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Refractory vasovagal syncope responds to DDD-CLS pacing
Washington – Help is finally at hand for the subgroup of patients who have severe refractory vasovagal syncope that recurs frequently and unpredictably, and is associated with a strong cardioinhibitory response on tilt table testing, Gonzalo Baron-Esquivias, MD, said at the annual meeting of the American College of Cardiology.
Results of the randomized, multicenter, double-blind, crossover, placebo-controlled SPAIN trial showed that implantation of a permanent pacemaker programmed to a closed loop stimulation (DDD-CLS) algorithm resulted in an 89% decrease in the risk of syncopal recurrences compared with sham DDI pacing, reported Dr. Baron-Esquivias, chief of clinical cardiology at Virgen del Rocio University Hospital in Seville, Spain. 
Moreover, the number needed to treat with DDD-CLS pacing for 1 year to prevent a syncopal episode was a mere 2.7 patients in the SPAIN trial, he noted.
The study included 46 patients who met strict criteria for participation and received a permanent pacemaker for which they had no conventional indication. In half of the subjects, the device was programmed to DDD-CLS pacing, while the other half received sham DDI pacing, making them a placebo-treated control group. After 12 months, each group was switched over to the other form of pacing.
Dr. Baron-Esquivias emphasized that the tough SPAIN eligibility criteria enabled investigators to accurately define a specific CSL-responsive subgroup. This is not a form of therapy that’s appropriate for most patients who experience vasovagal syncope. In the right population, however, DDD-CLS pacing is life transforming. The SPAIN investigators documented severely impaired quality of life in the study population, with dramatic improvement on CLS pacing.
Vasovagal syncope is by far the most common cause of syncope. But roughly 70 out of every 100 patients who present to the emergency department with vasovagal syncope will never have a repeat episode. And of the 30 who do, perhaps only 10 will have frequent recurrences refractory to conventional measures and that impose a severe effect on quality of life. This is the subgroup for whom consideration of pacemaker therapy is appropriate.
To be eligible for the SPAIN trial, patients had to have at least five previous episodes of neuromediated vasovagal syncope, including at least two within the past year. They also had to be at least 40 years old, since CLS-responsive vasovagal syncope is skewed toward an older age group. In addition, all participants had to have normal results on a complete physical examination that included an orthostatic test, 12-lead echocardiogram, two-dimensional echocardiography, carotid sinus massage, and 24-hour Holter monitoring. Only then were they eligible for a tilt-table test. A positive head-up tilt test demonstrating a cardioinhibitory response required a heart rate drop to less than 40 bpm for at least 10 sec or a greater than 3-sec pause.
The average age of the 46 subjects who fulfilled all of these criteria was 56 years – several decades older than most patients who present with syncope. They averaged 12 prior syncopal episodes, including 4.5 during the prior 12 months. Three-quarters of the patients demonstrated asystole during the tilt test, with an average duration of 15 sec.
Four of the 46 patients experienced a syncopal recurrence during their 12 months on DDD-CLS pacing, while 21 of the same group of 46 had recurrent syncope during their year on DDI sham pacing. This translated into an absolute 37% reduction in syncopal episodes with active pacemaker therapy. Patients had an 8.8-fold greater risk of syncopal recurrence while on DDI sham pacing compared with DDD-CLS.
Dr. Baron-Esquivias explained that the DDD-CLS algorithm is designed to detect impending syncope at an early and actionable stage. The algorithm identifies the combination of increased myocardial contractility and reduced right ventricular intracardiac impedance, which heralds the first stage of vasovagal syncope. It then directs the pacemaker to activate high-rate atrioventricular sequential pacing to prevent arterial hypotension, bradycardia, and overt syncope.
Discussant Kenneth A. Ellenbogen, MD, applauded Dr. Baron-Esquivias and coinvestigators for “having the strength and conviction to attack this problem where so many prior studies have failed.”
For example, the earlier European SYNPACE trial showed no benefit for dual-chamber pacemaker therapy in DDD-RDR (rate-drop response) mode in patients with recurrent severe cardioinhibitory vasovagal syncope (Eur Heart J. 2004 Oct;25[19]:1741-8), probably due to a combination of a less robust early-syncope detection algorithm than that of DDD-CLS and less restrictive patient selection criteria, observed Dr. Ellenbogen, chairman of the division of cardiology and director of clinical cardiology electrophysiology and pacing at the Medical College of Virginia, Richmond.
The SPAIN trial was funded by the Spanish Society of Cardiology. Dr. Baron-Esquivias reported having no financial conflicts.
A considerably larger randomized trial known as BIOSync CLS, sponsored by Biotronic, which developed the CLS program, is ongoing.
