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Possible mechanism for fluoroquinolone-induced aortopathy uncovered
A new study finds that patients taking fluoroquinolone antibiotics may be at higher risk of aortopathy in part because of human aortic myofibroblast–mediated extracellular matrix (ECM) dysregulation.
“Emerging evidence supports pharmacologic-associated aortopathy in patients receiving fluoroquinolone [FQ] antibiotics,” said first author David G. Guzzardi, PhD, and his colleagues, citing previous research showing that, “compared with patients receiving amoxicillin antibiotics, those receiving FQ have a 66% higher risk of aneurysm or dissection within a 2-month period after commencing FQ use.”
Based upon such data, the Food and Drug Administration issued a December 2018 warning about the increased risk of ruptures or tears in the aorta with fluoroquinolone antibiotics in certain patients, updating their May 2017 warning regarding “disabling and potentially permanent side effects of the tendons, muscles, joints, nerves, and central nervous system that can occur together in the same patient,” upon exposure to this class of antibiotics. Earlier in 2018, the FDA had reinforced their safety information about serious and potentially fatal low blood sugar levels and mental health side effects with fluoroquinolone antibiotics.
Dr. Guzzardi and his colleagues at the University of Calgary (Alta.) performed a study to attempt to determine the possible cellular mechanisms for the observed aortopathy. In their study published in the Journal of Thoracic and Cardiovascular Surgery, Dr. Guzzardi and his colleagues isolated human aortic myofibroblasts from nine patients with aortopathy who were undergoing elective ascending aortic resection.
Following exposure of cells to FQ, the researchers assessed secreted matrix metalloproteinases relative to tissue inhibitors of matrix metalloproteinases (TIMPs). In addition, they examined ECM degradation by using a three-dimensional gelatin-fluorescein isothiocyanate fluorescence microgel assay. Aortic cellular collagen type I expression following FQ exposure was determined by immunoblotting and immunofluorescent staining. Dr. Guzzardi and his colleagues also looked at cell apoptosis, necrosis, and metabolic viability using two versions of vital staining.
They found that FQ exposure significantly decreased aortic cell TIMP-1 (P less than .004) and TIMP-2 (P less than .0004) protein expression, compared with controls, and the ratio of matrix metalloproteinase 9/TIMP-2 was increased (P less than .01). This suggests an increased capacity for ECM degradation after FQ exposure, according to the researchers.
In addition, FQ exposure attenuated collagen type I expression as assessed by immunoblotting (P less than .002) and immunofluorescence (P less than .02).
“FQ induces human aortic myofibroblast–mediated ECM dysregulation by decreasing TIMP expression and preventing compensatory collagen deposition. These data provide novel insights into the mechanisms that may underlie the clinical association of FQ exposure and increased risk of acute aortic events in the community. Our data suggest cautious use of FQ in selected patient populations with preexistent aortopathy and connective tissue disorders,” the researchers concluded.
In an accompanying editorial, while warning that these are preliminary observations based upon a small number of patients with aortopathy, Ari A. Mennander, MD, PhD, of Tampere (Finland) University, wrote that, “for the first time, the wild theory of fluoroquinolone-associated aortopathy has a molecular hint that is based on collagen degeneration and progression of aortic disease. ... This theory is in line with previous observations revealing antifibrotic activity and decreased collagen-1 protein expression with fluoroquinolones. The enigmatic puzzle of the progression of some aortic events may alarmingly be iatrogenic, and the clinician may wisely consider a prudent use of fluoroquinolones in patients with aortic dilatation.”
The authors and commentators reported that they had no commercial conflicts to disclose.
SOURCE: Guzzardi DG et al. J Thorac Cardiovasc Surg. 2019;157:109-19.
The issue of fluoroquinolones is certainly of concern. I wonder how many of my patients who have suffered a ruptured aneurysm were on one of these drugs? In the last few years, Cipro (ciprofloxacin) and Levaquin (levofloxacin) were commonly used by our family practice and internal medicine colleagues for almost all outpatient infections. It was so common that even my wife, who is not a physician, would request Cipro whenever she had a sneeze. We would also bring large bottles of Cipro every time we went traveling to some exotic destination, reassuring ourselves that the only “runs” we would have would be in the airport trying to catch a flight. A cousin of mine, prescribed Levaquin by a well-meaning physician while he was cruising the Nile River, ruptured his Achilles tendon.
Russell H. Samson, MD, FACS, DFSVS , is a clinical professor of surgery at Florida State University, Sarasota, a senior surgeon at Sarasota Vascular Specialists, and President of the Mote Vascular Foundation.
The issue of fluoroquinolones is certainly of concern. I wonder how many of my patients who have suffered a ruptured aneurysm were on one of these drugs? In the last few years, Cipro (ciprofloxacin) and Levaquin (levofloxacin) were commonly used by our family practice and internal medicine colleagues for almost all outpatient infections. It was so common that even my wife, who is not a physician, would request Cipro whenever she had a sneeze. We would also bring large bottles of Cipro every time we went traveling to some exotic destination, reassuring ourselves that the only “runs” we would have would be in the airport trying to catch a flight. A cousin of mine, prescribed Levaquin by a well-meaning physician while he was cruising the Nile River, ruptured his Achilles tendon.
Russell H. Samson, MD, FACS, DFSVS , is a clinical professor of surgery at Florida State University, Sarasota, a senior surgeon at Sarasota Vascular Specialists, and President of the Mote Vascular Foundation.
The issue of fluoroquinolones is certainly of concern. I wonder how many of my patients who have suffered a ruptured aneurysm were on one of these drugs? In the last few years, Cipro (ciprofloxacin) and Levaquin (levofloxacin) were commonly used by our family practice and internal medicine colleagues for almost all outpatient infections. It was so common that even my wife, who is not a physician, would request Cipro whenever she had a sneeze. We would also bring large bottles of Cipro every time we went traveling to some exotic destination, reassuring ourselves that the only “runs” we would have would be in the airport trying to catch a flight. A cousin of mine, prescribed Levaquin by a well-meaning physician while he was cruising the Nile River, ruptured his Achilles tendon.
Russell H. Samson, MD, FACS, DFSVS , is a clinical professor of surgery at Florida State University, Sarasota, a senior surgeon at Sarasota Vascular Specialists, and President of the Mote Vascular Foundation.
A new study finds that patients taking fluoroquinolone antibiotics may be at higher risk of aortopathy in part because of human aortic myofibroblast–mediated extracellular matrix (ECM) dysregulation.
“Emerging evidence supports pharmacologic-associated aortopathy in patients receiving fluoroquinolone [FQ] antibiotics,” said first author David G. Guzzardi, PhD, and his colleagues, citing previous research showing that, “compared with patients receiving amoxicillin antibiotics, those receiving FQ have a 66% higher risk of aneurysm or dissection within a 2-month period after commencing FQ use.”
Based upon such data, the Food and Drug Administration issued a December 2018 warning about the increased risk of ruptures or tears in the aorta with fluoroquinolone antibiotics in certain patients, updating their May 2017 warning regarding “disabling and potentially permanent side effects of the tendons, muscles, joints, nerves, and central nervous system that can occur together in the same patient,” upon exposure to this class of antibiotics. Earlier in 2018, the FDA had reinforced their safety information about serious and potentially fatal low blood sugar levels and mental health side effects with fluoroquinolone antibiotics.
Dr. Guzzardi and his colleagues at the University of Calgary (Alta.) performed a study to attempt to determine the possible cellular mechanisms for the observed aortopathy. In their study published in the Journal of Thoracic and Cardiovascular Surgery, Dr. Guzzardi and his colleagues isolated human aortic myofibroblasts from nine patients with aortopathy who were undergoing elective ascending aortic resection.
Following exposure of cells to FQ, the researchers assessed secreted matrix metalloproteinases relative to tissue inhibitors of matrix metalloproteinases (TIMPs). In addition, they examined ECM degradation by using a three-dimensional gelatin-fluorescein isothiocyanate fluorescence microgel assay. Aortic cellular collagen type I expression following FQ exposure was determined by immunoblotting and immunofluorescent staining. Dr. Guzzardi and his colleagues also looked at cell apoptosis, necrosis, and metabolic viability using two versions of vital staining.
They found that FQ exposure significantly decreased aortic cell TIMP-1 (P less than .004) and TIMP-2 (P less than .0004) protein expression, compared with controls, and the ratio of matrix metalloproteinase 9/TIMP-2 was increased (P less than .01). This suggests an increased capacity for ECM degradation after FQ exposure, according to the researchers.
In addition, FQ exposure attenuated collagen type I expression as assessed by immunoblotting (P less than .002) and immunofluorescence (P less than .02).
“FQ induces human aortic myofibroblast–mediated ECM dysregulation by decreasing TIMP expression and preventing compensatory collagen deposition. These data provide novel insights into the mechanisms that may underlie the clinical association of FQ exposure and increased risk of acute aortic events in the community. Our data suggest cautious use of FQ in selected patient populations with preexistent aortopathy and connective tissue disorders,” the researchers concluded.
In an accompanying editorial, while warning that these are preliminary observations based upon a small number of patients with aortopathy, Ari A. Mennander, MD, PhD, of Tampere (Finland) University, wrote that, “for the first time, the wild theory of fluoroquinolone-associated aortopathy has a molecular hint that is based on collagen degeneration and progression of aortic disease. ... This theory is in line with previous observations revealing antifibrotic activity and decreased collagen-1 protein expression with fluoroquinolones. The enigmatic puzzle of the progression of some aortic events may alarmingly be iatrogenic, and the clinician may wisely consider a prudent use of fluoroquinolones in patients with aortic dilatation.”
The authors and commentators reported that they had no commercial conflicts to disclose.
