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Preventing cardiac neonatal lupus with hydroxychloroquine
SNOWMASS, COLO. – The prospect of preventing fetal heart block from neonatal lupus by using hydroxychloroquine to treat women with systemic lupus erythematosus and other anti-Ro antibody-positive rheumatologic diseases throughout pregnancy is drawing mounting physician interest.
"I think these new data are exciting. I actually now have changed my practice as a result of these two studies. I don’t think these studies demand that everybody else change what they’re doing, but I now give hydroxychloroquine to our pregnant patients who have anti-Ro antibodies," Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Maternal anti-Ro antibodies readily transfer across the placenta starting at about week 16 of gestation. Roughly 2% of fetuses whose mothers are positive for these antibodies develop congenital complete heart block caused by inflammation at the atrioventricular node. It’s an irreversible condition with significant morbidity and even mortality.
Moreover, if the mother has previously given birth to a baby with any manifestation of neonatal lupus – even if limited to neonatal rash – the risk of congenital complete heart block in subsequent pregnancies climbs to about 15%, according to Dr. Clowse, a rheumatologist and director of the Duke Autoimmunity in Pregnancy Registry at Duke University, Durham, N.C.
She and her coinvestigators at Duke conducted one of the two studies that have led to her change in practice. It was a retrospective observational study of the recent Duke experience with pregnancies complicated by the presence of maternal anti-Ro antibodies. Twenty of the 33 subjects had systemic lupus erythematosus (SLE); most of the rest had unspecified rheumatologic disease or Sjögren’s syndrome.
Only 1 of 14 women treated with 200-400 mg/day of hydroxychloroquine throughout pregnancy had a baby with congenital heart block, while 7 of 19 pregnancies where hydroxychloroquine wasn’t prescribed resulted in this fetal cardiac disorder. This translated into an 86% relative risk reduction of fetal congenital complete heart block in hydroxychloroquine recipients (Am. J. Obstet. Gynecol. 2013;208:64.e1-7).
Dr. Clowse noted that the Duke study confirms a recent report by investigators at New York University, who searched three databases in the United States, France, and England and identified 257 pregnancies involving mothers positive for anti-Ro antibodies, all of whom had previously given birth to a child with cardiac neonatal lupus. Forty of the women were on hydroxychloroquine starting before 10 weeks of gestation and continued throughout pregnancy; the other 217 didn’t take hydroxychloroquine during the pregnancy. The incidence of recurrent neonatal congenital heart block was 7.5% in the hydroxychloroquine group, compared with 21.2% in mothers who didn’t receive the drug, for a 77% relative risk reduction (Circulation 2012;126:76-82).
The New York University researchers are in the midst of a confirmatory prospective nonrandomized study in women with a history of pregnancy complicated by fetal complete heart block who are on hydroxychloroquine in a subsequent pregnancy. But because it will probably take several more years to accumulate sufficient pregnancies to draw statistically significant conclusions, and in light of hydroxychloroquine’s favorable risk: benefit ratio in pregnancy, Dr. Clowse has decided to change her own practice.
Hydroxychloroquine is rated Pregnancy Class C by the Food and Drug Administration. It readily crosses the placenta. It has not been associated with pregnancy loss, prematurity, congenital anomalies, or any other adverse fetal effects. Dr. Clowse considers hydroxychloroquine to be the best medication for prevention of SLE flares in pregnancy.
She reported serving as a consultant to UCB.
SNOWMASS, COLO. – The prospect of preventing fetal heart block from neonatal lupus by using hydroxychloroquine to treat women with systemic lupus erythematosus and other anti-Ro antibody-positive rheumatologic diseases throughout pregnancy is drawing mounting physician interest.
"I think these new data are exciting. I actually now have changed my practice as a result of these two studies. I don’t think these studies demand that everybody else change what they’re doing, but I now give hydroxychloroquine to our pregnant patients who have anti-Ro antibodies," Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Maternal anti-Ro antibodies readily transfer across the placenta starting at about week 16 of gestation. Roughly 2% of fetuses whose mothers are positive for these antibodies develop congenital complete heart block caused by inflammation at the atrioventricular node. It’s an irreversible condition with significant morbidity and even mortality.
Moreover, if the mother has previously given birth to a baby with any manifestation of neonatal lupus – even if limited to neonatal rash – the risk of congenital complete heart block in subsequent pregnancies climbs to about 15%, according to Dr. Clowse, a rheumatologist and director of the Duke Autoimmunity in Pregnancy Registry at Duke University, Durham, N.C.
She and her coinvestigators at Duke conducted one of the two studies that have led to her change in practice. It was a retrospective observational study of the recent Duke experience with pregnancies complicated by the presence of maternal anti-Ro antibodies. Twenty of the 33 subjects had systemic lupus erythematosus (SLE); most of the rest had unspecified rheumatologic disease or Sjögren’s syndrome.
Only 1 of 14 women treated with 200-400 mg/day of hydroxychloroquine throughout pregnancy had a baby with congenital heart block, while 7 of 19 pregnancies where hydroxychloroquine wasn’t prescribed resulted in this fetal cardiac disorder. This translated into an 86% relative risk reduction of fetal congenital complete heart block in hydroxychloroquine recipients (Am. J. Obstet. Gynecol. 2013;208:64.e1-7).
Dr. Clowse noted that the Duke study confirms a recent report by investigators at New York University, who searched three databases in the United States, France, and England and identified 257 pregnancies involving mothers positive for anti-Ro antibodies, all of whom had previously given birth to a child with cardiac neonatal lupus. Forty of the women were on hydroxychloroquine starting before 10 weeks of gestation and continued throughout pregnancy; the other 217 didn’t take hydroxychloroquine during the pregnancy. The incidence of recurrent neonatal congenital heart block was 7.5% in the hydroxychloroquine group, compared with 21.2% in mothers who didn’t receive the drug, for a 77% relative risk reduction (Circulation 2012;126:76-82).
The New York University researchers are in the midst of a confirmatory prospective nonrandomized study in women with a history of pregnancy complicated by fetal complete heart block who are on hydroxychloroquine in a subsequent pregnancy. But because it will probably take several more years to accumulate sufficient pregnancies to draw statistically significant conclusions, and in light of hydroxychloroquine’s favorable risk: benefit ratio in pregnancy, Dr. Clowse has decided to change her own practice.
Hydroxychloroquine is rated Pregnancy Class C by the Food and Drug Administration. It readily crosses the placenta. It has not been associated with pregnancy loss, prematurity, congenital anomalies, or any other adverse fetal effects. Dr. Clowse considers hydroxychloroquine to be the best medication for prevention of SLE flares in pregnancy.
She reported serving as a consultant to UCB.
SNOWMASS, COLO. – The prospect of preventing fetal heart block from neonatal lupus by using hydroxychloroquine to treat women with systemic lupus erythematosus and other anti-Ro antibody-positive rheumatologic diseases throughout pregnancy is drawing mounting physician interest.
"I think these new data are exciting. I actually now have changed my practice as a result of these two studies. I don’t think these studies demand that everybody else change what they’re doing, but I now give hydroxychloroquine to our pregnant patients who have anti-Ro antibodies," Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Maternal anti-Ro antibodies readily transfer across the placenta starting at about week 16 of gestation. Roughly 2% of fetuses whose mothers are positive for these antibodies develop congenital complete heart block caused by inflammation at the atrioventricular node. It’s an irreversible condition with significant morbidity and even mortality.
Moreover, if the mother has previously given birth to a baby with any manifestation of neonatal lupus – even if limited to neonatal rash – the risk of congenital complete heart block in subsequent pregnancies climbs to about 15%, according to Dr. Clowse, a rheumatologist and director of the Duke Autoimmunity in Pregnancy Registry at Duke University, Durham, N.C.
She and her coinvestigators at Duke conducted one of the two studies that have led to her change in practice. It was a retrospective observational study of the recent Duke experience with pregnancies complicated by the presence of maternal anti-Ro antibodies. Twenty of the 33 subjects had systemic lupus erythematosus (SLE); most of the rest had unspecified rheumatologic disease or Sjögren’s syndrome.
Only 1 of 14 women treated with 200-400 mg/day of hydroxychloroquine throughout pregnancy had a baby with congenital heart block, while 7 of 19 pregnancies where hydroxychloroquine wasn’t prescribed resulted in this fetal cardiac disorder. This translated into an 86% relative risk reduction of fetal congenital complete heart block in hydroxychloroquine recipients (Am. J. Obstet. Gynecol. 2013;208:64.e1-7).
Dr. Clowse noted that the Duke study confirms a recent report by investigators at New York University, who searched three databases in the United States, France, and England and identified 257 pregnancies involving mothers positive for anti-Ro antibodies, all of whom had previously given birth to a child with cardiac neonatal lupus. Forty of the women were on hydroxychloroquine starting before 10 weeks of gestation and continued throughout pregnancy; the other 217 didn’t take hydroxychloroquine during the pregnancy. The incidence of recurrent neonatal congenital heart block was 7.5% in the hydroxychloroquine group, compared with 21.2% in mothers who didn’t receive the drug, for a 77% relative risk reduction (Circulation 2012;126:76-82).
The New York University researchers are in the midst of a confirmatory prospective nonrandomized study in women with a history of pregnancy complicated by fetal complete heart block who are on hydroxychloroquine in a subsequent pregnancy. But because it will probably take several more years to accumulate sufficient pregnancies to draw statistically significant conclusions, and in light of hydroxychloroquine’s favorable risk: benefit ratio in pregnancy, Dr. Clowse has decided to change her own practice.
Hydroxychloroquine is rated Pregnancy Class C by the Food and Drug Administration. It readily crosses the placenta. It has not been associated with pregnancy loss, prematurity, congenital anomalies, or any other adverse fetal effects. Dr. Clowse considers hydroxychloroquine to be the best medication for prevention of SLE flares in pregnancy.
She reported serving as a consultant to UCB.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
Calcipotriene/ betamethasone dipropionate for psoriasis cut health care costs
WAIKOLOA, HAWAII – Topical calcipotriene/betamethasone diproprionate combination products as first-line therapy for newly diagnosed plaque psoriasis result in significantly fewer office visits and lower total health care costs than any other topical psoriasis medications.
That’s the central finding of a retrospective analysis of the MarketScan insurance claims database that included 1 year of follow-up of 7,307 patients placed on calcipotriene/betamethasone dipropionate combination products immediately after diagnosis of plaque psoriasis and 9,670 others who received prescriptions for other topical agents.
During that first year of treatment, patients on various formulations of calcipotriene/betamethasone dipropionate had a mean of 2.79 psoriasis-related office visits and 13.36 total office visits, compared with 4.25 and 16.08 visits, respectively, for patients on other topical psoriasis medications (P less than .0001), Dr. Steven R. Feldman reported in a poster at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.
Mean total health care costs per patient, including pharmacy costs and inpatient and outpatient care, also were significantly lower in the group on calcipotriene/betamethasone dipropionate at $7,786, compared with $11,757, according to Dr. Feldman, professor of dermatology, pathology, and public health sciences and director of the Center for Dermatology Research at Wake Forest University in Winston-Salem, N.C.
There were important baseline differences between the two groups. Of the patients treated with calcipotriene/betamethasone dipropionate, 88% had mild psoriasis, as did only 62% of the patients on other topicals. Psoriatic arthritis was present in 3% of patients on calcipotriene/betamethasone diproprionate, compared with 8% on other topical medications. In a statistical model that adjusted for these and other differences, health care costs during 1 year of follow-up remained significantly lower in the calcipotriene/betamethasone dipropionate group.
The study was funded by LEO Pharma. Dr. Feldman reported receiving research grants from LEO and a couple of dozen other pharmaceutical companies. He also serves as a consultant to 10 pharmaceutical companies.
SDEF and this news organization are owned by the same parent company.
WAIKOLOA, HAWAII – Topical calcipotriene/betamethasone diproprionate combination products as first-line therapy for newly diagnosed plaque psoriasis result in significantly fewer office visits and lower total health care costs than any other topical psoriasis medications.
That’s the central finding of a retrospective analysis of the MarketScan insurance claims database that included 1 year of follow-up of 7,307 patients placed on calcipotriene/betamethasone dipropionate combination products immediately after diagnosis of plaque psoriasis and 9,670 others who received prescriptions for other topical agents.
During that first year of treatment, patients on various formulations of calcipotriene/betamethasone dipropionate had a mean of 2.79 psoriasis-related office visits and 13.36 total office visits, compared with 4.25 and 16.08 visits, respectively, for patients on other topical psoriasis medications (P less than .0001), Dr. Steven R. Feldman reported in a poster at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.
Mean total health care costs per patient, including pharmacy costs and inpatient and outpatient care, also were significantly lower in the group on calcipotriene/betamethasone dipropionate at $7,786, compared with $11,757, according to Dr. Feldman, professor of dermatology, pathology, and public health sciences and director of the Center for Dermatology Research at Wake Forest University in Winston-Salem, N.C.
There were important baseline differences between the two groups. Of the patients treated with calcipotriene/betamethasone dipropionate, 88% had mild psoriasis, as did only 62% of the patients on other topicals. Psoriatic arthritis was present in 3% of patients on calcipotriene/betamethasone diproprionate, compared with 8% on other topical medications. In a statistical model that adjusted for these and other differences, health care costs during 1 year of follow-up remained significantly lower in the calcipotriene/betamethasone dipropionate group.
The study was funded by LEO Pharma. Dr. Feldman reported receiving research grants from LEO and a couple of dozen other pharmaceutical companies. He also serves as a consultant to 10 pharmaceutical companies.
SDEF and this news organization are owned by the same parent company.
WAIKOLOA, HAWAII – Topical calcipotriene/betamethasone diproprionate combination products as first-line therapy for newly diagnosed plaque psoriasis result in significantly fewer office visits and lower total health care costs than any other topical psoriasis medications.
That’s the central finding of a retrospective analysis of the MarketScan insurance claims database that included 1 year of follow-up of 7,307 patients placed on calcipotriene/betamethasone dipropionate combination products immediately after diagnosis of plaque psoriasis and 9,670 others who received prescriptions for other topical agents.
During that first year of treatment, patients on various formulations of calcipotriene/betamethasone dipropionate had a mean of 2.79 psoriasis-related office visits and 13.36 total office visits, compared with 4.25 and 16.08 visits, respectively, for patients on other topical psoriasis medications (P less than .0001), Dr. Steven R. Feldman reported in a poster at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.
Mean total health care costs per patient, including pharmacy costs and inpatient and outpatient care, also were significantly lower in the group on calcipotriene/betamethasone dipropionate at $7,786, compared with $11,757, according to Dr. Feldman, professor of dermatology, pathology, and public health sciences and director of the Center for Dermatology Research at Wake Forest University in Winston-Salem, N.C.
There were important baseline differences between the two groups. Of the patients treated with calcipotriene/betamethasone dipropionate, 88% had mild psoriasis, as did only 62% of the patients on other topicals. Psoriatic arthritis was present in 3% of patients on calcipotriene/betamethasone diproprionate, compared with 8% on other topical medications. In a statistical model that adjusted for these and other differences, health care costs during 1 year of follow-up remained significantly lower in the calcipotriene/betamethasone dipropionate group.
The study was funded by LEO Pharma. Dr. Feldman reported receiving research grants from LEO and a couple of dozen other pharmaceutical companies. He also serves as a consultant to 10 pharmaceutical companies.
SDEF and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM SDEF HAWAII DERMATOLOGY SEMINAR
Postop atrial fib onset occurs at two distinct times
DALLAS -- New-onset postoperative atrial fibrillation following cardiac surgery occurs in two distinct phases, with different risk factors for each.
That's the key finding in an analysis of the recent experience at the University of Alabama, Birmingham, where new-onset postoperative AF occurred in 27% of 1,583 consecutive patients who underwent coronary artery bypass graft and/or valve surgery.
The first peak in the onset of postoperative AF occurred in the first 3 hours after surgery. This was followed by a sharp decline in incidence over the next 24 hours. The second peak happened at postoperative day 2, followed by a more gradual tail off, Dr. Spencer J. Melby reported at the American Heart Association scientific sessions.
Ninety-six percent of all cases of postoperative AF in this retrospective chart review began within the first 7 days after surgery. Of the 423 patients who developed this common and vexing condition, 16% did so within the first 24 hours, 48% had their onset at 24-72 hours, and 36% did so after 72 hours, according to Dr. Melby, a cardiothoracic surgeon at the university.
In a multivariate analysis, the most potent risk factor for onset of postoperative AF during the first phase was mitral valve repair or replacement, which was associated with a 2.5-fold increased risk. The other significant risk factors for early-onset AF were older age -- with 70-year-olds having a 1.6-fold greater risk than 50-year-olds -- and longer ischemic time, with patients whose cross-clamp time was 70 minutes having a 1.3-fold greater risk compared with those who had a cross-clamp time of 35 minutes.