Washington – Help is finally at hand for the subgroup of patients who have severe refractory vasovagal syncope that recurs frequently and unpredictably, and is associated with a strong cardioinhibitory response on tilt table testing, Gonzalo Baron-Esquivias, MD, said at the annual meeting of the American College of Cardiology.
Results of the randomized, multicenter, double-blind, crossover, placebo-controlled SPAIN trial showed that implantation of a permanent pacemaker programmed to a closed loop stimulation (DDD-CLS) algorithm resulted in an 89% decrease in the risk of syncopal recurrences compared with sham DDI pacing, reported Dr. Baron-Esquivias, chief of clinical cardiology at Virgen del Rocio University Hospital in Seville, Spain.
Moreover, the number needed to treat with DDD-CLS pacing for 1 year to prevent a syncopal episode was a mere 2.7 patients in the SPAIN trial, he noted.
The study included 46 patients who met strict criteria for participation and received a permanent pacemaker for which they had no conventional indication. In half of the subjects, the device was programmed to DDD-CLS pacing, while the other half received sham DDI pacing, making them a placebo-treated control group. After 12 months, each group was switched over to the other form of pacing.
Dr. Baron-Esquivias emphasized that the tough SPAIN eligibility criteria enabled investigators to accurately define a specific CSL-responsive subgroup. This is not a form of therapy that’s appropriate for most patients who experience vasovagal syncope. In the right population, however, DDD-CLS pacing is life transforming. The SPAIN investigators documented severely impaired quality of life in the study population, with dramatic improvement on CLS pacing.
Vasovagal syncope is by far the most common cause of syncope. But roughly 70 out of every 100 patients who present to the emergency department with vasovagal syncope will never have a repeat episode. And of the 30 who do, perhaps only 10 will have frequent recurrences refractory to conventional measures and that impose a severe effect on quality of life. This is the subgroup for whom consideration of pacemaker therapy is appropriate.
To be eligible for the SPAIN trial, patients had to have at least five previous episodes of neuromediated vasovagal syncope, including at least two within the past year. They also had to be at least 40 years old, since CLS-responsive vasovagal syncope is skewed toward an older age group. In addition, all participants had to have normal results on a complete physical examination that included an orthostatic test, 12-lead echocardiogram, two-dimensional echocardiography, carotid sinus massage, and 24-hour Holter monitoring. Only then were they eligible for a tilt-table test. A positive head-up tilt test demonstrating a cardioinhibitory response required a heart rate drop to less than 40 bpm for at least 10 sec or a greater than 3-sec pause.
The average age of the 46 subjects who fulfilled all of these criteria was 56 years – several decades older than most patients who present with syncope. They averaged 12 prior syncopal episodes, including 4.5 during the prior 12 months. Three-quarters of the patients demonstrated asystole during the tilt test, with an average duration of 15 sec.
Four of the 46 patients experienced a syncopal recurrence during their 12 months on DDD-CLS pacing, while 21 of the same group of 46 had recurrent syncope during their year on DDI sham pacing. This translated into an absolute 37% reduction in syncopal episodes with active pacemaker therapy. Patients had an 8.8-fold greater risk of syncopal recurrence while on DDI sham pacing compared with DDD-CLS.
Dr. Baron-Esquivias explained that the DDD-CLS algorithm is designed to detect impending syncope at an early and actionable stage. The algorithm identifies the combination of increased myocardial contractility and reduced right ventricular intracardiac impedance, which heralds the first stage of vasovagal syncope. It then directs the pacemaker to activate high-rate atrioventricular sequential pacing to prevent arterial hypotension, bradycardia, and overt syncope.
Discussant Kenneth A. Ellenbogen, MD, applauded Dr. Baron-Esquivias and coinvestigators for “having the strength and conviction to attack this problem where so many prior studies have failed.”
For example, the earlier European SYNPACE trial showed no benefit for dual-chamber pacemaker therapy in DDD-RDR (rate-drop response) mode in patients with recurrent severe cardioinhibitory vasovagal syncope (Eur Heart J. 2004 Oct;25[19]:1741-8), probably due to a combination of a less robust early-syncope detection algorithm than that of DDD-CLS and less restrictive patient selection criteria, observed Dr. Ellenbogen, chairman of the division of cardiology and director of clinical cardiology electrophysiology and pacing at the Medical College of Virginia, Richmond.
The SPAIN trial was funded by the Spanish Society of Cardiology. Dr. Baron-Esquivias reported having no financial conflicts.
A considerably larger randomized trial known as BIOSync CLS, sponsored by Biotronic, which developed the CLS program, is ongoing.
