American Society for Preventive Cardiology, the National Lipid Association, and the Preventive Cardiovascular Nurses Association. It has been endorsed by the Society for Cardiovascular Angiography and Interventions.

The research had no commercial funding.

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

The latest clinical practice guideline for managing patients with chronic coronary disease (CCD) takes an evidence-based and patient-centered approach to care and includes key updates on revascularization, beta-blocker use, and routine functional and anatomic testing.

Developed by the American Heart Association, the American College of Cardiology, and other specialty societies, the 2023 guideline both updates and consolidates ACC/AHA guidelines previously published in 2012 and 2014 for the management of patients with stable ischemic heart disease.

It was published online in Circulation and the Journal of the American College of Cardiology .

Among the key recommendations were the following.

• Long-term beta-blocker therapy is no longer recommended for improving outcomes for patients with CCD in the absence of myocardial infarction within the past year, left ventricular ejection fraction (LVEF) less than or equal to 50%, or another primary indication for beta-blocker therapy. Either a calcium channel blocker or a beta-blocker is recommended as first-line antianginal therapy.
• Sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are recommended for select groups of patients with CCD, including individuals without diabetes, to improve outcomes.
• Statins remain first-line therapy for lipid lowering for patients with CCD. Several adjunctive therapies, such as ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, inclisiran, or bempedoic acid, may be used in select populations, although clinical outcomes data are not yet available for novel agents such as inclisiran and bempedoic acid.
• Shorter durations of dual antiplatelet therapy are safe and effective in many circumstances, particularly when the risk of bleeding is high and the ischemic risk is not high.
• The use of nonprescription or dietary supplements, including fish oil and omega-3 fatty acids or vitamins, is not recommended for patients with CCD, given the lack of benefit in reducing cardiovascular events.
• Revascularization is recommended in two scenarios: (1) for patients with lifestyle-limiting angina despite guideline-directed medical therapy and with coronary stenoses amenable to revascularization, with the goal of improving symptoms; and (2) for patients with significant left main disease or multivessel disease with severe LV dysfunction (LVEF ≤ 35%), for whom coronary artery bypass grafting plus medical therapy is recommended over medical therapy alone, with the goal of improving survival.
• Routine periodic anatomic or ischemic testing in the absence of a change in clinical or functional status is not recommended for risk stratification or to guide therapeutic decision-making for patients with CCD.
• Nondrug therapies, including healthy dietary habits and exercise, are recommended for all patients with CCD. When possible, patients should participate in regular physical activity, including activities to reduce sitting time and to increase aerobic and resistance exercise.
• Cardiac rehabilitation for eligible patients provides significant cardiovascular benefits, including decreased morbidity and mortality.
• Electronic cigarettes increase the odds of successful smoking cessation, but they are not recommended as first-line therapy, owing to the lack of long-term safety data and risks associated with sustained use.

Living document

The co-authors of a related editorial note that “CCD as defined in the 2023 guideline includes patients who may or may not have classic signs and symptoms of CAD.

“The 2023 guideline reflects this heterogeneity by including patients stabilized after acute coronary syndrome hospitalization, those with ischemic cardiomyopathy, stable angina or equivalent with or without a positive imaging test, vasospasm or microvascular disease, and positive noninvasive screening test leading to a clinician diagnosis of CAD,” write Sunil V. Rao, MD, with NYU Langone Health System, and co-authors.

“The focus of the guideline is on extending life and improving quality of life for CCD patients, taking into account patient priorities and the importance of equitable care. There is emphasis on shared decision-making that involves the patient’s preferences and values when considering treatment options,” they point out.

“Importantly, the guidelines exist to provide guidance and are meant to complement, not supplant, clinical judgment. As the evidence for the management of CCD continues to evolve, the guidelines will need to be a ‘living document’ to ensure that clinicians and patients can achieve their shared therapeutic goals of reducing mortality and improving quality of life,” they add.

The 2023 guideline on management of patients with CCD was developed in collaboration with and was endorsed by the American College of Clinical Pharmacy, the American Society for Preventive Cardiology, the National Lipid Association, and the Preventive Cardiovascular Nurses Association. It has been endorsed by the Society for Cardiovascular Angiography and Interventions.

The research had no commercial funding.

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

The latest clinical practice guideline for managing patients with chronic coronary disease (CCD) takes an evidence-based and patient-centered approach to care and includes key updates on revascularization, beta-blocker use, and routine functional and anatomic testing.

Developed by the American Heart Association, the American College of Cardiology, and other specialty societies, the 2023 guideline both updates and consolidates ACC/AHA guidelines previously published in 2012 and 2014 for the management of patients with stable ischemic heart disease.

It was published online in Circulation and the Journal of the American College of Cardiology .

Among the key recommendations were the following.

• Long-term beta-blocker therapy is no longer recommended for improving outcomes for patients with CCD in the absence of myocardial infarction within the past year, left ventricular ejection fraction (LVEF) less than or equal to 50%, or another primary indication for beta-blocker therapy. Either a calcium channel blocker or a beta-blocker is recommended as first-line antianginal therapy.
• Sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are recommended for select groups of patients with CCD, including individuals without diabetes, to improve outcomes.
• Statins remain first-line therapy for lipid lowering for patients with CCD. Several adjunctive therapies, such as ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, inclisiran, or bempedoic acid, may be used in select populations, although clinical outcomes data are not yet available for novel agents such as inclisiran and bempedoic acid.
• Shorter durations of dual antiplatelet therapy are safe and effective in many circumstances, particularly when the risk of bleeding is high and the ischemic risk is not high.
• The use of nonprescription or dietary supplements, including fish oil and omega-3 fatty acids or vitamins, is not recommended for patients with CCD, given the lack of benefit in reducing cardiovascular events.
• Revascularization is recommended in two scenarios: (1) for patients with lifestyle-limiting angina despite guideline-directed medical therapy and with coronary stenoses amenable to revascularization, with the goal of improving symptoms; and (2) for patients with significant left main disease or multivessel disease with severe LV dysfunction (LVEF ≤ 35%), for whom coronary artery bypass grafting plus medical therapy is recommended over medical therapy alone, with the goal of improving survival.
• Routine periodic anatomic or ischemic testing in the absence of a change in clinical or functional status is not recommended for risk stratification or to guide therapeutic decision-making for patients with CCD.
• Nondrug therapies, including healthy dietary habits and exercise, are recommended for all patients with CCD. When possible, patients should participate in regular physical activity, including activities to reduce sitting time and to increase aerobic and resistance exercise.
• Cardiac rehabilitation for eligible patients provides significant cardiovascular benefits, including decreased morbidity and mortality.
• Electronic cigarettes increase the odds of successful smoking cessation, but they are not recommended as first-line therapy, owing to the lack of long-term safety data and risks associated with sustained use.

Living document

The co-authors of a related editorial note that “CCD as defined in the 2023 guideline includes patients who may or may not have classic signs and symptoms of CAD.

“The 2023 guideline reflects this heterogeneity by including patients stabilized after acute coronary syndrome hospitalization, those with ischemic cardiomyopathy, stable angina or equivalent with or without a positive imaging test, vasospasm or microvascular disease, and positive noninvasive screening test leading to a clinician diagnosis of CAD,” write Sunil V. Rao, MD, with NYU Langone Health System, and co-authors.

“The focus of the guideline is on extending life and improving quality of life for CCD patients, taking into account patient priorities and the importance of equitable care. There is emphasis on shared decision-making that involves the patient’s preferences and values when considering treatment options,” they point out.

“Importantly, the guidelines exist to provide guidance and are meant to complement, not supplant, clinical judgment. As the evidence for the management of CCD continues to evolve, the guidelines will need to be a ‘living document’ to ensure that clinicians and patients can achieve their shared therapeutic goals of reducing mortality and improving quality of life,” they add.

The 2023 guideline on management of patients with CCD was developed in collaboration with and was endorsed by the American College of Clinical Pharmacy, the American Society for Preventive Cardiology, the National Lipid Association, and the Preventive Cardiovascular Nurses Association. It has been endorsed by the Society for Cardiovascular Angiography and Interventions.

The research had no commercial funding.

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

Questions about omega-3 fatty acid supplements come up often in the atrial fibrillation (AFib) clinic.

The story begins with the simple observation that populations who eat lots of oily fish have fewer coronary events. This correlation provoked great interest in concentrating fish oils in pill form and studying their use to promote health.

A small post hoc study from a group in Norway stimulated me to review what we do and don’t know about fish pills, as I call them in clinic.
 

OMENI secondary analysis

Peder Myhre, MD, and colleagues recently published a secondary analysis of the OMENI trial looking at both the risk and possible causes of AFib in the omega-3 group.

The OMENI trial randomly assigned slightly more than 1,000 older patients (mean age, 75 years) post–myocardial infarction to either 1.8 g/d of fish oil supplements versus placebo for 2 years. The supplements comprised 930 mg of eicosapentaenoic acid (EPA) and 660 mg of docosahexaenoic acid (DHA). The main trial reported no difference in a composite primary endpoint of MI, revascularization, stroke, death, or hospitalization for heart failure.

The secondary analysis explored the 75% of patients in the main trial who had no history of AFib. It looked at how many in each group developed either true clinical AFib or what the authors called micro-AFib, defined as short bursts of irregular atrial activity lasting seconds.

The sub-analysis had three main findings: Patients in the supplement arm had a 90% higher rate of AFib or micro-AFib, compared with patients on placebo, EPA had the strongest effect on the association, and there was a graded risk for AFib with increasing serum EPA levels.  

The authors raised the possibility that more micro-AFib might be a possible mediator of AFib risk.
 

Trials of low-dose EPA and DHA

First, the low-dose trials. In the ASCEND trial from 2018, more than 15,000 patients with diabetes were randomly assigned to either 1 g of omega-3 fatty acids (460-mg EPA and 380-mg DHA) or mineral oil.

The trial was neutral. After 7.4 years, the primary endpoint of MI, stroke, transient ischemic attack, or cardiovascular death occurred in 8.9% of the supplement group versus 9.2% of the placebo arm.The incidence of AFib was higher in the omega-3 group but did not reach statistical significance (2.1% vs. 1.7% for placebo; hazard ratio, 1.23; 95% confidence interval, 0.98-1.54).

Another neutral CV trial, VITAL, specifically studied the effects of marine omega-3 pills (460-mg EPA and 380-mg DHA) in older adults without heart disease, cancer, or AFib. After slightly more than 5 years, AFib occurred at a similar rate in the active arm and placebo arms (3.7% vs. 3.4% for placebo; HR, 1.09; 95% CI, 0.96-1.24; P = .19)
 

Trials of very high-dose marine omega-3s

Next came trials of higher doses in higher-risk populations.

In 2020, JAMA published the STRENGTH trial, which compared 4 g/d of a carboxylic acid formulation of EPA and DHA with a corn oil placebo in more than 13,000 patients who either had established atherosclerotic CV disease (ASCVD) or were at high risk for ASCVD.

The trial was terminated early because of futility and a signal of increased AFib risk in the supplement arm.

Nearly the same number of patients in the supplement versus placebo arm experienced a primary composite endpoint of major adverse cardiac events: 12.0% versus 12.2%, respectively.

AFib was a tertiary endpoint in this trial. An increase in investigator-reported new-onset AFib was observed in the omega-3 group: 2.2% vs. 1.3% for corn oil (HR, 1.69; 95% CI, 1.29-2.21; nominal P < .001).

The REDUCE-IT trial randomly assigned more than 8,000 patients who had ASCVD or diabetes and high ASCVD risk and elevated triglyceride levels to either 4 g of icosapent ethyl daily, a concentrated form of EPA, or a mineral oil placebo.

After nearly 5 years, there was a 4.8% absolute risk reduction in the primary endpoint of CV death, MI, stroke, revascularization, or unstable angina with icosapent ethyl. An increase in atherogenic biomarkers in the mineral oil placebo complicated interpretation of this trial.

Hospitalization for AFib or flutter occurred in 3.1% of the active arm versus 2.1% of the mineral oil group (P = .004).
 

Meta-analysis of marine omega-3 supplement trials

In 2021, Baris Gencer and colleagues performed a meta-analysis of these five trials plus 2 more (GISSI-HF and RP) looking specifically at risk for AFib. Their final analysis included more than 81,000 patients followed for nearly 5 years.