Advanced age was also a risk factor for late-phase onset of AF, but it was a stronger risk factor there than for early onset AF, with 70-year-olds being at threefold greater risk than 50-year-olds -- nearly twice as great a risk as for early-onset postoperative AF. The other significant risk factors for late-phase postoperative AF in a multivariate analysis were white race, with a 1.9-fold increased risk, and heavier body weight, with patients weighing 100 kg being at 1.6-fold greater risk than those tipping the scales at 70 kg.
"We believe that these different risk factors at each time phase are indicative of change over time in the mechanisms that drive postoperative atrial fibrillation," the surgeon said.
The first peak may be the result of tissue trauma, which is typically greater with more complex operations having longer cross-clamp times. And mitral valve procedures often entail contact with the left atrium.
"We?ve found that in patients with onset in the second peak there?s a polymorphonuclear leukocyte riot going on in the pericardial space after surgery. Inflammation is high, oxidative stress is high. Troponin levels are extremely high in the pericardial fluid, so there are problems in the heart muscle itself. The body is trying to heal and may be overdoing it as reflected by the inflammation in that space," Dr. Melby explained.
Dr. Brendan M. Everett, session cochair, noted that postoperative day 2 is when a host of process-of-care issues potentially relevant to postoperative AF come into play.
"Postop day 2 is when pain control begins to slip a bit. Patients are mobilize; chest tubes are pulled. A lot of factors are going on that are very important overall to getting a patient up and out of the hospital but are serious stimuli -- adrenergic and otherwise -- that may force a patient to go into atrial fibrillation," observed Dr. Everett, director of the general cardiology inpatient service at Brigham and Women's Hospital, Boston.
Audience members praised Dr. Melby's study as having "tremendous implications" for clinical practice, especially with regard to patient management guidelines. Dr. Melby noted that postoperative AF is a costly matter: It increases hospital length of stay by 1-2 days at a cost of roughly $10,000 per episode. Nationally, postoperative AF costs $4 billion per year.
Dr. Melby reported having no financial conflicts regarding his study.
DALLAS -- New-onset postoperative atrial fibrillation following cardiac surgery occurs in two distinct phases, with different risk factors for each.
That's the key finding in an analysis of the recent experience at the University of Alabama, Birmingham, where new-onset postoperative AF occurred in 27% of 1,583 consecutive patients who underwent coronary artery bypass graft and/or valve surgery.
The first peak in the onset of postoperative AF occurred in the first 3 hours after surgery. This was followed by a sharp decline in incidence over the next 24 hours. The second peak happened at postoperative day 2, followed by a more gradual tail off, Dr. Spencer J. Melby reported at the American Heart Association scientific sessions.
Ninety-six percent of all cases of postoperative AF in this retrospective chart review began within the first 7 days after surgery. Of the 423 patients who developed this common and vexing condition, 16% did so within the first 24 hours, 48% had their onset at 24-72 hours, and 36% did so after 72 hours, according to Dr. Melby, a cardiothoracic surgeon at the university.
In a multivariate analysis, the most potent risk factor for onset of postoperative AF during the first phase was mitral valve repair or replacement, which was associated with a 2.5-fold increased risk. The other significant risk factors for early-onset AF were older age -- with 70-year-olds having a 1.6-fold greater risk than 50-year-olds -- and longer ischemic time, with patients whose cross-clamp time was 70 minutes having a 1.3-fold greater risk compared with those who had a cross-clamp time of 35 minutes.
Advanced age was also a risk factor for late-phase onset of AF, but it was a stronger risk factor there than for early onset AF, with 70-year-olds being at threefold greater risk than 50-year-olds -- nearly twice as great a risk as for early-onset postoperative AF. The other significant risk factors for late-phase postoperative AF in a multivariate analysis were white race, with a 1.9-fold increased risk, and heavier body weight, with patients weighing 100 kg being at 1.6-fold greater risk than those tipping the scales at 70 kg.
"We believe that these different risk factors at each time phase are indicative of change over time in the mechanisms that drive postoperative atrial fibrillation," the surgeon said.
The first peak may be the result of tissue trauma, which is typically greater with more complex operations having longer cross-clamp times. And mitral valve procedures often entail contact with the left atrium.
"We?ve found that in patients with onset in the second peak there?s a polymorphonuclear leukocyte riot going on in the pericardial space after surgery. Inflammation is high, oxidative stress is high. Troponin levels are extremely high in the pericardial fluid, so there are problems in the heart muscle itself. The body is trying to heal and may be overdoing it as reflected by the inflammation in that space," Dr. Melby explained.
Dr. Brendan M. Everett, session cochair, noted that postoperative day 2 is when a host of process-of-care issues potentially relevant to postoperative AF come into play.
"Postop day 2 is when pain control begins to slip a bit. Patients are mobilize; chest tubes are pulled. A lot of factors are going on that are very important overall to getting a patient up and out of the hospital but are serious stimuli -- adrenergic and otherwise -- that may force a patient to go into atrial fibrillation," observed Dr. Everett, director of the general cardiology inpatient service at Brigham and Women's Hospital, Boston.
Audience members praised Dr. Melby's study as having "tremendous implications" for clinical practice, especially with regard to patient management guidelines. Dr. Melby noted that postoperative AF is a costly matter: It increases hospital length of stay by 1-2 days at a cost of roughly $10,000 per episode. Nationally, postoperative AF costs $4 billion per year.
Dr. Melby reported having no financial conflicts regarding his study.
DALLAS -- New-onset postoperative atrial fibrillation following cardiac surgery occurs in two distinct phases, with different risk factors for each.
That's the key finding in an analysis of the recent experience at the University of Alabama, Birmingham, where new-onset postoperative AF occurred in 27% of 1,583 consecutive patients who underwent coronary artery bypass graft and/or valve surgery.
The first peak in the onset of postoperative AF occurred in the first 3 hours after surgery. This was followed by a sharp decline in incidence over the next 24 hours. The second peak happened at postoperative day 2, followed by a more gradual tail off, Dr. Spencer J. Melby reported at the American Heart Association scientific sessions.
Ninety-six percent of all cases of postoperative AF in this retrospective chart review began within the first 7 days after surgery. Of the 423 patients who developed this common and vexing condition, 16% did so within the first 24 hours, 48% had their onset at 24-72 hours, and 36% did so after 72 hours, according to Dr. Melby, a cardiothoracic surgeon at the university.
In a multivariate analysis, the most potent risk factor for onset of postoperative AF during the first phase was mitral valve repair or replacement, which was associated with a 2.5-fold increased risk. The other significant risk factors for early-onset AF were older age -- with 70-year-olds having a 1.6-fold greater risk than 50-year-olds -- and longer ischemic time, with patients whose cross-clamp time was 70 minutes having a 1.3-fold greater risk compared with those who had a cross-clamp time of 35 minutes.
Advanced age was also a risk factor for late-phase onset of AF, but it was a stronger risk factor there than for early onset AF, with 70-year-olds being at threefold greater risk than 50-year-olds -- nearly twice as great a risk as for early-onset postoperative AF. The other significant risk factors for late-phase postoperative AF in a multivariate analysis were white race, with a 1.9-fold increased risk, and heavier body weight, with patients weighing 100 kg being at 1.6-fold greater risk than those tipping the scales at 70 kg.
"We believe that these different risk factors at each time phase are indicative of change over time in the mechanisms that drive postoperative atrial fibrillation," the surgeon said.
The first peak may be the result of tissue trauma, which is typically greater with more complex operations having longer cross-clamp times. And mitral valve procedures often entail contact with the left atrium.
"We?ve found that in patients with onset in the second peak there?s a polymorphonuclear leukocyte riot going on in the pericardial space after surgery. Inflammation is high, oxidative stress is high. Troponin levels are extremely high in the pericardial fluid, so there are problems in the heart muscle itself. The body is trying to heal and may be overdoing it as reflected by the inflammation in that space," Dr. Melby explained.
Dr. Brendan M. Everett, session cochair, noted that postoperative day 2 is when a host of process-of-care issues potentially relevant to postoperative AF come into play.
"Postop day 2 is when pain control begins to slip a bit. Patients are mobilize; chest tubes are pulled. A lot of factors are going on that are very important overall to getting a patient up and out of the hospital but are serious stimuli -- adrenergic and otherwise -- that may force a patient to go into atrial fibrillation," observed Dr. Everett, director of the general cardiology inpatient service at Brigham and Women's Hospital, Boston.
Audience members praised Dr. Melby's study as having "tremendous implications" for clinical practice, especially with regard to patient management guidelines. Dr. Melby noted that postoperative AF is a costly matter: It increases hospital length of stay by 1-2 days at a cost of roughly $10,000 per episode. Nationally, postoperative AF costs $4 billion per year.
Dr. Melby reported having no financial conflicts regarding his study.
Colchicine: Old drug with a new trick
SNOWMASS, COLO. – Colchicine, a venerable drug Hippocrates proposed as a gout remedy some 2,400 years ago, shows fresh potential as a novel treatment for osteoarthritis.
"I’m going out on a limb here: Could colchicine improve osteoarthritis pain and function? I won’t tell you to do it, but there are a couple of studies that say it may be of some value – and they are intriguing," Dr. Michael H. Pillinger said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Moreover, there is evidence of a biologically plausible mechanism of benefit because osteoarthritis, contrary to conventional wisdom, may actually be an inflammatory disease, added Dr. Pillinger, a rheumatologist at New York University.
Investigators at Tehran (Iran) University of Medical Sciences randomized 61 postmenopausal women with moderate to severe knee osteoarthritis (OA) and no evidence of calcium pyrophosphate deposition disease on x-ray to 0.5 mg twice daily of colchicine or placebo in a double-blind clinical trial. After 3 months of prospective follow-up, the colchicine-treated group showed a mean 11.1-point improvement on a 15-point patient global assessment visual analog scale, compared with a 3.1-point improvement in controls.
The colchicine group also had a 9.8-point improvement on the 15-point physician global assessment, compared with a 3.7-point gain among controls. The mean daily consumption of acetaminophen – used as a rescue analgesic – was 879 mg in the colchicine group and nearly twice as great in controls at 1,621 mg (Clin. Exp. Rheumatol. 2011;29:513-8).
The Iranian study recapitulates an earlier double-blind randomized trial conducted by investigators at King George’s Medical College in Lucknow, India. They randomized 36 patients on background nonsteroidal anti-inflammatory drug (NSAID) therapy for OA of the knee to colchicine at 0.5 mg twice daily or placebo. The coprimary outcomes were the proportions of patients showing at least a 30% improvement in symptoms at 20 weeks as measured by the total WOMAC (Western Ontario and McMaster Universities) osteoarthritis index and a visual analog scale for knee pain. That threshold was achieved on the WOMAC osteoarthritis index by 58% of the colchicine group, compared with 24% of controls, and on the knee pain score by 53% of colchicine-treated patients and 18% of controls (Arthritis Rheum. 2002;47:280-4).
Turning to colchicine’s putative mechanism of benefit in OA, Dr. Pillinger commented that the drug has well-established anti-inflammatory effects on neutrophils. It also curbs tumor necrosis factor–alpha receptor expression on both macrophages and endothelial cells, with resultant inhibition of TNF-alpha secretion. Calcium-containing crystals are common in patients with primary OA, and it has been hypothesized that they activate the inflammasome, which drives production of interleukin-1 (IL-1), a key mediator of cartilage breakdown in OA. Colchicine inhibits this calcium crystal–induced inflammation.
In addition, Dr. Pillinger noted, investigators at Duke University in Durham, N.C., have shown that synovial fluid uric acid levels in 159 patients with OA and no gout were strongly correlated with both synovial fluid IL-1 levels and OA severity. They have proposed that uric acid is released into diseased joints by damaged chondrocytes as a danger signal, and that this uric acid crystallizes at a microscopic level in joints and cartilage, promoting chronic subacute IL-1–mediated inflammation (Proc. Natl. Acad. Sci. U.S.A. 2011;108:2088-93).
Gout and OA appear to be fellow travelers, according to Dr. Pillinger. He cited a study by his New York University colleague Dr. Rennie G. Howard, who conducted a rigorous evaluation of OA in 25 patients who presented with gout, 25 others with hyperuricemia, and 25 controls. All were men over age 65. She found that the men with gout were twice as likely as controls to meet American College of Rheumatology (ACR) criteria for OA. They were also more likely to have bilateral knee OA by x-ray.
Dr. Pillinger reported receiving research grants from Savient and Takeda, which markets colchicine under the brand name Colcrys.
SNOWMASS, COLO. – Colchicine, a venerable drug Hippocrates proposed as a gout remedy some 2,400 years ago, shows fresh potential as a novel treatment for osteoarthritis.
"I’m going out on a limb here: Could colchicine improve osteoarthritis pain and function? I won’t tell you to do it, but there are a couple of studies that say it may be of some value – and they are intriguing," Dr. Michael H. Pillinger said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Moreover, there is evidence of a biologically plausible mechanism of benefit because osteoarthritis, contrary to conventional wisdom, may actually be an inflammatory disease, added Dr. Pillinger, a rheumatologist at New York University.
Investigators at Tehran (Iran) University of Medical Sciences randomized 61 postmenopausal women with moderate to severe knee osteoarthritis (OA) and no evidence of calcium pyrophosphate deposition disease on x-ray to 0.5 mg twice daily of colchicine or placebo in a double-blind clinical trial. After 3 months of prospective follow-up, the colchicine-treated group showed a mean 11.1-point improvement on a 15-point patient global assessment visual analog scale, compared with a 3.1-point improvement in controls.
The colchicine group also had a 9.8-point improvement on the 15-point physician global assessment, compared with a 3.7-point gain among controls. The mean daily consumption of acetaminophen – used as a rescue analgesic – was 879 mg in the colchicine group and nearly twice as great in controls at 1,621 mg (Clin. Exp. Rheumatol. 2011;29:513-8).
The Iranian study recapitulates an earlier double-blind randomized trial conducted by investigators at King George’s Medical College in Lucknow, India. They randomized 36 patients on background nonsteroidal anti-inflammatory drug (NSAID) therapy for OA of the knee to colchicine at 0.5 mg twice daily or placebo. The coprimary outcomes were the proportions of patients showing at least a 30% improvement in symptoms at 20 weeks as measured by the total WOMAC (Western Ontario and McMaster Universities) osteoarthritis index and a visual analog scale for knee pain. That threshold was achieved on the WOMAC osteoarthritis index by 58% of the colchicine group, compared with 24% of controls, and on the knee pain score by 53% of colchicine-treated patients and 18% of controls (Arthritis Rheum. 2002;47:280-4).
Turning to colchicine’s putative mechanism of benefit in OA, Dr. Pillinger commented that the drug has well-established anti-inflammatory effects on neutrophils. It also curbs tumor necrosis factor–alpha receptor expression on both macrophages and endothelial cells, with resultant inhibition of TNF-alpha secretion. Calcium-containing crystals are common in patients with primary OA, and it has been hypothesized that they activate the inflammasome, which drives production of interleukin-1 (IL-1), a key mediator of cartilage breakdown in OA. Colchicine inhibits this calcium crystal–induced inflammation.
In addition, Dr. Pillinger noted, investigators at Duke University in Durham, N.C., have shown that synovial fluid uric acid levels in 159 patients with OA and no gout were strongly correlated with both synovial fluid IL-1 levels and OA severity. They have proposed that uric acid is released into diseased joints by damaged chondrocytes as a danger signal, and that this uric acid crystallizes at a microscopic level in joints and cartilage, promoting chronic subacute IL-1–mediated inflammation (Proc. Natl. Acad. Sci. U.S.A. 2011;108:2088-93).
Gout and OA appear to be fellow travelers, according to Dr. Pillinger. He cited a study by his New York University colleague Dr. Rennie G. Howard, who conducted a rigorous evaluation of OA in 25 patients who presented with gout, 25 others with hyperuricemia, and 25 controls. All were men over age 65. She found that the men with gout were twice as likely as controls to meet American College of Rheumatology (ACR) criteria for OA. They were also more likely to have bilateral knee OA by x-ray.
Dr. Pillinger reported receiving research grants from Savient and Takeda, which markets colchicine under the brand name Colcrys.
SNOWMASS, COLO. – Colchicine, a venerable drug Hippocrates proposed as a gout remedy some 2,400 years ago, shows fresh potential as a novel treatment for osteoarthritis.