Washington – Help is finally at hand for the subgroup of patients who have severe refractory vasovagal syncope that recurs frequently and unpredictably, and is associated with a strong cardioinhibitory response on tilt table testing, Gonzalo Baron-Esquivias, MD, said at the annual meeting of the American College of Cardiology.
Results of the randomized, multicenter, double-blind, crossover, placebo-controlled SPAIN trial showed that implantation of a permanent pacemaker programmed to a closed loop stimulation (DDD-CLS) algorithm resulted in an 89% decrease in the risk of syncopal recurrences compared with sham DDI pacing, reported Dr. Baron-Esquivias, chief of clinical cardiology at Virgen del Rocio University Hospital in Seville, Spain.
Moreover, the number needed to treat with DDD-CLS pacing for 1 year to prevent a syncopal episode was a mere 2.7 patients in the SPAIN trial, he noted.
The study included 46 patients who met strict criteria for participation and received a permanent pacemaker for which they had no conventional indication. In half of the subjects, the device was programmed to DDD-CLS pacing, while the other half received sham DDI pacing, making them a placebo-treated control group. After 12 months, each group was switched over to the other form of pacing.
Dr. Baron-Esquivias emphasized that the tough SPAIN eligibility criteria enabled investigators to accurately define a specific CSL-responsive subgroup. This is not a form of therapy that’s appropriate for most patients who experience vasovagal syncope. In the right population, however, DDD-CLS pacing is life transforming. The SPAIN investigators documented severely impaired quality of life in the study population, with dramatic improvement on CLS pacing.
Vasovagal syncope is by far the most common cause of syncope. But roughly 70 out of every 100 patients who present to the emergency department with vasovagal syncope will never have a repeat episode. And of the 30 who do, perhaps only 10 will have frequent recurrences refractory to conventional measures and that impose a severe effect on quality of life. This is the subgroup for whom consideration of pacemaker therapy is appropriate.
To be eligible for the SPAIN trial, patients had to have at least five previous episodes of neuromediated vasovagal syncope, including at least two within the past year. They also had to be at least 40 years old, since CLS-responsive vasovagal syncope is skewed toward an older age group. In addition, all participants had to have normal results on a complete physical examination that included an orthostatic test, 12-lead echocardiogram, two-dimensional echocardiography, carotid sinus massage, and 24-hour Holter monitoring. Only then were they eligible for a tilt-table test. A positive head-up tilt test demonstrating a cardioinhibitory response required a heart rate drop to less than 40 bpm for at least 10 sec or a greater than 3-sec pause.
The average age of the 46 subjects who fulfilled all of these criteria was 56 years – several decades older than most patients who present with syncope. They averaged 12 prior syncopal episodes, including 4.5 during the prior 12 months. Three-quarters of the patients demonstrated asystole during the tilt test, with an average duration of 15 sec.
Four of the 46 patients experienced a syncopal recurrence during their 12 months on DDD-CLS pacing, while 21 of the same group of 46 had recurrent syncope during their year on DDI sham pacing. This translated into an absolute 37% reduction in syncopal episodes with active pacemaker therapy. Patients had an 8.8-fold greater risk of syncopal recurrence while on DDI sham pacing compared with DDD-CLS.
Dr. Baron-Esquivias explained that the DDD-CLS algorithm is designed to detect impending syncope at an early and actionable stage. The algorithm identifies the combination of increased myocardial contractility and reduced right ventricular intracardiac impedance, which heralds the first stage of vasovagal syncope. It then directs the pacemaker to activate high-rate atrioventricular sequential pacing to prevent arterial hypotension, bradycardia, and overt syncope.
Discussant Kenneth A. Ellenbogen, MD, applauded Dr. Baron-Esquivias and coinvestigators for “having the strength and conviction to attack this problem where so many prior studies have failed.”
For example, the earlier European SYNPACE trial showed no benefit for dual-chamber pacemaker therapy in DDD-RDR (rate-drop response) mode in patients with recurrent severe cardioinhibitory vasovagal syncope (Eur Heart J. 2004 Oct;25[19]:1741-8), probably due to a combination of a less robust early-syncope detection algorithm than that of DDD-CLS and less restrictive patient selection criteria, observed Dr. Ellenbogen, chairman of the division of cardiology and director of clinical cardiology electrophysiology and pacing at the Medical College of Virginia, Richmond.
The SPAIN trial was funded by the Spanish Society of Cardiology. Dr. Baron-Esquivias reported having no financial conflicts.
A considerably larger randomized trial known as BIOSync CLS, sponsored by Biotronic, which developed the CLS program, is ongoing.