SOURCE: Guzzardi DG et al. J Thorac Cardiovasc Surg. 2019;157:109-19.
A new study finds that patients taking fluoroquinolone antibiotics may be at higher risk of aortopathy in part because of human aortic myofibroblast–mediated extracellular matrix (ECM) dysregulation.
“Emerging evidence supports pharmacologic-associated aortopathy in patients receiving fluoroquinolone [FQ] antibiotics,” said first author David G. Guzzardi, PhD, and his colleagues, citing previous research showing that, “compared with patients receiving amoxicillin antibiotics, those receiving FQ have a 66% higher risk of aneurysm or dissection within a 2-month period after commencing FQ use.”
Based upon such data, the Food and Drug Administration issued a December 2018 warning about the increased risk of ruptures or tears in the aorta with fluoroquinolone antibiotics in certain patients, updating their May 2017 warning regarding “disabling and potentially permanent side effects of the tendons, muscles, joints, nerves, and central nervous system that can occur together in the same patient,” upon exposure to this class of antibiotics. Earlier in 2018, the FDA had reinforced their safety information about serious and potentially fatal low blood sugar levels and mental health side effects with fluoroquinolone antibiotics.
Dr. Guzzardi and his colleagues at the University of Calgary (Alta.) performed a study to attempt to determine the possible cellular mechanisms for the observed aortopathy. In their study published in the Journal of Thoracic and Cardiovascular Surgery, Dr. Guzzardi and his colleagues isolated human aortic myofibroblasts from nine patients with aortopathy who were undergoing elective ascending aortic resection.
Following exposure of cells to FQ, the researchers assessed secreted matrix metalloproteinases relative to tissue inhibitors of matrix metalloproteinases (TIMPs). In addition, they examined ECM degradation by using a three-dimensional gelatin-fluorescein isothiocyanate fluorescence microgel assay. Aortic cellular collagen type I expression following FQ exposure was determined by immunoblotting and immunofluorescent staining. Dr. Guzzardi and his colleagues also looked at cell apoptosis, necrosis, and metabolic viability using two versions of vital staining.
They found that FQ exposure significantly decreased aortic cell TIMP-1 (P less than .004) and TIMP-2 (P less than .0004) protein expression, compared with controls, and the ratio of matrix metalloproteinase 9/TIMP-2 was increased (P less than .01). This suggests an increased capacity for ECM degradation after FQ exposure, according to the researchers.
In addition, FQ exposure attenuated collagen type I expression as assessed by immunoblotting (P less than .002) and immunofluorescence (P less than .02).
“FQ induces human aortic myofibroblast–mediated ECM dysregulation by decreasing TIMP expression and preventing compensatory collagen deposition. These data provide novel insights into the mechanisms that may underlie the clinical association of FQ exposure and increased risk of acute aortic events in the community. Our data suggest cautious use of FQ in selected patient populations with preexistent aortopathy and connective tissue disorders,” the researchers concluded.
In an accompanying editorial, while warning that these are preliminary observations based upon a small number of patients with aortopathy, Ari A. Mennander, MD, PhD, of Tampere (Finland) University, wrote that, “for the first time, the wild theory of fluoroquinolone-associated aortopathy has a molecular hint that is based on collagen degeneration and progression of aortic disease. ... This theory is in line with previous observations revealing antifibrotic activity and decreased collagen-1 protein expression with fluoroquinolones. The enigmatic puzzle of the progression of some aortic events may alarmingly be iatrogenic, and the clinician may wisely consider a prudent use of fluoroquinolones in patients with aortic dilatation.”
The authors and commentators reported that they had no commercial conflicts to disclose.
SOURCE: Guzzardi DG et al. J Thorac Cardiovasc Surg. 2019;157:109-19.
FROM THE JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
Hormone therapy in transgender individuals may up risk of CV events
when compared with the general population, according to a study that analyzed medical records of more than 6,000 patients.
“In light of our results, we urge both physicians and transgender individuals to be aware of this increased cardiovascular risk,” first author Nienke M. Nota, MD, said in a press release for the study, which was published online Feb. 18 in Circulation. “It may be helpful to reduce risk factors by stopping smoking, exercising, eating a healthy diet, and losing weight, if needed, before starting therapy, and clinicians should continue to evaluate patients on an ongoing basis thereafter.”Dr. Nota and her colleagues at the Amsterdam University Medical Center analyzed the risk of cardiovascular events by comparing the medical records of 6,793 individuals, including only patients who received hormone therapy at their center or affiliate. They did not include those who had discontinued hormone therapy for an extended period or had alternated female and male sex hormones.
They defined transmen as indiviuals assigned female sex at birth but who had male gender identity, and transwomen as those assigned male sex at birth but with female gender identity.*
Researchers analyzed 2,517 transwomen (median age 30 years) and 1,358 transmen (median age 23 years) who received hormone therapy (defined as estrogen with and without androgen-suppressors for transwomen and testosterone for transmen) at the center gender’s clinic between 1972 and 2015. These records were compared with those of cisgender women and men (individuals whose gender identity matches their assigned birth gender).
The mean follow-up duration was 9.07 years for transwomen and 8.10 years for transmen. The researchers compared observed cases of stroke, myocardial infarction (MI), and venous thromboembolism (VTE) with expected cases using cisgender reference women and men. There were 29 stroke events, 30 MIs, and 73 VTE events for transwomen and 6 stroke, 11 MIs, and 2 VTE events for transmen.
There was a greater risk of stroke for transwomen, compared with cisgender women (standardized incidence ratio [SIR] = 2.42) and cisgender men (1.80), and a significantly greater risk of VTE, compared with cisgender women (5.52) and cisgender men (4.55).
The rate of MI was also significantly higher in transwomen, compared with cisgender women (2.64) and in transmen compared with cisgender women (3.69).
In a subgroup analysis, the researchers found ethinylestradiol use prior to 2001 did not significantly change the incident rate of cardiovascular events, but noted there was a lower rate of VTE when transwomen who began hormone therapy prior to 2001 were excluded from the analysis.
The researchers noted that hormone therapy may increase the risk of cardiovascular events in transgender individuals, in part, due to hormone therapy’s effect on cardiovascular risk factors such as lipid levels. Although a previous study analyzed the risk of cardiovascular events in transwomen and transmen, the researchers said that study could not conclude there was an increased risk of cardiovascular events for transmen.
The researchers said the results may be limited by study design, and their analysis of medical records could not account for potential confounders such as psychosocial stressors and smoking, as well as the decreasing risk of cardiovascular events over the period of the study, and assessing cardiovascular events differently than reference studies used.
The study had no specific funding, and the authors reported no relevant conflicts of interest.
SOURCE: Nota NM et al. Circulation. 2019 Feb 18. doi: 10.1161/CIRCULATIONAHA.118.038584
*Correction 2/25/2019: An earlier version of this story incorrectly defined transwomen and transmen. The definitions are now accurate.
when compared with the general population, according to a study that analyzed medical records of more than 6,000 patients.
“In light of our results, we urge both physicians and transgender individuals to be aware of this increased cardiovascular risk,” first author Nienke M. Nota, MD, said in a press release for the study, which was published online Feb. 18 in Circulation. “It may be helpful to reduce risk factors by stopping smoking, exercising, eating a healthy diet, and losing weight, if needed, before starting therapy, and clinicians should continue to evaluate patients on an ongoing basis thereafter.”Dr. Nota and her colleagues at the Amsterdam University Medical Center analyzed the risk of cardiovascular events by comparing the medical records of 6,793 individuals, including only patients who received hormone therapy at their center or affiliate. They did not include those who had discontinued hormone therapy for an extended period or had alternated female and male sex hormones.
They defined transmen as indiviuals assigned female sex at birth but who had male gender identity, and transwomen as those assigned male sex at birth but with female gender identity.*
Researchers analyzed 2,517 transwomen (median age 30 years) and 1,358 transmen (median age 23 years) who received hormone therapy (defined as estrogen with and without androgen-suppressors for transwomen and testosterone for transmen) at the center gender’s clinic between 1972 and 2015. These records were compared with those of cisgender women and men (individuals whose gender identity matches their assigned birth gender).
The mean follow-up duration was 9.07 years for transwomen and 8.10 years for transmen. The researchers compared observed cases of stroke, myocardial infarction (MI), and venous thromboembolism (VTE) with expected cases using cisgender reference women and men. There were 29 stroke events, 30 MIs, and 73 VTE events for transwomen and 6 stroke, 11 MIs, and 2 VTE events for transmen.
There was a greater risk of stroke for transwomen, compared with cisgender women (standardized incidence ratio [SIR] = 2.42) and cisgender men (1.80), and a significantly greater risk of VTE, compared with cisgender women (5.52) and cisgender men (4.55).
The rate of MI was also significantly higher in transwomen, compared with cisgender women (2.64) and in transmen compared with cisgender women (3.69).
In a subgroup analysis, the researchers found ethinylestradiol use prior to 2001 did not significantly change the incident rate of cardiovascular events, but noted there was a lower rate of VTE when transwomen who began hormone therapy prior to 2001 were excluded from the analysis.
The researchers noted that hormone therapy may increase the risk of cardiovascular events in transgender individuals, in part, due to hormone therapy’s effect on cardiovascular risk factors such as lipid levels. Although a previous study analyzed the risk of cardiovascular events in transwomen and transmen, the researchers said that study could not conclude there was an increased risk of cardiovascular events for transmen.
The researchers said the results may be limited by study design, and their analysis of medical records could not account for potential confounders such as psychosocial stressors and smoking, as well as the decreasing risk of cardiovascular events over the period of the study, and assessing cardiovascular events differently than reference studies used.
The study had no specific funding, and the authors reported no relevant conflicts of interest.