Omega 3 fatty acid supplements associated with a 25% increase in the risk for AFib (HR, 1.25; 95% CI, 1.07-1.46P =.013). Exploring further, they noted a dose-dependent relationship. Most of the increased risk occurred in trials that tested greater than 1 g/d.
 

Summary

When faced with surprise findings, I like to think things through.

First about plausibility. Omega-3 fatty acids clearly exert electrophysiologic effects on cardiac cells, an increase in AFib risk is plausible. The exact underlying mechanism may be unknown, but exact mechanisms are less important than actual clinical effects (see sodium-glucose cotransporter 2 inhibitors).

What about causality? Factors supporting causality include plausibility, consistency of increased AFib risk in multiple studies, and a dose-response relationship.

I see multiple clinical implications of this observation.

The first is the power of the randomized trial to inform practice. If we relied only on observational evidence, we might have assumed that since high fish consumption in populations associated with lower rates of cardiac events, fish oil supplementation would also reduce cardiac events. Other than the outlier trial, REDUCE-IT, with its mineral oil placebo, the preponderance of the randomized controlled trial evidence does not support fish oils for the reduction of CV events.

Randomized controlled trials also exposed the AFib risk. This would have been difficult to sort out in nonrandom observational studies.

Another underappreciated lesson is the notion that drugs, including supplements, can have off-target effects.

Consider the case of statin drugs. It is widely assumed that statins reduce cardiac events by lowering low-density lipoprotein cholesterol (LDL-C). Yet, statins became a mainstay not because of LDL-C lowering but because multiple trials found that this class of drugs reduced cardiac events without increasing adverse effects.

Omega-3 fatty acids reduce triglyceride levels, but this is not enough to adopt the use of these pills. The lack of consistent reduction in CV events and the off-target signal of AFib risk argue against routine use of fish-oil pills.

I will close with uncertainty. Though there is plausibility and multiple reasons to infer causality of marine omega-3s in increasing AFib risk, the effect size remains unknown.

In an editorial accompanying the recent meta-analysis, epidemiologist Michelle Samuel, MPH, PhD, and electrophysiologist Stanley Nattel, MD, cautioned readers on a technical but important point. It concerns the matter of competing risks, such as death, in the analysis of AFib risk, meaning that patients who died may have developed AFib had they lived. They provide a detailed explanation in the open access article, but the take-home is that the exact effect size is difficult to quantify without patient-level original data.

No matter. I find the signal of increased AFib risk an important one to use at the bedside.

Intermittent AFib has an unpredictable natural history. It often resolves as mysteriously as it arises. When patients take fish-oil supplements, I cite these studies, note the lack of CV protection, then I recommend stopping the pills.

This allows for one of the most important interventions in AFib care: time.

Dr. Mandrola is a clinical electrophysiologist with Baptist Medical Associates, Louisville, Ky. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Questions about omega-3 fatty acid supplements come up often in the atrial fibrillation (AFib) clinic.

The story begins with the simple observation that populations who eat lots of oily fish have fewer coronary events. This correlation provoked great interest in concentrating fish oils in pill form and studying their use to promote health.

A small post hoc study from a group in Norway stimulated me to review what we do and don’t know about fish pills, as I call them in clinic.
 

OMENI secondary analysis

Peder Myhre, MD, and colleagues recently published a secondary analysis of the OMENI trial looking at both the risk and possible causes of AFib in the omega-3 group.

The OMENI trial randomly assigned slightly more than 1,000 older patients (mean age, 75 years) post–myocardial infarction to either 1.8 g/d of fish oil supplements versus placebo for 2 years. The supplements comprised 930 mg of eicosapentaenoic acid (EPA) and 660 mg of docosahexaenoic acid (DHA). The main trial reported no difference in a composite primary endpoint of MI, revascularization, stroke, death, or hospitalization for heart failure.

The secondary analysis explored the 75% of patients in the main trial who had no history of AFib. It looked at how many in each group developed either true clinical AFib or what the authors called micro-AFib, defined as short bursts of irregular atrial activity lasting seconds.

The sub-analysis had three main findings: Patients in the supplement arm had a 90% higher rate of AFib or micro-AFib, compared with patients on placebo, EPA had the strongest effect on the association, and there was a graded risk for AFib with increasing serum EPA levels.  

The authors raised the possibility that more micro-AFib might be a possible mediator of AFib risk.
 

Trials of low-dose EPA and DHA

First, the low-dose trials. In the ASCEND trial from 2018, more than 15,000 patients with diabetes were randomly assigned to either 1 g of omega-3 fatty acids (460-mg EPA and 380-mg DHA) or mineral oil.

The trial was neutral. After 7.4 years, the primary endpoint of MI, stroke, transient ischemic attack, or cardiovascular death occurred in 8.9% of the supplement group versus 9.2% of the placebo arm.The incidence of AFib was higher in the omega-3 group but did not reach statistical significance (2.1% vs. 1.7% for placebo; hazard ratio, 1.23; 95% confidence interval, 0.98-1.54).

Another neutral CV trial, VITAL, specifically studied the effects of marine omega-3 pills (460-mg EPA and 380-mg DHA) in older adults without heart disease, cancer, or AFib. After slightly more than 5 years, AFib occurred at a similar rate in the active arm and placebo arms (3.7% vs. 3.4% for placebo; HR, 1.09; 95% CI, 0.96-1.24; P = .19)
 

Trials of very high-dose marine omega-3s

Next came trials of higher doses in higher-risk populations.

In 2020, JAMA published the STRENGTH trial, which compared 4 g/d of a carboxylic acid formulation of EPA and DHA with a corn oil placebo in more than 13,000 patients who either had established atherosclerotic CV disease (ASCVD) or were at high risk for ASCVD.

The trial was terminated early because of futility and a signal of increased AFib risk in the supplement arm.

Nearly the same number of patients in the supplement versus placebo arm experienced a primary composite endpoint of major adverse cardiac events: 12.0% versus 12.2%, respectively.

AFib was a tertiary endpoint in this trial. An increase in investigator-reported new-onset AFib was observed in the omega-3 group: 2.2% vs. 1.3% for corn oil (HR, 1.69; 95% CI, 1.29-2.21; nominal P < .001).

The REDUCE-IT trial randomly assigned more than 8,000 patients who had ASCVD or diabetes and high ASCVD risk and elevated triglyceride levels to either 4 g of icosapent ethyl daily, a concentrated form of EPA, or a mineral oil placebo.

After nearly 5 years, there was a 4.8% absolute risk reduction in the primary endpoint of CV death, MI, stroke, revascularization, or unstable angina with icosapent ethyl. An increase in atherogenic biomarkers in the mineral oil placebo complicated interpretation of this trial.

Hospitalization for AFib or flutter occurred in 3.1% of the active arm versus 2.1% of the mineral oil group (P = .004).
 

Meta-analysis of marine omega-3 supplement trials

In 2021, Baris Gencer and colleagues performed a meta-analysis of these five trials plus 2 more (GISSI-HF and RP) looking specifically at risk for AFib. Their final analysis included more than 81,000 patients followed for nearly 5 years.

Omega 3 fatty acid supplements associated with a 25% increase in the risk for AFib (HR, 1.25; 95% CI, 1.07-1.46P =.013). Exploring further, they noted a dose-dependent relationship. Most of the increased risk occurred in trials that tested greater than 1 g/d.
 

Summary

When faced with surprise findings, I like to think things through.

First about plausibility. Omega-3 fatty acids clearly exert electrophysiologic effects on cardiac cells, an increase in AFib risk is plausible. The exact underlying mechanism may be unknown, but exact mechanisms are less important than actual clinical effects (see sodium-glucose cotransporter 2 inhibitors).

What about causality? Factors supporting causality include plausibility, consistency of increased AFib risk in multiple studies, and a dose-response relationship.

I see multiple clinical implications of this observation.

The first is the power of the randomized trial to inform practice. If we relied only on observational evidence, we might have assumed that since high fish consumption in populations associated with lower rates of cardiac events, fish oil supplementation would also reduce cardiac events. Other than the outlier trial, REDUCE-IT, with its mineral oil placebo, the preponderance of the randomized controlled trial evidence does not support fish oils for the reduction of CV events.

Randomized controlled trials also exposed the AFib risk. This would have been difficult to sort out in nonrandom observational studies.

Another underappreciated lesson is the notion that drugs, including supplements, can have off-target effects.

Consider the case of statin drugs. It is widely assumed that statins reduce cardiac events by lowering low-density lipoprotein cholesterol (LDL-C). Yet, statins became a mainstay not because of LDL-C lowering but because multiple trials found that this class of drugs reduced cardiac events without increasing adverse effects.

Omega-3 fatty acids reduce triglyceride levels, but this is not enough to adopt the use of these pills. The lack of consistent reduction in CV events and the off-target signal of AFib risk argue against routine use of fish-oil pills.

I will close with uncertainty. Though there is plausibility and multiple reasons to infer causality of marine omega-3s in increasing AFib risk, the effect size remains unknown.

In an editorial accompanying the recent meta-analysis, epidemiologist Michelle Samuel, MPH, PhD, and electrophysiologist Stanley Nattel, MD, cautioned readers on a technical but important point. It concerns the matter of competing risks, such as death, in the analysis of AFib risk, meaning that patients who died may have developed AFib had they lived. They provide a detailed explanation in the open access article, but the take-home is that the exact effect size is difficult to quantify without patient-level original data.

No matter. I find the signal of increased AFib risk an important one to use at the bedside.

Intermittent AFib has an unpredictable natural history. It often resolves as mysteriously as it arises. When patients take fish-oil supplements, I cite these studies, note the lack of CV protection, then I recommend stopping the pills.

This allows for one of the most important interventions in AFib care: time.

Dr. Mandrola is a clinical electrophysiologist with Baptist Medical Associates, Louisville, Ky. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Questions about omega-3 fatty acid supplements come up often in the atrial fibrillation (AFib) clinic.

The story begins with the simple observation that populations who eat lots of oily fish have fewer coronary events. This correlation provoked great interest in concentrating fish oils in pill form and studying their use to promote health.

A small post hoc study from a group in Norway stimulated me to review what we do and don’t know about fish pills, as I call them in clinic.
 

OMENI secondary analysis

Peder Myhre, MD, and colleagues recently published a secondary analysis of the OMENI trial looking at both the risk and possible causes of AFib in the omega-3 group.

The OMENI trial randomly assigned slightly more than 1,000 older patients (mean age, 75 years) post–myocardial infarction to either 1.8 g/d of fish oil supplements versus placebo for 2 years. The supplements comprised 930 mg of eicosapentaenoic acid (EPA) and 660 mg of docosahexaenoic acid (DHA). The main trial reported no difference in a composite primary endpoint of MI, revascularization, stroke, death, or hospitalization for heart failure.

The secondary analysis explored the 75% of patients in the main trial who had no history of AFib. It looked at how many in each group developed either true clinical AFib or what the authors called micro-AFib, defined as short bursts of irregular atrial activity lasting seconds.

The sub-analysis had three main findings: Patients in the supplement arm had a 90% higher rate of AFib or micro-AFib, compared with patients on placebo, EPA had the strongest effect on the association, and there was a graded risk for AFib with increasing serum EPA levels.  

The authors raised the possibility that more micro-AFib might be a possible mediator of AFib risk.
 

Trials of low-dose EPA and DHA

First, the low-dose trials. In the ASCEND trial from 2018, more than 15,000 patients with diabetes were randomly assigned to either 1 g of omega-3 fatty acids (460-mg EPA and 380-mg DHA) or mineral oil.

The trial was neutral. After 7.4 years, the primary endpoint of MI, stroke, transient ischemic attack, or cardiovascular death occurred in 8.9% of the supplement group versus 9.2% of the placebo arm.The incidence of AFib was higher in the omega-3 group but did not reach statistical significance (2.1% vs. 1.7% for placebo; hazard ratio, 1.23; 95% confidence interval, 0.98-1.54).

Another neutral CV trial, VITAL, specifically studied the effects of marine omega-3 pills (460-mg EPA and 380-mg DHA) in older adults without heart disease, cancer, or AFib. After slightly more than 5 years, AFib occurred at a similar rate in the active arm and placebo arms (3.7% vs. 3.4% for placebo; HR, 1.09; 95% CI, 0.96-1.24; P = .19)
 

Trials of very high-dose marine omega-3s

Next came trials of higher doses in higher-risk populations.