At ACC 17
Key clinical point:
Major finding: The number of patients with severe recurrent cardioinhibitory reflex vasovagal syncope needed to be treated with DDD-CLS pacing for 1 year to prevent a recurrent episode is 2.7.
Data source: SPAIN, a 2-year randomized, multicenter, double-blind, prospective, placebo-controlled crossover trial of 46 patients with severe recurrent vasovagal syncope treated via pacemaker therapy.
Disclosures: The Spanish Society of Cardiology funded the study. The presenter reported having no financial conflicts.
Sacubitril/valsartan enhances glycemic control in diabetic patients with heart failure
Washington – Patients with heart failure with reduced ejection fraction and comorbid diabetes whose heart failure was treated with sacubitril/valsartan experienced significantly enhanced glycemic control in addition to reduced morbidity and mortality due to heart failure in the landmark PARADIGM-HF trial, Jelena P. Seferovic, MD, reported at the annual meeting of the American College of Cardiology.
PARADIGM-HF was a randomized, double-blind clinical trial of oral sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor, or ARNI, at 97 mg/103 mg twice daily versus enalapril at 10 mg twice daily in 8,442 patients with heart failure with reduced ejection fraction (HFrEF). The primary results, which demonstrated significant reductions in heart failure morbidity and mortality in the sacubitril/valsartan group, have been published (N Engl J Med. 2014 Sep 11;371[11]:993-1004). The findings led to Food and Drug Administration approval of the drug, marketed as Entresto, for HFrEF, as well as a top level Class I recommendation for the drug’s use in the 2016 ACC/AHA heart failure management guidelines.
Dr. Seferovic presented a new post hoc secondary analysis of PARADIGM-HF focused on the 3,778 participants with HFrEF and diabetes. During the first year of study follow-up, hemoglobin A1c decreased by 0.26% from a baseline of 7.44% in the ARNI group, significantly greater than the 0.16% reduction in enalapril-treated controls. This benefit persisted during years 2 and 3.
Moreover, this effect was accompanied by a 29% reduction in new use of insulin in the ARNI group, 7% of whom began insulin therapy during follow-up compared with 10% of controls. Similarly, a 23% reduction in new use of oral antihyperglycemic drugs was seen in the ARNI group, reported Dr. Seferovic of Brigham and Women’s Hospital, Boston.
“Our post hoc study findings should be considered hypothesis-generating, but they suggest that sacubitril/valsartan, which has already been proven to reduce morbidity and mortality in heart failure, might provide additional metabolic benefits in patients with diabetes. Also, our findings suggest that diabetic patients who are treated with sacubitril/valsartan for their heart failure may require dose adjustment of their antihyperglycemic therapy,” she said.
Dr. Seferovic added that this need for dose adjustment is not just a theoretical concern. It actually occurred during the PARADIGM-HF trial.
The impetus for the post hoc analysis was driven in part by animal studies demonstrating that neprilysin inhibition improves insulin sensitivity. Although the mechanism of metabolic benefit for sacubitril/valsartan is not fully understood, it’s known that neprilysin is expressed in adipocytes, cardiac myocytes, smooth muscle cells, and endothelial cells. Neprilysin increases postprandial lipid oxidation, promotes adiponectin release, and boosts the oxidative capacity of muscle. Moreover, neprilysin is responsible for breakdown of natriuretic peptides as well as glucagon-like peptide 1.
“We hypothesize that the beneficial antihyperglycemic effect of sacubitril/valsartan revealed in this analysis is most probably due to the neprilysin inhibition and modulation of its circulating substrates,” said Dr. Seferovic.
One audience member asked Dr. Seferovic if she deemed the 0.14% greater absolute reduction in HbA1c achieved with the ARNI over the course of 3 years to be clinically meaningful. She responded with an emphatic yes.
“We believe any decrease in HbA1c is clinically important,” she declared.
Comorbid diabetes is present in up to 40% of patients with heart failure and has been shown to be a strong independent risk factor for heart failure progression.
Simultaneously with her presentation of the new PARADIGM-HF analysis at ACC 17, the study results were published online in The Lancet Diabetes & Endocrinology.
In an accompanying editorial, Gregory Giamouzis, MD, and Javed Butler, MD, cited a handful of reasons why the new findings are important and exciting. For example, polypharmacy has been linked to poor treatment adherence in heart failure, so a drug that can simultaneously improve diabetes and heart failure is attractive. Also, beta blockers and diuretics – cornerstones of heart failure therapy – have been implicated in worsening hyperglycemia.