"I’m going out on a limb here: Could colchicine improve osteoarthritis pain and function? I won’t tell you to do it, but there are a couple of studies that say it may be of some value – and they are intriguing," Dr. Michael H. Pillinger said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Moreover, there is evidence of a biologically plausible mechanism of benefit because osteoarthritis, contrary to conventional wisdom, may actually be an inflammatory disease, added Dr. Pillinger, a rheumatologist at New York University.
Investigators at Tehran (Iran) University of Medical Sciences randomized 61 postmenopausal women with moderate to severe knee osteoarthritis (OA) and no evidence of calcium pyrophosphate deposition disease on x-ray to 0.5 mg twice daily of colchicine or placebo in a double-blind clinical trial. After 3 months of prospective follow-up, the colchicine-treated group showed a mean 11.1-point improvement on a 15-point patient global assessment visual analog scale, compared with a 3.1-point improvement in controls.
The colchicine group also had a 9.8-point improvement on the 15-point physician global assessment, compared with a 3.7-point gain among controls. The mean daily consumption of acetaminophen – used as a rescue analgesic – was 879 mg in the colchicine group and nearly twice as great in controls at 1,621 mg (Clin. Exp. Rheumatol. 2011;29:513-8).
The Iranian study recapitulates an earlier double-blind randomized trial conducted by investigators at King George’s Medical College in Lucknow, India. They randomized 36 patients on background nonsteroidal anti-inflammatory drug (NSAID) therapy for OA of the knee to colchicine at 0.5 mg twice daily or placebo. The coprimary outcomes were the proportions of patients showing at least a 30% improvement in symptoms at 20 weeks as measured by the total WOMAC (Western Ontario and McMaster Universities) osteoarthritis index and a visual analog scale for knee pain. That threshold was achieved on the WOMAC osteoarthritis index by 58% of the colchicine group, compared with 24% of controls, and on the knee pain score by 53% of colchicine-treated patients and 18% of controls (Arthritis Rheum. 2002;47:280-4).
Turning to colchicine’s putative mechanism of benefit in OA, Dr. Pillinger commented that the drug has well-established anti-inflammatory effects on neutrophils. It also curbs tumor necrosis factor–alpha receptor expression on both macrophages and endothelial cells, with resultant inhibition of TNF-alpha secretion. Calcium-containing crystals are common in patients with primary OA, and it has been hypothesized that they activate the inflammasome, which drives production of interleukin-1 (IL-1), a key mediator of cartilage breakdown in OA. Colchicine inhibits this calcium crystal–induced inflammation.
In addition, Dr. Pillinger noted, investigators at Duke University in Durham, N.C., have shown that synovial fluid uric acid levels in 159 patients with OA and no gout were strongly correlated with both synovial fluid IL-1 levels and OA severity. They have proposed that uric acid is released into diseased joints by damaged chondrocytes as a danger signal, and that this uric acid crystallizes at a microscopic level in joints and cartilage, promoting chronic subacute IL-1–mediated inflammation (Proc. Natl. Acad. Sci. U.S.A. 2011;108:2088-93).
Gout and OA appear to be fellow travelers, according to Dr. Pillinger. He cited a study by his New York University colleague Dr. Rennie G. Howard, who conducted a rigorous evaluation of OA in 25 patients who presented with gout, 25 others with hyperuricemia, and 25 controls. All were men over age 65. She found that the men with gout were twice as likely as controls to meet American College of Rheumatology (ACR) criteria for OA. They were also more likely to have bilateral knee OA by x-ray.
Dr. Pillinger reported receiving research grants from Savient and Takeda, which markets colchicine under the brand name Colcrys.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
Mini-VADs could transform heart failure therapy
SNOWMASS, COLO. – Survival in patients with advanced heart failure who receive a left ventricular assist device as destination therapy or as a bridge to transplant has increased dramatically in recent years – and the best may be yet to come.
"There is a robust pipeline of mini-VADs [mini–ventricular assist devices] providing partial circulatory support that should allow wider applicability," Dr. Michael J. Mack said at the Annual Cardiovascular Conference at Snowmass.
This new generation of smaller, ever-more-high-tech VADs now entering clinical trials is made up of devices designed for implantation via a shorter, less invasive, off-pump hybrid surgical procedure, which should reduce operative morbidity and mortality. The rechargeable battery will also be implanted. Some of the devices are even earmarked for implantation nonsurgically in the cath lab, explained Dr. Mack, a cardiothoracic surgeon who is medical director of the Baylor Health Care System in Plano, Tex.
The ease of implantation of these next-gen mini-VADs makes them suitable for use at an earlier stage in the development of heart failure than the two left ventricular assist devices (LVADs) now approved for long-term use in the United States. The expectation is that this earlier mechanical intervention might further improve patient outcomes, he added.
Two-year survival following implantation of the HeartMate II, the current workhorse LVAD, is 65%, the same as with heart transplantation. To put that in perspective, in the REMATCH trial, which more than a decade ago led to Food and Drug Administration (FDA) approval of the first LVAD as long-term therapy, 2-year survival with device therapy was just 25%.
Today at many top institutions, Dr. Mack said, the number of LVADs implanted as destination therapy – that is, as an alternative to heart transplantation – now dwarfs the number of heart transplants done. This reflects a widespread recognition that the organ donor pool is unlikely to grow larger despite many efforts. Indeed, the number of heart transplants performed in North America has remained constant at roughly 2,300 per year for the past 20 years.
The other LVAD approved as destination therapy or bridge to transplant is the HeartWare VAD. The FDA granted approval based upon the results of the 30-center, prospective ADVANCE trial, which demonstrated that the HeartWare VAD’s performance was noninferior to that of the HeartMate II (Circulation 2012;125:3191-200).
Both LVADs are small continuous-flow devices with only a single moving part. They are quiet and energy efficient. Their simplicity of design makes them less susceptible to mechanical wear and much more reliable than earlier-generation LVADs. Three-year device replacement rates are now less than 10%, according to Dr. Mack.
But the current LVADs have significant shortcomings. In a worldwide series of close to 6,000 patients who have received a device as destination therapy or bridge to transplant, the 3-year combined rate of bleeding, stroke, infection, device malfunction, or death was 86%. The 3-year stroke incidence was 19% (J. Heart Lung Transpl. 2013;32:141-56).
Bleeding is a major problem with these devices for three reasons. Virtually all LVAD recipients develop acquired von Willebrand’s disease. Moreover, patients are on warfarin because of their high stroke risk. And gastrointestinal bleeding is a significant problem due to the angiodysplasia and arteriovenous malformations that result from the nonpulsatile continuous blood flow.
Among the mini-VADs well along in the developmental pipeline are the MicroMed HeartAssist 5, which is 71 x 30 mm in size and weighs only 92 g. Also in development are the HeartWare Miniaturized VAD (MVAD), which is about the size of a golf ball, and the HeartMate III.
The device drawing the most interest from cardiac surgeons, however, is the CircuLite Synergy mini-VAD, which is the size of an AA battery. It’s implanted off-pump with a small right thoracotomy for left atrial access. The device sits in a pocket in the right deltoid-pectoral groove for axillary artery access. The inflow is from the left atrium, with outflow into the right subclavian artery.
This device will undergo further modification to a totally endovascular concept that avoids the right thoracotomy. Inflow will be through the subclavian vein via a transseptal puncture approach, with outflow into the subclavian artery.
"The idea is that this will become a cath lab procedure. The device will sit in a pocket similar to a pacemaker," Dr. Mack explained.
Although the future looks bright for mini-VADs, plenty of key questions about them still await answers, the surgeon noted. Among them: Will partial circulatory support be sufficient for all patients with advanced heart failure? Will it be possible to predict which patients with New York Heart Association class III heart failure are destined to progress to advanced disease, and if so, will early implantation of a partial support device in these less-sick patients have a favorable effect on their quality of life? Might it slow progression of heart failure, and perhaps even induce remission?
The answers are expected to come from ongoing and planned clinical trials of these investigational devices.
Dr. Clyde W. Yancy, who chaired the writing committee for the 2013 ACC/AHA (American College of Cardiology/American Heart Association) Guideline for the Management of Heart Failure (J. Am. Coll. Cardiol. 2013;62:e147-239), noted that the guidelines endorse LVADs as destination therapy or bridge to transplant or recovery in carefully selected patients with advanced heart failure with reduced ejection fraction, with a class IIa/level of evidence B recommendation.
"Mechanical circulatory support is no longer a Hail Mary pass. This is no longer an experimental intervention. This really should be incorporated in our usual thought processes in advanced heart failure," said Dr. Yancy, professor of medicine and of medical social sciences and chief of cardiology at Northwestern University, Chicago.
He noted that the guidelines list a number of clinical events and other findings that are useful in identifying patients who have progressed to advanced heart failure, at which point he said it’s time to communicate with a center that can evaluate the patient for a possible LVAD or heart transplantation. These indicators include two or more hospitalizations or emergency department visits for heart failure in the past year, progressive deterioration in renal function, intolerance to beta-blocker therapy, unexplained weight loss, or inability to walk one block on level ground because of fatigue or shortness of breath.
Dr. Mack and Dr. Yancy reported having no financial conflicts.
SNOWMASS, COLO. – Survival in patients with advanced heart failure who receive a left ventricular assist device as destination therapy or as a bridge to transplant has increased dramatically in recent years – and the best may be yet to come.
"There is a robust pipeline of mini-VADs [mini–ventricular assist devices] providing partial circulatory support that should allow wider applicability," Dr. Michael J. Mack said at the Annual Cardiovascular Conference at Snowmass.
This new generation of smaller, ever-more-high-tech VADs now entering clinical trials is made up of devices designed for implantation via a shorter, less invasive, off-pump hybrid surgical procedure, which should reduce operative morbidity and mortality. The rechargeable battery will also be implanted. Some of the devices are even earmarked for implantation nonsurgically in the cath lab, explained Dr. Mack, a cardiothoracic surgeon who is medical director of the Baylor Health Care System in Plano, Tex.
The ease of implantation of these next-gen mini-VADs makes them suitable for use at an earlier stage in the development of heart failure than the two left ventricular assist devices (LVADs) now approved for long-term use in the United States. The expectation is that this earlier mechanical intervention might further improve patient outcomes, he added.
Two-year survival following implantation of the HeartMate II, the current workhorse LVAD, is 65%, the same as with heart transplantation. To put that in perspective, in the REMATCH trial, which more than a decade ago led to Food and Drug Administration (FDA) approval of the first LVAD as long-term therapy, 2-year survival with device therapy was just 25%.
Today at many top institutions, Dr. Mack said, the number of LVADs implanted as destination therapy – that is, as an alternative to heart transplantation – now dwarfs the number of heart transplants done. This reflects a widespread recognition that the organ donor pool is unlikely to grow larger despite many efforts. Indeed, the number of heart transplants performed in North America has remained constant at roughly 2,300 per year for the past 20 years.
The other LVAD approved as destination therapy or bridge to transplant is the HeartWare VAD. The FDA granted approval based upon the results of the 30-center, prospective ADVANCE trial, which demonstrated that the HeartWare VAD’s performance was noninferior to that of the HeartMate II (Circulation 2012;125:3191-200).
Both LVADs are small continuous-flow devices with only a single moving part. They are quiet and energy efficient. Their simplicity of design makes them less susceptible to mechanical wear and much more reliable than earlier-generation LVADs. Three-year device replacement rates are now less than 10%, according to Dr. Mack.
But the current LVADs have significant shortcomings. In a worldwide series of close to 6,000 patients who have received a device as destination therapy or bridge to transplant, the 3-year combined rate of bleeding, stroke, infection, device malfunction, or death was 86%. The 3-year stroke incidence was 19% (J. Heart Lung Transpl. 2013;32:141-56).
Bleeding is a major problem with these devices for three reasons. Virtually all LVAD recipients develop acquired von Willebrand’s disease. Moreover, patients are on warfarin because of their high stroke risk. And gastrointestinal bleeding is a significant problem due to the angiodysplasia and arteriovenous malformations that result from the nonpulsatile continuous blood flow.
Among the mini-VADs well along in the developmental pipeline are the MicroMed HeartAssist 5, which is 71 x 30 mm in size and weighs only 92 g. Also in development are the HeartWare Miniaturized VAD (MVAD), which is about the size of a golf ball, and the HeartMate III.
The device drawing the most interest from cardiac surgeons, however, is the CircuLite Synergy mini-VAD, which is the size of an AA battery. It’s implanted off-pump with a small right thoracotomy for left atrial access. The device sits in a pocket in the right deltoid-pectoral groove for axillary artery access. The inflow is from the left atrium, with outflow into the right subclavian artery.
This device will undergo further modification to a totally endovascular concept that avoids the right thoracotomy. Inflow will be through the subclavian vein via a transseptal puncture approach, with outflow into the subclavian artery.
"The idea is that this will become a cath lab procedure. The device will sit in a pocket similar to a pacemaker," Dr. Mack explained.
Although the future looks bright for mini-VADs, plenty of key questions about them still await answers, the surgeon noted. Among them: Will partial circulatory support be sufficient for all patients with advanced heart failure? Will it be possible to predict which patients with New York Heart Association class III heart failure are destined to progress to advanced disease, and if so, will early implantation of a partial support device in these less-sick patients have a favorable effect on their quality of life? Might it slow progression of heart failure, and perhaps even induce remission?
The answers are expected to come from ongoing and planned clinical trials of these investigational devices.
Dr. Clyde W. Yancy, who chaired the writing committee for the 2013 ACC/AHA (American College of Cardiology/American Heart Association) Guideline for the Management of Heart Failure (J. Am. Coll. Cardiol. 2013;62:e147-239), noted that the guidelines endorse LVADs as destination therapy or bridge to transplant or recovery in carefully selected patients with advanced heart failure with reduced ejection fraction, with a class IIa/level of evidence B recommendation.
"Mechanical circulatory support is no longer a Hail Mary pass. This is no longer an experimental intervention. This really should be incorporated in our usual thought processes in advanced heart failure," said Dr. Yancy, professor of medicine and of medical social sciences and chief of cardiology at Northwestern University, Chicago.
He noted that the guidelines list a number of clinical events and other findings that are useful in identifying patients who have progressed to advanced heart failure, at which point he said it’s time to communicate with a center that can evaluate the patient for a possible LVAD or heart transplantation. These indicators include two or more hospitalizations or emergency department visits for heart failure in the past year, progressive deterioration in renal function, intolerance to beta-blocker therapy, unexplained weight loss, or inability to walk one block on level ground because of fatigue or shortness of breath.
Dr. Mack and Dr. Yancy reported having no financial conflicts.
SNOWMASS, COLO. – Survival in patients with advanced heart failure who receive a left ventricular assist device as destination therapy or as a bridge to transplant has increased dramatically in recent years – and the best may be yet to come.
"There is a robust pipeline of mini-VADs [mini–ventricular assist devices] providing partial circulatory support that should allow wider applicability," Dr. Michael J. Mack said at the Annual Cardiovascular Conference at Snowmass.
This new generation of smaller, ever-more-high-tech VADs now entering clinical trials is made up of devices designed for implantation via a shorter, less invasive, off-pump hybrid surgical procedure, which should reduce operative morbidity and mortality. The rechargeable battery will also be implanted. Some of the devices are even earmarked for implantation nonsurgically in the cath lab, explained Dr. Mack, a cardiothoracic surgeon who is medical director of the Baylor Health Care System in Plano, Tex.
The ease of implantation of these next-gen mini-VADs makes them suitable for use at an earlier stage in the development of heart failure than the two left ventricular assist devices (LVADs) now approved for long-term use in the United States. The expectation is that this earlier mechanical intervention might further improve patient outcomes, he added.
Two-year survival following implantation of the HeartMate II, the current workhorse LVAD, is 65%, the same as with heart transplantation. To put that in perspective, in the REMATCH trial, which more than a decade ago led to Food and Drug Administration (FDA) approval of the first LVAD as long-term therapy, 2-year survival with device therapy was just 25%.
Today at many top institutions, Dr. Mack said, the number of LVADs implanted as destination therapy – that is, as an alternative to heart transplantation – now dwarfs the number of heart transplants done. This reflects a widespread recognition that the organ donor pool is unlikely to grow larger despite many efforts. Indeed, the number of heart transplants performed in North America has remained constant at roughly 2,300 per year for the past 20 years.
The other LVAD approved as destination therapy or bridge to transplant is the HeartWare VAD. The FDA granted approval based upon the results of the 30-center, prospective ADVANCE trial, which demonstrated that the HeartWare VAD’s performance was noninferior to that of the HeartMate II (Circulation 2012;125:3191-200).
Both LVADs are small continuous-flow devices with only a single moving part. They are quiet and energy efficient. Their simplicity of design makes them less susceptible to mechanical wear and much more reliable than earlier-generation LVADs. Three-year device replacement rates are now less than 10%, according to Dr. Mack.