In 2020, JAMA published the STRENGTH trial, which compared 4 g/d of a carboxylic acid formulation of EPA and DHA with a corn oil placebo in more than 13,000 patients who either had established atherosclerotic CV disease (ASCVD) or were at high risk for ASCVD.

The trial was terminated early because of futility and a signal of increased AFib risk in the supplement arm.

Nearly the same number of patients in the supplement versus placebo arm experienced a primary composite endpoint of major adverse cardiac events: 12.0% versus 12.2%, respectively.

AFib was a tertiary endpoint in this trial. An increase in investigator-reported new-onset AFib was observed in the omega-3 group: 2.2% vs. 1.3% for corn oil (HR, 1.69; 95% CI, 1.29-2.21; nominal P < .001).

The REDUCE-IT trial randomly assigned more than 8,000 patients who had ASCVD or diabetes and high ASCVD risk and elevated triglyceride levels to either 4 g of icosapent ethyl daily, a concentrated form of EPA, or a mineral oil placebo.

After nearly 5 years, there was a 4.8% absolute risk reduction in the primary endpoint of CV death, MI, stroke, revascularization, or unstable angina with icosapent ethyl. An increase in atherogenic biomarkers in the mineral oil placebo complicated interpretation of this trial.

Hospitalization for AFib or flutter occurred in 3.1% of the active arm versus 2.1% of the mineral oil group (P = .004).
 

Meta-analysis of marine omega-3 supplement trials

In 2021, Baris Gencer and colleagues performed a meta-analysis of these five trials plus 2 more (GISSI-HF and RP) looking specifically at risk for AFib. Their final analysis included more than 81,000 patients followed for nearly 5 years.

Omega 3 fatty acid supplements associated with a 25% increase in the risk for AFib (HR, 1.25; 95% CI, 1.07-1.46P =.013). Exploring further, they noted a dose-dependent relationship. Most of the increased risk occurred in trials that tested greater than 1 g/d.
 

Summary

When faced with surprise findings, I like to think things through.

First about plausibility. Omega-3 fatty acids clearly exert electrophysiologic effects on cardiac cells, an increase in AFib risk is plausible. The exact underlying mechanism may be unknown, but exact mechanisms are less important than actual clinical effects (see sodium-glucose cotransporter 2 inhibitors).

What about causality? Factors supporting causality include plausibility, consistency of increased AFib risk in multiple studies, and a dose-response relationship.

I see multiple clinical implications of this observation.

The first is the power of the randomized trial to inform practice. If we relied only on observational evidence, we might have assumed that since high fish consumption in populations associated with lower rates of cardiac events, fish oil supplementation would also reduce cardiac events. Other than the outlier trial, REDUCE-IT, with its mineral oil placebo, the preponderance of the randomized controlled trial evidence does not support fish oils for the reduction of CV events.

Randomized controlled trials also exposed the AFib risk. This would have been difficult to sort out in nonrandom observational studies.

Another underappreciated lesson is the notion that drugs, including supplements, can have off-target effects.

Consider the case of statin drugs. It is widely assumed that statins reduce cardiac events by lowering low-density lipoprotein cholesterol (LDL-C). Yet, statins became a mainstay not because of LDL-C lowering but because multiple trials found that this class of drugs reduced cardiac events without increasing adverse effects.

Omega-3 fatty acids reduce triglyceride levels, but this is not enough to adopt the use of these pills. The lack of consistent reduction in CV events and the off-target signal of AFib risk argue against routine use of fish-oil pills.

I will close with uncertainty. Though there is plausibility and multiple reasons to infer causality of marine omega-3s in increasing AFib risk, the effect size remains unknown.

In an editorial accompanying the recent meta-analysis, epidemiologist Michelle Samuel, MPH, PhD, and electrophysiologist Stanley Nattel, MD, cautioned readers on a technical but important point. It concerns the matter of competing risks, such as death, in the analysis of AFib risk, meaning that patients who died may have developed AFib had they lived. They provide a detailed explanation in the open access article, but the take-home is that the exact effect size is difficult to quantify without patient-level original data.

No matter. I find the signal of increased AFib risk an important one to use at the bedside.

Intermittent AFib has an unpredictable natural history. It often resolves as mysteriously as it arises. When patients take fish-oil supplements, I cite these studies, note the lack of CV protection, then I recommend stopping the pills.

This allows for one of the most important interventions in AFib care: time.

Dr. Mandrola is a clinical electrophysiologist with Baptist Medical Associates, Louisville, Ky. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Isometric exercise training emerged as the most effective mode to reduce blood pressure in a systematic review and meta-analysis of 270 randomized trials with close to 16,000 participants.

The findings support the development of new exercise guidelines for blood pressure control, the authors said.

Previous research, based on older data that excluded high-intensity interval training (HIIT) and isometric exercise training (IET), led to aerobic exercise training (AET) being recommended for managing blood pressure, according to the authors.

Although AET, HIIT, dynamic resistance training (RT), and combined training (CT) are also effective in reducing both systolic and diastolic blood pressure, the new analysis suggests that IET does it best.

The analysis showed reductions in blood pressure of 8.24/4 mm Hg after IET, compared with 4.49/2.53 mm Hg after AET; 4.55/3.04 mm Hg after RT; 6.04/2.54 mm Hg after CT; and 4.08/2.50 mm Hg after HIIT.

“These findings mirror our smaller-scale trials, and therefore we anticipated that isometrics would be largely effective,” Jamie O’Driscoll, PhD, of Canterbury (England) Christ Church University, said in an interview. However, “the magnitude of difference between isometrics and some other modes was surprising.”

The study was published online in the British Journal of Sports Medicine.
 

All modes effective

The investigators analyzed data from 270 randomized controlled trials including 15,827 people published between 1990 and February 2023. For consistency, the protocol/intensity of each included paper was screened against the Exercise Prescription in Everyday Practice and Rehabilitative Training tool to be defined and categorized.

All protocols were then stratified as AET, RT, CT, HIIT or IET.

As appropriate, protocols were then further stratified into subgroups: AET included walking, running, and cycling; HIIT included sprint interval training and aerobic interval training; and IET included isometric leg extension and isometric wall squat.

Healthy resting blood pressure was defined as a reading below 130/85 mm Hg, prehypertension as 130-139/85-89 mm Hg, and hypertension as 140/90 mm Hg or higher.

All exercise modes led to statistically significant reductions in systolic BP in normal blood pressure cohorts; however, all reductions were substantially larger in individuals with hypertension.

Pairwise analyses showed significant reductions in resting systolic BP and diastolic BP following AET (−4.49/–2.53 mm Hg); RT (–4.55/–3.04 mm Hg), CT (–6.04/–2.54 mm Hg), HIT (–4.08/–2.50 mm Hg); and IET (–8.24/–4.00 mm Hg).

In the network meta-analysis, the rank order of effectiveness for systolic BP based on surface under the cumulative ranking curve values were IET (SUCRA: 98.3%), CT (75.7%), RT (46.1%), AET (40.5%), and HIIT (39.4%).

Secondary network meta-analyses showed that isometric wall squat was the most effective submode for reducing systolic BP (90.4%), followed by isometric leg extension, isometric hand grip, cycling, running, CT, sprint interval training, other aerobic, RT, aerobic interval training, and walking.

Running was the most effective submode for lowering diastolic BP (91.3%), followed by isometric wall squat, isometric handgrip, isometric leg extension, cycling, sprint interval training, RT, AIT, other aerobic, CT, and walking.

The authors acknowledged limitations, including variability in exercise interventions, missing data, variable quality of exercise monitoring and analyses, lack of blinding to group allocation, varying participant populations, and publication bias.

Nevertheless, they concluded, “the results of this analysis should inform future exercise guideline recommendations for the prevention and treatment of arterial hypertension.”
 

Guideline changing?

“There are numerous organizations involved in providing and communicating population exercise guidelines,” including World Health Organization, American and European exercise guidelines, and the National Institute for Health and Care Excellence, Dr. O’Driscoll said. “We are currently developing an international collaborative project with other world leaders in the area to develop this line of enquiry.”

In addition, the team is exploring the prescription of IET within England’s National Health Service and extending the study to wider clinical populations.

In a comment, John A. Osborne, MD, PhD, founder and director of State of the Heart Cardiology in Southlake, Tex., said: “This study further lends credence that other forms of exercise, beyond the usually recommended aerobic exercise promulgated in prior guidelines, have significant value for blood pressure lowering, and, potentially, may offer even greater benefits for ... controlling hypertension.”

“This study should inform contemporary nonpharmacological approaches to blood pressure management and allows providers more flexibility in different strategies of exercise to combat high blood pressure,” said Dr. Osborne, a volunteer spokesperson for the American Heart Association.

That said, “while this study by itself is extremely provocative, thoughtful, and rigorously performed, it should be used as hypothesis generating and hopefully [will be followed by] head-to-head studies of aerobic exercise versus resistance training to confirm the findings.”

The study received no funding. Dr. O’Driscoll and Dr. Osborne reported no relevant financial relationships.

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

Isometric exercise training emerged as the most effective mode to reduce blood pressure in a systematic review and meta-analysis of 270 randomized trials with close to 16,000 participants.

The findings support the development of new exercise guidelines for blood pressure control, the authors said.

Previous research, based on older data that excluded high-intensity interval training (HIIT) and isometric exercise training (IET), led to aerobic exercise training (AET) being recommended for managing blood pressure, according to the authors.

Although AET, HIIT, dynamic resistance training (RT), and combined training (CT) are also effective in reducing both systolic and diastolic blood pressure, the new analysis suggests that IET does it best.

The analysis showed reductions in blood pressure of 8.24/4 mm Hg after IET, compared with 4.49/2.53 mm Hg after AET; 4.55/3.04 mm Hg after RT; 6.04/2.54 mm Hg after CT; and 4.08/2.50 mm Hg after HIIT.

“These findings mirror our smaller-scale trials, and therefore we anticipated that isometrics would be largely effective,” Jamie O’Driscoll, PhD, of Canterbury (England) Christ Church University, said in an interview. However, “the magnitude of difference between isometrics and some other modes was surprising.”

The study was published online in the British Journal of Sports Medicine.
 

All modes effective

The investigators analyzed data from 270 randomized controlled trials including 15,827 people published between 1990 and February 2023. For consistency, the protocol/intensity of each included paper was screened against the Exercise Prescription in Everyday Practice and Rehabilitative Training tool to be defined and categorized.

All protocols were then stratified as AET, RT, CT, HIIT or IET.

As appropriate, protocols were then further stratified into subgroups: AET included walking, running, and cycling; HIIT included sprint interval training and aerobic interval training; and IET included isometric leg extension and isometric wall squat.

Healthy resting blood pressure was defined as a reading below 130/85 mm Hg, prehypertension as 130-139/85-89 mm Hg, and hypertension as 140/90 mm Hg or higher.

All exercise modes led to statistically significant reductions in systolic BP in normal blood pressure cohorts; however, all reductions were substantially larger in individuals with hypertension.

Pairwise analyses showed significant reductions in resting systolic BP and diastolic BP following AET (−4.49/–2.53 mm Hg); RT (–4.55/–3.04 mm Hg), CT (–6.04/–2.54 mm Hg), HIT (–4.08/–2.50 mm Hg); and IET (–8.24/–4.00 mm Hg).

In the network meta-analysis, the rank order of effectiveness for systolic BP based on surface under the cumulative ranking curve values were IET (SUCRA: 98.3%), CT (75.7%), RT (46.1%), AET (40.5%), and HIIT (39.4%).

Secondary network meta-analyses showed that isometric wall squat was the most effective submode for reducing systolic BP (90.4%), followed by isometric leg extension, isometric hand grip, cycling, running, CT, sprint interval training, other aerobic, RT, aerobic interval training, and walking.

Running was the most effective submode for lowering diastolic BP (91.3%), followed by isometric wall squat, isometric handgrip, isometric leg extension, cycling, sprint interval training, RT, AIT, other aerobic, CT, and walking.

The authors acknowledged limitations, including variability in exercise interventions, missing data, variable quality of exercise monitoring and analyses, lack of blinding to group allocation, varying participant populations, and publication bias.