“Thus, any heart failure therapy that is protective against incident diabetes or worsening glycemic control is a welcome addition,” according to Dr. Giamouzis of the University of Thessaly, Greece, and Dr. Butler of Stony Brook (N.Y.) University.
They added that important unresolved questions include whether sacubitril/valsartan will provide meaningful metabolic benefits in patients with heart failure and comorbid metabolic syndrome, as well as the effects of the ARNI in diabetic patients with heart failure with preserved ejection fraction. The latter issue is the focus of the ongoing major multicenter PARAGON-HF trial.
The PARADIGM-HF trial was sponsored by Novartis. Dr. Seferovic reported having no financial conflicts.
Washington – Patients with heart failure with reduced ejection fraction and comorbid diabetes whose heart failure was treated with sacubitril/valsartan experienced significantly enhanced glycemic control in addition to reduced morbidity and mortality due to heart failure in the landmark PARADIGM-HF trial, Jelena P. Seferovic, MD, reported at the annual meeting of the American College of Cardiology.
PARADIGM-HF was a randomized, double-blind clinical trial of oral sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor, or ARNI, at 97 mg/103 mg twice daily versus enalapril at 10 mg twice daily in 8,442 patients with heart failure with reduced ejection fraction (HFrEF). The primary results, which demonstrated significant reductions in heart failure morbidity and mortality in the sacubitril/valsartan group, have been published (N Engl J Med. 2014 Sep 11;371[11]:993-1004). The findings led to Food and Drug Administration approval of the drug, marketed as Entresto, for HFrEF, as well as a top level Class I recommendation for the drug’s use in the 2016 ACC/AHA heart failure management guidelines.
Dr. Seferovic presented a new post hoc secondary analysis of PARADIGM-HF focused on the 3,778 participants with HFrEF and diabetes. During the first year of study follow-up, hemoglobin A1c decreased by 0.26% from a baseline of 7.44% in the ARNI group, significantly greater than the 0.16% reduction in enalapril-treated controls. This benefit persisted during years 2 and 3.
Moreover, this effect was accompanied by a 29% reduction in new use of insulin in the ARNI group, 7% of whom began insulin therapy during follow-up compared with 10% of controls. Similarly, a 23% reduction in new use of oral antihyperglycemic drugs was seen in the ARNI group, reported Dr. Seferovic of Brigham and Women’s Hospital, Boston.
“Our post hoc study findings should be considered hypothesis-generating, but they suggest that sacubitril/valsartan, which has already been proven to reduce morbidity and mortality in heart failure, might provide additional metabolic benefits in patients with diabetes. Also, our findings suggest that diabetic patients who are treated with sacubitril/valsartan for their heart failure may require dose adjustment of their antihyperglycemic therapy,” she said.
Dr. Seferovic added that this need for dose adjustment is not just a theoretical concern. It actually occurred during the PARADIGM-HF trial.
The impetus for the post hoc analysis was driven in part by animal studies demonstrating that neprilysin inhibition improves insulin sensitivity. Although the mechanism of metabolic benefit for sacubitril/valsartan is not fully understood, it’s known that neprilysin is expressed in adipocytes, cardiac myocytes, smooth muscle cells, and endothelial cells. Neprilysin increases postprandial lipid oxidation, promotes adiponectin release, and boosts the oxidative capacity of muscle. Moreover, neprilysin is responsible for breakdown of natriuretic peptides as well as glucagon-like peptide 1.
“We hypothesize that the beneficial antihyperglycemic effect of sacubitril/valsartan revealed in this analysis is most probably due to the neprilysin inhibition and modulation of its circulating substrates,” said Dr. Seferovic.
One audience member asked Dr. Seferovic if she deemed the 0.14% greater absolute reduction in HbA1c achieved with the ARNI over the course of 3 years to be clinically meaningful. She responded with an emphatic yes.
“We believe any decrease in HbA1c is clinically important,” she declared.
Comorbid diabetes is present in up to 40% of patients with heart failure and has been shown to be a strong independent risk factor for heart failure progression.
Simultaneously with her presentation of the new PARADIGM-HF analysis at ACC 17, the study results were published online in The Lancet Diabetes & Endocrinology.
In an accompanying editorial, Gregory Giamouzis, MD, and Javed Butler, MD, cited a handful of reasons why the new findings are important and exciting. For example, polypharmacy has been linked to poor treatment adherence in heart failure, so a drug that can simultaneously improve diabetes and heart failure is attractive. Also, beta blockers and diuretics – cornerstones of heart failure therapy – have been implicated in worsening hyperglycemia.
“Thus, any heart failure therapy that is protective against incident diabetes or worsening glycemic control is a welcome addition,” according to Dr. Giamouzis of the University of Thessaly, Greece, and Dr. Butler of Stony Brook (N.Y.) University.