But the current LVADs have significant shortcomings. In a worldwide series of close to 6,000 patients who have received a device as destination therapy or bridge to transplant, the 3-year combined rate of bleeding, stroke, infection, device malfunction, or death was 86%. The 3-year stroke incidence was 19% (J. Heart Lung Transpl. 2013;32:141-56).
Bleeding is a major problem with these devices for three reasons. Virtually all LVAD recipients develop acquired von Willebrand’s disease. Moreover, patients are on warfarin because of their high stroke risk. And gastrointestinal bleeding is a significant problem due to the angiodysplasia and arteriovenous malformations that result from the nonpulsatile continuous blood flow.
Among the mini-VADs well along in the developmental pipeline are the MicroMed HeartAssist 5, which is 71 x 30 mm in size and weighs only 92 g. Also in development are the HeartWare Miniaturized VAD (MVAD), which is about the size of a golf ball, and the HeartMate III.
The device drawing the most interest from cardiac surgeons, however, is the CircuLite Synergy mini-VAD, which is the size of an AA battery. It’s implanted off-pump with a small right thoracotomy for left atrial access. The device sits in a pocket in the right deltoid-pectoral groove for axillary artery access. The inflow is from the left atrium, with outflow into the right subclavian artery.
This device will undergo further modification to a totally endovascular concept that avoids the right thoracotomy. Inflow will be through the subclavian vein via a transseptal puncture approach, with outflow into the subclavian artery.
"The idea is that this will become a cath lab procedure. The device will sit in a pocket similar to a pacemaker," Dr. Mack explained.
Although the future looks bright for mini-VADs, plenty of key questions about them still await answers, the surgeon noted. Among them: Will partial circulatory support be sufficient for all patients with advanced heart failure? Will it be possible to predict which patients with New York Heart Association class III heart failure are destined to progress to advanced disease, and if so, will early implantation of a partial support device in these less-sick patients have a favorable effect on their quality of life? Might it slow progression of heart failure, and perhaps even induce remission?
The answers are expected to come from ongoing and planned clinical trials of these investigational devices.
Dr. Clyde W. Yancy, who chaired the writing committee for the 2013 ACC/AHA (American College of Cardiology/American Heart Association) Guideline for the Management of Heart Failure (J. Am. Coll. Cardiol. 2013;62:e147-239), noted that the guidelines endorse LVADs as destination therapy or bridge to transplant or recovery in carefully selected patients with advanced heart failure with reduced ejection fraction, with a class IIa/level of evidence B recommendation.
"Mechanical circulatory support is no longer a Hail Mary pass. This is no longer an experimental intervention. This really should be incorporated in our usual thought processes in advanced heart failure," said Dr. Yancy, professor of medicine and of medical social sciences and chief of cardiology at Northwestern University, Chicago.
He noted that the guidelines list a number of clinical events and other findings that are useful in identifying patients who have progressed to advanced heart failure, at which point he said it’s time to communicate with a center that can evaluate the patient for a possible LVAD or heart transplantation. These indicators include two or more hospitalizations or emergency department visits for heart failure in the past year, progressive deterioration in renal function, intolerance to beta-blocker therapy, unexplained weight loss, or inability to walk one block on level ground because of fatigue or shortness of breath.
Dr. Mack and Dr. Yancy reported having no financial conflicts.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
Recent data support preventive multivessel PCI in STEMI patients
SNOWMASS, COLO. – ST-elevation MI guidelines released just last year by the American College of Cardiology/American Heart Association are already in need of revision in light of important new evidence about the benefits of complete rather than culprit vessel–only revascularization at the time of primary percutaneous coronary intervention.
"The guidelines need a facelift," Dr. David R. Holmes Jr. said at the Annual Cardiovascular Conference at Snowmass.
The 2013 ACC/AHA guidelines deem PCI of a noninfarct artery at the time of primary PCI in STEMI patients without hemodynamic compromise to be harmful. This practice is categorized as class IIIB, meaning "don’t do it" (J. Am. Coll. Cardiol. 2013;e78-140). Similarly, the 2012 European Society of Cardiology STEMI guidelines state, "Primary PCI should be limited to the culprit vessel with the exception of cardiogenic shock and persistent ischemia after PCI of the supposed culprit lesion" (Eur. Heart J. 2012;33:2569-619).
But the recently published PRAMI (Preventive Angioplasty in Myocardial Infarction) trial is a game changer in this regard. Investigators at five U.K. centers randomized 465 acute STEMI patients to infarct artery–only primary PCI or to preventive primary PCI of both the culprit vessel and noninfarct coronary arteries with major stenoses.
"I like the concept of prevention through intervention. It makes sense, I think," commented Dr. Holmes, professor of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.
The tricky part will be to craft the revised guideline recommendations so as to encourage preventive PCI while avoiding the all-too-human temptation to overestimate lesion severity and engage the well-known oculostenotic reflex, he added.
During a mean follow-up of 23 months in the PRAMI study, the primary outcome – a composite of cardiac death, nonfatal myocardial infarction (MI), or refractory angina – occurred in 21 patients assigned to preventive PCI, compared with 53 randomized to infarct artery–only PCI, for a highly significant 65% relative risk reduction (N. Engl. J. Med. 2013;369:1115-23).
"Do the STEMI guidelines need a facelift?" Dr. Holmes asked the next speaker at the conference, who just happened to be ACC President-elect Patrick T. O’Gara, M.D., chair of the ACC/AHA STEMI Guideline Writing Committee.
"I think, actually, there are several areas in the STEMI guidelines that require revision within the year of their publication," responded Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.
"I think this preventive PCI concept is one – and we need to get good minds together to hit the right mark. Another is routine use of thrombus aspiration at the time of primary PCI. A third area might be the logistics around hypothermia in out-of-hospital cardiac arrest survivors: Are we trying to achieve a certain temperature or achieve some other outcome? We anticipate that the writing committee will be re-impaneled, probably in the next 3 months, to take these on," Dr. O’Gara said.
Dr. Holmes welcomed PRAMI because it sheds new light on what has been a cloudy area of research. For example, a new Canadian meta-analysis of 26 published studies totaling 38,438 STEMI patients who underwent culprit vessel–only primary PCI and 7,886 others with multivessel primary PCI concluded there was no difference between the two strategies in terms of hospital mortality; in other words, multivessel primary PCI provided no added benefit. However, among the three randomized studies included in the meta-analysis, there was a highly significant 76% reduction in hospital mortality with multivessel primary PCI (Am. J. Heart J. 2014;167:1-14.e2). With PRAMI, that makes a total of four positive and no negative randomized trials.
In other developments pertaining to multivessel primary PCI in STEMI, Dr. Holmes noted that this intervention recently received support when applied in the setting of the STEMI patient with multivessel disease who presents with cardiogenic shock and resuscitated cardiac arrest. French investigators published a prospective observational study involving 169 such patients, 66 of whom received multivessel primary PCI while the other 109 underwent culprit vessel–only primary PCI. The primary endpoint, a 6-month composite of recurrent cardiac arrest and death due to cardiogenic shock, occurred in 50% of those who got multivessel PCI, compared with 68% of those with culprit vessel-only PCI (JACC Cardiovasc. Interv. 2013;6:115-25).
"The conclusion is, if somebody comes in with STEMI and cardiogenic shock and they’ve arrested, you should treat everything you can. Go for it." Dr. Holmes said.
A couple of noteworthy recent studies looked at the effect of chronic total occlusion (CTO) in a non–infarct-related artery in STEMI patients. Dutch investigators reported on 5,018 consecutive unselected STEMI patients. Twelve percent had cardiogenic shock, 64% had single-vessel disease, 23% had multivessel disease with CTO in a non–infarct-related artery, and 13% had multivessel disease without a CTO. Thirty-day mortality was 11% in STEMI patients with multivessel disease and a CTO, 4.3% in those with multivessel disease without a CTO in a non–infarct-related artery, and 3% in those with single-vessel disease. In the group with cardiogenic shock, 30-day mortality was 61% in patients with a CTO, 42% in those with multivessel disease but no CTO, and 26% with single-vessel disease (Eur. J. Heart Fail. 2013;15:425-32).
Investigators from the HORIZONS-AMI trial also recently evaluated the effect of a CTO in a non–infarct-related artery. The study population included 3,283 patients undergoing primary PCI for STEMI. The 283 patients with multivessel disease and a CTO in a non–infarct-related artery had an adjusted 2.88-fold greater 30-day mortality and 2.27-fold greater 3-year mortality than those with single-vessel disease. The 1,477 patients with multivessel disease but no CTO had a 1.75-fold greater 30-day mortality than those with single-vessel disease, but no increased risk through 3 years (Eur. Heart J. 2012;33:768-75).
"Does this mean you should bring patients back to do the CTO? Probably. We don’t do that enough, but probably that’s indeed the case," Dr. Holmes commented.
He reported having no financial conflicts of interest.
SNOWMASS, COLO. – ST-elevation MI guidelines released just last year by the American College of Cardiology/American Heart Association are already in need of revision in light of important new evidence about the benefits of complete rather than culprit vessel–only revascularization at the time of primary percutaneous coronary intervention.
"The guidelines need a facelift," Dr. David R. Holmes Jr. said at the Annual Cardiovascular Conference at Snowmass.
The 2013 ACC/AHA guidelines deem PCI of a noninfarct artery at the time of primary PCI in STEMI patients without hemodynamic compromise to be harmful. This practice is categorized as class IIIB, meaning "don’t do it" (J. Am. Coll. Cardiol. 2013;e78-140). Similarly, the 2012 European Society of Cardiology STEMI guidelines state, "Primary PCI should be limited to the culprit vessel with the exception of cardiogenic shock and persistent ischemia after PCI of the supposed culprit lesion" (Eur. Heart J. 2012;33:2569-619).
But the recently published PRAMI (Preventive Angioplasty in Myocardial Infarction) trial is a game changer in this regard. Investigators at five U.K. centers randomized 465 acute STEMI patients to infarct artery–only primary PCI or to preventive primary PCI of both the culprit vessel and noninfarct coronary arteries with major stenoses.
"I like the concept of prevention through intervention. It makes sense, I think," commented Dr. Holmes, professor of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.
The tricky part will be to craft the revised guideline recommendations so as to encourage preventive PCI while avoiding the all-too-human temptation to overestimate lesion severity and engage the well-known oculostenotic reflex, he added.
During a mean follow-up of 23 months in the PRAMI study, the primary outcome – a composite of cardiac death, nonfatal myocardial infarction (MI), or refractory angina – occurred in 21 patients assigned to preventive PCI, compared with 53 randomized to infarct artery–only PCI, for a highly significant 65% relative risk reduction (N. Engl. J. Med. 2013;369:1115-23).
"Do the STEMI guidelines need a facelift?" Dr. Holmes asked the next speaker at the conference, who just happened to be ACC President-elect Patrick T. O’Gara, M.D., chair of the ACC/AHA STEMI Guideline Writing Committee.
"I think, actually, there are several areas in the STEMI guidelines that require revision within the year of their publication," responded Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.
"I think this preventive PCI concept is one – and we need to get good minds together to hit the right mark. Another is routine use of thrombus aspiration at the time of primary PCI. A third area might be the logistics around hypothermia in out-of-hospital cardiac arrest survivors: Are we trying to achieve a certain temperature or achieve some other outcome? We anticipate that the writing committee will be re-impaneled, probably in the next 3 months, to take these on," Dr. O’Gara said.
Dr. Holmes welcomed PRAMI because it sheds new light on what has been a cloudy area of research. For example, a new Canadian meta-analysis of 26 published studies totaling 38,438 STEMI patients who underwent culprit vessel–only primary PCI and 7,886 others with multivessel primary PCI concluded there was no difference between the two strategies in terms of hospital mortality; in other words, multivessel primary PCI provided no added benefit. However, among the three randomized studies included in the meta-analysis, there was a highly significant 76% reduction in hospital mortality with multivessel primary PCI (Am. J. Heart J. 2014;167:1-14.e2). With PRAMI, that makes a total of four positive and no negative randomized trials.
In other developments pertaining to multivessel primary PCI in STEMI, Dr. Holmes noted that this intervention recently received support when applied in the setting of the STEMI patient with multivessel disease who presents with cardiogenic shock and resuscitated cardiac arrest. French investigators published a prospective observational study involving 169 such patients, 66 of whom received multivessel primary PCI while the other 109 underwent culprit vessel–only primary PCI. The primary endpoint, a 6-month composite of recurrent cardiac arrest and death due to cardiogenic shock, occurred in 50% of those who got multivessel PCI, compared with 68% of those with culprit vessel-only PCI (JACC Cardiovasc. Interv. 2013;6:115-25).
"The conclusion is, if somebody comes in with STEMI and cardiogenic shock and they’ve arrested, you should treat everything you can. Go for it." Dr. Holmes said.
A couple of noteworthy recent studies looked at the effect of chronic total occlusion (CTO) in a non–infarct-related artery in STEMI patients. Dutch investigators reported on 5,018 consecutive unselected STEMI patients. Twelve percent had cardiogenic shock, 64% had single-vessel disease, 23% had multivessel disease with CTO in a non–infarct-related artery, and 13% had multivessel disease without a CTO. Thirty-day mortality was 11% in STEMI patients with multivessel disease and a CTO, 4.3% in those with multivessel disease without a CTO in a non–infarct-related artery, and 3% in those with single-vessel disease. In the group with cardiogenic shock, 30-day mortality was 61% in patients with a CTO, 42% in those with multivessel disease but no CTO, and 26% with single-vessel disease (Eur. J. Heart Fail. 2013;15:425-32).
Investigators from the HORIZONS-AMI trial also recently evaluated the effect of a CTO in a non–infarct-related artery. The study population included 3,283 patients undergoing primary PCI for STEMI. The 283 patients with multivessel disease and a CTO in a non–infarct-related artery had an adjusted 2.88-fold greater 30-day mortality and 2.27-fold greater 3-year mortality than those with single-vessel disease. The 1,477 patients with multivessel disease but no CTO had a 1.75-fold greater 30-day mortality than those with single-vessel disease, but no increased risk through 3 years (Eur. Heart J. 2012;33:768-75).
"Does this mean you should bring patients back to do the CTO? Probably. We don’t do that enough, but probably that’s indeed the case," Dr. Holmes commented.
He reported having no financial conflicts of interest.
SNOWMASS, COLO. – ST-elevation MI guidelines released just last year by the American College of Cardiology/American Heart Association are already in need of revision in light of important new evidence about the benefits of complete rather than culprit vessel–only revascularization at the time of primary percutaneous coronary intervention.
"The guidelines need a facelift," Dr. David R. Holmes Jr. said at the Annual Cardiovascular Conference at Snowmass.
The 2013 ACC/AHA guidelines deem PCI of a noninfarct artery at the time of primary PCI in STEMI patients without hemodynamic compromise to be harmful. This practice is categorized as class IIIB, meaning "don’t do it" (J. Am. Coll. Cardiol. 2013;e78-140). Similarly, the 2012 European Society of Cardiology STEMI guidelines state, "Primary PCI should be limited to the culprit vessel with the exception of cardiogenic shock and persistent ischemia after PCI of the supposed culprit lesion" (Eur. Heart J. 2012;33:2569-619).
But the recently published PRAMI (Preventive Angioplasty in Myocardial Infarction) trial is a game changer in this regard. Investigators at five U.K. centers randomized 465 acute STEMI patients to infarct artery–only primary PCI or to preventive primary PCI of both the culprit vessel and noninfarct coronary arteries with major stenoses.
"I like the concept of prevention through intervention. It makes sense, I think," commented Dr. Holmes, professor of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.
The tricky part will be to craft the revised guideline recommendations so as to encourage preventive PCI while avoiding the all-too-human temptation to overestimate lesion severity and engage the well-known oculostenotic reflex, he added.
During a mean follow-up of 23 months in the PRAMI study, the primary outcome – a composite of cardiac death, nonfatal myocardial infarction (MI), or refractory angina – occurred in 21 patients assigned to preventive PCI, compared with 53 randomized to infarct artery–only PCI, for a highly significant 65% relative risk reduction (N. Engl. J. Med. 2013;369:1115-23).
"Do the STEMI guidelines need a facelift?" Dr. Holmes asked the next speaker at the conference, who just happened to be ACC President-elect Patrick T. O’Gara, M.D., chair of the ACC/AHA STEMI Guideline Writing Committee.
"I think, actually, there are several areas in the STEMI guidelines that require revision within the year of their publication," responded Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.