Nevertheless, they concluded, “the results of this analysis should inform future exercise guideline recommendations for the prevention and treatment of arterial hypertension.”
 

Guideline changing?

“There are numerous organizations involved in providing and communicating population exercise guidelines,” including World Health Organization, American and European exercise guidelines, and the National Institute for Health and Care Excellence, Dr. O’Driscoll said. “We are currently developing an international collaborative project with other world leaders in the area to develop this line of enquiry.”

In addition, the team is exploring the prescription of IET within England’s National Health Service and extending the study to wider clinical populations.

In a comment, John A. Osborne, MD, PhD, founder and director of State of the Heart Cardiology in Southlake, Tex., said: “This study further lends credence that other forms of exercise, beyond the usually recommended aerobic exercise promulgated in prior guidelines, have significant value for blood pressure lowering, and, potentially, may offer even greater benefits for ... controlling hypertension.”

“This study should inform contemporary nonpharmacological approaches to blood pressure management and allows providers more flexibility in different strategies of exercise to combat high blood pressure,” said Dr. Osborne, a volunteer spokesperson for the American Heart Association.

That said, “while this study by itself is extremely provocative, thoughtful, and rigorously performed, it should be used as hypothesis generating and hopefully [will be followed by] head-to-head studies of aerobic exercise versus resistance training to confirm the findings.”

The study received no funding. Dr. O’Driscoll and Dr. Osborne reported no relevant financial relationships.

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

Isometric exercise training emerged as the most effective mode to reduce blood pressure in a systematic review and meta-analysis of 270 randomized trials with close to 16,000 participants.

The findings support the development of new exercise guidelines for blood pressure control, the authors said.

Previous research, based on older data that excluded high-intensity interval training (HIIT) and isometric exercise training (IET), led to aerobic exercise training (AET) being recommended for managing blood pressure, according to the authors.

Although AET, HIIT, dynamic resistance training (RT), and combined training (CT) are also effective in reducing both systolic and diastolic blood pressure, the new analysis suggests that IET does it best.

The analysis showed reductions in blood pressure of 8.24/4 mm Hg after IET, compared with 4.49/2.53 mm Hg after AET; 4.55/3.04 mm Hg after RT; 6.04/2.54 mm Hg after CT; and 4.08/2.50 mm Hg after HIIT.

“These findings mirror our smaller-scale trials, and therefore we anticipated that isometrics would be largely effective,” Jamie O’Driscoll, PhD, of Canterbury (England) Christ Church University, said in an interview. However, “the magnitude of difference between isometrics and some other modes was surprising.”

The study was published online in the British Journal of Sports Medicine.
 

All modes effective

The investigators analyzed data from 270 randomized controlled trials including 15,827 people published between 1990 and February 2023. For consistency, the protocol/intensity of each included paper was screened against the Exercise Prescription in Everyday Practice and Rehabilitative Training tool to be defined and categorized.

All protocols were then stratified as AET, RT, CT, HIIT or IET.

As appropriate, protocols were then further stratified into subgroups: AET included walking, running, and cycling; HIIT included sprint interval training and aerobic interval training; and IET included isometric leg extension and isometric wall squat.

Healthy resting blood pressure was defined as a reading below 130/85 mm Hg, prehypertension as 130-139/85-89 mm Hg, and hypertension as 140/90 mm Hg or higher.

All exercise modes led to statistically significant reductions in systolic BP in normal blood pressure cohorts; however, all reductions were substantially larger in individuals with hypertension.

Pairwise analyses showed significant reductions in resting systolic BP and diastolic BP following AET (−4.49/–2.53 mm Hg); RT (–4.55/–3.04 mm Hg), CT (–6.04/–2.54 mm Hg), HIT (–4.08/–2.50 mm Hg); and IET (–8.24/–4.00 mm Hg).

In the network meta-analysis, the rank order of effectiveness for systolic BP based on surface under the cumulative ranking curve values were IET (SUCRA: 98.3%), CT (75.7%), RT (46.1%), AET (40.5%), and HIIT (39.4%).

Secondary network meta-analyses showed that isometric wall squat was the most effective submode for reducing systolic BP (90.4%), followed by isometric leg extension, isometric hand grip, cycling, running, CT, sprint interval training, other aerobic, RT, aerobic interval training, and walking.

Running was the most effective submode for lowering diastolic BP (91.3%), followed by isometric wall squat, isometric handgrip, isometric leg extension, cycling, sprint interval training, RT, AIT, other aerobic, CT, and walking.

The authors acknowledged limitations, including variability in exercise interventions, missing data, variable quality of exercise monitoring and analyses, lack of blinding to group allocation, varying participant populations, and publication bias.

Nevertheless, they concluded, “the results of this analysis should inform future exercise guideline recommendations for the prevention and treatment of arterial hypertension.”
 

Guideline changing?

“There are numerous organizations involved in providing and communicating population exercise guidelines,” including World Health Organization, American and European exercise guidelines, and the National Institute for Health and Care Excellence, Dr. O’Driscoll said. “We are currently developing an international collaborative project with other world leaders in the area to develop this line of enquiry.”

In addition, the team is exploring the prescription of IET within England’s National Health Service and extending the study to wider clinical populations.

In a comment, John A. Osborne, MD, PhD, founder and director of State of the Heart Cardiology in Southlake, Tex., said: “This study further lends credence that other forms of exercise, beyond the usually recommended aerobic exercise promulgated in prior guidelines, have significant value for blood pressure lowering, and, potentially, may offer even greater benefits for ... controlling hypertension.”

“This study should inform contemporary nonpharmacological approaches to blood pressure management and allows providers more flexibility in different strategies of exercise to combat high blood pressure,” said Dr. Osborne, a volunteer spokesperson for the American Heart Association.

That said, “while this study by itself is extremely provocative, thoughtful, and rigorously performed, it should be used as hypothesis generating and hopefully [will be followed by] head-to-head studies of aerobic exercise versus resistance training to confirm the findings.”

The study received no funding. Dr. O’Driscoll and Dr. Osborne reported no relevant financial relationships.

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

Young people diagnosed with a genetic heart disease (GHD) predisposing them to ventricular arrhythmia are at very low risk for a cardiac event while playing video games or other electronic games, provided their condition is properly treated, say researchers based on their large, single-center study.

Among more than 3,000 patients in the study with such a genetic vulnerability, just 6 – or less than 0.2% – experienced an electronic gaming–associated cardiac event.

A previous study had concluded that e-gaming, particularly with war games, might trigger potentially fatal arrhythmias in some vulnerable children. That study “sparked controversy in the field, with both clinicians and patients wondering whether electronic gaming is safe for patients with GHDs,” Michael J. Ackerman, MD, PhD, of Mayo Clinic in Rochester, Minn., said in an interview.

Dr. Ackerman and colleagues conducted the current study, published online in the Journal of the American College of Cardiology, to determine just how often e-gaming triggered cardiac events (CE) in these patients – and who was most at risk.
 

‘Extremely low’ risk

The investigators looked at records from all patients evaluated and treated at the Mayo Clinic’s genetic heart rhythm clinic from 2000 to 2022. They identified those with a history of playing electronic games at the time of their CE, defined here as such an event occurring before diagnosis, or breakthrough cardiac event (BCE), meaning an event occurring after diagnosis.

A total of 3,370 patients with a GHD (55% female) were included in the analysis. More than half (52%) were diagnosed with long-QT syndrome (LQTS). The remainder had various GHDs including, among others, catecholaminergic polymorphic ventricular tachycardia (CPVT) or hypertrophic cardiomyopathy (HCM).

The mean age at first evaluation was 27; 14% of the participants were age 6 or younger, 33% were age 7-20, and 53% were 21 or older. Most patients in each of the three age groups were diagnosed with either LQTS or CPVT.

Of the 3,370 GHD patients, 1,079 (32%) had a CE before diagnosis.

Six patients (0.5%) had a CE in the setting of e-gaming, including five for whom it was the sentinel CE. Five also had CEs in settings not involving e-gaming. Their average age at the time of the CE was 13.

Three of the six patients were diagnosed with CPVT (including two CPVT1 and one CPVT2). Of the others, one was diagnosed with LQT1, one with ventricular fibrillation triggered by premature ventricular contractions, and one with catecholamine-sensitive right ventricular outflow tract ventricular tachycardia (RVOT-VT).

After appropriate treatment, none of the six experienced a BCE during follow-ups ranging from 7 months to 4 years.

Among the full cohort of 3370 patients with GHD, 431 (13%) experienced one or more BCE during follow-up. Of those, one with catecholamine-sensitive RVOT-VT experienced an e-gaming–associated BCE.

“Although anecdotal e-gaming–associated cardiac events, including [sudden cardiac death], have been reported, the absolute risk is extremely low,” the authors wrote.

“Although there are no clear health benefits associated with e-gaming,” Dr. Ackerman said, “the risk of sudden death should not be used as an argument in an effort to curtail the amount of time patients spend e-gaming.”

Furthermore, he added, e-gaming is important to some patients’ quality of life. If patients are “properly diagnosed, risk stratified, and treated, it is okay to engage in e-gaming.”

However, “given that e-gaming may pose some risks, especially when compounded with additional factors such as dehydration, sleep deprivation, and use of performance-enhancing substances such as energy drinks, patients need to be counseled on the potential adverse health consequences,” Dr. Ackerman said.

“To this end,” he added, “we are proponents of incorporating e-gaming status into the clinical evaluation and electronic health record.”

“We would continue to urge common sense and individual risk assessment, with shared decision-making, for those where this may be an issue,” Claire M. Lawley, MBBS, PhD, Children’s Hospital at Westmead (Australia), said in an interview.

“Additionally, syncope during electronic gaming should prompt medical review,” said Dr. Lawley, lead author of the study that prompted Ackerman and colleagues to investigate the issue further.
 

Buddy system

Maully J. Shah, MBBS, led a study published in 2020 focusing on two case reports of syncope and potentially life-threatening ventricular arrhythmias provoked by emotional surges during play with violent video games. 

Nevertheless, “we do not restrict patients from participating in e-games,” Dr. Shah, a pediatric cardiac electrophysiologist at the Cardiac Center at Children’s Hospital of Philadelphia, said in an interview. “We inform them about the available data regarding the very rare but possible occurrence of an event from e-gaming so that they can make an informed decision.”

Dr. Shah agreed that, “even in children not known to have a cardiac condition, syncope associated with emotional responses during violent video games should prompt cardiac evaluation, similar to exercise-induced syncope.”

If a patient wishes to play e-games, clinicians should ensure medication compliance and recommend a “buddy” system. “Don’t be alone while playing,” she said.

“The present study and previous reports make one pause to think whether these CEs and catecholaminergic drives can occur with sports only. If we now consider electronic gaming as a potential risk, what other activities need to be included?” wrote the authors of an accompanying editorial, led by Shankar Baskar, MD, Cincinnati Children’s Medical Center.

“A catecholaminergic drive can occur in many settings with activities of daily living or activities not considered to be competitive,” the editorialists wrote. “Ultimately these events [are] rare, but they can have life-threatening consequences, and at the same time they might not be altogether preventable and, as in electronic gaming, might be an activity that improves quality of life, especially in those who might be restricted from other sports.”

Dr. Ackerman disclosed consulting for Abbott, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Invitae, Medtronic, Tenaya Therapeutics, and UpToDate. Dr. Ackerman and the Mayo Clinic have license agreements with AliveCor, Anumana, ARMGO Pharma, Pfizer, and Thryv Therapeutics. The other coauthors reported no relevant relationships. Dr. Baskar and colleagues reported no relevant relationships. Dr. Shah disclosed she is a consultant to Medtronic.

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

Young people diagnosed with a genetic heart disease (GHD) predisposing them to ventricular arrhythmia are at very low risk for a cardiac event while playing video games or other electronic games, provided their condition is properly treated, say researchers based on their large, single-center study.

Among more than 3,000 patients in the study with such a genetic vulnerability, just 6 – or less than 0.2% – experienced an electronic gaming–associated cardiac event.

A previous study had concluded that e-gaming, particularly with war games, might trigger potentially fatal arrhythmias in some vulnerable children. That study “sparked controversy in the field, with both clinicians and patients wondering whether electronic gaming is safe for patients with GHDs,” Michael J. Ackerman, MD, PhD, of Mayo Clinic in Rochester, Minn., said in an interview.