They added that important unresolved questions include whether sacubitril/valsartan will provide meaningful metabolic benefits in patients with heart failure and comorbid metabolic syndrome, as well as the effects of the ARNI in diabetic patients with heart failure with preserved ejection fraction. The latter issue is the focus of the ongoing major multicenter PARAGON-HF trial.
The PARADIGM-HF trial was sponsored by Novartis. Dr. Seferovic reported having no financial conflicts.
Washington – Patients with heart failure with reduced ejection fraction and comorbid diabetes whose heart failure was treated with sacubitril/valsartan experienced significantly enhanced glycemic control in addition to reduced morbidity and mortality due to heart failure in the landmark PARADIGM-HF trial, Jelena P. Seferovic, MD, reported at the annual meeting of the American College of Cardiology.
PARADIGM-HF was a randomized, double-blind clinical trial of oral sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor, or ARNI, at 97 mg/103 mg twice daily versus enalapril at 10 mg twice daily in 8,442 patients with heart failure with reduced ejection fraction (HFrEF). The primary results, which demonstrated significant reductions in heart failure morbidity and mortality in the sacubitril/valsartan group, have been published (N Engl J Med. 2014 Sep 11;371[11]:993-1004). The findings led to Food and Drug Administration approval of the drug, marketed as Entresto, for HFrEF, as well as a top level Class I recommendation for the drug’s use in the 2016 ACC/AHA heart failure management guidelines.
Dr. Seferovic presented a new post hoc secondary analysis of PARADIGM-HF focused on the 3,778 participants with HFrEF and diabetes. During the first year of study follow-up, hemoglobin A1c decreased by 0.26% from a baseline of 7.44% in the ARNI group, significantly greater than the 0.16% reduction in enalapril-treated controls. This benefit persisted during years 2 and 3.
Moreover, this effect was accompanied by a 29% reduction in new use of insulin in the ARNI group, 7% of whom began insulin therapy during follow-up compared with 10% of controls. Similarly, a 23% reduction in new use of oral antihyperglycemic drugs was seen in the ARNI group, reported Dr. Seferovic of Brigham and Women’s Hospital, Boston.
“Our post hoc study findings should be considered hypothesis-generating, but they suggest that sacubitril/valsartan, which has already been proven to reduce morbidity and mortality in heart failure, might provide additional metabolic benefits in patients with diabetes. Also, our findings suggest that diabetic patients who are treated with sacubitril/valsartan for their heart failure may require dose adjustment of their antihyperglycemic therapy,” she said.
Dr. Seferovic added that this need for dose adjustment is not just a theoretical concern. It actually occurred during the PARADIGM-HF trial.
The impetus for the post hoc analysis was driven in part by animal studies demonstrating that neprilysin inhibition improves insulin sensitivity. Although the mechanism of metabolic benefit for sacubitril/valsartan is not fully understood, it’s known that neprilysin is expressed in adipocytes, cardiac myocytes, smooth muscle cells, and endothelial cells. Neprilysin increases postprandial lipid oxidation, promotes adiponectin release, and boosts the oxidative capacity of muscle. Moreover, neprilysin is responsible for breakdown of natriuretic peptides as well as glucagon-like peptide 1.
“We hypothesize that the beneficial antihyperglycemic effect of sacubitril/valsartan revealed in this analysis is most probably due to the neprilysin inhibition and modulation of its circulating substrates,” said Dr. Seferovic.
One audience member asked Dr. Seferovic if she deemed the 0.14% greater absolute reduction in HbA1c achieved with the ARNI over the course of 3 years to be clinically meaningful. She responded with an emphatic yes.
“We believe any decrease in HbA1c is clinically important,” she declared.
Comorbid diabetes is present in up to 40% of patients with heart failure and has been shown to be a strong independent risk factor for heart failure progression.
Simultaneously with her presentation of the new PARADIGM-HF analysis at ACC 17, the study results were published online in The Lancet Diabetes & Endocrinology.
In an accompanying editorial, Gregory Giamouzis, MD, and Javed Butler, MD, cited a handful of reasons why the new findings are important and exciting. For example, polypharmacy has been linked to poor treatment adherence in heart failure, so a drug that can simultaneously improve diabetes and heart failure is attractive. Also, beta blockers and diuretics – cornerstones of heart failure therapy – have been implicated in worsening hyperglycemia.
“Thus, any heart failure therapy that is protective against incident diabetes or worsening glycemic control is a welcome addition,” according to Dr. Giamouzis of the University of Thessaly, Greece, and Dr. Butler of Stony Brook (N.Y.) University.