SOURCE: Nota NM et al. Circulation. 2019 Feb 18. doi: 10.1161/CIRCULATIONAHA.118.038584
*Correction 2/25/2019: An earlier version of this story incorrectly defined transwomen and transmen. The definitions are now accurate.
when compared with the general population, according to a study that analyzed medical records of more than 6,000 patients.
“In light of our results, we urge both physicians and transgender individuals to be aware of this increased cardiovascular risk,” first author Nienke M. Nota, MD, said in a press release for the study, which was published online Feb. 18 in Circulation. “It may be helpful to reduce risk factors by stopping smoking, exercising, eating a healthy diet, and losing weight, if needed, before starting therapy, and clinicians should continue to evaluate patients on an ongoing basis thereafter.”Dr. Nota and her colleagues at the Amsterdam University Medical Center analyzed the risk of cardiovascular events by comparing the medical records of 6,793 individuals, including only patients who received hormone therapy at their center or affiliate. They did not include those who had discontinued hormone therapy for an extended period or had alternated female and male sex hormones.
They defined transmen as indiviuals assigned female sex at birth but who had male gender identity, and transwomen as those assigned male sex at birth but with female gender identity.*
Researchers analyzed 2,517 transwomen (median age 30 years) and 1,358 transmen (median age 23 years) who received hormone therapy (defined as estrogen with and without androgen-suppressors for transwomen and testosterone for transmen) at the center gender’s clinic between 1972 and 2015. These records were compared with those of cisgender women and men (individuals whose gender identity matches their assigned birth gender).
The mean follow-up duration was 9.07 years for transwomen and 8.10 years for transmen. The researchers compared observed cases of stroke, myocardial infarction (MI), and venous thromboembolism (VTE) with expected cases using cisgender reference women and men. There were 29 stroke events, 30 MIs, and 73 VTE events for transwomen and 6 stroke, 11 MIs, and 2 VTE events for transmen.
There was a greater risk of stroke for transwomen, compared with cisgender women (standardized incidence ratio [SIR] = 2.42) and cisgender men (1.80), and a significantly greater risk of VTE, compared with cisgender women (5.52) and cisgender men (4.55).
The rate of MI was also significantly higher in transwomen, compared with cisgender women (2.64) and in transmen compared with cisgender women (3.69).
In a subgroup analysis, the researchers found ethinylestradiol use prior to 2001 did not significantly change the incident rate of cardiovascular events, but noted there was a lower rate of VTE when transwomen who began hormone therapy prior to 2001 were excluded from the analysis.
The researchers noted that hormone therapy may increase the risk of cardiovascular events in transgender individuals, in part, due to hormone therapy’s effect on cardiovascular risk factors such as lipid levels. Although a previous study analyzed the risk of cardiovascular events in transwomen and transmen, the researchers said that study could not conclude there was an increased risk of cardiovascular events for transmen.
The researchers said the results may be limited by study design, and their analysis of medical records could not account for potential confounders such as psychosocial stressors and smoking, as well as the decreasing risk of cardiovascular events over the period of the study, and assessing cardiovascular events differently than reference studies used.
The study had no specific funding, and the authors reported no relevant conflicts of interest.
SOURCE: Nota NM et al. Circulation. 2019 Feb 18. doi: 10.1161/CIRCULATIONAHA.118.038584
*Correction 2/25/2019: An earlier version of this story incorrectly defined transwomen and transmen. The definitions are now accurate.
FROM CIRCULATION
Mediterranean diet cut Parkinson’s risk
‘Telereferrals’ improved mental health referral follow-through for children. How to take action to cut cardiovascular disease risk in rheumatoid patients. And the U.S. Preventive Services Task Force recommends counseling for perinatal depression prevention.
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Apple Podcasts
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Spotify
‘Telereferrals’ improved mental health referral follow-through for children. How to take action to cut cardiovascular disease risk in rheumatoid patients. And the U.S. Preventive Services Task Force recommends counseling for perinatal depression prevention.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
‘Telereferrals’ improved mental health referral follow-through for children. How to take action to cut cardiovascular disease risk in rheumatoid patients. And the U.S. Preventive Services Task Force recommends counseling for perinatal depression prevention.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
What cardiologists need to know about ARVC
SNOWMASS, COLO. – Electrophysiologist N.A. Mark Estes III, MD, has a piece of advice for his general cardiology colleagues regarding arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited arrhythmia syndrome that’s one of the most common causes of sudden death in athletes under the age of 40 years.
“When you have a patient with syncope and an ECG abnormality that suggests ARVC, you immediately restrict activity and immediately go on to imaging. And then it’s time to get that patient off to somebody who deals with these patients all the time,” he said at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
ARVC is thought to affect 1 in 5,000 people. It’s the cause of sudden death in roughly 5% of young athletes in the United States and 25% in Italy, with the disparity believed to be largely caused by underrecognition of the disease.
Dr. Estes was a coauthor of a 2015 international task force consensus statement on the treatment of ARVC (Eur Heart J. 2015 Dec 7;36[46]:3227-37). An updated report that incorporates much new information is due to be released in May 2019.
“The new guidelines are going to put some very clear limits on physical activity: Less than 7 METs [metabolic equivalents], which is about a brisk walk. Exercise is not good with ARVC,” said Dr. Estes, professor of medicine at the University of Pittsburgh.
Patients with ARVC absolutely must be restricted from participation in competitive sports, a step whose importance was demonstrated in the North American Multidisciplinary Study of ARVC, for which Dr. Estes was a coauthor. That study, too recent for inclusion in the 2015 task force consensus statement, showed that competitive sport was associated with a 100% increased risk of ventricular tachyarrhythmias and death, as well as earlier presentation with symptoms, compared with patients with ARVC who engaged in much less intense recreational athletic activity, who in turn didn’t have a risk level any different from inactive patients. That being said, however, the investigators also noted that the absolute risk of ventricular tachyarrhythmias or death remained high even in the inactive and recreational sports participants, at 23% by 2 years post diagnosis (Eur Heart J. 2015 Jul 14;36[27]:1735-43).
ARVC has three phases: An early concealed phase, with an associated high rate of syncope or sudden cardiac death; an intermediate phase marked by frequent arrhythmias; and a late phase involving cardiomyopathy and heart failure. Pathologically, the disease involves progressive loss of myocytes caused by abnormalities of plakoglobin and plakophilin, which Dr. Estes described as “essentially the glue that holds the sarcomeres together.” As myocytes are lost they are replaced by fibrofatty deposits, mostly in the right ventricle, creating a substrate for ventricular arrhythmias.
When to suspect ARVC?
“Anyone who has syncope with exertion automatically has a red flag because there is almost certainly something causing that event that’s potentially malignant,” according to the cardiologist.
An early, sensitive, and reasonably specific hallmark of ARVC on the 12-lead ECG is T wave inversion in right precordial leads V1, V2, and V3 or beyond. An epsilon wave – a small positive deflection at the end of the QRS complex – is present in about one in five patients with ARVC and is diagnostic of the condition.
“It’s an ECG you want to commit to memory. And when you see it, think ARVC,” Dr. Estes advised.
Abnormalities on MRI and 2D echocardiography include right ventricular enlargement and wall motion abnormalities, with left ventricular involvement becoming common in more advanced disease.
The detailed structural, electrographic, functional imaging, histologic, and clinical diagnostic criteria for ARVC, known as the 2010 Task Force Criteria, are readily available (Circulation. 2010 Apr 6;121[13]:1533-41). So are guidelines on genetic testing, which practitioners need to understand is now the standard of care for patients with ARVC and, in the event they are found to have a pathogenic mutation, in first-degree family members as well (Europace. 2011 Aug;13(8):1077-109).
“These days all you need to do is simply Google ‘syncope’ and ‘ARVC’ and you will get to the guidelines,” Dr. Estes advised. “It’s virtually impossible to keep up with all this information, but you should know how to access it and apply it in an individual patient. And learn the role of genetic testing. It’s very much an evolving area, quite mature for the long QT syndromes, but not a robust database for ARVC now. Yet there’s no doubt it’s going to be used more and more for diagnosis, risk stratification, and therapy of ARVC in the future.”
Once the diagnosis of ARVC is made in accordance with the 2010 Task Force Criteria, risk stratification and decision making about definitive therapy become paramount. The international task force consensus statement gives a Class I recommendation to implantable cardioverter defibrillator (ICD) therapy in high-risk ARVC patients, defined as those who’ve had a cardiac arrest, sustained ventricular tachycardia, or have severe right and/or left ventricular dysfunction. ICD therapy gets a Class IIa recommendation in those with at least one of the major risk factors: syncope, nonsustained ventricular tachycardia, and moderate ventricular dysfunction. For ARVC patients with one or more minor risk factors, which include frequent premature ventricular contractions and inducible ventricular tachycardia upon electrophysiological testing, the strength of the recommendation for ICD therapy drops to Class IIb, or “may be considered.” And for low-risk patients, those with confirmed ARVC but no phenotypic expressions of the disorder, the ICD recommendation is Class III, meaning nonindicated.
“There’s a very low threshold for putting in an ICD in patients with ARVC because if you eliminate the arrhythmic mortality, progression to heart failure needing advanced therapies or transplant is extremely rare as long as they’re restricted from athletics,” Dr. Estes said.
He reported serving as a consultant to Boston Scientific, Medtronic, and St. Jude Medical.bjancin@mdedge.com
SNOWMASS, COLO. – Electrophysiologist N.A. Mark Estes III, MD, has a piece of advice for his general cardiology colleagues regarding arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited arrhythmia syndrome that’s one of the most common causes of sudden death in athletes under the age of 40 years.