"I think this preventive PCI concept is one – and we need to get good minds together to hit the right mark. Another is routine use of thrombus aspiration at the time of primary PCI. A third area might be the logistics around hypothermia in out-of-hospital cardiac arrest survivors: Are we trying to achieve a certain temperature or achieve some other outcome? We anticipate that the writing committee will be re-impaneled, probably in the next 3 months, to take these on," Dr. O’Gara said.
Dr. Holmes welcomed PRAMI because it sheds new light on what has been a cloudy area of research. For example, a new Canadian meta-analysis of 26 published studies totaling 38,438 STEMI patients who underwent culprit vessel–only primary PCI and 7,886 others with multivessel primary PCI concluded there was no difference between the two strategies in terms of hospital mortality; in other words, multivessel primary PCI provided no added benefit. However, among the three randomized studies included in the meta-analysis, there was a highly significant 76% reduction in hospital mortality with multivessel primary PCI (Am. J. Heart J. 2014;167:1-14.e2). With PRAMI, that makes a total of four positive and no negative randomized trials.
In other developments pertaining to multivessel primary PCI in STEMI, Dr. Holmes noted that this intervention recently received support when applied in the setting of the STEMI patient with multivessel disease who presents with cardiogenic shock and resuscitated cardiac arrest. French investigators published a prospective observational study involving 169 such patients, 66 of whom received multivessel primary PCI while the other 109 underwent culprit vessel–only primary PCI. The primary endpoint, a 6-month composite of recurrent cardiac arrest and death due to cardiogenic shock, occurred in 50% of those who got multivessel PCI, compared with 68% of those with culprit vessel-only PCI (JACC Cardiovasc. Interv. 2013;6:115-25).
"The conclusion is, if somebody comes in with STEMI and cardiogenic shock and they’ve arrested, you should treat everything you can. Go for it." Dr. Holmes said.
A couple of noteworthy recent studies looked at the effect of chronic total occlusion (CTO) in a non–infarct-related artery in STEMI patients. Dutch investigators reported on 5,018 consecutive unselected STEMI patients. Twelve percent had cardiogenic shock, 64% had single-vessel disease, 23% had multivessel disease with CTO in a non–infarct-related artery, and 13% had multivessel disease without a CTO. Thirty-day mortality was 11% in STEMI patients with multivessel disease and a CTO, 4.3% in those with multivessel disease without a CTO in a non–infarct-related artery, and 3% in those with single-vessel disease. In the group with cardiogenic shock, 30-day mortality was 61% in patients with a CTO, 42% in those with multivessel disease but no CTO, and 26% with single-vessel disease (Eur. J. Heart Fail. 2013;15:425-32).
Investigators from the HORIZONS-AMI trial also recently evaluated the effect of a CTO in a non–infarct-related artery. The study population included 3,283 patients undergoing primary PCI for STEMI. The 283 patients with multivessel disease and a CTO in a non–infarct-related artery had an adjusted 2.88-fold greater 30-day mortality and 2.27-fold greater 3-year mortality than those with single-vessel disease. The 1,477 patients with multivessel disease but no CTO had a 1.75-fold greater 30-day mortality than those with single-vessel disease, but no increased risk through 3 years (Eur. Heart J. 2012;33:768-75).
"Does this mean you should bring patients back to do the CTO? Probably. We don’t do that enough, but probably that’s indeed the case," Dr. Holmes commented.
He reported having no financial conflicts of interest.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
Preoperative organ dysfunction worsens SAVR outcomes
SNOWMASS, COLO. – The presence of preoperative dysfunction in more than any one of four key organ systems profoundly reduces survival in patients undergoing surgical aortic valve replacement, a study showed.
"If you have two or more dysfunctional organ systems, you really need to think about what you’re doing for this patient. At 5 years, only about 40% of these patients are alive. It makes a lot of sense to me to say that if you have a patient with severe COPD [chronic obstructive pulmonary disease] and renal dysfunction, that patient should probably never get a surgical valve," Dr. Vinod H. Thourani said at the Annual Cardiovascular Conference at Snowmass.
In a retrospective analysis of a registry with prospectively entered data, 29% of 1,759 patients who underwent surgical aortic valve replacement (SAVR) with or without coronary artery bypass grafting at Emory University during 2002-2010 had preoperative dysfunction of one or more of four organ systems under scrutiny. Eighty-five patients had severe COPD, as defined by a forced expiratory volume in 1 second (FEV1) that was less than 50% of predicted, 140 had chronic renal failure, 149 had a prior stroke, and 241 had heart failure with a left ventricular ejection less than 35%.
Patients with chronic renal failure had far and away the worst 30-day and long-term outcomes. Half were dead within 3 years. The 7-year survival rate was just 11.7%.
The second-worst outcomes were seen in patients with severe COPD preoperatively. Their 7-year survival rate was 30.8%.
"Anyone with an FEV1 below about 40% becomes a higher-risk surgical candidate; think instead of TAVR [transcatheter aortic valve replacement],"advised Dr. Thourani of the division of cardiothoracic surgery at Emory University, Atlanta.
In contrast, outcomes in patients with either heart failure or prior stroke "were not that bad," he said, pointing to 7-year survival rates of 55.9% and 48.6%, respectively.
Ninety-five patients (5.4%) in this recently published study (Ann. Thorac. Surg. 2013;95:838-45) had more than one dysfunctional organ system prior to SAVR. Median survival in patients without dysfunction in any of the four organ systems was 8.2 years and counting. With one dysfunctional organ, it was still good at 7.2 years. However, with two dysfunctional organ systems, the median survival dropped precipitously to 4.1 years. With three dysfunctional organ systems, it was 5.9 years.
Dr. Thourini serves as a consultant to Edwards Lifesciences, Sorin, and St. Jude Medical.
SNOWMASS, COLO. – The presence of preoperative dysfunction in more than any one of four key organ systems profoundly reduces survival in patients undergoing surgical aortic valve replacement, a study showed.
"If you have two or more dysfunctional organ systems, you really need to think about what you’re doing for this patient. At 5 years, only about 40% of these patients are alive. It makes a lot of sense to me to say that if you have a patient with severe COPD [chronic obstructive pulmonary disease] and renal dysfunction, that patient should probably never get a surgical valve," Dr. Vinod H. Thourani said at the Annual Cardiovascular Conference at Snowmass.
In a retrospective analysis of a registry with prospectively entered data, 29% of 1,759 patients who underwent surgical aortic valve replacement (SAVR) with or without coronary artery bypass grafting at Emory University during 2002-2010 had preoperative dysfunction of one or more of four organ systems under scrutiny. Eighty-five patients had severe COPD, as defined by a forced expiratory volume in 1 second (FEV1) that was less than 50% of predicted, 140 had chronic renal failure, 149 had a prior stroke, and 241 had heart failure with a left ventricular ejection less than 35%.
Patients with chronic renal failure had far and away the worst 30-day and long-term outcomes. Half were dead within 3 years. The 7-year survival rate was just 11.7%.
The second-worst outcomes were seen in patients with severe COPD preoperatively. Their 7-year survival rate was 30.8%.
"Anyone with an FEV1 below about 40% becomes a higher-risk surgical candidate; think instead of TAVR [transcatheter aortic valve replacement],"advised Dr. Thourani of the division of cardiothoracic surgery at Emory University, Atlanta.
In contrast, outcomes in patients with either heart failure or prior stroke "were not that bad," he said, pointing to 7-year survival rates of 55.9% and 48.6%, respectively.
Ninety-five patients (5.4%) in this recently published study (Ann. Thorac. Surg. 2013;95:838-45) had more than one dysfunctional organ system prior to SAVR. Median survival in patients without dysfunction in any of the four organ systems was 8.2 years and counting. With one dysfunctional organ, it was still good at 7.2 years. However, with two dysfunctional organ systems, the median survival dropped precipitously to 4.1 years. With three dysfunctional organ systems, it was 5.9 years.
Dr. Thourini serves as a consultant to Edwards Lifesciences, Sorin, and St. Jude Medical.
SNOWMASS, COLO. – The presence of preoperative dysfunction in more than any one of four key organ systems profoundly reduces survival in patients undergoing surgical aortic valve replacement, a study showed.
"If you have two or more dysfunctional organ systems, you really need to think about what you’re doing for this patient. At 5 years, only about 40% of these patients are alive. It makes a lot of sense to me to say that if you have a patient with severe COPD [chronic obstructive pulmonary disease] and renal dysfunction, that patient should probably never get a surgical valve," Dr. Vinod H. Thourani said at the Annual Cardiovascular Conference at Snowmass.
In a retrospective analysis of a registry with prospectively entered data, 29% of 1,759 patients who underwent surgical aortic valve replacement (SAVR) with or without coronary artery bypass grafting at Emory University during 2002-2010 had preoperative dysfunction of one or more of four organ systems under scrutiny. Eighty-five patients had severe COPD, as defined by a forced expiratory volume in 1 second (FEV1) that was less than 50% of predicted, 140 had chronic renal failure, 149 had a prior stroke, and 241 had heart failure with a left ventricular ejection less than 35%.
Patients with chronic renal failure had far and away the worst 30-day and long-term outcomes. Half were dead within 3 years. The 7-year survival rate was just 11.7%.
The second-worst outcomes were seen in patients with severe COPD preoperatively. Their 7-year survival rate was 30.8%.
"Anyone with an FEV1 below about 40% becomes a higher-risk surgical candidate; think instead of TAVR [transcatheter aortic valve replacement],"advised Dr. Thourani of the division of cardiothoracic surgery at Emory University, Atlanta.
In contrast, outcomes in patients with either heart failure or prior stroke "were not that bad," he said, pointing to 7-year survival rates of 55.9% and 48.6%, respectively.
Ninety-five patients (5.4%) in this recently published study (Ann. Thorac. Surg. 2013;95:838-45) had more than one dysfunctional organ system prior to SAVR. Median survival in patients without dysfunction in any of the four organ systems was 8.2 years and counting. With one dysfunctional organ, it was still good at 7.2 years. However, with two dysfunctional organ systems, the median survival dropped precipitously to 4.1 years. With three dysfunctional organ systems, it was 5.9 years.
Dr. Thourini serves as a consultant to Edwards Lifesciences, Sorin, and St. Jude Medical.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
New tools for stroke prediction in atrial fibrillation
SNOWMASS, COLO. – High-sensitivity troponin T and brain natriuretic peptide levels are better predictors of stroke risk in patients with atrial fibrillation than the CHA2DS2-VASc score that will replace the CHADS2 score in the forthcoming revised American College of Cardiology/American Heart Association guidelines.
Recent evidence indicates the biomarkers may be novel tools for improved stroke prediction in atrial fibrillation (AF), with prognostic value above and beyond that provided by the CHA2DS2-VASc scores.
These findings raise important unanswered questions about the relationship between AF and stroke. Conventional wisdom has held that left atrial thrombus is the cause of most strokes in patients with AF. But it’s not that simple, Dr. Bernard J. Gersh asserted at the Annual Cardiovascular Conference at Snowmass.
"What are we measuring with these biomarkers? This is what we really don’t understand. What has high-sensitivity troponin T got to do with left atrial thrombus?" asked Dr. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.
It seems increasingly clear that it’s not just the atrial arrhythmia that’s important in stroke risk, it’s also the company AF keeps. In a substantial but still uncertain proportion of patients, AF is a marker of vascular disease burden expressed through atrial and vascular endothelial dysfunction, vascular inflammation, left atrial dilatation and fibrosis, and a hypercoagulable state, the cardiologist continued.
He was a coinvestigator on a couple of recent groundbreaking studies that show the prognostic power of biomarkers in predicting both stroke risk and cardiac death in AF patients.
In one report, the investigators looked at baseline high-sensitivity troponin T (hsTnT) levels, clinical risk factors for stroke, and CHA2DS2-VASc scores in 12,892 patients with AF who were randomized to apixaban or warfarin in the prospective, double-blind ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial (N. Engl. J. Med. 2011;365:981-92). During a median 1.9 years of follow-up, patients in the highest quartile for baseline hsTnT had roughly a twofold greater risk of stroke or systemic embolism than did those in the lowest quartile.
Moreover, patients with a low-risk CHA2DS2-VASc score of 0 or 1 but in the top quartile for hsTnT, with a level in excess of 13 ng/L, had a very substantial stroke rate of 2.7% per year despite anticoagulation with apixaban (Eliquis) or warfarin. The relationship was even stronger for cardiac death, where subjects with a low-risk CHA2DS2-VASc score who were in the top quartile for hsTnT had a 6% annual risk. A higher baseline hsTnT was also independently associated with sharply increased risk of major bleeding in a multivariate regression analysis (J. Am. Coll. Cardiol. 2014;63:52-61).
In another recently published study, he and his international coworkers showed in ARISTOTLE participants with baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels that this biomarker also improved stroke prediction in AF, providing added value to CHA2DS2-VASc scores. Subjects in the top quartile for baseline NT-proBNP had an adjusted 2.35-fold greater risk of stroke or systemic embolism than those in the lowest quartile, irrespective of CHA2DS2-VASc score. They also had a 2.5-fold greater risk of cardiac death (J. Am. Coll. Cardiol. 2013;61:2274-84).
A study Dr. Gersh highlighted as "extremely interesting" involved the use of brain natriuretic peptide (BNP) as a marker to rule out delayed AF in stroke patients. The study, led by investigators at the University Hospital Center of Nice (France) and known as TARGET-AF, included 300 consecutive acute stroke patients with no history of AF and no AF on their baseline ECG. During a median 6.8 days of in-hospital Holter monitoring, 17% of the stroke patients developed newly diagnosed AF.
The strongest predictor of delayed AF was baseline plasma BNP. It outperformed the CHA2DS2-VASc score and all the other parameters examined, including anterior circulation location of the stroke, P-wave initial force, gender, National Institutes of Health Stroke Scale score, age, left atrial dilatation, and Score for the Targeting of AF (STAF) score. A BNP level greater than 131 pg/mL had a 98.1% sensitivity, 71.4% specificity, and 99.4% negative predictive value for delayed AF.
"Our data indicate that a BNP level of 131 pg/mL or less might rule out delayed AF in stroke survivors and could be included in algorithms for AF detection," the French investigators concluded (J. Stroke Cerebrovasc. Dis. 2013;22:e103-10).
There is plenty of direct evidence from transesophageal echocardiography studies and other sources that a substantial proportion of thromboemboli are directly the result of AF. However, indirect evidence points to additional causal factors. For example, there is a high incidence of thromboembolic events in AF patients without left atrial appendage thrombus. Plus, in natural history studies patients with AF without additional risk factors have a low incidence of stroke. And CHADS2 and CHA2DS2-VASc scores predict vascular events but don’t correlate with left atrial appendage thrombus, Dr. Gersh noted.
He said the CHA2DS2-VASc score is clearly an improvement over CHADS2, and its adoption in the forthcoming ACC/AHA guidelines is to be welcomed. The CHA2DS2-VASc score increases the number of patients considered at significant risk of stroke and therefore warranting anticoagulation. For example, in a large Danish registry of nearly 48,000 AF patients with a CHADS2 score of 0-1 not on anticoagulation, patients with a CHADS2 score of 1 but a CHA2DS2-VASc score of 2 had twice the stroke risk of patients with a CHA2DS2-VASc of 1 (Thromb. Haemost. 2012;107:1172-9).
That being said, neither risk score is all that impressive. The C-statistic, a measure of a test’s predictive power, is 0.56 for CHADS2 and it was 0.62 for CHA2DS2-VASc in the ARISTOTLE analysis. To put those figures in perspective, a coin toss has a C-statistic of 0.50.
"The individual predictive values are not good. We use CHADS2 and CHA2DS2-VASc in practice and in the guidelines, but we should not pretend they are highly predictive. We need new risk stratification schemes," according to Dr. Gersh.
He reported serving as an adviser to Boston Scientific and St. Jude Medical.
Evidence indicates that at least 25% of AF-related strokes are potentially preventable with adherence to evidence-based care, namely the use of the CHADS2, and now the more refined CHA2DS2-VASc risk stratification systems which use clinical risk factors to guide the prophylaxis decision. However, a body of evidence is growing that indicates these methods may provide relatively modest overall performance as predictors of stroke.
 |
| Dr. Hiren Shah |
There are three important considerations to these studies. Since the results were extrapolated from the ARISTOTLE trial, all patients were on anticoagulation, making it difficult to translate its findings on stroke risk and cardiac death. Thus, clear validation is needed for these novel biomarkers in settings in which no anticoagulation has been given within the study design before their use is incorporated into current guidelines.
Second, clinical trial settings are not always replicated in real world populations where patient inclusion criteria can differ significantly. For instance the very elderly, who have a higher stroke risk, were not represented in these studies.