They added that important unresolved questions include whether sacubitril/valsartan will provide meaningful metabolic benefits in patients with heart failure and comorbid metabolic syndrome, as well as the effects of the ARNI in diabetic patients with heart failure with preserved ejection fraction. The latter issue is the focus of the ongoing major multicenter PARAGON-HF trial.
The PARADIGM-HF trial was sponsored by Novartis. Dr. Seferovic reported having no financial conflicts.
At ACC 17
Key clinical point:
Major finding: Sacubitril/valsartan reduced the need for new use of insulin by 29% in diabetic patients with heart failure with reduced ejection fraction.
Data source: A secondary post hoc analysis of the 3,778 participants in the randomized pivotal PARADIGM-HF trial who had heart failure with reduced ejection fraction and comorbid diabetes.
Disclosures: The PARADIGM-HF trial was sponsored by Novartis. The study presenter reported having no financial conflicts.
‘Sobering’ high 10-year mortality post-MI after age 65
WASHINGTON – Patients who experience an acute MI at age 65 or older have unsettlingly high 5- and 10-year mortality in community practice settings despite excellent rates of evidence-based medications being prescribed at discharge, Ajar Kochar, MD, reported at the annual meeting of the American College of Cardiology.
This observation is based upon more than 22,000 patients aged 65 years or older treated for an acute MI during 2004-2006 at 344 U.S. hospitals participating in the CRUSADE registry. Their median age at the time of MI was 77 years. But 10-year all-cause mortality remained high even among relatively younger patients aged 65-74 whom one would expect to have a favorable long-term prognosis because they had additional survival-enhancing factors working in their favor, including having undergone coronary revascularization during their index hospitalization and surviving their first year post-MI, observed Dr. Kochar of the Duke Clinical Research Institute in Durham, N.C.
This unmet need will increasingly clamor for attention as the aging of the American population accelerates like a runaway freight train. By 2030, an estimated 20% of Americans will be aged 65 or older. That’s more than 71 million people. And more than half of all MIs occur in individuals above age 65, he noted.
Dr. Kochar presented a CRUSADE analysis which included 19,755 older Americans with a non–ST elevation MI (NSTEMI) and 2,540 with a STEMI. The overall group’s 1-year mortality was 24%, with a 5-year cumulative mortality of 51% and a whopping 10-year mortality of 72%.
According to the Centers for Disease Control and Prevention, the expected additional lifespan of someone who was 65 years old in 2015 is 19 years. In contrast, the median survival of patients in the CRUSADE registry who were 65-69 at the time of their MI was less than half of that, at 8.3 years.
Among the key findings from the CRUSADE analysis:
• Unadjusted 10-year all-cause mortality was significantly greater in patients with NSTEMI than STEMI, by a margin of 73% versus 60%. Notably, however, NSTEMI patients were far less likely to undergo coronary revascularization: 32% of them had percutaneous coronary intervention during their index hospitalization, and 8.7% underwent coronary artery bypass grafting, in contrast to rates of 65.5% for PCI and 8.0% for CABG in the STEMI patients. After adjustment for these and other differences in care, NSTEMI patients actually had a 7% lower risk of long-term mortality than the STEMI group.
• Even after limiting the analysis to the youngest elderly – patients aged 65-74 when their MI occurred – 10-year mortality remained high, at 53%.
• After excluding the 24% of patients who died within 1 year after MI, 10-year mortality was still quite high, at 63%. Dr. Kochar and his coinvestigators chose to reanalyze the data in this way because the 1-year mark is an important time point clinically, since it’s when decisions regarding extended dual-antiplatelet therapy are made.
Patients who underwent coronary revascularization during their index hospitalization had a much-improved long-term prognosis, compared with those with medical management only. The 10-year cumulative mortality rate was 57% in patients who had PCI, identical at 57% in those who received CABG, and 84% in medically managed patients.
Ninety-five percent of patients were discharged on aspirin, 94% on a beta blocker, 81% on a statin, and 73% on clopidogrel. Discharge prescriptions for statins and clopidogrel were more common for the STEMI group. Unfortunately, the CRUSADE registry doesn’t include data on long-term medication adherence or prescription refill rates.
Dr. Kochar named several potential strategies aimed at reducing the high long-term mortality rates in older patients with MI as documented in this study. These include structured efforts to improve adherence to evidence-based medications for secondary prevention, as well as making percutaneous revascularization more widely available for older patients with NSTEMI. He noted that while in 2004-2006, 32% of CRUSADE participants with NSTEMI underwent PCI during their index hospitalization, by 2011-2012 that rate had inched upward only to 36%.