“When you have a patient with syncope and an ECG abnormality that suggests ARVC, you immediately restrict activity and immediately go on to imaging. And then it’s time to get that patient off to somebody who deals with these patients all the time,” he said at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
ARVC is thought to affect 1 in 5,000 people. It’s the cause of sudden death in roughly 5% of young athletes in the United States and 25% in Italy, with the disparity believed to be largely caused by underrecognition of the disease.
Dr. Estes was a coauthor of a 2015 international task force consensus statement on the treatment of ARVC (Eur Heart J. 2015 Dec 7;36[46]:3227-37). An updated report that incorporates much new information is due to be released in May 2019.
“The new guidelines are going to put some very clear limits on physical activity: Less than 7 METs [metabolic equivalents], which is about a brisk walk. Exercise is not good with ARVC,” said Dr. Estes, professor of medicine at the University of Pittsburgh.
Patients with ARVC absolutely must be restricted from participation in competitive sports, a step whose importance was demonstrated in the North American Multidisciplinary Study of ARVC, for which Dr. Estes was a coauthor. That study, too recent for inclusion in the 2015 task force consensus statement, showed that competitive sport was associated with a 100% increased risk of ventricular tachyarrhythmias and death, as well as earlier presentation with symptoms, compared with patients with ARVC who engaged in much less intense recreational athletic activity, who in turn didn’t have a risk level any different from inactive patients. That being said, however, the investigators also noted that the absolute risk of ventricular tachyarrhythmias or death remained high even in the inactive and recreational sports participants, at 23% by 2 years post diagnosis (Eur Heart J. 2015 Jul 14;36[27]:1735-43).
ARVC has three phases: An early concealed phase, with an associated high rate of syncope or sudden cardiac death; an intermediate phase marked by frequent arrhythmias; and a late phase involving cardiomyopathy and heart failure. Pathologically, the disease involves progressive loss of myocytes caused by abnormalities of plakoglobin and plakophilin, which Dr. Estes described as “essentially the glue that holds the sarcomeres together.” As myocytes are lost they are replaced by fibrofatty deposits, mostly in the right ventricle, creating a substrate for ventricular arrhythmias.
When to suspect ARVC?
“Anyone who has syncope with exertion automatically has a red flag because there is almost certainly something causing that event that’s potentially malignant,” according to the cardiologist.
An early, sensitive, and reasonably specific hallmark of ARVC on the 12-lead ECG is T wave inversion in right precordial leads V1, V2, and V3 or beyond. An epsilon wave – a small positive deflection at the end of the QRS complex – is present in about one in five patients with ARVC and is diagnostic of the condition.
“It’s an ECG you want to commit to memory. And when you see it, think ARVC,” Dr. Estes advised.
Abnormalities on MRI and 2D echocardiography include right ventricular enlargement and wall motion abnormalities, with left ventricular involvement becoming common in more advanced disease.
The detailed structural, electrographic, functional imaging, histologic, and clinical diagnostic criteria for ARVC, known as the 2010 Task Force Criteria, are readily available (Circulation. 2010 Apr 6;121[13]:1533-41). So are guidelines on genetic testing, which practitioners need to understand is now the standard of care for patients with ARVC and, in the event they are found to have a pathogenic mutation, in first-degree family members as well (Europace. 2011 Aug;13(8):1077-109).
“These days all you need to do is simply Google ‘syncope’ and ‘ARVC’ and you will get to the guidelines,” Dr. Estes advised. “It’s virtually impossible to keep up with all this information, but you should know how to access it and apply it in an individual patient. And learn the role of genetic testing. It’s very much an evolving area, quite mature for the long QT syndromes, but not a robust database for ARVC now. Yet there’s no doubt it’s going to be used more and more for diagnosis, risk stratification, and therapy of ARVC in the future.”
Once the diagnosis of ARVC is made in accordance with the 2010 Task Force Criteria, risk stratification and decision making about definitive therapy become paramount. The international task force consensus statement gives a Class I recommendation to implantable cardioverter defibrillator (ICD) therapy in high-risk ARVC patients, defined as those who’ve had a cardiac arrest, sustained ventricular tachycardia, or have severe right and/or left ventricular dysfunction. ICD therapy gets a Class IIa recommendation in those with at least one of the major risk factors: syncope, nonsustained ventricular tachycardia, and moderate ventricular dysfunction. For ARVC patients with one or more minor risk factors, which include frequent premature ventricular contractions and inducible ventricular tachycardia upon electrophysiological testing, the strength of the recommendation for ICD therapy drops to Class IIb, or “may be considered.” And for low-risk patients, those with confirmed ARVC but no phenotypic expressions of the disorder, the ICD recommendation is Class III, meaning nonindicated.
“There’s a very low threshold for putting in an ICD in patients with ARVC because if you eliminate the arrhythmic mortality, progression to heart failure needing advanced therapies or transplant is extremely rare as long as they’re restricted from athletics,” Dr. Estes said.
He reported serving as a consultant to Boston Scientific, Medtronic, and St. Jude Medical.bjancin@mdedge.com
SNOWMASS, COLO. – Electrophysiologist N.A. Mark Estes III, MD, has a piece of advice for his general cardiology colleagues regarding arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited arrhythmia syndrome that’s one of the most common causes of sudden death in athletes under the age of 40 years.
“When you have a patient with syncope and an ECG abnormality that suggests ARVC, you immediately restrict activity and immediately go on to imaging. And then it’s time to get that patient off to somebody who deals with these patients all the time,” he said at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
ARVC is thought to affect 1 in 5,000 people. It’s the cause of sudden death in roughly 5% of young athletes in the United States and 25% in Italy, with the disparity believed to be largely caused by underrecognition of the disease.
Dr. Estes was a coauthor of a 2015 international task force consensus statement on the treatment of ARVC (Eur Heart J. 2015 Dec 7;36[46]:3227-37). An updated report that incorporates much new information is due to be released in May 2019.
“The new guidelines are going to put some very clear limits on physical activity: Less than 7 METs [metabolic equivalents], which is about a brisk walk. Exercise is not good with ARVC,” said Dr. Estes, professor of medicine at the University of Pittsburgh.
Patients with ARVC absolutely must be restricted from participation in competitive sports, a step whose importance was demonstrated in the North American Multidisciplinary Study of ARVC, for which Dr. Estes was a coauthor. That study, too recent for inclusion in the 2015 task force consensus statement, showed that competitive sport was associated with a 100% increased risk of ventricular tachyarrhythmias and death, as well as earlier presentation with symptoms, compared with patients with ARVC who engaged in much less intense recreational athletic activity, who in turn didn’t have a risk level any different from inactive patients. That being said, however, the investigators also noted that the absolute risk of ventricular tachyarrhythmias or death remained high even in the inactive and recreational sports participants, at 23% by 2 years post diagnosis (Eur Heart J. 2015 Jul 14;36[27]:1735-43).
ARVC has three phases: An early concealed phase, with an associated high rate of syncope or sudden cardiac death; an intermediate phase marked by frequent arrhythmias; and a late phase involving cardiomyopathy and heart failure. Pathologically, the disease involves progressive loss of myocytes caused by abnormalities of plakoglobin and plakophilin, which Dr. Estes described as “essentially the glue that holds the sarcomeres together.” As myocytes are lost they are replaced by fibrofatty deposits, mostly in the right ventricle, creating a substrate for ventricular arrhythmias.
When to suspect ARVC?
“Anyone who has syncope with exertion automatically has a red flag because there is almost certainly something causing that event that’s potentially malignant,” according to the cardiologist.
An early, sensitive, and reasonably specific hallmark of ARVC on the 12-lead ECG is T wave inversion in right precordial leads V1, V2, and V3 or beyond. An epsilon wave – a small positive deflection at the end of the QRS complex – is present in about one in five patients with ARVC and is diagnostic of the condition.
“It’s an ECG you want to commit to memory. And when you see it, think ARVC,” Dr. Estes advised.
Abnormalities on MRI and 2D echocardiography include right ventricular enlargement and wall motion abnormalities, with left ventricular involvement becoming common in more advanced disease.
The detailed structural, electrographic, functional imaging, histologic, and clinical diagnostic criteria for ARVC, known as the 2010 Task Force Criteria, are readily available (Circulation. 2010 Apr 6;121[13]:1533-41). So are guidelines on genetic testing, which practitioners need to understand is now the standard of care for patients with ARVC and, in the event they are found to have a pathogenic mutation, in first-degree family members as well (Europace. 2011 Aug;13(8):1077-109).
“These days all you need to do is simply Google ‘syncope’ and ‘ARVC’ and you will get to the guidelines,” Dr. Estes advised. “It’s virtually impossible to keep up with all this information, but you should know how to access it and apply it in an individual patient. And learn the role of genetic testing. It’s very much an evolving area, quite mature for the long QT syndromes, but not a robust database for ARVC now. Yet there’s no doubt it’s going to be used more and more for diagnosis, risk stratification, and therapy of ARVC in the future.”
Once the diagnosis of ARVC is made in accordance with the 2010 Task Force Criteria, risk stratification and decision making about definitive therapy become paramount. The international task force consensus statement gives a Class I recommendation to implantable cardioverter defibrillator (ICD) therapy in high-risk ARVC patients, defined as those who’ve had a cardiac arrest, sustained ventricular tachycardia, or have severe right and/or left ventricular dysfunction. ICD therapy gets a Class IIa recommendation in those with at least one of the major risk factors: syncope, nonsustained ventricular tachycardia, and moderate ventricular dysfunction. For ARVC patients with one or more minor risk factors, which include frequent premature ventricular contractions and inducible ventricular tachycardia upon electrophysiological testing, the strength of the recommendation for ICD therapy drops to Class IIb, or “may be considered.” And for low-risk patients, those with confirmed ARVC but no phenotypic expressions of the disorder, the ICD recommendation is Class III, meaning nonindicated.