Finally, although more robust risk-stratification systems have the potential to improve outcomes, it is important to remember ensuring their use is not guaranteed. Studies indicate that on average, only 50% of patients with AF are on risk appropriate prophylaxis.
Dr. Hiren Shah is medical director of the medicine and cardiac telemetry hospitalist unit at Northwestern Memorial Hospital in Chicago.
Evidence indicates that at least 25% of AF-related strokes are potentially preventable with adherence to evidence-based care, namely the use of the CHADS2, and now the more refined CHA2DS2-VASc risk stratification systems which use clinical risk factors to guide the prophylaxis decision. However, a body of evidence is growing that indicates these methods may provide relatively modest overall performance as predictors of stroke.
|
| Dr. Hiren Shah |
There are three important considerations to these studies. Since the results were extrapolated from the ARISTOTLE trial, all patients were on anticoagulation, making it difficult to translate its findings on stroke risk and cardiac death. Thus, clear validation is needed for these novel biomarkers in settings in which no anticoagulation has been given within the study design before their use is incorporated into current guidelines.
Second, clinical trial settings are not always replicated in real world populations where patient inclusion criteria can differ significantly. For instance the very elderly, who have a higher stroke risk, were not represented in these studies.
Finally, although more robust risk-stratification systems have the potential to improve outcomes, it is important to remember ensuring their use is not guaranteed. Studies indicate that on average, only 50% of patients with AF are on risk appropriate prophylaxis.
Dr. Hiren Shah is medical director of the medicine and cardiac telemetry hospitalist unit at Northwestern Memorial Hospital in Chicago.
Evidence indicates that at least 25% of AF-related strokes are potentially preventable with adherence to evidence-based care, namely the use of the CHADS2, and now the more refined CHA2DS2-VASc risk stratification systems which use clinical risk factors to guide the prophylaxis decision. However, a body of evidence is growing that indicates these methods may provide relatively modest overall performance as predictors of stroke.
|
| Dr. Hiren Shah |
There are three important considerations to these studies. Since the results were extrapolated from the ARISTOTLE trial, all patients were on anticoagulation, making it difficult to translate its findings on stroke risk and cardiac death. Thus, clear validation is needed for these novel biomarkers in settings in which no anticoagulation has been given within the study design before their use is incorporated into current guidelines.
Second, clinical trial settings are not always replicated in real world populations where patient inclusion criteria can differ significantly. For instance the very elderly, who have a higher stroke risk, were not represented in these studies.
Finally, although more robust risk-stratification systems have the potential to improve outcomes, it is important to remember ensuring their use is not guaranteed. Studies indicate that on average, only 50% of patients with AF are on risk appropriate prophylaxis.
Dr. Hiren Shah is medical director of the medicine and cardiac telemetry hospitalist unit at Northwestern Memorial Hospital in Chicago.
SNOWMASS, COLO. – High-sensitivity troponin T and brain natriuretic peptide levels are better predictors of stroke risk in patients with atrial fibrillation than the CHA2DS2-VASc score that will replace the CHADS2 score in the forthcoming revised American College of Cardiology/American Heart Association guidelines.
Recent evidence indicates the biomarkers may be novel tools for improved stroke prediction in atrial fibrillation (AF), with prognostic value above and beyond that provided by the CHA2DS2-VASc scores.
These findings raise important unanswered questions about the relationship between AF and stroke. Conventional wisdom has held that left atrial thrombus is the cause of most strokes in patients with AF. But it’s not that simple, Dr. Bernard J. Gersh asserted at the Annual Cardiovascular Conference at Snowmass.
"What are we measuring with these biomarkers? This is what we really don’t understand. What has high-sensitivity troponin T got to do with left atrial thrombus?" asked Dr. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.
It seems increasingly clear that it’s not just the atrial arrhythmia that’s important in stroke risk, it’s also the company AF keeps. In a substantial but still uncertain proportion of patients, AF is a marker of vascular disease burden expressed through atrial and vascular endothelial dysfunction, vascular inflammation, left atrial dilatation and fibrosis, and a hypercoagulable state, the cardiologist continued.
He was a coinvestigator on a couple of recent groundbreaking studies that show the prognostic power of biomarkers in predicting both stroke risk and cardiac death in AF patients.
In one report, the investigators looked at baseline high-sensitivity troponin T (hsTnT) levels, clinical risk factors for stroke, and CHA2DS2-VASc scores in 12,892 patients with AF who were randomized to apixaban or warfarin in the prospective, double-blind ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial (N. Engl. J. Med. 2011;365:981-92). During a median 1.9 years of follow-up, patients in the highest quartile for baseline hsTnT had roughly a twofold greater risk of stroke or systemic embolism than did those in the lowest quartile.
Moreover, patients with a low-risk CHA2DS2-VASc score of 0 or 1 but in the top quartile for hsTnT, with a level in excess of 13 ng/L, had a very substantial stroke rate of 2.7% per year despite anticoagulation with apixaban (Eliquis) or warfarin. The relationship was even stronger for cardiac death, where subjects with a low-risk CHA2DS2-VASc score who were in the top quartile for hsTnT had a 6% annual risk. A higher baseline hsTnT was also independently associated with sharply increased risk of major bleeding in a multivariate regression analysis (J. Am. Coll. Cardiol. 2014;63:52-61).
In another recently published study, he and his international coworkers showed in ARISTOTLE participants with baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels that this biomarker also improved stroke prediction in AF, providing added value to CHA2DS2-VASc scores. Subjects in the top quartile for baseline NT-proBNP had an adjusted 2.35-fold greater risk of stroke or systemic embolism than those in the lowest quartile, irrespective of CHA2DS2-VASc score. They also had a 2.5-fold greater risk of cardiac death (J. Am. Coll. Cardiol. 2013;61:2274-84).
A study Dr. Gersh highlighted as "extremely interesting" involved the use of brain natriuretic peptide (BNP) as a marker to rule out delayed AF in stroke patients. The study, led by investigators at the University Hospital Center of Nice (France) and known as TARGET-AF, included 300 consecutive acute stroke patients with no history of AF and no AF on their baseline ECG. During a median 6.8 days of in-hospital Holter monitoring, 17% of the stroke patients developed newly diagnosed AF.
The strongest predictor of delayed AF was baseline plasma BNP. It outperformed the CHA2DS2-VASc score and all the other parameters examined, including anterior circulation location of the stroke, P-wave initial force, gender, National Institutes of Health Stroke Scale score, age, left atrial dilatation, and Score for the Targeting of AF (STAF) score. A BNP level greater than 131 pg/mL had a 98.1% sensitivity, 71.4% specificity, and 99.4% negative predictive value for delayed AF.
"Our data indicate that a BNP level of 131 pg/mL or less might rule out delayed AF in stroke survivors and could be included in algorithms for AF detection," the French investigators concluded (J. Stroke Cerebrovasc. Dis. 2013;22:e103-10).
There is plenty of direct evidence from transesophageal echocardiography studies and other sources that a substantial proportion of thromboemboli are directly the result of AF. However, indirect evidence points to additional causal factors. For example, there is a high incidence of thromboembolic events in AF patients without left atrial appendage thrombus. Plus, in natural history studies patients with AF without additional risk factors have a low incidence of stroke. And CHADS2 and CHA2DS2-VASc scores predict vascular events but don’t correlate with left atrial appendage thrombus, Dr. Gersh noted.
He said the CHA2DS2-VASc score is clearly an improvement over CHADS2, and its adoption in the forthcoming ACC/AHA guidelines is to be welcomed. The CHA2DS2-VASc score increases the number of patients considered at significant risk of stroke and therefore warranting anticoagulation. For example, in a large Danish registry of nearly 48,000 AF patients with a CHADS2 score of 0-1 not on anticoagulation, patients with a CHADS2 score of 1 but a CHA2DS2-VASc score of 2 had twice the stroke risk of patients with a CHA2DS2-VASc of 1 (Thromb. Haemost. 2012;107:1172-9).
That being said, neither risk score is all that impressive. The C-statistic, a measure of a test’s predictive power, is 0.56 for CHADS2 and it was 0.62 for CHA2DS2-VASc in the ARISTOTLE analysis. To put those figures in perspective, a coin toss has a C-statistic of 0.50.
"The individual predictive values are not good. We use CHADS2 and CHA2DS2-VASc in practice and in the guidelines, but we should not pretend they are highly predictive. We need new risk stratification schemes," according to Dr. Gersh.
He reported serving as an adviser to Boston Scientific and St. Jude Medical.
SNOWMASS, COLO. – High-sensitivity troponin T and brain natriuretic peptide levels are better predictors of stroke risk in patients with atrial fibrillation than the CHA2DS2-VASc score that will replace the CHADS2 score in the forthcoming revised American College of Cardiology/American Heart Association guidelines.
Recent evidence indicates the biomarkers may be novel tools for improved stroke prediction in atrial fibrillation (AF), with prognostic value above and beyond that provided by the CHA2DS2-VASc scores.
These findings raise important unanswered questions about the relationship between AF and stroke. Conventional wisdom has held that left atrial thrombus is the cause of most strokes in patients with AF. But it’s not that simple, Dr. Bernard J. Gersh asserted at the Annual Cardiovascular Conference at Snowmass.
"What are we measuring with these biomarkers? This is what we really don’t understand. What has high-sensitivity troponin T got to do with left atrial thrombus?" asked Dr. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.
It seems increasingly clear that it’s not just the atrial arrhythmia that’s important in stroke risk, it’s also the company AF keeps. In a substantial but still uncertain proportion of patients, AF is a marker of vascular disease burden expressed through atrial and vascular endothelial dysfunction, vascular inflammation, left atrial dilatation and fibrosis, and a hypercoagulable state, the cardiologist continued.
He was a coinvestigator on a couple of recent groundbreaking studies that show the prognostic power of biomarkers in predicting both stroke risk and cardiac death in AF patients.
In one report, the investigators looked at baseline high-sensitivity troponin T (hsTnT) levels, clinical risk factors for stroke, and CHA2DS2-VASc scores in 12,892 patients with AF who were randomized to apixaban or warfarin in the prospective, double-blind ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial (N. Engl. J. Med. 2011;365:981-92). During a median 1.9 years of follow-up, patients in the highest quartile for baseline hsTnT had roughly a twofold greater risk of stroke or systemic embolism than did those in the lowest quartile.
Moreover, patients with a low-risk CHA2DS2-VASc score of 0 or 1 but in the top quartile for hsTnT, with a level in excess of 13 ng/L, had a very substantial stroke rate of 2.7% per year despite anticoagulation with apixaban (Eliquis) or warfarin. The relationship was even stronger for cardiac death, where subjects with a low-risk CHA2DS2-VASc score who were in the top quartile for hsTnT had a 6% annual risk. A higher baseline hsTnT was also independently associated with sharply increased risk of major bleeding in a multivariate regression analysis (J. Am. Coll. Cardiol. 2014;63:52-61).
In another recently published study, he and his international coworkers showed in ARISTOTLE participants with baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels that this biomarker also improved stroke prediction in AF, providing added value to CHA2DS2-VASc scores. Subjects in the top quartile for baseline NT-proBNP had an adjusted 2.35-fold greater risk of stroke or systemic embolism than those in the lowest quartile, irrespective of CHA2DS2-VASc score. They also had a 2.5-fold greater risk of cardiac death (J. Am. Coll. Cardiol. 2013;61:2274-84).
A study Dr. Gersh highlighted as "extremely interesting" involved the use of brain natriuretic peptide (BNP) as a marker to rule out delayed AF in stroke patients. The study, led by investigators at the University Hospital Center of Nice (France) and known as TARGET-AF, included 300 consecutive acute stroke patients with no history of AF and no AF on their baseline ECG. During a median 6.8 days of in-hospital Holter monitoring, 17% of the stroke patients developed newly diagnosed AF.
The strongest predictor of delayed AF was baseline plasma BNP. It outperformed the CHA2DS2-VASc score and all the other parameters examined, including anterior circulation location of the stroke, P-wave initial force, gender, National Institutes of Health Stroke Scale score, age, left atrial dilatation, and Score for the Targeting of AF (STAF) score. A BNP level greater than 131 pg/mL had a 98.1% sensitivity, 71.4% specificity, and 99.4% negative predictive value for delayed AF.
"Our data indicate that a BNP level of 131 pg/mL or less might rule out delayed AF in stroke survivors and could be included in algorithms for AF detection," the French investigators concluded (J. Stroke Cerebrovasc. Dis. 2013;22:e103-10).
There is plenty of direct evidence from transesophageal echocardiography studies and other sources that a substantial proportion of thromboemboli are directly the result of AF. However, indirect evidence points to additional causal factors. For example, there is a high incidence of thromboembolic events in AF patients without left atrial appendage thrombus. Plus, in natural history studies patients with AF without additional risk factors have a low incidence of stroke. And CHADS2 and CHA2DS2-VASc scores predict vascular events but don’t correlate with left atrial appendage thrombus, Dr. Gersh noted.
He said the CHA2DS2-VASc score is clearly an improvement over CHADS2, and its adoption in the forthcoming ACC/AHA guidelines is to be welcomed. The CHA2DS2-VASc score increases the number of patients considered at significant risk of stroke and therefore warranting anticoagulation. For example, in a large Danish registry of nearly 48,000 AF patients with a CHADS2 score of 0-1 not on anticoagulation, patients with a CHADS2 score of 1 but a CHA2DS2-VASc score of 2 had twice the stroke risk of patients with a CHA2DS2-VASc of 1 (Thromb. Haemost. 2012;107:1172-9).
That being said, neither risk score is all that impressive. The C-statistic, a measure of a test’s predictive power, is 0.56 for CHADS2 and it was 0.62 for CHA2DS2-VASc in the ARISTOTLE analysis. To put those figures in perspective, a coin toss has a C-statistic of 0.50.
"The individual predictive values are not good. We use CHADS2 and CHA2DS2-VASc in practice and in the guidelines, but we should not pretend they are highly predictive. We need new risk stratification schemes," according to Dr. Gersh.
He reported serving as an adviser to Boston Scientific and St. Jude Medical.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
Shift in approach needed for managing inflammatory arthritis in pregnancy
SNOWMASS, COLO. – The common strategy of managing inflammatory arthritis during pregnancy by stopping all prepregnancy medications and prescribing prednisone is counterproductive, Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
"This sort of safe approach is actually not the safest or best approach. We all need to shift our attitude and get comfortable with at least a couple of other medications in order to help our patients have better outcomes," asserted Dr. Clowse, director of the Duke Autoimmunity in Pregnancy (DAP) Registry at Duke University, Durham, N.C.
It’s often true that rheumatoid arthritis (RA) tends to get better in pregnancy. Nonetheless, pregnancy may not be enough to control disease activity in many women, as illustrated by a nationwide Dutch study in which half of RA patients had moderate to severe disease activity by their third trimester (Arthritis Rheum. 2008;59:1241-8).
"In my experience, the patients who were on tumor necrosis factor inhibitors prepregnancy do not do as well when they come off them. So pregnancy might be good for RA disease activity, but it’s definitely not as good as a tumor necrosis factor inhibitor," according to the rheumatologist.
Roughly one-quarter of the more than 230 prospectively studied pregnancies in the DAP Registry have been in women with RA or other inflammatory arthritides. The preterm birth rate in RA patients in DAP, as in other RA registries, is higher than in the general population. Notably, all of the DAP patients with RA who had preterm birth had moderate to severe disease activity in the first and second trimesters, compared with just a single RA patient with a term delivery.
"Allowing disease to flare may actually harm the pregnancy," Dr. Clowse commented.
Her two top recommendations for nonbiologic treatment of inflammatory arthritis during pregnancy are hydroxychloroquine and sulfasalazine. Hydroxychloroquine is effective for mild arthritis, and it’s rated by the Food and Drug Administration as Pregnancy Category C, with no reports of human toxicity. Sulfasalazine has a good safety profile in pregnancy – it is Pregnancy Category B – and has good efficacy for peripheral arthritis.
"These are two very important medications that are much better – and definitely much safer – options than prednisone. These are just great options, and I try to encourage patients to take them. It’s definitely better than letting patients flare while off methotrexate before they deliver," she continued.
"TNF [tumor necrosis factor] inhibitors are, I think, another reasonable option, particularly in the population with moderate to severe disease activity. If any of these medications help you avoid prednisone, then I think you come out ahead," Dr. Clowse said.