Dr. Ackerman and colleagues conducted the current study, published online in the Journal of the American College of Cardiology, to determine just how often e-gaming triggered cardiac events (CE) in these patients – and who was most at risk.
 

‘Extremely low’ risk

The investigators looked at records from all patients evaluated and treated at the Mayo Clinic’s genetic heart rhythm clinic from 2000 to 2022. They identified those with a history of playing electronic games at the time of their CE, defined here as such an event occurring before diagnosis, or breakthrough cardiac event (BCE), meaning an event occurring after diagnosis.

A total of 3,370 patients with a GHD (55% female) were included in the analysis. More than half (52%) were diagnosed with long-QT syndrome (LQTS). The remainder had various GHDs including, among others, catecholaminergic polymorphic ventricular tachycardia (CPVT) or hypertrophic cardiomyopathy (HCM).

The mean age at first evaluation was 27; 14% of the participants were age 6 or younger, 33% were age 7-20, and 53% were 21 or older. Most patients in each of the three age groups were diagnosed with either LQTS or CPVT.

Of the 3,370 GHD patients, 1,079 (32%) had a CE before diagnosis.

Six patients (0.5%) had a CE in the setting of e-gaming, including five for whom it was the sentinel CE. Five also had CEs in settings not involving e-gaming. Their average age at the time of the CE was 13.

Three of the six patients were diagnosed with CPVT (including two CPVT1 and one CPVT2). Of the others, one was diagnosed with LQT1, one with ventricular fibrillation triggered by premature ventricular contractions, and one with catecholamine-sensitive right ventricular outflow tract ventricular tachycardia (RVOT-VT).

After appropriate treatment, none of the six experienced a BCE during follow-ups ranging from 7 months to 4 years.

Among the full cohort of 3370 patients with GHD, 431 (13%) experienced one or more BCE during follow-up. Of those, one with catecholamine-sensitive RVOT-VT experienced an e-gaming–associated BCE.

“Although anecdotal e-gaming–associated cardiac events, including [sudden cardiac death], have been reported, the absolute risk is extremely low,” the authors wrote.

“Although there are no clear health benefits associated with e-gaming,” Dr. Ackerman said, “the risk of sudden death should not be used as an argument in an effort to curtail the amount of time patients spend e-gaming.”

Furthermore, he added, e-gaming is important to some patients’ quality of life. If patients are “properly diagnosed, risk stratified, and treated, it is okay to engage in e-gaming.”

However, “given that e-gaming may pose some risks, especially when compounded with additional factors such as dehydration, sleep deprivation, and use of performance-enhancing substances such as energy drinks, patients need to be counseled on the potential adverse health consequences,” Dr. Ackerman said.

“To this end,” he added, “we are proponents of incorporating e-gaming status into the clinical evaluation and electronic health record.”

“We would continue to urge common sense and individual risk assessment, with shared decision-making, for those where this may be an issue,” Claire M. Lawley, MBBS, PhD, Children’s Hospital at Westmead (Australia), said in an interview.

“Additionally, syncope during electronic gaming should prompt medical review,” said Dr. Lawley, lead author of the study that prompted Ackerman and colleagues to investigate the issue further.
 

Buddy system

Maully J. Shah, MBBS, led a study published in 2020 focusing on two case reports of syncope and potentially life-threatening ventricular arrhythmias provoked by emotional surges during play with violent video games. 

Nevertheless, “we do not restrict patients from participating in e-games,” Dr. Shah, a pediatric cardiac electrophysiologist at the Cardiac Center at Children’s Hospital of Philadelphia, said in an interview. “We inform them about the available data regarding the very rare but possible occurrence of an event from e-gaming so that they can make an informed decision.”

Dr. Shah agreed that, “even in children not known to have a cardiac condition, syncope associated with emotional responses during violent video games should prompt cardiac evaluation, similar to exercise-induced syncope.”

If a patient wishes to play e-games, clinicians should ensure medication compliance and recommend a “buddy” system. “Don’t be alone while playing,” she said.

“The present study and previous reports make one pause to think whether these CEs and catecholaminergic drives can occur with sports only. If we now consider electronic gaming as a potential risk, what other activities need to be included?” wrote the authors of an accompanying editorial, led by Shankar Baskar, MD, Cincinnati Children’s Medical Center.

“A catecholaminergic drive can occur in many settings with activities of daily living or activities not considered to be competitive,” the editorialists wrote. “Ultimately these events [are] rare, but they can have life-threatening consequences, and at the same time they might not be altogether preventable and, as in electronic gaming, might be an activity that improves quality of life, especially in those who might be restricted from other sports.”

Dr. Ackerman disclosed consulting for Abbott, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Invitae, Medtronic, Tenaya Therapeutics, and UpToDate. Dr. Ackerman and the Mayo Clinic have license agreements with AliveCor, Anumana, ARMGO Pharma, Pfizer, and Thryv Therapeutics. The other coauthors reported no relevant relationships. Dr. Baskar and colleagues reported no relevant relationships. Dr. Shah disclosed she is a consultant to Medtronic.

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

Young people diagnosed with a genetic heart disease (GHD) predisposing them to ventricular arrhythmia are at very low risk for a cardiac event while playing video games or other electronic games, provided their condition is properly treated, say researchers based on their large, single-center study.

Among more than 3,000 patients in the study with such a genetic vulnerability, just 6 – or less than 0.2% – experienced an electronic gaming–associated cardiac event.

A previous study had concluded that e-gaming, particularly with war games, might trigger potentially fatal arrhythmias in some vulnerable children. That study “sparked controversy in the field, with both clinicians and patients wondering whether electronic gaming is safe for patients with GHDs,” Michael J. Ackerman, MD, PhD, of Mayo Clinic in Rochester, Minn., said in an interview.

Dr. Ackerman and colleagues conducted the current study, published online in the Journal of the American College of Cardiology, to determine just how often e-gaming triggered cardiac events (CE) in these patients – and who was most at risk.
 

‘Extremely low’ risk

The investigators looked at records from all patients evaluated and treated at the Mayo Clinic’s genetic heart rhythm clinic from 2000 to 2022. They identified those with a history of playing electronic games at the time of their CE, defined here as such an event occurring before diagnosis, or breakthrough cardiac event (BCE), meaning an event occurring after diagnosis.

A total of 3,370 patients with a GHD (55% female) were included in the analysis. More than half (52%) were diagnosed with long-QT syndrome (LQTS). The remainder had various GHDs including, among others, catecholaminergic polymorphic ventricular tachycardia (CPVT) or hypertrophic cardiomyopathy (HCM).

The mean age at first evaluation was 27; 14% of the participants were age 6 or younger, 33% were age 7-20, and 53% were 21 or older. Most patients in each of the three age groups were diagnosed with either LQTS or CPVT.

Of the 3,370 GHD patients, 1,079 (32%) had a CE before diagnosis.

Six patients (0.5%) had a CE in the setting of e-gaming, including five for whom it was the sentinel CE. Five also had CEs in settings not involving e-gaming. Their average age at the time of the CE was 13.

Three of the six patients were diagnosed with CPVT (including two CPVT1 and one CPVT2). Of the others, one was diagnosed with LQT1, one with ventricular fibrillation triggered by premature ventricular contractions, and one with catecholamine-sensitive right ventricular outflow tract ventricular tachycardia (RVOT-VT).

After appropriate treatment, none of the six experienced a BCE during follow-ups ranging from 7 months to 4 years.

Among the full cohort of 3370 patients with GHD, 431 (13%) experienced one or more BCE during follow-up. Of those, one with catecholamine-sensitive RVOT-VT experienced an e-gaming–associated BCE.

“Although anecdotal e-gaming–associated cardiac events, including [sudden cardiac death], have been reported, the absolute risk is extremely low,” the authors wrote.

“Although there are no clear health benefits associated with e-gaming,” Dr. Ackerman said, “the risk of sudden death should not be used as an argument in an effort to curtail the amount of time patients spend e-gaming.”

Furthermore, he added, e-gaming is important to some patients’ quality of life. If patients are “properly diagnosed, risk stratified, and treated, it is okay to engage in e-gaming.”

However, “given that e-gaming may pose some risks, especially when compounded with additional factors such as dehydration, sleep deprivation, and use of performance-enhancing substances such as energy drinks, patients need to be counseled on the potential adverse health consequences,” Dr. Ackerman said.

“To this end,” he added, “we are proponents of incorporating e-gaming status into the clinical evaluation and electronic health record.”

“We would continue to urge common sense and individual risk assessment, with shared decision-making, for those where this may be an issue,” Claire M. Lawley, MBBS, PhD, Children’s Hospital at Westmead (Australia), said in an interview.

“Additionally, syncope during electronic gaming should prompt medical review,” said Dr. Lawley, lead author of the study that prompted Ackerman and colleagues to investigate the issue further.
 

Buddy system

Maully J. Shah, MBBS, led a study published in 2020 focusing on two case reports of syncope and potentially life-threatening ventricular arrhythmias provoked by emotional surges during play with violent video games. 

Nevertheless, “we do not restrict patients from participating in e-games,” Dr. Shah, a pediatric cardiac electrophysiologist at the Cardiac Center at Children’s Hospital of Philadelphia, said in an interview. “We inform them about the available data regarding the very rare but possible occurrence of an event from e-gaming so that they can make an informed decision.”

Dr. Shah agreed that, “even in children not known to have a cardiac condition, syncope associated with emotional responses during violent video games should prompt cardiac evaluation, similar to exercise-induced syncope.”

If a patient wishes to play e-games, clinicians should ensure medication compliance and recommend a “buddy” system. “Don’t be alone while playing,” she said.

“The present study and previous reports make one pause to think whether these CEs and catecholaminergic drives can occur with sports only. If we now consider electronic gaming as a potential risk, what other activities need to be included?” wrote the authors of an accompanying editorial, led by Shankar Baskar, MD, Cincinnati Children’s Medical Center.

“A catecholaminergic drive can occur in many settings with activities of daily living or activities not considered to be competitive,” the editorialists wrote. “Ultimately these events [are] rare, but they can have life-threatening consequences, and at the same time they might not be altogether preventable and, as in electronic gaming, might be an activity that improves quality of life, especially in those who might be restricted from other sports.”

Dr. Ackerman disclosed consulting for Abbott, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Invitae, Medtronic, Tenaya Therapeutics, and UpToDate. Dr. Ackerman and the Mayo Clinic have license agreements with AliveCor, Anumana, ARMGO Pharma, Pfizer, and Thryv Therapeutics. The other coauthors reported no relevant relationships. Dr. Baskar and colleagues reported no relevant relationships. Dr. Shah disclosed she is a consultant to Medtronic.

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

As with porridge, so with blood pressure: Just right makes all the difference.

Ill-fitting blood pressure measurement cuffs produce erroneous readings that impair hypertension treatment, according to research published in JAMA Internal Medicine.

People whose mid-upper arm circumference exceeds 32 cm require larger cuffs than the standard size, but in many cases the regular-sized cuff is used on everyone. As a result, patients with larger arms may be falsely diagnosed with high blood pressure because of a too-small cuff, leading to overprescribing of medications that could make their health worse, according to the researchers.  

“A person whose blood pressure is 120/80, which is normal – if they’re using the wrong cuff, they could get a measurement that says 140/90, let’s say,” said study author Tammy M. Brady, MD, PhD, vice chair for clinical research in the department of pediatrics at Johns Hopkins University, Baltimore. “They might think they not only have hypertension, but stage 2 hypertension. Providers might give one or even two medicines to lower this, which could lead to hypotension,” Dr. Brady said.

Conversely, someone with smaller arms whose cuff is too big may present with an artificially low blood pressure. The implications of using ill-fitting cuffs are well known. Dr. Brady, among others, has studied the topic extensively. Even so, she said the measurement errors in the latest study were larger than expected.
 

The Goldilocks test

People with an arm circumference of 20-25 cm should use a smaller cuff than the regular size, Dr. Brady and colleagues reported. Circumferences of 25.1-32 cm require a regular-sized cuff; large cuffs are for circumferences of 32.1-40 cm; and extra-large cuffs should be used at 40.1-55 cm.

The study included 195 residents of Baltimore (128 women, 67 men; 132 Black, 58 White, 5 Hispanic) with an average age of 54 years. The researchers measured every participant’s blood pressure using an automated device on four occasions, taking three measurements each time.