“There’s a very low threshold for putting in an ICD in patients with ARVC because if you eliminate the arrhythmic mortality, progression to heart failure needing advanced therapies or transplant is extremely rare as long as they’re restricted from athletics,” Dr. Estes said.
He reported serving as a consultant to Boston Scientific, Medtronic, and St. Jude Medical.bjancin@mdedge.com
REPORTING FROM ACC SNOWMASS 2019
Statin adherence lower in women, minorities
Women, younger patients, and individuals from minority groups are significantly less likely to be adherent with their statins, and are at greater risk of hospitalization and death, a study has found.
In JAMA Cardiology, researchers report the outcomes of a retrospective cohort analysis involving 347,104 adults with atherosclerotic cardiovascular disease and stable statin prescriptions, who were treated within the Veterans Affairs Health System.
Statin adherence – defined as a medication possession ratio of 80% or above – was 87.7%. Patients on a moderate intensity of statin therapy were slightly more adherent than were patients on low- or high-intensity therapy.
The lowest levels of adherence were seen in the youngest patients. Those aged under 35 years had a 60% lower likelihood of adherence compared with the reference group aged 65-74 years, and those aged 35-44 years had a 47% lower likelihood of adherence. From age 55 on, adherence improved.
Women were 11% less likely to be adherent to statin therapy than were men. Adherence was significantly different among persons of different racial backgrounds and ethnicities: black patients were 42% less likely to be adherent compared with non-Hispanic whites, Asian patients were 18% less likely to be adherent, and Hispanic patients were 27% less likely to be adherent.
. Among patients with a medication possession ratio less than 50%, 13.4% were hospitalized for ischemic heart disease or ischemic stroke, compared with 11.5% of patients who had a medication possession ratio of 90% or above, even after adjustment for baseline characteristics.
Researchers saw a dose-response association between lower adherence and higher mortality. The incidence of death in the first year was 8.8% in patients with a medication possession ration below 50%, 7.5% for those with a ratio of 50%-69%, 6.3% for those with a ratio between 70% and 89%, and 5.7% among those with a medication possession ratio at or above 90%.
This effect was slightly attenuated by adjustment for adherence to other cardiac medications, but the association remained significant.
“Although statins are among the most effective drugs for the secondary prevention of [atherosclerotic cardiovascular disease], low adherence is a common problem,” wrote Dr. Fatima Rodriguez of Stanford (Calif.) University’s Division of Cardiovascular Medicine, and her coauthors. “Minorities have not been well represented in statin-related trials and more work is needed to implement strategies to improve guideline adherence in these populations.”
Stanford’s Division of Cardiovascular Medicine supported the study. The investigators have received funding from the Doris Duke Charitable Trust, the Department of Veterans Affairs Health Services Research and Development Service, the National Lipid Association, and Duke Clinical Research Institute.
SOURCE: Rodriguez F et al. JAMA Cardiol. 2019 Feb 13. doi: 10.1001/jamacardio.2018.4936.
Women, younger patients, and individuals from minority groups are significantly less likely to be adherent with their statins, and are at greater risk of hospitalization and death, a study has found.
In JAMA Cardiology, researchers report the outcomes of a retrospective cohort analysis involving 347,104 adults with atherosclerotic cardiovascular disease and stable statin prescriptions, who were treated within the Veterans Affairs Health System.
Statin adherence – defined as a medication possession ratio of 80% or above – was 87.7%. Patients on a moderate intensity of statin therapy were slightly more adherent than were patients on low- or high-intensity therapy.
The lowest levels of adherence were seen in the youngest patients. Those aged under 35 years had a 60% lower likelihood of adherence compared with the reference group aged 65-74 years, and those aged 35-44 years had a 47% lower likelihood of adherence. From age 55 on, adherence improved.
Women were 11% less likely to be adherent to statin therapy than were men. Adherence was significantly different among persons of different racial backgrounds and ethnicities: black patients were 42% less likely to be adherent compared with non-Hispanic whites, Asian patients were 18% less likely to be adherent, and Hispanic patients were 27% less likely to be adherent.
. Among patients with a medication possession ratio less than 50%, 13.4% were hospitalized for ischemic heart disease or ischemic stroke, compared with 11.5% of patients who had a medication possession ratio of 90% or above, even after adjustment for baseline characteristics.
Researchers saw a dose-response association between lower adherence and higher mortality. The incidence of death in the first year was 8.8% in patients with a medication possession ration below 50%, 7.5% for those with a ratio of 50%-69%, 6.3% for those with a ratio between 70% and 89%, and 5.7% among those with a medication possession ratio at or above 90%.
This effect was slightly attenuated by adjustment for adherence to other cardiac medications, but the association remained significant.
“Although statins are among the most effective drugs for the secondary prevention of [atherosclerotic cardiovascular disease], low adherence is a common problem,” wrote Dr. Fatima Rodriguez of Stanford (Calif.) University’s Division of Cardiovascular Medicine, and her coauthors. “Minorities have not been well represented in statin-related trials and more work is needed to implement strategies to improve guideline adherence in these populations.”
Stanford’s Division of Cardiovascular Medicine supported the study. The investigators have received funding from the Doris Duke Charitable Trust, the Department of Veterans Affairs Health Services Research and Development Service, the National Lipid Association, and Duke Clinical Research Institute.
SOURCE: Rodriguez F et al. JAMA Cardiol. 2019 Feb 13. doi: 10.1001/jamacardio.2018.4936.
Women, younger patients, and individuals from minority groups are significantly less likely to be adherent with their statins, and are at greater risk of hospitalization and death, a study has found.
In JAMA Cardiology, researchers report the outcomes of a retrospective cohort analysis involving 347,104 adults with atherosclerotic cardiovascular disease and stable statin prescriptions, who were treated within the Veterans Affairs Health System.
Statin adherence – defined as a medication possession ratio of 80% or above – was 87.7%. Patients on a moderate intensity of statin therapy were slightly more adherent than were patients on low- or high-intensity therapy.
The lowest levels of adherence were seen in the youngest patients. Those aged under 35 years had a 60% lower likelihood of adherence compared with the reference group aged 65-74 years, and those aged 35-44 years had a 47% lower likelihood of adherence. From age 55 on, adherence improved.
Women were 11% less likely to be adherent to statin therapy than were men. Adherence was significantly different among persons of different racial backgrounds and ethnicities: black patients were 42% less likely to be adherent compared with non-Hispanic whites, Asian patients were 18% less likely to be adherent, and Hispanic patients were 27% less likely to be adherent.
. Among patients with a medication possession ratio less than 50%, 13.4% were hospitalized for ischemic heart disease or ischemic stroke, compared with 11.5% of patients who had a medication possession ratio of 90% or above, even after adjustment for baseline characteristics.
Researchers saw a dose-response association between lower adherence and higher mortality. The incidence of death in the first year was 8.8% in patients with a medication possession ration below 50%, 7.5% for those with a ratio of 50%-69%, 6.3% for those with a ratio between 70% and 89%, and 5.7% among those with a medication possession ratio at or above 90%.
This effect was slightly attenuated by adjustment for adherence to other cardiac medications, but the association remained significant.
“Although statins are among the most effective drugs for the secondary prevention of [atherosclerotic cardiovascular disease], low adherence is a common problem,” wrote Dr. Fatima Rodriguez of Stanford (Calif.) University’s Division of Cardiovascular Medicine, and her coauthors. “Minorities have not been well represented in statin-related trials and more work is needed to implement strategies to improve guideline adherence in these populations.”
Stanford’s Division of Cardiovascular Medicine supported the study. The investigators have received funding from the Doris Duke Charitable Trust, the Department of Veterans Affairs Health Services Research and Development Service, the National Lipid Association, and Duke Clinical Research Institute.
SOURCE: Rodriguez F et al. JAMA Cardiol. 2019 Feb 13. doi: 10.1001/jamacardio.2018.4936.
FROM JAMA CARDIOLOGY
Key clinical point: Women, nonwhite, and younger patients are significantly less likely to be adherent to statin therapy.
Major finding: Women are 11% less likely than are men to adhere to statin therapy.
Study details: Retrospective cohort analysis involving 347,104 adults with atherosclerotic cardiovascular disease.
Disclosures: The Division of Cardiovascular Medicine at Stanford (Calif.) University supported the study. The investigators have received funding from the Doris Duke Charitable Trust, the Department of Veterans Affairs Health Services Research and Development Service, the National Lipid Association, and Duke Clinical Research Institute.
Source: Rodriguez F et al. JAMA Cardiol. 2019, Feb 13. doi: 10.1001/jamacardio.2018.4936.
What comes first with SGLT2 inhibitors – diabetes or heart failure?
This week in MDedge Cardiocast: Most tPA-eligible stroke patients now get treated within an hour, atrial fib patients with prior hemorrhagic stroke who get their LAA closed can be safely treated, , and the MESA cardiovascular disease risk calculator can be an improvement on the ACC/AHA version.
This week in MDedge Cardiocast: Most tPA-eligible stroke patients now get treated within an hour, atrial fib patients with prior hemorrhagic stroke who get their LAA closed can be safely treated, , and the MESA cardiovascular disease risk calculator can be an improvement on the ACC/AHA version.
This week in MDedge Cardiocast: Most tPA-eligible stroke patients now get treated within an hour, atrial fib patients with prior hemorrhagic stroke who get their LAA closed can be safely treated, , and the MESA cardiovascular disease risk calculator can be an improvement on the ACC/AHA version.
Deferoxamine does not improve 90-day outcomes after ICH
HONOLULU – (ICH), according to trial results described at the International Stroke Conference sponsored by the American Heart Association. However, the drug is safe and well tolerated and data suggest that it may improve outcomes at 180 days.