Reassuring data regarding the safety of anti-TNF biologics in pregnancy comes from several sources. A systematic literature review by Dr. Evelyne Vinet and her coworkers at McGill University, Montreal, found no evidence of excess risk of adverse pregnancy or fetal outcomes in women exposed to etanercept (Enbrel), infliximab (Remicade), or adalimumab (Humira) during pregnancy (Arthritis Rheum. 2009;61:587-92). A report from the Organization of Teratology Information Specialists (OTIS) Registry, presented at the 2012 annual meeting of the American College of Rheumatology, found no significant difference between RA patients exposed to adalimumab in pregnancy and RA controls in rates of live birth, miscarriage, stillbirth, congenital abnormalities, or serious infections in the first year of life.
Moreover, DAP Registry data support the notion that for some patients, anti-TNF biologics during pregnancy may be a good option. In Dr. Clowse’s series of 29 RA patients, disease activity during the first trimester neatly delineated three distinct groups. Eleven patients who had a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) averaging 1.5 in the first trimester required neither TNF inhibitors nor prednisone during their pregnancy, and they had no abnormal outcomes. Seven patients with significant first-trimester disease activity as defined by an average DAS28-CRP score of 3.4 went back on their TNF inhibitor during pregnancy, and their disease essentially went into remission, with only one preterm birth. In contrast, 11 other patients with significant first-trimester disease activity went on prednisone because they rejected TNF inhibitor therapy; their disease activity remained substantial, and 6 of the 11 had a preterm birth and/or preeclampsia.
"All of the preeclampsia occurred in the prednisone group. They also had a lot of disease activity postpartum," Dr. Clowse observed.
Infliximab and adalimumab freely pass across the placenta; etanercept and certolizumab pegol (Cimzia) do not. Regardless, no infant exposed in utero to a TNF inhibitor should receive the rotavirus vaccine during the first 5 months of life. That’s the only live-virus vaccine given during infancy in the United States; all the other vaccines can safely be given according to schedule.
Dr. Clowse said there is essentially no published literature regarding psoriatic arthritis in pregnancy. The DAP registry experience includes seven pregnancies in women with psoriatic arthritis. There were no pregnancy losses, one preterm birth, and two cases of preeclampsia.
"What I see is dramatically increased disease activity when women with psoriatic arthritis stop their TNF inhibitor. The worst psoriasis I’ve ever seen is in pregnant patients; they are really miserable off their TNF inhibitors," she said.
There is also very little in the literature about axial spondyloarthritis in pregnancy. The DAP registry’s 10 cases constitute one of the largest series. There were no pregnancy losses, no preeclampsia, and one preterm birth. Eight of the women were delivered by C-section.
"That reflects my personal bias, which is that the position required for vaginal delivery is pretty horrible for sacroiliac joint pain and leads to significant flares postpartum. That’s particularly true if the patient has an epidural and doesn’t know how hard she’s pushing on those SI joints," according to the rheumatologist.
Dr. Clowse reported serving as a consultant to UCB, which markets certolizumab pegol.
SNOWMASS, COLO. – The common strategy of managing inflammatory arthritis during pregnancy by stopping all prepregnancy medications and prescribing prednisone is counterproductive, Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
"This sort of safe approach is actually not the safest or best approach. We all need to shift our attitude and get comfortable with at least a couple of other medications in order to help our patients have better outcomes," asserted Dr. Clowse, director of the Duke Autoimmunity in Pregnancy (DAP) Registry at Duke University, Durham, N.C.
It’s often true that rheumatoid arthritis (RA) tends to get better in pregnancy. Nonetheless, pregnancy may not be enough to control disease activity in many women, as illustrated by a nationwide Dutch study in which half of RA patients had moderate to severe disease activity by their third trimester (Arthritis Rheum. 2008;59:1241-8).
"In my experience, the patients who were on tumor necrosis factor inhibitors prepregnancy do not do as well when they come off them. So pregnancy might be good for RA disease activity, but it’s definitely not as good as a tumor necrosis factor inhibitor," according to the rheumatologist.
Roughly one-quarter of the more than 230 prospectively studied pregnancies in the DAP Registry have been in women with RA or other inflammatory arthritides. The preterm birth rate in RA patients in DAP, as in other RA registries, is higher than in the general population. Notably, all of the DAP patients with RA who had preterm birth had moderate to severe disease activity in the first and second trimesters, compared with just a single RA patient with a term delivery.
"Allowing disease to flare may actually harm the pregnancy," Dr. Clowse commented.
Her two top recommendations for nonbiologic treatment of inflammatory arthritis during pregnancy are hydroxychloroquine and sulfasalazine. Hydroxychloroquine is effective for mild arthritis, and it’s rated by the Food and Drug Administration as Pregnancy Category C, with no reports of human toxicity. Sulfasalazine has a good safety profile in pregnancy – it is Pregnancy Category B – and has good efficacy for peripheral arthritis.
"These are two very important medications that are much better – and definitely much safer – options than prednisone. These are just great options, and I try to encourage patients to take them. It’s definitely better than letting patients flare while off methotrexate before they deliver," she continued.
"TNF [tumor necrosis factor] inhibitors are, I think, another reasonable option, particularly in the population with moderate to severe disease activity. If any of these medications help you avoid prednisone, then I think you come out ahead," Dr. Clowse said.
Reassuring data regarding the safety of anti-TNF biologics in pregnancy comes from several sources. A systematic literature review by Dr. Evelyne Vinet and her coworkers at McGill University, Montreal, found no evidence of excess risk of adverse pregnancy or fetal outcomes in women exposed to etanercept (Enbrel), infliximab (Remicade), or adalimumab (Humira) during pregnancy (Arthritis Rheum. 2009;61:587-92). A report from the Organization of Teratology Information Specialists (OTIS) Registry, presented at the 2012 annual meeting of the American College of Rheumatology, found no significant difference between RA patients exposed to adalimumab in pregnancy and RA controls in rates of live birth, miscarriage, stillbirth, congenital abnormalities, or serious infections in the first year of life.
Moreover, DAP Registry data support the notion that for some patients, anti-TNF biologics during pregnancy may be a good option. In Dr. Clowse’s series of 29 RA patients, disease activity during the first trimester neatly delineated three distinct groups. Eleven patients who had a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) averaging 1.5 in the first trimester required neither TNF inhibitors nor prednisone during their pregnancy, and they had no abnormal outcomes. Seven patients with significant first-trimester disease activity as defined by an average DAS28-CRP score of 3.4 went back on their TNF inhibitor during pregnancy, and their disease essentially went into remission, with only one preterm birth. In contrast, 11 other patients with significant first-trimester disease activity went on prednisone because they rejected TNF inhibitor therapy; their disease activity remained substantial, and 6 of the 11 had a preterm birth and/or preeclampsia.
"All of the preeclampsia occurred in the prednisone group. They also had a lot of disease activity postpartum," Dr. Clowse observed.
Infliximab and adalimumab freely pass across the placenta; etanercept and certolizumab pegol (Cimzia) do not. Regardless, no infant exposed in utero to a TNF inhibitor should receive the rotavirus vaccine during the first 5 months of life. That’s the only live-virus vaccine given during infancy in the United States; all the other vaccines can safely be given according to schedule.
Dr. Clowse said there is essentially no published literature regarding psoriatic arthritis in pregnancy. The DAP registry experience includes seven pregnancies in women with psoriatic arthritis. There were no pregnancy losses, one preterm birth, and two cases of preeclampsia.
"What I see is dramatically increased disease activity when women with psoriatic arthritis stop their TNF inhibitor. The worst psoriasis I’ve ever seen is in pregnant patients; they are really miserable off their TNF inhibitors," she said.
There is also very little in the literature about axial spondyloarthritis in pregnancy. The DAP registry’s 10 cases constitute one of the largest series. There were no pregnancy losses, no preeclampsia, and one preterm birth. Eight of the women were delivered by C-section.
"That reflects my personal bias, which is that the position required for vaginal delivery is pretty horrible for sacroiliac joint pain and leads to significant flares postpartum. That’s particularly true if the patient has an epidural and doesn’t know how hard she’s pushing on those SI joints," according to the rheumatologist.
Dr. Clowse reported serving as a consultant to UCB, which markets certolizumab pegol.
SNOWMASS, COLO. – The common strategy of managing inflammatory arthritis during pregnancy by stopping all prepregnancy medications and prescribing prednisone is counterproductive, Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
"This sort of safe approach is actually not the safest or best approach. We all need to shift our attitude and get comfortable with at least a couple of other medications in order to help our patients have better outcomes," asserted Dr. Clowse, director of the Duke Autoimmunity in Pregnancy (DAP) Registry at Duke University, Durham, N.C.
It’s often true that rheumatoid arthritis (RA) tends to get better in pregnancy. Nonetheless, pregnancy may not be enough to control disease activity in many women, as illustrated by a nationwide Dutch study in which half of RA patients had moderate to severe disease activity by their third trimester (Arthritis Rheum. 2008;59:1241-8).
"In my experience, the patients who were on tumor necrosis factor inhibitors prepregnancy do not do as well when they come off them. So pregnancy might be good for RA disease activity, but it’s definitely not as good as a tumor necrosis factor inhibitor," according to the rheumatologist.
Roughly one-quarter of the more than 230 prospectively studied pregnancies in the DAP Registry have been in women with RA or other inflammatory arthritides. The preterm birth rate in RA patients in DAP, as in other RA registries, is higher than in the general population. Notably, all of the DAP patients with RA who had preterm birth had moderate to severe disease activity in the first and second trimesters, compared with just a single RA patient with a term delivery.
"Allowing disease to flare may actually harm the pregnancy," Dr. Clowse commented.
Her two top recommendations for nonbiologic treatment of inflammatory arthritis during pregnancy are hydroxychloroquine and sulfasalazine. Hydroxychloroquine is effective for mild arthritis, and it’s rated by the Food and Drug Administration as Pregnancy Category C, with no reports of human toxicity. Sulfasalazine has a good safety profile in pregnancy – it is Pregnancy Category B – and has good efficacy for peripheral arthritis.
"These are two very important medications that are much better – and definitely much safer – options than prednisone. These are just great options, and I try to encourage patients to take them. It’s definitely better than letting patients flare while off methotrexate before they deliver," she continued.
"TNF [tumor necrosis factor] inhibitors are, I think, another reasonable option, particularly in the population with moderate to severe disease activity. If any of these medications help you avoid prednisone, then I think you come out ahead," Dr. Clowse said.
Reassuring data regarding the safety of anti-TNF biologics in pregnancy comes from several sources. A systematic literature review by Dr. Evelyne Vinet and her coworkers at McGill University, Montreal, found no evidence of excess risk of adverse pregnancy or fetal outcomes in women exposed to etanercept (Enbrel), infliximab (Remicade), or adalimumab (Humira) during pregnancy (Arthritis Rheum. 2009;61:587-92). A report from the Organization of Teratology Information Specialists (OTIS) Registry, presented at the 2012 annual meeting of the American College of Rheumatology, found no significant difference between RA patients exposed to adalimumab in pregnancy and RA controls in rates of live birth, miscarriage, stillbirth, congenital abnormalities, or serious infections in the first year of life.
Moreover, DAP Registry data support the notion that for some patients, anti-TNF biologics during pregnancy may be a good option. In Dr. Clowse’s series of 29 RA patients, disease activity during the first trimester neatly delineated three distinct groups. Eleven patients who had a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) averaging 1.5 in the first trimester required neither TNF inhibitors nor prednisone during their pregnancy, and they had no abnormal outcomes. Seven patients with significant first-trimester disease activity as defined by an average DAS28-CRP score of 3.4 went back on their TNF inhibitor during pregnancy, and their disease essentially went into remission, with only one preterm birth. In contrast, 11 other patients with significant first-trimester disease activity went on prednisone because they rejected TNF inhibitor therapy; their disease activity remained substantial, and 6 of the 11 had a preterm birth and/or preeclampsia.
"All of the preeclampsia occurred in the prednisone group. They also had a lot of disease activity postpartum," Dr. Clowse observed.
Infliximab and adalimumab freely pass across the placenta; etanercept and certolizumab pegol (Cimzia) do not. Regardless, no infant exposed in utero to a TNF inhibitor should receive the rotavirus vaccine during the first 5 months of life. That’s the only live-virus vaccine given during infancy in the United States; all the other vaccines can safely be given according to schedule.
Dr. Clowse said there is essentially no published literature regarding psoriatic arthritis in pregnancy. The DAP registry experience includes seven pregnancies in women with psoriatic arthritis. There were no pregnancy losses, one preterm birth, and two cases of preeclampsia.
"What I see is dramatically increased disease activity when women with psoriatic arthritis stop their TNF inhibitor. The worst psoriasis I’ve ever seen is in pregnant patients; they are really miserable off their TNF inhibitors," she said.
There is also very little in the literature about axial spondyloarthritis in pregnancy. The DAP registry’s 10 cases constitute one of the largest series. There were no pregnancy losses, no preeclampsia, and one preterm birth. Eight of the women were delivered by C-section.
"That reflects my personal bias, which is that the position required for vaginal delivery is pretty horrible for sacroiliac joint pain and leads to significant flares postpartum. That’s particularly true if the patient has an epidural and doesn’t know how hard she’s pushing on those SI joints," according to the rheumatologist.
Dr. Clowse reported serving as a consultant to UCB, which markets certolizumab pegol.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
New quality indicator for rheumatologists: vaccination rates
SNOWMASS, COLO. – Most rheumatologists view their patients’ vaccination status as a matter within the sphere of primary care medicine, but payers and health policy makers see things otherwise.
"You and I will soon be judged as to whether we’re good rheumatologists on the basis of whether our patients have gotten vaccinated, with almost complete certainty in my mind. This as a quality measure – ‘Are your patients getting vaccinated?’ – is undergoing measure-specification testing now by the American College of Rheumatology," Dr. Jeffrey R. Curtis said at the Winter Rheumatology Symposium sponsored by the ACR.
Flu, pneumococcal, HPV vaccines underused
Vaccination rates in patients with rheumatic diseases are unacceptably low, as highlighted in a study by Dr. Curtis and coinvestigators. They looked retrospectively at vaccination rates over a 5-year period in 141,140 rheumatoid arthritis (RA) patients, 6,300 others with psoriatic arthritis, and 770,520 osteoarthritis patients. Only 19%-22% of patients in the three groups received the influenza vaccine in all 5 years, and 29%-33% were vaccinated against pneumococcus.
Patients with RA or systemic lupus erythematosus (SLE) have been shown to be at 1.5-fold increased risk of high-grade cervical dysplasia, compared with the general population, yet less than 14% of females and less than 1% of males with autoimmune diseases have received the three-dose recombinant human papillomavirus (HPV) vaccine, as reported by Dr. Seoyoung C. Kim of Brigham and Women’s Hospital, Boston, and coworkers at the ACR 2013 annual meeting.
"My point is that we keep seeing this recurring theme: Our patients are at higher risk for infections and cervical cancer, we have vaccines that work to prevent those things, but we’re not using them and in most cases neither is primary care," said Dr. Curtis, director of the arthritis clinical intervention program and associate director of the Center for Education and Research on Therapeutics of Musculoskeletal Disorders at the University of Alabama, Birmingham.
"Regardless of whether you say this is a primary care thing and work with primary care to make sure it gets done, or you help enfranchise patients so they take control over this, or you’re going to do it your own self, you and I are going to be judged on this. It will be part of the new quality measures. This is happening," he emphasized.
One strategy Dr. Curtis said has been shown to be "reasonably effective" in several studies is to delegate responsibility for vaccinations to a mid-level practitioner, not on a patient-by-patient basis, but for the whole rheumatology practice.
Most studies indicate that long-term efficacy of vaccines is generally adequate in patients on methotrexate and/or biologics, albeit not as good as in the general population. The exception is rituximab (Rituxan): Patients on this drug have a greatly diminished humoral response to the PPSV-23 pneumococcal vaccine (Pneumovax) as well as to trivalent influenza vaccine. However, Dutch investigators showed that while the humoral response was seriously reduced in RA patients who got the flu vaccine 4-8 weeks after receiving rituximab, the immune response was modestly better when patients got the vaccine 6-10 months post rituximab (Arthritis Rheum. 2010;62:75-81).
"It matters when you got rituximab. If a patient got it a month or two ago, I wouldn’t bother vaccinating against influenza. Patients will have no response. But if it has been 6 or more months, it probably is worth doing," Dr. Curtis said.
Herpes zoster vaccination
RA patients are at 1.5- to 2-fold increased risk for herpes zoster, compared with the age-matched general population. The risk in lupus patients is even greater. Yet very few patients with these diseases get the live-virus herpes zoster vaccine.