The first three sets of measurements used, respectively, an appropriate cuff size for each person’s arm circumference; a cuff that was too big; and a cuff that was too small. This study design ensured that a regular-sized cuff would be used during one of the three measurements – sometimes that cuff was too small, sometimes it was appropriate, and other times it was too big.

The final set of three measurements used the appropriate cuff size for a person’s arm every time. Dr. Brady and colleagues then compared people’s blood pressure measurements when using the right-sized cuff to measurements with a regular-sized cuff that was not suited for them.

They found that using a cuff that was too large for the patient’s arm (i.e., using a regular cuff when a small cuff was the right choice) led to understating systolic blood pressure by –3.6 mm Hg (95% confidence interval [CI], –5.6 to –1.7). A cuff that was one size too small – using regular instead of a large – overestimated systolic blood pressure by 4.8 (3.0-6.6) mm Hg. And a cuff that was two sizes too small – someone who should have received an extra-large cuff but received the regular size – overestimated systolic blood pressure by 19.5 (16.1-22.9) mm Hg. All differences were statistically significant, the researchers reported.

“To our knowledge, this is the first randomized cross-over trial to examine the effect of miscuffing on automated blood pressure readings,” Mathias Lalika, MD, MPH, of the Mayo Clinic in Rochester, Minn.; Stephen P. Juraschek, MD, PhD, of Beth Israel Deaconess Medical Center in Boston; and LaPrincess C. Brewer, MD, MPH, of the Mayo Clinic, wrote in an editorial accompanying the journal article.

“Interestingly, the degree of underestimation or overestimation increased as the appropriate cuff size progressed from the regular to extra-large BP cuff. More importantly, the effect of miscuffing did not vary with BP or obesity status,” they wrote.

“This was more of a pragmatic trial to see real world, all comers,” Dr. Brady said, when regular-sized cuffs are used whether or not that made sense.

“This study reaffirms findings of previous studies and highlights a major source of error in blood pressure measurement,” Raj Padwal, MD, director of the University of Alberta Hypertension Clinic, Edmonton, Alta., said in an interview. Dr. Padwal, who was not involved in the study, said the findings highlight the importance of ensuring that technicians who typically measure blood pressure understand the value of using the right-sized cuff.

Dr. Brady noted that measuring arm circumference takes about 15 seconds. He advised health organizations and clinics to carry multiple cuffs sizes to avoid a scramble to find a right-sized cuff. In the editorial, Dr. Lalika, Dr. Juraschek, and Dr. Brewer call for particular attention to providing the right-sized cuffs to facilities that work with underserved populations, such as federally qualified health centers.

Dr. Padwal added that even a perfectly measured blood pressure test at a clinic indicates pressure at a moment in time. Ten minutes later the story could be different. For this reason, he and other clinicians recommend frequent home blood pressure measurements rather than relying solely on the sparse number of readings collected in the clinic setting.

“A properly educated patient can give many readings that are separated in space and time and, when averaged, can give a much better picture of overall blood pressure and future risk,” Dr. Padwal said. 

Dr. Brady agreed with the value of home readings but said home-based readings also can be erroneous if the patient uses a cuff that is the wrong size. She cochairs a committee for the American Medical Association that recommends validated home blood pressure measurement devices on a periodically updated website called Validate BP. The details for each device listing show the cuff sizes available per device. Many devices provide only the standard cuff, Dr. Brady noted, but some offer multiple cuff sizes.

“One of the things that would be great if it came out of this paper is if patients were empowered to ask physicians to measure their arm” and then use that information to select the appropriate cuff for their home device, she said.

Dr. Brady and Dr. Padwal reported no relevant financial relationships. This study was supported by Resolve to Save Lives, which is funded by Bloomberg Philanthropies, the Bill & Melinda Gates Foundation, and Gates Philanthropy Partners, which is funded with support from the Chan Zuckerberg Foundation.

A version of this article appeared on Medscape.com.

As with porridge, so with blood pressure: Just right makes all the difference.

Ill-fitting blood pressure measurement cuffs produce erroneous readings that impair hypertension treatment, according to research published in JAMA Internal Medicine.

People whose mid-upper arm circumference exceeds 32 cm require larger cuffs than the standard size, but in many cases the regular-sized cuff is used on everyone. As a result, patients with larger arms may be falsely diagnosed with high blood pressure because of a too-small cuff, leading to overprescribing of medications that could make their health worse, according to the researchers.  

“A person whose blood pressure is 120/80, which is normal – if they’re using the wrong cuff, they could get a measurement that says 140/90, let’s say,” said study author Tammy M. Brady, MD, PhD, vice chair for clinical research in the department of pediatrics at Johns Hopkins University, Baltimore. “They might think they not only have hypertension, but stage 2 hypertension. Providers might give one or even two medicines to lower this, which could lead to hypotension,” Dr. Brady said.

Conversely, someone with smaller arms whose cuff is too big may present with an artificially low blood pressure. The implications of using ill-fitting cuffs are well known. Dr. Brady, among others, has studied the topic extensively. Even so, she said the measurement errors in the latest study were larger than expected.
 

The Goldilocks test

People with an arm circumference of 20-25 cm should use a smaller cuff than the regular size, Dr. Brady and colleagues reported. Circumferences of 25.1-32 cm require a regular-sized cuff; large cuffs are for circumferences of 32.1-40 cm; and extra-large cuffs should be used at 40.1-55 cm.

The study included 195 residents of Baltimore (128 women, 67 men; 132 Black, 58 White, 5 Hispanic) with an average age of 54 years. The researchers measured every participant’s blood pressure using an automated device on four occasions, taking three measurements each time.

The first three sets of measurements used, respectively, an appropriate cuff size for each person’s arm circumference; a cuff that was too big; and a cuff that was too small. This study design ensured that a regular-sized cuff would be used during one of the three measurements – sometimes that cuff was too small, sometimes it was appropriate, and other times it was too big.

The final set of three measurements used the appropriate cuff size for a person’s arm every time. Dr. Brady and colleagues then compared people’s blood pressure measurements when using the right-sized cuff to measurements with a regular-sized cuff that was not suited for them.

They found that using a cuff that was too large for the patient’s arm (i.e., using a regular cuff when a small cuff was the right choice) led to understating systolic blood pressure by –3.6 mm Hg (95% confidence interval [CI], –5.6 to –1.7). A cuff that was one size too small – using regular instead of a large – overestimated systolic blood pressure by 4.8 (3.0-6.6) mm Hg. And a cuff that was two sizes too small – someone who should have received an extra-large cuff but received the regular size – overestimated systolic blood pressure by 19.5 (16.1-22.9) mm Hg. All differences were statistically significant, the researchers reported.

“To our knowledge, this is the first randomized cross-over trial to examine the effect of miscuffing on automated blood pressure readings,” Mathias Lalika, MD, MPH, of the Mayo Clinic in Rochester, Minn.; Stephen P. Juraschek, MD, PhD, of Beth Israel Deaconess Medical Center in Boston; and LaPrincess C. Brewer, MD, MPH, of the Mayo Clinic, wrote in an editorial accompanying the journal article.

“Interestingly, the degree of underestimation or overestimation increased as the appropriate cuff size progressed from the regular to extra-large BP cuff. More importantly, the effect of miscuffing did not vary with BP or obesity status,” they wrote.

“This was more of a pragmatic trial to see real world, all comers,” Dr. Brady said, when regular-sized cuffs are used whether or not that made sense.

“This study reaffirms findings of previous studies and highlights a major source of error in blood pressure measurement,” Raj Padwal, MD, director of the University of Alberta Hypertension Clinic, Edmonton, Alta., said in an interview. Dr. Padwal, who was not involved in the study, said the findings highlight the importance of ensuring that technicians who typically measure blood pressure understand the value of using the right-sized cuff.

Dr. Brady noted that measuring arm circumference takes about 15 seconds. He advised health organizations and clinics to carry multiple cuffs sizes to avoid a scramble to find a right-sized cuff. In the editorial, Dr. Lalika, Dr. Juraschek, and Dr. Brewer call for particular attention to providing the right-sized cuffs to facilities that work with underserved populations, such as federally qualified health centers.

Dr. Padwal added that even a perfectly measured blood pressure test at a clinic indicates pressure at a moment in time. Ten minutes later the story could be different. For this reason, he and other clinicians recommend frequent home blood pressure measurements rather than relying solely on the sparse number of readings collected in the clinic setting.

“A properly educated patient can give many readings that are separated in space and time and, when averaged, can give a much better picture of overall blood pressure and future risk,” Dr. Padwal said. 

Dr. Brady agreed with the value of home readings but said home-based readings also can be erroneous if the patient uses a cuff that is the wrong size. She cochairs a committee for the American Medical Association that recommends validated home blood pressure measurement devices on a periodically updated website called Validate BP. The details for each device listing show the cuff sizes available per device. Many devices provide only the standard cuff, Dr. Brady noted, but some offer multiple cuff sizes.

“One of the things that would be great if it came out of this paper is if patients were empowered to ask physicians to measure their arm” and then use that information to select the appropriate cuff for their home device, she said.

Dr. Brady and Dr. Padwal reported no relevant financial relationships. This study was supported by Resolve to Save Lives, which is funded by Bloomberg Philanthropies, the Bill & Melinda Gates Foundation, and Gates Philanthropy Partners, which is funded with support from the Chan Zuckerberg Foundation.

A version of this article appeared on Medscape.com.

As with porridge, so with blood pressure: Just right makes all the difference.

Ill-fitting blood pressure measurement cuffs produce erroneous readings that impair hypertension treatment, according to research published in JAMA Internal Medicine.

People whose mid-upper arm circumference exceeds 32 cm require larger cuffs than the standard size, but in many cases the regular-sized cuff is used on everyone. As a result, patients with larger arms may be falsely diagnosed with high blood pressure because of a too-small cuff, leading to overprescribing of medications that could make their health worse, according to the researchers.  

“A person whose blood pressure is 120/80, which is normal – if they’re using the wrong cuff, they could get a measurement that says 140/90, let’s say,” said study author Tammy M. Brady, MD, PhD, vice chair for clinical research in the department of pediatrics at Johns Hopkins University, Baltimore. “They might think they not only have hypertension, but stage 2 hypertension. Providers might give one or even two medicines to lower this, which could lead to hypotension,” Dr. Brady said.

Conversely, someone with smaller arms whose cuff is too big may present with an artificially low blood pressure. The implications of using ill-fitting cuffs are well known. Dr. Brady, among others, has studied the topic extensively. Even so, she said the measurement errors in the latest study were larger than expected.
 

The Goldilocks test

People with an arm circumference of 20-25 cm should use a smaller cuff than the regular size, Dr. Brady and colleagues reported. Circumferences of 25.1-32 cm require a regular-sized cuff; large cuffs are for circumferences of 32.1-40 cm; and extra-large cuffs should be used at 40.1-55 cm.

The study included 195 residents of Baltimore (128 women, 67 men; 132 Black, 58 White, 5 Hispanic) with an average age of 54 years. The researchers measured every participant’s blood pressure using an automated device on four occasions, taking three measurements each time.

The first three sets of measurements used, respectively, an appropriate cuff size for each person’s arm circumference; a cuff that was too big; and a cuff that was too small. This study design ensured that a regular-sized cuff would be used during one of the three measurements – sometimes that cuff was too small, sometimes it was appropriate, and other times it was too big.

The final set of three measurements used the appropriate cuff size for a person’s arm every time. Dr. Brady and colleagues then compared people’s blood pressure measurements when using the right-sized cuff to measurements with a regular-sized cuff that was not suited for them.

They found that using a cuff that was too large for the patient’s arm (i.e., using a regular cuff when a small cuff was the right choice) led to understating systolic blood pressure by –3.6 mm Hg (95% confidence interval [CI], –5.6 to –1.7). A cuff that was one size too small – using regular instead of a large – overestimated systolic blood pressure by 4.8 (3.0-6.6) mm Hg. And a cuff that was two sizes too small – someone who should have received an extra-large cuff but received the regular size – overestimated systolic blood pressure by 19.5 (16.1-22.9) mm Hg. All differences were statistically significant, the researchers reported.