Animal studies indicate that iron, which is released from hemolyzed red blood cells, accumulates in the brain after ICH and is associated with secondary neuronal injury and death. Researchers have found that deferoxamine, an iron chelator, provides neuroprotection and improves recovery after experimental ICH. The drug also has anti-inflammatory, antiapoptotic, and BP-lowering effects. Deferoxamine has been approved since the 1960s.
Magdy H. Selim, MD, PhD, a neurologist at Beth Israel Deaconess Medical Center in Boston, and colleagues hypothesized that treatment with deferoxamine could improve outcomes in patients with ICH. The researchers conducted a phase 2 clinical trial to evaluate whether deferoxamine should be studied in a phase 3 efficacy trial. In their multicenter, double-blind study, Dr. Selim and his colleagues randomized patients with spontaneous supratentorial ICH in equal groups to 32 mg/kg per day of deferoxamine or saline placebo. Treatments were administered as intravenous infusions for 3 consecutive days, and therapy was initiated within 24 hours after ICH onset. The follow-up period was 6 months.
Eligible participants had an National Institutes of Health Stroke Scale score of 6 or higher, a Glasgow Coma Scale score greater than 6, and had been functionally independent before the hemorrhage. The researchers excluded patients with a secondary cause for ICH or coagulopathy.
The primary endpoint in the futility analysis was the proportion of participants with a good clinical outcome – defined as a modified Rankin Scale (mRS) score of 0-2 – at 90 days and 180 days. The secondary endpoint was good outcome, defined as an mRS score of 0-3, at 90 days. Safety endpoints included all deferoxamine-related adverse events until day 7 or discharge (whichever was earlier) and serious adverse events through day 90.
Dr. Selim and his colleagues enrolled 294 participants in their trial, 3 of whom did not receive treatment. Of these included participants, 147 (50.5%) were randomized to placebo and 144 (49.5%) were randomized to deferoxamine. Participants’ mean age was 60.3 years, and 38.5% of the population was female.
Overall, the two study arms did not differ significantly according to demographic and clinical characteristics, however, there were more nonwhite patients in the deferoxamine arm than in the placebo arm, however. In addition, thalamic hemorrhage and intraventricular hemorrhage were more common in the placebo-treated group and hemorrhages in the putamen and basal ganglia were more common in the deferoxamine-treated group.
The rates of adverse events were comparable between the two study arms. Dr. Selim and his colleagues found no unexpected safety issues. Mortality was low, and the 90-day and 180-day mortality rates were comparable between the two treatment arms.
Approximately 34% of deferoxamine-treated patients and 33% of placebo-treated patients had an mRS score of 0-2 at 90 days. The adjusted absolute risk difference between arms was 0.6%; this result did not surpass the predefined futility threshold. The risk difference between groups for mRS score of 0-2 at 180 days was 8.6% in favor of deferoxamine, which did surpass the futility threshold.
The risk difference for meeting the secondary endpoint was 6.2% in favor of deferoxamine; this result did not surpass the futility threshold. Patients in both treatment groups improved between day 90 and day 180. The likelihood of good outcome was approximately 10% higher in the deferoxamine group at day 90 and 26% higher in the deferoxamine group at day 180.
“It is futile to conduct a phase 3 trial with the anticipation that treatment with deferoxamine would improve outcome, defined as mRS score of 0-2 at 90 days,” said Dr. Selim. “These data, together with the data from MISTIE and CLEAR, suggest that ICH trials need to have a longer follow-up period to capture the full extent of recovery after ICH. Several of our secondary analyses tended to favor deferoxamine over the placebo arm and leave open the possibility that deferoxamine might lead to improved outcome at 180 days.”
The researchers received support from the NIH and the National Institute of Neurological Disorders and Stroke.
SOURCE: Selim MH et al. ISC 2019, Abstract LB22.
HONOLULU – (ICH), according to trial results described at the International Stroke Conference sponsored by the American Heart Association. However, the drug is safe and well tolerated and data suggest that it may improve outcomes at 180 days.
Animal studies indicate that iron, which is released from hemolyzed red blood cells, accumulates in the brain after ICH and is associated with secondary neuronal injury and death. Researchers have found that deferoxamine, an iron chelator, provides neuroprotection and improves recovery after experimental ICH. The drug also has anti-inflammatory, antiapoptotic, and BP-lowering effects. Deferoxamine has been approved since the 1960s.
Magdy H. Selim, MD, PhD, a neurologist at Beth Israel Deaconess Medical Center in Boston, and colleagues hypothesized that treatment with deferoxamine could improve outcomes in patients with ICH. The researchers conducted a phase 2 clinical trial to evaluate whether deferoxamine should be studied in a phase 3 efficacy trial. In their multicenter, double-blind study, Dr. Selim and his colleagues randomized patients with spontaneous supratentorial ICH in equal groups to 32 mg/kg per day of deferoxamine or saline placebo. Treatments were administered as intravenous infusions for 3 consecutive days, and therapy was initiated within 24 hours after ICH onset. The follow-up period was 6 months.
Eligible participants had an National Institutes of Health Stroke Scale score of 6 or higher, a Glasgow Coma Scale score greater than 6, and had been functionally independent before the hemorrhage. The researchers excluded patients with a secondary cause for ICH or coagulopathy.
The primary endpoint in the futility analysis was the proportion of participants with a good clinical outcome – defined as a modified Rankin Scale (mRS) score of 0-2 – at 90 days and 180 days. The secondary endpoint was good outcome, defined as an mRS score of 0-3, at 90 days. Safety endpoints included all deferoxamine-related adverse events until day 7 or discharge (whichever was earlier) and serious adverse events through day 90.
Dr. Selim and his colleagues enrolled 294 participants in their trial, 3 of whom did not receive treatment. Of these included participants, 147 (50.5%) were randomized to placebo and 144 (49.5%) were randomized to deferoxamine. Participants’ mean age was 60.3 years, and 38.5% of the population was female.
Overall, the two study arms did not differ significantly according to demographic and clinical characteristics, however, there were more nonwhite patients in the deferoxamine arm than in the placebo arm, however. In addition, thalamic hemorrhage and intraventricular hemorrhage were more common in the placebo-treated group and hemorrhages in the putamen and basal ganglia were more common in the deferoxamine-treated group.
The rates of adverse events were comparable between the two study arms. Dr. Selim and his colleagues found no unexpected safety issues. Mortality was low, and the 90-day and 180-day mortality rates were comparable between the two treatment arms.
Approximately 34% of deferoxamine-treated patients and 33% of placebo-treated patients had an mRS score of 0-2 at 90 days. The adjusted absolute risk difference between arms was 0.6%; this result did not surpass the predefined futility threshold. The risk difference between groups for mRS score of 0-2 at 180 days was 8.6% in favor of deferoxamine, which did surpass the futility threshold.
The risk difference for meeting the secondary endpoint was 6.2% in favor of deferoxamine; this result did not surpass the futility threshold. Patients in both treatment groups improved between day 90 and day 180. The likelihood of good outcome was approximately 10% higher in the deferoxamine group at day 90 and 26% higher in the deferoxamine group at day 180.
“It is futile to conduct a phase 3 trial with the anticipation that treatment with deferoxamine would improve outcome, defined as mRS score of 0-2 at 90 days,” said Dr. Selim. “These data, together with the data from MISTIE and CLEAR, suggest that ICH trials need to have a longer follow-up period to capture the full extent of recovery after ICH. Several of our secondary analyses tended to favor deferoxamine over the placebo arm and leave open the possibility that deferoxamine might lead to improved outcome at 180 days.”
The researchers received support from the NIH and the National Institute of Neurological Disorders and Stroke.
SOURCE: Selim MH et al. ISC 2019, Abstract LB22.
HONOLULU – (ICH), according to trial results described at the International Stroke Conference sponsored by the American Heart Association. However, the drug is safe and well tolerated and data suggest that it may improve outcomes at 180 days.
Animal studies indicate that iron, which is released from hemolyzed red blood cells, accumulates in the brain after ICH and is associated with secondary neuronal injury and death. Researchers have found that deferoxamine, an iron chelator, provides neuroprotection and improves recovery after experimental ICH. The drug also has anti-inflammatory, antiapoptotic, and BP-lowering effects. Deferoxamine has been approved since the 1960s.
Magdy H. Selim, MD, PhD, a neurologist at Beth Israel Deaconess Medical Center in Boston, and colleagues hypothesized that treatment with deferoxamine could improve outcomes in patients with ICH. The researchers conducted a phase 2 clinical trial to evaluate whether deferoxamine should be studied in a phase 3 efficacy trial. In their multicenter, double-blind study, Dr. Selim and his colleagues randomized patients with spontaneous supratentorial ICH in equal groups to 32 mg/kg per day of deferoxamine or saline placebo. Treatments were administered as intravenous infusions for 3 consecutive days, and therapy was initiated within 24 hours after ICH onset. The follow-up period was 6 months.
Eligible participants had an National Institutes of Health Stroke Scale score of 6 or higher, a Glasgow Coma Scale score greater than 6, and had been functionally independent before the hemorrhage. The researchers excluded patients with a secondary cause for ICH or coagulopathy.
The primary endpoint in the futility analysis was the proportion of participants with a good clinical outcome – defined as a modified Rankin Scale (mRS) score of 0-2 – at 90 days and 180 days. The secondary endpoint was good outcome, defined as an mRS score of 0-3, at 90 days. Safety endpoints included all deferoxamine-related adverse events until day 7 or discharge (whichever was earlier) and serious adverse events through day 90.
Dr. Selim and his colleagues enrolled 294 participants in their trial, 3 of whom did not receive treatment. Of these included participants, 147 (50.5%) were randomized to placebo and 144 (49.5%) were randomized to deferoxamine. Participants’ mean age was 60.3 years, and 38.5% of the population was female.