The jury is still out as to whether anti–tumor necrosis factor therapies further raise that risk; the evidence is mixed. However, a particularly large study conducted by Dr. Curtis and coworkers in 24,000 older RA patients who were new users of anti-TNF biologics and nearly 12,000 who were new users of methotrexate and other nonbiologic DMARDs found that the rate of herpes zoster in the new users was 12.6 cases per 1,000 person-years, no higher than in those starting on nonbiologic DMARDs (JAMA 2013;309:887-95).
In contrast, a consistent finding in multiple studies is that the risk of herpes zoster is nearly twofold greater in RA patients receiving prednisone at greater than 7.5-10 mg/day. For example, the JAMA study by Dr. Curtis and coinvestigators found that baseline use of prednisone at more than 10 mg/day was independently associated with a 1.87-fold increased risk of zoster.
Tofacitinib (Xeljanz) clearly confers an increased risk of herpes zoster. At last fall’s annual ACR meeting, Dr. Curtis presented highlights of the worldwide clinical trial experience with tofacitinib in RA, totaling five phase III and six phase II randomized trials as well as two long-term extension studies. Tofacitinib was associated with a herpes zoster rate of 40-50 cases per 1,000 person-years, which is more than threefold higher than the rate with any anti-TNF agent.
"I think from a clinical perspective this definitely needs to be on our radar screen. Hopefully it makes the case that vaccination with the live-virus zoster vaccine, Zostavax, is compelling. I suspect that it’s not tofacitinib in particular, because early data for some of the other janus kinase inhibitors has suggested this problem is a class effect," Dr. Curtis said.
In vaccinating patients with RA and other rheumatic diseases, the recommended approach is whenever possible to give the vaccines before starting methotrexate or a biologic agent. That’s going to result in the greatest possible protection. The humoral response won’t be as robust if vaccines are given to patients already on treatment, but it’s still probably worth doing, except if they’ve recently received rituximab, he continued.
Vaccination guidelines not necessarily correct
Dr. Curtis cautioned that the major guidelines regarding vaccination of adults with rheumatic diseases should not automatically be taken as truth. For example, the ACR recommends against giving the live-virus herpes zoster vaccine to patients who are taking a biologic agent (Arthritis Care Res. 2012;64:625-39). But the European League Against Rheumatism (EULAR) guidelines state that the vaccine "may be considered" in such patients (Ann. Rheum. Dis. 2011;70:414-22).
Consistent with the EULAR stance, a study conducted by Dr. Curtis and coworkers in more than 463,000 elderly patients with RA or one of four other autoimmune diseases found that no safety issues arose in patients who were given the herpes zoster vaccine while on a TNF antagonist, a non-TNF biologic, or a nonbiologic DMARD. Moreover, the vaccine’s protective effect in RA patients on an anti-TNF biologic was similar to that seen in individuals without RA, with a 39% relative risk reduction, compared with unvaccinated individuals (JAMA 2012;308:43-9).
Here’s another point of contention regarding major practice guidelines: Recommendations from the Centers for Disease Control and Prevention state that glucocorticoid therapy is not a contraindication to administering live-virus vaccine to immunocompromised patients provided they are on low- to moderate-dose prednisone, which the CDC defines as less than 20 mg/day of prednisone for less than 14 days. Dr. Curtis disagrees.
"I consider 15 mg of prednisone more immunosuppressive than the biologics that we give," he said.
Dr. Curtis reported receiving funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, and 10 pharmaceutical companies.
SNOWMASS, COLO. – Most rheumatologists view their patients’ vaccination status as a matter within the sphere of primary care medicine, but payers and health policy makers see things otherwise.
"You and I will soon be judged as to whether we’re good rheumatologists on the basis of whether our patients have gotten vaccinated, with almost complete certainty in my mind. This as a quality measure – ‘Are your patients getting vaccinated?’ – is undergoing measure-specification testing now by the American College of Rheumatology," Dr. Jeffrey R. Curtis said at the Winter Rheumatology Symposium sponsored by the ACR.
Flu, pneumococcal, HPV vaccines underused
Vaccination rates in patients with rheumatic diseases are unacceptably low, as highlighted in a study by Dr. Curtis and coinvestigators. They looked retrospectively at vaccination rates over a 5-year period in 141,140 rheumatoid arthritis (RA) patients, 6,300 others with psoriatic arthritis, and 770,520 osteoarthritis patients. Only 19%-22% of patients in the three groups received the influenza vaccine in all 5 years, and 29%-33% were vaccinated against pneumococcus.
Patients with RA or systemic lupus erythematosus (SLE) have been shown to be at 1.5-fold increased risk of high-grade cervical dysplasia, compared with the general population, yet less than 14% of females and less than 1% of males with autoimmune diseases have received the three-dose recombinant human papillomavirus (HPV) vaccine, as reported by Dr. Seoyoung C. Kim of Brigham and Women’s Hospital, Boston, and coworkers at the ACR 2013 annual meeting.
"My point is that we keep seeing this recurring theme: Our patients are at higher risk for infections and cervical cancer, we have vaccines that work to prevent those things, but we’re not using them and in most cases neither is primary care," said Dr. Curtis, director of the arthritis clinical intervention program and associate director of the Center for Education and Research on Therapeutics of Musculoskeletal Disorders at the University of Alabama, Birmingham.
"Regardless of whether you say this is a primary care thing and work with primary care to make sure it gets done, or you help enfranchise patients so they take control over this, or you’re going to do it your own self, you and I are going to be judged on this. It will be part of the new quality measures. This is happening," he emphasized.
One strategy Dr. Curtis said has been shown to be "reasonably effective" in several studies is to delegate responsibility for vaccinations to a mid-level practitioner, not on a patient-by-patient basis, but for the whole rheumatology practice.
Most studies indicate that long-term efficacy of vaccines is generally adequate in patients on methotrexate and/or biologics, albeit not as good as in the general population. The exception is rituximab (Rituxan): Patients on this drug have a greatly diminished humoral response to the PPSV-23 pneumococcal vaccine (Pneumovax) as well as to trivalent influenza vaccine. However, Dutch investigators showed that while the humoral response was seriously reduced in RA patients who got the flu vaccine 4-8 weeks after receiving rituximab, the immune response was modestly better when patients got the vaccine 6-10 months post rituximab (Arthritis Rheum. 2010;62:75-81).
"It matters when you got rituximab. If a patient got it a month or two ago, I wouldn’t bother vaccinating against influenza. Patients will have no response. But if it has been 6 or more months, it probably is worth doing," Dr. Curtis said.
Herpes zoster vaccination
RA patients are at 1.5- to 2-fold increased risk for herpes zoster, compared with the age-matched general population. The risk in lupus patients is even greater. Yet very few patients with these diseases get the live-virus herpes zoster vaccine.
The jury is still out as to whether anti–tumor necrosis factor therapies further raise that risk; the evidence is mixed. However, a particularly large study conducted by Dr. Curtis and coworkers in 24,000 older RA patients who were new users of anti-TNF biologics and nearly 12,000 who were new users of methotrexate and other nonbiologic DMARDs found that the rate of herpes zoster in the new users was 12.6 cases per 1,000 person-years, no higher than in those starting on nonbiologic DMARDs (JAMA 2013;309:887-95).
In contrast, a consistent finding in multiple studies is that the risk of herpes zoster is nearly twofold greater in RA patients receiving prednisone at greater than 7.5-10 mg/day. For example, the JAMA study by Dr. Curtis and coinvestigators found that baseline use of prednisone at more than 10 mg/day was independently associated with a 1.87-fold increased risk of zoster.
Tofacitinib (Xeljanz) clearly confers an increased risk of herpes zoster. At last fall’s annual ACR meeting, Dr. Curtis presented highlights of the worldwide clinical trial experience with tofacitinib in RA, totaling five phase III and six phase II randomized trials as well as two long-term extension studies. Tofacitinib was associated with a herpes zoster rate of 40-50 cases per 1,000 person-years, which is more than threefold higher than the rate with any anti-TNF agent.
"I think from a clinical perspective this definitely needs to be on our radar screen. Hopefully it makes the case that vaccination with the live-virus zoster vaccine, Zostavax, is compelling. I suspect that it’s not tofacitinib in particular, because early data for some of the other janus kinase inhibitors has suggested this problem is a class effect," Dr. Curtis said.
In vaccinating patients with RA and other rheumatic diseases, the recommended approach is whenever possible to give the vaccines before starting methotrexate or a biologic agent. That’s going to result in the greatest possible protection. The humoral response won’t be as robust if vaccines are given to patients already on treatment, but it’s still probably worth doing, except if they’ve recently received rituximab, he continued.
Vaccination guidelines not necessarily correct
Dr. Curtis cautioned that the major guidelines regarding vaccination of adults with rheumatic diseases should not automatically be taken as truth. For example, the ACR recommends against giving the live-virus herpes zoster vaccine to patients who are taking a biologic agent (Arthritis Care Res. 2012;64:625-39). But the European League Against Rheumatism (EULAR) guidelines state that the vaccine "may be considered" in such patients (Ann. Rheum. Dis. 2011;70:414-22).
Consistent with the EULAR stance, a study conducted by Dr. Curtis and coworkers in more than 463,000 elderly patients with RA or one of four other autoimmune diseases found that no safety issues arose in patients who were given the herpes zoster vaccine while on a TNF antagonist, a non-TNF biologic, or a nonbiologic DMARD. Moreover, the vaccine’s protective effect in RA patients on an anti-TNF biologic was similar to that seen in individuals without RA, with a 39% relative risk reduction, compared with unvaccinated individuals (JAMA 2012;308:43-9).
Here’s another point of contention regarding major practice guidelines: Recommendations from the Centers for Disease Control and Prevention state that glucocorticoid therapy is not a contraindication to administering live-virus vaccine to immunocompromised patients provided they are on low- to moderate-dose prednisone, which the CDC defines as less than 20 mg/day of prednisone for less than 14 days. Dr. Curtis disagrees.
"I consider 15 mg of prednisone more immunosuppressive than the biologics that we give," he said.
Dr. Curtis reported receiving funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, and 10 pharmaceutical companies.
SNOWMASS, COLO. – Most rheumatologists view their patients’ vaccination status as a matter within the sphere of primary care medicine, but payers and health policy makers see things otherwise.
"You and I will soon be judged as to whether we’re good rheumatologists on the basis of whether our patients have gotten vaccinated, with almost complete certainty in my mind. This as a quality measure – ‘Are your patients getting vaccinated?’ – is undergoing measure-specification testing now by the American College of Rheumatology," Dr. Jeffrey R. Curtis said at the Winter Rheumatology Symposium sponsored by the ACR.
Flu, pneumococcal, HPV vaccines underused
Vaccination rates in patients with rheumatic diseases are unacceptably low, as highlighted in a study by Dr. Curtis and coinvestigators. They looked retrospectively at vaccination rates over a 5-year period in 141,140 rheumatoid arthritis (RA) patients, 6,300 others with psoriatic arthritis, and 770,520 osteoarthritis patients. Only 19%-22% of patients in the three groups received the influenza vaccine in all 5 years, and 29%-33% were vaccinated against pneumococcus.
Patients with RA or systemic lupus erythematosus (SLE) have been shown to be at 1.5-fold increased risk of high-grade cervical dysplasia, compared with the general population, yet less than 14% of females and less than 1% of males with autoimmune diseases have received the three-dose recombinant human papillomavirus (HPV) vaccine, as reported by Dr. Seoyoung C. Kim of Brigham and Women’s Hospital, Boston, and coworkers at the ACR 2013 annual meeting.
"My point is that we keep seeing this recurring theme: Our patients are at higher risk for infections and cervical cancer, we have vaccines that work to prevent those things, but we’re not using them and in most cases neither is primary care," said Dr. Curtis, director of the arthritis clinical intervention program and associate director of the Center for Education and Research on Therapeutics of Musculoskeletal Disorders at the University of Alabama, Birmingham.
"Regardless of whether you say this is a primary care thing and work with primary care to make sure it gets done, or you help enfranchise patients so they take control over this, or you’re going to do it your own self, you and I are going to be judged on this. It will be part of the new quality measures. This is happening," he emphasized.
One strategy Dr. Curtis said has been shown to be "reasonably effective" in several studies is to delegate responsibility for vaccinations to a mid-level practitioner, not on a patient-by-patient basis, but for the whole rheumatology practice.
Most studies indicate that long-term efficacy of vaccines is generally adequate in patients on methotrexate and/or biologics, albeit not as good as in the general population. The exception is rituximab (Rituxan): Patients on this drug have a greatly diminished humoral response to the PPSV-23 pneumococcal vaccine (Pneumovax) as well as to trivalent influenza vaccine. However, Dutch investigators showed that while the humoral response was seriously reduced in RA patients who got the flu vaccine 4-8 weeks after receiving rituximab, the immune response was modestly better when patients got the vaccine 6-10 months post rituximab (Arthritis Rheum. 2010;62:75-81).
"It matters when you got rituximab. If a patient got it a month or two ago, I wouldn’t bother vaccinating against influenza. Patients will have no response. But if it has been 6 or more months, it probably is worth doing," Dr. Curtis said.
Herpes zoster vaccination
RA patients are at 1.5- to 2-fold increased risk for herpes zoster, compared with the age-matched general population. The risk in lupus patients is even greater. Yet very few patients with these diseases get the live-virus herpes zoster vaccine.
The jury is still out as to whether anti–tumor necrosis factor therapies further raise that risk; the evidence is mixed. However, a particularly large study conducted by Dr. Curtis and coworkers in 24,000 older RA patients who were new users of anti-TNF biologics and nearly 12,000 who were new users of methotrexate and other nonbiologic DMARDs found that the rate of herpes zoster in the new users was 12.6 cases per 1,000 person-years, no higher than in those starting on nonbiologic DMARDs (JAMA 2013;309:887-95).
In contrast, a consistent finding in multiple studies is that the risk of herpes zoster is nearly twofold greater in RA patients receiving prednisone at greater than 7.5-10 mg/day. For example, the JAMA study by Dr. Curtis and coinvestigators found that baseline use of prednisone at more than 10 mg/day was independently associated with a 1.87-fold increased risk of zoster.
Tofacitinib (Xeljanz) clearly confers an increased risk of herpes zoster. At last fall’s annual ACR meeting, Dr. Curtis presented highlights of the worldwide clinical trial experience with tofacitinib in RA, totaling five phase III and six phase II randomized trials as well as two long-term extension studies. Tofacitinib was associated with a herpes zoster rate of 40-50 cases per 1,000 person-years, which is more than threefold higher than the rate with any anti-TNF agent.
"I think from a clinical perspective this definitely needs to be on our radar screen. Hopefully it makes the case that vaccination with the live-virus zoster vaccine, Zostavax, is compelling. I suspect that it’s not tofacitinib in particular, because early data for some of the other janus kinase inhibitors has suggested this problem is a class effect," Dr. Curtis said.
In vaccinating patients with RA and other rheumatic diseases, the recommended approach is whenever possible to give the vaccines before starting methotrexate or a biologic agent. That’s going to result in the greatest possible protection. The humoral response won’t be as robust if vaccines are given to patients already on treatment, but it’s still probably worth doing, except if they’ve recently received rituximab, he continued.
Vaccination guidelines not necessarily correct
Dr. Curtis cautioned that the major guidelines regarding vaccination of adults with rheumatic diseases should not automatically be taken as truth. For example, the ACR recommends against giving the live-virus herpes zoster vaccine to patients who are taking a biologic agent (Arthritis Care Res. 2012;64:625-39). But the European League Against Rheumatism (EULAR) guidelines state that the vaccine "may be considered" in such patients (Ann. Rheum. Dis. 2011;70:414-22).
Consistent with the EULAR stance, a study conducted by Dr. Curtis and coworkers in more than 463,000 elderly patients with RA or one of four other autoimmune diseases found that no safety issues arose in patients who were given the herpes zoster vaccine while on a TNF antagonist, a non-TNF biologic, or a nonbiologic DMARD. Moreover, the vaccine’s protective effect in RA patients on an anti-TNF biologic was similar to that seen in individuals without RA, with a 39% relative risk reduction, compared with unvaccinated individuals (JAMA 2012;308:43-9).
Here’s another point of contention regarding major practice guidelines: Recommendations from the Centers for Disease Control and Prevention state that glucocorticoid therapy is not a contraindication to administering live-virus vaccine to immunocompromised patients provided they are on low- to moderate-dose prednisone, which the CDC defines as less than 20 mg/day of prednisone for less than 14 days. Dr. Curtis disagrees.
"I consider 15 mg of prednisone more immunosuppressive than the biologics that we give," he said.
Dr. Curtis reported receiving funding from the National Institutes of Health, the Agency for Healthcare Research and Quality, and 10 pharmaceutical companies.
EXPERT ANALYSIS FROM THE ACR WINTER RHEUMATOLOGY SYMPOSIUM