“To our knowledge, this is the first randomized cross-over trial to examine the effect of miscuffing on automated blood pressure readings,” Mathias Lalika, MD, MPH, of the Mayo Clinic in Rochester, Minn.; Stephen P. Juraschek, MD, PhD, of Beth Israel Deaconess Medical Center in Boston; and LaPrincess C. Brewer, MD, MPH, of the Mayo Clinic, wrote in an editorial accompanying the journal article.

“Interestingly, the degree of underestimation or overestimation increased as the appropriate cuff size progressed from the regular to extra-large BP cuff. More importantly, the effect of miscuffing did not vary with BP or obesity status,” they wrote.

“This was more of a pragmatic trial to see real world, all comers,” Dr. Brady said, when regular-sized cuffs are used whether or not that made sense.

“This study reaffirms findings of previous studies and highlights a major source of error in blood pressure measurement,” Raj Padwal, MD, director of the University of Alberta Hypertension Clinic, Edmonton, Alta., said in an interview. Dr. Padwal, who was not involved in the study, said the findings highlight the importance of ensuring that technicians who typically measure blood pressure understand the value of using the right-sized cuff.

Dr. Brady noted that measuring arm circumference takes about 15 seconds. He advised health organizations and clinics to carry multiple cuffs sizes to avoid a scramble to find a right-sized cuff. In the editorial, Dr. Lalika, Dr. Juraschek, and Dr. Brewer call for particular attention to providing the right-sized cuffs to facilities that work with underserved populations, such as federally qualified health centers.

Dr. Padwal added that even a perfectly measured blood pressure test at a clinic indicates pressure at a moment in time. Ten minutes later the story could be different. For this reason, he and other clinicians recommend frequent home blood pressure measurements rather than relying solely on the sparse number of readings collected in the clinic setting.

“A properly educated patient can give many readings that are separated in space and time and, when averaged, can give a much better picture of overall blood pressure and future risk,” Dr. Padwal said. 

Dr. Brady agreed with the value of home readings but said home-based readings also can be erroneous if the patient uses a cuff that is the wrong size. She cochairs a committee for the American Medical Association that recommends validated home blood pressure measurement devices on a periodically updated website called Validate BP. The details for each device listing show the cuff sizes available per device. Many devices provide only the standard cuff, Dr. Brady noted, but some offer multiple cuff sizes.

“One of the things that would be great if it came out of this paper is if patients were empowered to ask physicians to measure their arm” and then use that information to select the appropriate cuff for their home device, she said.

Dr. Brady and Dr. Padwal reported no relevant financial relationships. This study was supported by Resolve to Save Lives, which is funded by Bloomberg Philanthropies, the Bill & Melinda Gates Foundation, and Gates Philanthropy Partners, which is funded with support from the Chan Zuckerberg Foundation.

A version of this article appeared on Medscape.com.

A daily prednisolone dose of 5 mg or higher is associated with increased risk for major adverse cardiovascular events (MACE) among patients with rheumatoid arthritis (RA), data suggest. Patients taking daily doses below this threshold did not appear to have an increased risk of MACE, compared with those not taking glucocorticoids (GCs).

Chinese University of Hong Kong

Is there a ‘safe’ dose for glucocorticoids?

To analyze this relationship, Dr. Lam and colleagues used the Hospital Authority Data Collaboration Laboratory, a citywide health care database. The investigators recruited patients with RA who had no history of MACE from 2006 to 2015 and followed them until the end of 2018. The primary outcome was the first occurrence of a MACE, defined as a composite of myocardial infarction (MI), unstable angina, ischemic or hemorrhagic cerebrovascular accident, transient ischemic attack, and CV death.

The study was published in Annals of the Rheumatic Diseases.

The analysis included 12,233 patients with RA and had over 105,826 person-years of follow-up. The average follow-up time was 8.7 years. During the study period, 860 patients had their first MACE. After controlling for confounding factors, a daily prednisolone dose of 5 mg or higher doubled the risk for MACE, compared with GC nonusers. MACE risk increased by 7% per month.

University of Wisconsin School of Medicine and Public Health

Long-term glucocorticoid use discouraged

Daily doses of less than 5 mg were not associated with higher MACE risk, but more research is necessary to understand whether these low doses are clinically efficacious, Dr. Tam said. “The study results suggest that a very-low-dose GC (less than 5 mg prednisolone daily) may be cardiovascular risk–neutral. However, further evaluation is needed to determine whether this dose is therapeutic. Other potential side effects, such as bone loss, increased infection risk, dyslipidemia, and hyperglycemia, should also be considered.”

Both the American College of Rheumatology and the European Alliance of Associations for Rheumatology acknowledge that short-term GCs may be necessary for some RA patients, but they emphasize using the smallest necessary dose for the shortest period possible because of the known toxicity of GCs.

“We recommend stopping GCs as soon as it is clinically feasible, in line with previous recommendations, until these issues are investigated further,” Dr. Tam added.

Dr. Bartels agreed that long-term use of GCs should be avoided if possible, even at lower doses, because although CV risk may be less of an issue, studies have shown an increased risk for infection even at GC doses of less than 5 mg a day.
 

How might risk increase with dose?

While the study showed a distinct difference in risk with doses of prednisolone higher and lower than 5 mg, more information on how risk increases with dose could be useful, said Beth Wallace, MD, an assistant professor in internal medicine at the University of Michigan, Ann Arbor, and a staff rheumatologist at the VA Ann Arbor Healthcare Center. She was also unaffiliated with the research. “If someone is on 5-10 mg ... how much better is that than being on 10-20 mg or being on 20-30 mg?” she asked. While these study findings are “very important,” she said, it would be useful to know the risk associated with 7.5 mg vs. a higher dose.

University of Michigan

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

A daily prednisolone dose of 5 mg or higher is associated with increased risk for major adverse cardiovascular events (MACE) among patients with rheumatoid arthritis (RA), data suggest. Patients taking daily doses below this threshold did not appear to have an increased risk of MACE, compared with those not taking glucocorticoids (GCs).

Chinese University of Hong Kong

Is there a ‘safe’ dose for glucocorticoids?

To analyze this relationship, Dr. Lam and colleagues used the Hospital Authority Data Collaboration Laboratory, a citywide health care database. The investigators recruited patients with RA who had no history of MACE from 2006 to 2015 and followed them until the end of 2018. The primary outcome was the first occurrence of a MACE, defined as a composite of myocardial infarction (MI), unstable angina, ischemic or hemorrhagic cerebrovascular accident, transient ischemic attack, and CV death.

The study was published in Annals of the Rheumatic Diseases.

The analysis included 12,233 patients with RA and had over 105,826 person-years of follow-up. The average follow-up time was 8.7 years. During the study period, 860 patients had their first MACE. After controlling for confounding factors, a daily prednisolone dose of 5 mg or higher doubled the risk for MACE, compared with GC nonusers. MACE risk increased by 7% per month.

University of Wisconsin School of Medicine and Public Health

Long-term glucocorticoid use discouraged

Daily doses of less than 5 mg were not associated with higher MACE risk, but more research is necessary to understand whether these low doses are clinically efficacious, Dr. Tam said. “The study results suggest that a very-low-dose GC (less than 5 mg prednisolone daily) may be cardiovascular risk–neutral. However, further evaluation is needed to determine whether this dose is therapeutic. Other potential side effects, such as bone loss, increased infection risk, dyslipidemia, and hyperglycemia, should also be considered.”

Both the American College of Rheumatology and the European Alliance of Associations for Rheumatology acknowledge that short-term GCs may be necessary for some RA patients, but they emphasize using the smallest necessary dose for the shortest period possible because of the known toxicity of GCs.

“We recommend stopping GCs as soon as it is clinically feasible, in line with previous recommendations, until these issues are investigated further,” Dr. Tam added.

Dr. Bartels agreed that long-term use of GCs should be avoided if possible, even at lower doses, because although CV risk may be less of an issue, studies have shown an increased risk for infection even at GC doses of less than 5 mg a day.
 

How might risk increase with dose?

While the study showed a distinct difference in risk with doses of prednisolone higher and lower than 5 mg, more information on how risk increases with dose could be useful, said Beth Wallace, MD, an assistant professor in internal medicine at the University of Michigan, Ann Arbor, and a staff rheumatologist at the VA Ann Arbor Healthcare Center. She was also unaffiliated with the research. “If someone is on 5-10 mg ... how much better is that than being on 10-20 mg or being on 20-30 mg?” she asked. While these study findings are “very important,” she said, it would be useful to know the risk associated with 7.5 mg vs. a higher dose.

University of Michigan

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

A daily prednisolone dose of 5 mg or higher is associated with increased risk for major adverse cardiovascular events (MACE) among patients with rheumatoid arthritis (RA), data suggest. Patients taking daily doses below this threshold did not appear to have an increased risk of MACE, compared with those not taking glucocorticoids (GCs).

Chinese University of Hong Kong

Is there a ‘safe’ dose for glucocorticoids?

To analyze this relationship, Dr. Lam and colleagues used the Hospital Authority Data Collaboration Laboratory, a citywide health care database. The investigators recruited patients with RA who had no history of MACE from 2006 to 2015 and followed them until the end of 2018. The primary outcome was the first occurrence of a MACE, defined as a composite of myocardial infarction (MI), unstable angina, ischemic or hemorrhagic cerebrovascular accident, transient ischemic attack, and CV death.

The study was published in Annals of the Rheumatic Diseases.

The analysis included 12,233 patients with RA and had over 105,826 person-years of follow-up. The average follow-up time was 8.7 years. During the study period, 860 patients had their first MACE. After controlling for confounding factors, a daily prednisolone dose of 5 mg or higher doubled the risk for MACE, compared with GC nonusers. MACE risk increased by 7% per month.

University of Wisconsin School of Medicine and Public Health

Long-term glucocorticoid use discouraged

Daily doses of less than 5 mg were not associated with higher MACE risk, but more research is necessary to understand whether these low doses are clinically efficacious, Dr. Tam said. “The study results suggest that a very-low-dose GC (less than 5 mg prednisolone daily) may be cardiovascular risk–neutral. However, further evaluation is needed to determine whether this dose is therapeutic. Other potential side effects, such as bone loss, increased infection risk, dyslipidemia, and hyperglycemia, should also be considered.”

Both the American College of Rheumatology and the European Alliance of Associations for Rheumatology acknowledge that short-term GCs may be necessary for some RA patients, but they emphasize using the smallest necessary dose for the shortest period possible because of the known toxicity of GCs.

“We recommend stopping GCs as soon as it is clinically feasible, in line with previous recommendations, until these issues are investigated further,” Dr. Tam added.

Dr. Bartels agreed that long-term use of GCs should be avoided if possible, even at lower doses, because although CV risk may be less of an issue, studies have shown an increased risk for infection even at GC doses of less than 5 mg a day.
 

How might risk increase with dose?

While the study showed a distinct difference in risk with doses of prednisolone higher and lower than 5 mg, more information on how risk increases with dose could be useful, said Beth Wallace, MD, an assistant professor in internal medicine at the University of Michigan, Ann Arbor, and a staff rheumatologist at the VA Ann Arbor Healthcare Center. She was also unaffiliated with the research. “If someone is on 5-10 mg ... how much better is that than being on 10-20 mg or being on 20-30 mg?” she asked. While these study findings are “very important,” she said, it would be useful to know the risk associated with 7.5 mg vs. a higher dose.

University of Michigan

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

Obesity, in and of itself, and independent of other cardiovascular risk factors, may cause changes to the heart that can lead to sudden cardiac death, a new case-control study suggests.

Researchers who analyzed hearts taken at autopsy from people who had died from sudden cardiac death found that a number of the hearts obtained from obese decedents were heavier than those from normal-weight decedents and that the hazard ratio of unexplained cardiomegaly in this cohort was 5.3, compared with normal-weight individuals.

“Even when we ruled out any conditions that could potentially cause enlargement of the heart, including hypertension, heart valve problems, diabetes, and other cardiovascular risk factors, the association with obesity cardiomyopathy, or OCM, and sudden cardiac death remained,” lead author Joseph Westaby, PhD, from the Cardiac Risk in the Young (CRY) Cardiovascular Pathology Laboratories at St George’s University of London, said in an interview.

The study was published online in JACC: Advances.