Overall, the two study arms did not differ significantly according to demographic and clinical characteristics, however, there were more nonwhite patients in the deferoxamine arm than in the placebo arm, however. In addition, thalamic hemorrhage and intraventricular hemorrhage were more common in the placebo-treated group and hemorrhages in the putamen and basal ganglia were more common in the deferoxamine-treated group.
The rates of adverse events were comparable between the two study arms. Dr. Selim and his colleagues found no unexpected safety issues. Mortality was low, and the 90-day and 180-day mortality rates were comparable between the two treatment arms.
Approximately 34% of deferoxamine-treated patients and 33% of placebo-treated patients had an mRS score of 0-2 at 90 days. The adjusted absolute risk difference between arms was 0.6%; this result did not surpass the predefined futility threshold. The risk difference between groups for mRS score of 0-2 at 180 days was 8.6% in favor of deferoxamine, which did surpass the futility threshold.
The risk difference for meeting the secondary endpoint was 6.2% in favor of deferoxamine; this result did not surpass the futility threshold. Patients in both treatment groups improved between day 90 and day 180. The likelihood of good outcome was approximately 10% higher in the deferoxamine group at day 90 and 26% higher in the deferoxamine group at day 180.
“It is futile to conduct a phase 3 trial with the anticipation that treatment with deferoxamine would improve outcome, defined as mRS score of 0-2 at 90 days,” said Dr. Selim. “These data, together with the data from MISTIE and CLEAR, suggest that ICH trials need to have a longer follow-up period to capture the full extent of recovery after ICH. Several of our secondary analyses tended to favor deferoxamine over the placebo arm and leave open the possibility that deferoxamine might lead to improved outcome at 180 days.”
The researchers received support from the NIH and the National Institute of Neurological Disorders and Stroke.
SOURCE: Selim MH et al. ISC 2019, Abstract LB22.
REPORTING FROM ISC 2019
Key clinical point: Deferoxamine does not improve disability at 90 days after intracranial hemorrhage.
Major finding: Approximately one-third of patients in both treatment groups had a good outcome.
Study details: A multicenter, randomized, double-blind study of 294 participants with intracranial hemorrhage.
Disclosures: The National Institutes of Health and National Institute of Neurological Disorders and Stroke supported this study.
Source: Selim MH et al. ISC 2019, Abstract LB22.
Take action to mitigate CVD risk in RA patients
Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.
The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.
“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.
It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.
With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.
“But also, RA characteristics played a big role,” he said.
Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).
Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.
To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.
The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.
“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.
As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.
Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.
Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.
Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).
The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:
- CVD screening every 5 years.
- Use of a 1.5 multiplier for risk scores.
- Secondary screening with imaging for select patients.
- Management of traditional risk factors according to local guidelines.
- Minimization of the use of NSAIDs and corticosteroids.
- Emphasis on lifestyle management.
Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.
“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.
That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.
He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.
“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.
A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.
For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.
Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.
Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.
Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.
Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.
The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.
“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.
It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.
With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.
“But also, RA characteristics played a big role,” he said.
Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).
Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.
To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.
The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.
“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.
As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.
Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.
Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.
Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).
The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:
- CVD screening every 5 years.
- Use of a 1.5 multiplier for risk scores.
- Secondary screening with imaging for select patients.
- Management of traditional risk factors according to local guidelines.
- Minimization of the use of NSAIDs and corticosteroids.
- Emphasis on lifestyle management.
Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.
“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.
That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.
He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.
“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.
A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.
For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.
Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.
Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.
Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.
Emerging understanding of the increased incidence of cardiovascular disease in patients with rheumatoid arthritis is providing greater insight regarding mitigation of risk, according to Jon T. Giles, MD.
The mechanisms of increased cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) are multifactorial; in addition to traditional risk factors for CVD, chronically elevated levels of systemic inflammatory cytokines likely play a major role in atherogenesis and myocardial dysfunction in RA patients, and the interactions between those elevated cytokine levels and traditional risk factors also play a likely role, Dr. Giles, a rheumatologist, epidemiologist, and clinical researcher in the division of rheumatology at Columbia University, New York, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
In addition, the relationship between traditional fasting lipids and atherosclerosis is different in RA patients from that in non-RA patients, he said, noting that this has important implications for CVD screening and risk management. The phenotype of CVD in RA based on the current literature is also one involving more coronary atherosclerosis in which the atherosclerotic plaques are more inflamed.
“There’s more myocardial dysfunction,” Dr. Giles said, noting that this dysfunction may be partly mediated by more myocardial fibrosis and possibly active subclinical low-grade myocarditis.
It is possible that traditional CVD risk factors such as smoking and hypertension have a greater impact in RA patients, but it’s likely that most of the differences are related to RA-specific factors such as autoimmunity, inflammation, and genetics, as well as some nontraditional CVD risk factors such as stress, anxiety, and depression that may be increased in RA patients, he noted.
With respect to traditional CVD risk factors, a recent study of more than 5,600 RA patients without CVD who were followed for an average of almost 6 years at 13 centers in Europe and the United States showed that 389 experienced CVD events, and the most common CVD risk factors in those patients were smoking – particularly in men – and hypertension.
“But also, RA characteristics played a big role,” he said.
Disease activity was one of the major risk factors for CVD events in RA patients, and the traditional CVD risk factor of hyperlipidemia, and particularly elevated low-density lipoprotein (LDL) levels, had less influence in RA patients than in the general population. In men it was “a negative predictor” of CVD events, he said (Ann Rheum Dis. 2018;77:48-54).
Prior studies have also shown a “strange relationship” between lipids and CVD risk in RA patients. For example, RA patients with very low LDL cholesterol have been shown to have higher CVD event rates – a phenomenon known as the “lipid paradox” – and it may be related to inflammation, but the mechanism is unclear,” he said.
To further assess whether RA patients with abnormally low LDL cholesterol levels without the use of statin therapy had more atherosclerotic burden, Dr. Giles and his colleagues looked at more than 600 RA patients and more than 1,000 non-RA patients (Arthritis Rheumatol. 2015;67[suppl 10]:Abstract 2127). They found that RA patients did, indeed, have a greater atherosclerotic burden, which was “quite shocking,” he said.
The burden rivaled that seen in patients with LDL levels greater than 160 mg/dL, he noted.
“Interestingly, these patients did not have higher levels of inflammatory markers, and they did not have higher disease activity scores. They looked exactly the same as the rest of the RA patients,” he said, noting that investigation into why the LDL levels in these patients are so low is ongoing.
As for how atherogenic lipoproteins allow for atherosclerosis and atherogenesis to occur in the setting of low LDL in RA patients, it turns out it’s not just the amount, but also the characteristics of the lipoproteins, such as the size and oxidization of the LDL, which change in the context of systemic inflammation, he explained.
Further, during an acute-phase reaction, high-density lipoprotein (HDL) composition changes rapidly from antiatherogenic to proinflammatory.
Extensive evidence shows that endothelial function is diminished in RA, and that RA patients have these and other proatherogenic mechanisms, as well as other elements of immunity that are associated with atherogenesis, including aspects of both innate and adaptive immune function, he said.
Given the emerging understanding of CVD risk in RA, mitigation of that risk is an important consideration. In fact, the European League Against Rheumatism updated its CVD management guidelines in 2015/2016, including a statement that rheumatologists are responsible for CVD risk management in RA patients (Ann Rheum Dis. 2017;76:17-28).
The guidelines are intended for all inflammatory arthritis, and the recommendation with the strongest level of evidence relates to optimization of disease activity. Also recommended are:
- CVD screening every 5 years.
- Use of a 1.5 multiplier for risk scores.
- Secondary screening with imaging for select patients.
- Management of traditional risk factors according to local guidelines.
- Minimization of the use of NSAIDs and corticosteroids.
- Emphasis on lifestyle management.
Importantly, research has suggested that screening for hyperlipidemia is substandard in RA, and that standard risk stratification tools underperform in the setting of RA, he said.
“So my approach, and this is not evidence based yet ... comes down to what [a patient’s] apparent risk is. So if an RA patient is high risk based on your apparent risk prediction, then they are likely high risk and maybe even higher than estimated,” Dr. Giles said. These patients need optimization of their traditional risk factors and their inflammatory factors and should therefore receive a high-intensity statin regardless of lipid levels, he said.
That means atorvastatin at a dose of at least 40 mg or rosuvastatin at a dose of at least 20 mg, he said, adding that some studies have suggested that statins work as well in RA patients as in non-RA patients, and that RA patients with CVD risk do better with a statin than without.
He considers patients who have intermediate risk based on the risk calculation to actually be high risk in most cases, and they, too, need maximal optimization of traditional CVD risk factors and inflammatory factors.
“Consider one-time secondary imaging for all of these patients,” he advised, noting that a coronary calcium score from a chest CT scan is a good option that has low radiation, can be quantified, and is increasingly covered by insurance.
A coronary calcium score of 0 on chest CT is highly reassuring, and a score that is greater than what is expected for age, gender, and/or race can help define the intensity of intervention, he said.
For example, if a patient’s score is 300 but should be 50, that patient should be treated as if he or she has coronary artery disease. Patients with high scores in general – particularly those with scores over 300 – should also be maximally managed, he said.
Patients at low risk based on risk calculations usually are low risk, but some can be high risk, so again, maximal optimization of risk factors is recommended.
Secondary imaging can be considered in some of these patients, and while it’s not entirely clear which are at greatest risk, Dr. Giles said he recommends screening those with treatment-resistant active disease, those with high disease severity, and those with abnormally low LDL.