Intrigued by this finding, Dr. Westaby and associates sought to characterize the clinical and pathological features of OCM associated with sudden cardiac death by comparing this population to two control groups: sudden cardiac death patients who were either obese or of normal weight, and had morphologically normal hearts.

Their group is uniquely positioned to do such research, Dr. Westaby explained.

“Here at St George’s University of London, we have a specialized cardiovascular pathology service. ... All hearts obtained at autopsy from individuals who have died from sudden cardiac death, or who were suspected to have had a cardiovascular cause of death, anywhere in the U.K., are referred to the CRY Centre for further analysis,” he said.

Patients were divided into two groups according to body mass index: an obesity group (BMI > 30 kg/m²) and a normal-weight group (BMI, 18.5-24.9).

An increased heart weight above 550 g in men and 450 g in women in the absence of coronary artery disease, hypertension, diabetes, or valvular disease was classified as unexplained cardiomegaly, and individuals with obesity and cardiomegaly were defined as obesity cardiomyopathy.

Age- and sex-matched controls with obesity (n = 106) were selected based on a BMI greater than 30, with a morphologically normal heart weighing less than 550 g in men and than 450 g in women. 

Age- and sex-matched normal weight controls (n = 106) were selected based on a BMI of 18.5-24.9 and a morphologically normal heart weighing less than 550 g in men and less than 450 g in women. 

The researchers identified 53 OCM cases from a cohort of more than 4,500 sudden cardiac death cases that had BMI measurements. In normal-weight patients, there were 14 cases of unexplained cardiomegaly.

The mean age at death of individuals with OCM was 42 years (range, 30-54 years). Most of the deaths occurred in men (n = 34; 64%), who also died younger than women (40 ± 13 years vs. 45 ± 10 years; P = .036).

The average heart weight in OCM patients was 598 ± 93 g. Risk of sudden cardiac death increased when BMI reached 35.

Compared with matched controls, there were increases in right and left ventricular wall thickness (all P < .05) in OCM cases. Right ventricular epicardial fat was increased in OCM cases, compared with normal-weight controls only.

Left ventricular fibrosis was identified in seven (13%) OCM cases.
 

Role of genetics to be explored

“This study highlights the need for further investigation into these individuals because, at the moment, we can’t be sure that the only contributing factor to this is the obesity,” said Dr. Westaby.

In the works are plans to see if there may be an underlying genetic predisposition in obese individuals that may have contributed to the development of an enlarged heart. The group also plans to study the families of the deceased individuals to determine if they are at risk of developing cardiomegaly, he said.

“This paper makes an important contribution to the literature that raises many important questions for future research,” Timothy P. Fitzgibbons, MD, PhD, from the University of Massachusetts, Worcester, wrote in an accompanying editorial.

Being able to access so many autopsy samples gives the current study considerable heft, Dr. Fitzgibbons said in an interview.

“A lot has been made of the obesity paradox and the perhaps benign nature of obesity but this paper suggests the opposite, that it is a very serious problem and can, in fact, in and of itself, cause heart abnormalities that could cause sudden death,” he noted.

The fact that only 13% of OCM cases had fibrosis on histology suggests that fibrosis was not the main cause of sudden cardiac death, he said.

“Often we will do MRIs to look for areas of fibrosis within the heart because those areas make patients prone to re-entry arrhythmias, in particular, ventricular tachycardia. But the authors suggest that the enlarged myocytes may themselves be predisposing to arrhythmias, rather than fibrosis,” Dr. Fitzgibbons said.

The study was supported by Cardiac Risk in the Young. Dr. Westaby and Dr. Fitzgibbons have reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Obesity, in and of itself, and independent of other cardiovascular risk factors, may cause changes to the heart that can lead to sudden cardiac death, a new case-control study suggests.

Researchers who analyzed hearts taken at autopsy from people who had died from sudden cardiac death found that a number of the hearts obtained from obese decedents were heavier than those from normal-weight decedents and that the hazard ratio of unexplained cardiomegaly in this cohort was 5.3, compared with normal-weight individuals.

“Even when we ruled out any conditions that could potentially cause enlargement of the heart, including hypertension, heart valve problems, diabetes, and other cardiovascular risk factors, the association with obesity cardiomyopathy, or OCM, and sudden cardiac death remained,” lead author Joseph Westaby, PhD, from the Cardiac Risk in the Young (CRY) Cardiovascular Pathology Laboratories at St George’s University of London, said in an interview.

The study was published online in JACC: Advances.

Intrigued by this finding, Dr. Westaby and associates sought to characterize the clinical and pathological features of OCM associated with sudden cardiac death by comparing this population to two control groups: sudden cardiac death patients who were either obese or of normal weight, and had morphologically normal hearts.

Their group is uniquely positioned to do such research, Dr. Westaby explained.

“Here at St George’s University of London, we have a specialized cardiovascular pathology service. ... All hearts obtained at autopsy from individuals who have died from sudden cardiac death, or who were suspected to have had a cardiovascular cause of death, anywhere in the U.K., are referred to the CRY Centre for further analysis,” he said.

Patients were divided into two groups according to body mass index: an obesity group (BMI > 30 kg/m²) and a normal-weight group (BMI, 18.5-24.9).

An increased heart weight above 550 g in men and 450 g in women in the absence of coronary artery disease, hypertension, diabetes, or valvular disease was classified as unexplained cardiomegaly, and individuals with obesity and cardiomegaly were defined as obesity cardiomyopathy.

Age- and sex-matched controls with obesity (n = 106) were selected based on a BMI greater than 30, with a morphologically normal heart weighing less than 550 g in men and than 450 g in women. 

Age- and sex-matched normal weight controls (n = 106) were selected based on a BMI of 18.5-24.9 and a morphologically normal heart weighing less than 550 g in men and less than 450 g in women. 

The researchers identified 53 OCM cases from a cohort of more than 4,500 sudden cardiac death cases that had BMI measurements. In normal-weight patients, there were 14 cases of unexplained cardiomegaly.

The mean age at death of individuals with OCM was 42 years (range, 30-54 years). Most of the deaths occurred in men (n = 34; 64%), who also died younger than women (40 ± 13 years vs. 45 ± 10 years; P = .036).

The average heart weight in OCM patients was 598 ± 93 g. Risk of sudden cardiac death increased when BMI reached 35.

Compared with matched controls, there were increases in right and left ventricular wall thickness (all P < .05) in OCM cases. Right ventricular epicardial fat was increased in OCM cases, compared with normal-weight controls only.

Left ventricular fibrosis was identified in seven (13%) OCM cases.
 

Role of genetics to be explored

“This study highlights the need for further investigation into these individuals because, at the moment, we can’t be sure that the only contributing factor to this is the obesity,” said Dr. Westaby.

In the works are plans to see if there may be an underlying genetic predisposition in obese individuals that may have contributed to the development of an enlarged heart. The group also plans to study the families of the deceased individuals to determine if they are at risk of developing cardiomegaly, he said.

“This paper makes an important contribution to the literature that raises many important questions for future research,” Timothy P. Fitzgibbons, MD, PhD, from the University of Massachusetts, Worcester, wrote in an accompanying editorial.

Being able to access so many autopsy samples gives the current study considerable heft, Dr. Fitzgibbons said in an interview.

“A lot has been made of the obesity paradox and the perhaps benign nature of obesity but this paper suggests the opposite, that it is a very serious problem and can, in fact, in and of itself, cause heart abnormalities that could cause sudden death,” he noted.

The fact that only 13% of OCM cases had fibrosis on histology suggests that fibrosis was not the main cause of sudden cardiac death, he said.

“Often we will do MRIs to look for areas of fibrosis within the heart because those areas make patients prone to re-entry arrhythmias, in particular, ventricular tachycardia. But the authors suggest that the enlarged myocytes may themselves be predisposing to arrhythmias, rather than fibrosis,” Dr. Fitzgibbons said.

The study was supported by Cardiac Risk in the Young. Dr. Westaby and Dr. Fitzgibbons have reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Obesity, in and of itself, and independent of other cardiovascular risk factors, may cause changes to the heart that can lead to sudden cardiac death, a new case-control study suggests.

Researchers who analyzed hearts taken at autopsy from people who had died from sudden cardiac death found that a number of the hearts obtained from obese decedents were heavier than those from normal-weight decedents and that the hazard ratio of unexplained cardiomegaly in this cohort was 5.3, compared with normal-weight individuals.

“Even when we ruled out any conditions that could potentially cause enlargement of the heart, including hypertension, heart valve problems, diabetes, and other cardiovascular risk factors, the association with obesity cardiomyopathy, or OCM, and sudden cardiac death remained,” lead author Joseph Westaby, PhD, from the Cardiac Risk in the Young (CRY) Cardiovascular Pathology Laboratories at St George’s University of London, said in an interview.

The study was published online in JACC: Advances.

Intrigued by this finding, Dr. Westaby and associates sought to characterize the clinical and pathological features of OCM associated with sudden cardiac death by comparing this population to two control groups: sudden cardiac death patients who were either obese or of normal weight, and had morphologically normal hearts.

Their group is uniquely positioned to do such research, Dr. Westaby explained.

“Here at St George’s University of London, we have a specialized cardiovascular pathology service. ... All hearts obtained at autopsy from individuals who have died from sudden cardiac death, or who were suspected to have had a cardiovascular cause of death, anywhere in the U.K., are referred to the CRY Centre for further analysis,” he said.

Patients were divided into two groups according to body mass index: an obesity group (BMI > 30 kg/m²) and a normal-weight group (BMI, 18.5-24.9).

An increased heart weight above 550 g in men and 450 g in women in the absence of coronary artery disease, hypertension, diabetes, or valvular disease was classified as unexplained cardiomegaly, and individuals with obesity and cardiomegaly were defined as obesity cardiomyopathy.

Age- and sex-matched controls with obesity (n = 106) were selected based on a BMI greater than 30, with a morphologically normal heart weighing less than 550 g in men and than 450 g in women. 

Age- and sex-matched normal weight controls (n = 106) were selected based on a BMI of 18.5-24.9 and a morphologically normal heart weighing less than 550 g in men and less than 450 g in women. 

The researchers identified 53 OCM cases from a cohort of more than 4,500 sudden cardiac death cases that had BMI measurements. In normal-weight patients, there were 14 cases of unexplained cardiomegaly.

The mean age at death of individuals with OCM was 42 years (range, 30-54 years). Most of the deaths occurred in men (n = 34; 64%), who also died younger than women (40 ± 13 years vs. 45 ± 10 years; P = .036).

The average heart weight in OCM patients was 598 ± 93 g. Risk of sudden cardiac death increased when BMI reached 35.

Compared with matched controls, there were increases in right and left ventricular wall thickness (all P < .05) in OCM cases. Right ventricular epicardial fat was increased in OCM cases, compared with normal-weight controls only.

Left ventricular fibrosis was identified in seven (13%) OCM cases.
 

Role of genetics to be explored

“This study highlights the need for further investigation into these individuals because, at the moment, we can’t be sure that the only contributing factor to this is the obesity,” said Dr. Westaby.

In the works are plans to see if there may be an underlying genetic predisposition in obese individuals that may have contributed to the development of an enlarged heart. The group also plans to study the families of the deceased individuals to determine if they are at risk of developing cardiomegaly, he said.

“This paper makes an important contribution to the literature that raises many important questions for future research,” Timothy P. Fitzgibbons, MD, PhD, from the University of Massachusetts, Worcester, wrote in an accompanying editorial.

Being able to access so many autopsy samples gives the current study considerable heft, Dr. Fitzgibbons said in an interview.

“A lot has been made of the obesity paradox and the perhaps benign nature of obesity but this paper suggests the opposite, that it is a very serious problem and can, in fact, in and of itself, cause heart abnormalities that could cause sudden death,” he noted.

The fact that only 13% of OCM cases had fibrosis on histology suggests that fibrosis was not the main cause of sudden cardiac death, he said.

“Often we will do MRIs to look for areas of fibrosis within the heart because those areas make patients prone to re-entry arrhythmias, in particular, ventricular tachycardia. But the authors suggest that the enlarged myocytes may themselves be predisposing to arrhythmias, rather than fibrosis,” Dr. Fitzgibbons said.

The study was supported by Cardiac Risk in the Young. Dr. Westaby and Dr. Fitzgibbons have reported no relevant financial relationships.

A version of this article appeared on Medscape.com.