Dr. Giles is a consultant for Genentech, Lilly, Horizon, Bristol-Myers Squibb, and UCB, and he has received grant support from Pfizer.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
PTSD, cardiovascular disease link likely caused by higher comorbidity burden
Although PTSD is strongly linked to cardiovascular disease, it is not an independent risk factor, results of a recent analysis suggest.
Instead, the association between PTSD and cardiovascular disease (CVD) is likely explained by factors such as smoking and physical and psychiatric disorders, according to authors of the analysis based on EHR data for more than 4,000 U.S. veterans.
Individuals with PTSD were 41% more likely than those without it to develop cardiovascular disease, according to the researchers, led by Jeffrey F. Scherrer, PhD, of Saint Louis University and the Harry S. Truman Veterans Administration Medical Center in Columbia, Mo.
However, PTSD was not associated with CVD in the study after adjustment for physical, psychiatric, and behavioral conditions, Dr. Scherrer and his colleagues reported in the Journal of the American Heart Association.
“Recognizing that PTSD does not preordain CVD may empower patients to seek care to prevent and/or manage CVD risk factors,” they wrote.
Health behavior change and management of chronic disease can mitigate risk of CVD in patients with or without PTSD, they added.
This result contrasts with earlier work associating PTSD with CVD, the authors wrote. In particular, a few well-designed studies did indicate that the link between PTSD and CVD was weakened, but still significant, when controlling for traditional CVD risk factors such as smoking, diabetes, and hypertension.
In the current study, investigators controlled for a variety of physical and psychiatric conditions, as well as smoking, in data for Veterans Affairs patients, of whom 2,519 had a PTSD diagnosis and 1,659 did not. These patients were 87% male, 60% white, and had an average age of 50 years.
The investigators found that PTSD was significantly associated with incident CVD after adjusting for age, with a hazard ratio of 1.41 (95% confidence interval, 1.21-1.63; P less than .0001).
That association remained significant after adjusting for diabetes, obesity, hypertension, and hyperlipidemia, but the magnitude of the association dropped considerably (HR, 1.23; 95% CI, 1.06-1.44; P less than .007) and dropped out altogether after controlling for smoking, substance abuse, sleep disorders, anxiety, and depression (HR, 0.96; 95% CI, 0.81-1.15; P = .691).
Taken together, these findings suggest the association with incident CVD may be explained by combinations of comorbidities that are more prevalent in patients who have PTSD than in those who do not, Dr. Scherrer and his coauthors wrote.
“Because these conditions are more common in patients with PTSD, closer monitoring for comorbidities may be warranted,” they concluded. “Early detection and effective management may reduce the burden of CVD associated with PTSD.”
One study coinvestigator reported consulting for Noblis Therapeutics and grant-related disclosures with the Department of Veterans Affairs, Department of Defense, and National Institute of Mental Health.
SOURCE: Scherrer JF et al. J Am Heart Assoc. 2019 Feb 13. doi: 10.1161/JAHA.118.011133.
Although PTSD is strongly linked to cardiovascular disease, it is not an independent risk factor, results of a recent analysis suggest.
Instead, the association between PTSD and cardiovascular disease (CVD) is likely explained by factors such as smoking and physical and psychiatric disorders, according to authors of the analysis based on EHR data for more than 4,000 U.S. veterans.
Individuals with PTSD were 41% more likely than those without it to develop cardiovascular disease, according to the researchers, led by Jeffrey F. Scherrer, PhD, of Saint Louis University and the Harry S. Truman Veterans Administration Medical Center in Columbia, Mo.
However, PTSD was not associated with CVD in the study after adjustment for physical, psychiatric, and behavioral conditions, Dr. Scherrer and his colleagues reported in the Journal of the American Heart Association.
“Recognizing that PTSD does not preordain CVD may empower patients to seek care to prevent and/or manage CVD risk factors,” they wrote.
Health behavior change and management of chronic disease can mitigate risk of CVD in patients with or without PTSD, they added.
This result contrasts with earlier work associating PTSD with CVD, the authors wrote. In particular, a few well-designed studies did indicate that the link between PTSD and CVD was weakened, but still significant, when controlling for traditional CVD risk factors such as smoking, diabetes, and hypertension.
In the current study, investigators controlled for a variety of physical and psychiatric conditions, as well as smoking, in data for Veterans Affairs patients, of whom 2,519 had a PTSD diagnosis and 1,659 did not. These patients were 87% male, 60% white, and had an average age of 50 years.
The investigators found that PTSD was significantly associated with incident CVD after adjusting for age, with a hazard ratio of 1.41 (95% confidence interval, 1.21-1.63; P less than .0001).
That association remained significant after adjusting for diabetes, obesity, hypertension, and hyperlipidemia, but the magnitude of the association dropped considerably (HR, 1.23; 95% CI, 1.06-1.44; P less than .007) and dropped out altogether after controlling for smoking, substance abuse, sleep disorders, anxiety, and depression (HR, 0.96; 95% CI, 0.81-1.15; P = .691).
Taken together, these findings suggest the association with incident CVD may be explained by combinations of comorbidities that are more prevalent in patients who have PTSD than in those who do not, Dr. Scherrer and his coauthors wrote.
“Because these conditions are more common in patients with PTSD, closer monitoring for comorbidities may be warranted,” they concluded. “Early detection and effective management may reduce the burden of CVD associated with PTSD.”
One study coinvestigator reported consulting for Noblis Therapeutics and grant-related disclosures with the Department of Veterans Affairs, Department of Defense, and National Institute of Mental Health.
SOURCE: Scherrer JF et al. J Am Heart Assoc. 2019 Feb 13. doi: 10.1161/JAHA.118.011133.
Although PTSD is strongly linked to cardiovascular disease, it is not an independent risk factor, results of a recent analysis suggest.
Instead, the association between PTSD and cardiovascular disease (CVD) is likely explained by factors such as smoking and physical and psychiatric disorders, according to authors of the analysis based on EHR data for more than 4,000 U.S. veterans.
Individuals with PTSD were 41% more likely than those without it to develop cardiovascular disease, according to the researchers, led by Jeffrey F. Scherrer, PhD, of Saint Louis University and the Harry S. Truman Veterans Administration Medical Center in Columbia, Mo.
However, PTSD was not associated with CVD in the study after adjustment for physical, psychiatric, and behavioral conditions, Dr. Scherrer and his colleagues reported in the Journal of the American Heart Association.
“Recognizing that PTSD does not preordain CVD may empower patients to seek care to prevent and/or manage CVD risk factors,” they wrote.
Health behavior change and management of chronic disease can mitigate risk of CVD in patients with or without PTSD, they added.
This result contrasts with earlier work associating PTSD with CVD, the authors wrote. In particular, a few well-designed studies did indicate that the link between PTSD and CVD was weakened, but still significant, when controlling for traditional CVD risk factors such as smoking, diabetes, and hypertension.
In the current study, investigators controlled for a variety of physical and psychiatric conditions, as well as smoking, in data for Veterans Affairs patients, of whom 2,519 had a PTSD diagnosis and 1,659 did not. These patients were 87% male, 60% white, and had an average age of 50 years.
The investigators found that PTSD was significantly associated with incident CVD after adjusting for age, with a hazard ratio of 1.41 (95% confidence interval, 1.21-1.63; P less than .0001).
That association remained significant after adjusting for diabetes, obesity, hypertension, and hyperlipidemia, but the magnitude of the association dropped considerably (HR, 1.23; 95% CI, 1.06-1.44; P less than .007) and dropped out altogether after controlling for smoking, substance abuse, sleep disorders, anxiety, and depression (HR, 0.96; 95% CI, 0.81-1.15; P = .691).
Taken together, these findings suggest the association with incident CVD may be explained by combinations of comorbidities that are more prevalent in patients who have PTSD than in those who do not, Dr. Scherrer and his coauthors wrote.
“Because these conditions are more common in patients with PTSD, closer monitoring for comorbidities may be warranted,” they concluded. “Early detection and effective management may reduce the burden of CVD associated with PTSD.”
One study coinvestigator reported consulting for Noblis Therapeutics and grant-related disclosures with the Department of Veterans Affairs, Department of Defense, and National Institute of Mental Health.
SOURCE: Scherrer JF et al. J Am Heart Assoc. 2019 Feb 13. doi: 10.1161/JAHA.118.011133.
FROM THE JOURNAL OF THE AMERICAN HEART ASSOCIATION
Key clinical point: The link between PTSD and cardiovascular disease may be explained by higher prevalence of comorbidities in individuals with the disorder, rather than the disorder itself.
Major finding: PTSD was significantly associated with incident cardiovascular disease after adjusting for age, but was no longer associated with cardiovascular disease after further adjustment for physical and psychological comorbidities and smoking (hazard ratio, 0.96; 95% confidence interval, 0.81-1.15; P = 0.691).
Study details: A retrospective study of EHR data for Veterans Affairs patients, of whom 2,519 had a PTSD diagnosis and 1,659 did not.
Disclosures: One study author reported financial disclosures related to Noblis Therapeutics, the Department of Veterans Affairs, Department of Defense, the National Institute of Mental Health.
Source: Scherrer JF et al. J Am Heart Assoc. 2019 Feb 13. doi: 10.1161/JAHA.118.011133.
Conservatism spreads in prostate cancer
, the United States now has more than 100 measles cases for the year, e-cigarette use reverses progress in reducing teens’ tobacco use, and consider adopting the MESA 10-year coronary heart disease risk calculator.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
, the United States now has more than 100 measles cases for the year, e-cigarette use reverses progress in reducing teens’ tobacco use, and consider adopting the MESA 10-year coronary heart disease risk calculator.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
, the United States now has more than 100 measles cases for the year, e-cigarette use reverses progress in reducing teens’ tobacco use, and consider adopting the MESA 10-year coronary heart disease risk calculator.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