Several physicians commented that the high long-term all-cause mortality rates in older CRUSADE participants may paint a grim picture, in part because the aged face growing risks of cancer and other noncardiovascular competing causes of death. But Dr. Kochar replied that while the lack of information on specific causes of death is a study limitation, he and his coinvestigators are convinced based upon data from other studies that most of the deaths in CRUSADE were cardiovascular in nature.
He reported having no financial conflicts regarding his study.
WASHINGTON – Patients who experience an acute MI at age 65 or older have unsettlingly high 5- and 10-year mortality in community practice settings despite excellent rates of evidence-based medications being prescribed at discharge, Ajar Kochar, MD, reported at the annual meeting of the American College of Cardiology.
This observation is based upon more than 22,000 patients aged 65 years or older treated for an acute MI during 2004-2006 at 344 U.S. hospitals participating in the CRUSADE registry. Their median age at the time of MI was 77 years. But 10-year all-cause mortality remained high even among relatively younger patients aged 65-74 whom one would expect to have a favorable long-term prognosis because they had additional survival-enhancing factors working in their favor, including having undergone coronary revascularization during their index hospitalization and surviving their first year post-MI, observed Dr. Kochar of the Duke Clinical Research Institute in Durham, N.C.
This unmet need will increasingly clamor for attention as the aging of the American population accelerates like a runaway freight train. By 2030, an estimated 20% of Americans will be aged 65 or older. That’s more than 71 million people. And more than half of all MIs occur in individuals above age 65, he noted.
Dr. Kochar presented a CRUSADE analysis which included 19,755 older Americans with a non–ST elevation MI (NSTEMI) and 2,540 with a STEMI. The overall group’s 1-year mortality was 24%, with a 5-year cumulative mortality of 51% and a whopping 10-year mortality of 72%.
According to the Centers for Disease Control and Prevention, the expected additional lifespan of someone who was 65 years old in 2015 is 19 years. In contrast, the median survival of patients in the CRUSADE registry who were 65-69 at the time of their MI was less than half of that, at 8.3 years.
Among the key findings from the CRUSADE analysis:
• Unadjusted 10-year all-cause mortality was significantly greater in patients with NSTEMI than STEMI, by a margin of 73% versus 60%. Notably, however, NSTEMI patients were far less likely to undergo coronary revascularization: 32% of them had percutaneous coronary intervention during their index hospitalization, and 8.7% underwent coronary artery bypass grafting, in contrast to rates of 65.5% for PCI and 8.0% for CABG in the STEMI patients. After adjustment for these and other differences in care, NSTEMI patients actually had a 7% lower risk of long-term mortality than the STEMI group.
• Even after limiting the analysis to the youngest elderly – patients aged 65-74 when their MI occurred – 10-year mortality remained high, at 53%.
• After excluding the 24% of patients who died within 1 year after MI, 10-year mortality was still quite high, at 63%. Dr. Kochar and his coinvestigators chose to reanalyze the data in this way because the 1-year mark is an important time point clinically, since it’s when decisions regarding extended dual-antiplatelet therapy are made.
Patients who underwent coronary revascularization during their index hospitalization had a much-improved long-term prognosis, compared with those with medical management only. The 10-year cumulative mortality rate was 57% in patients who had PCI, identical at 57% in those who received CABG, and 84% in medically managed patients.
Ninety-five percent of patients were discharged on aspirin, 94% on a beta blocker, 81% on a statin, and 73% on clopidogrel. Discharge prescriptions for statins and clopidogrel were more common for the STEMI group. Unfortunately, the CRUSADE registry doesn’t include data on long-term medication adherence or prescription refill rates.
Dr. Kochar named several potential strategies aimed at reducing the high long-term mortality rates in older patients with MI as documented in this study. These include structured efforts to improve adherence to evidence-based medications for secondary prevention, as well as making percutaneous revascularization more widely available for older patients with NSTEMI. He noted that while in 2004-2006, 32% of CRUSADE participants with NSTEMI underwent PCI during their index hospitalization, by 2011-2012 that rate had inched upward only to 36%.
Several physicians commented that the high long-term all-cause mortality rates in older CRUSADE participants may paint a grim picture, in part because the aged face growing risks of cancer and other noncardiovascular competing causes of death. But Dr. Kochar replied that while the lack of information on specific causes of death is a study limitation, he and his coinvestigators are convinced based upon data from other studies that most of the deaths in CRUSADE were cardiovascular in nature.
He reported having no financial conflicts regarding his study.
WASHINGTON – Patients who experience an acute MI at age 65 or older have unsettlingly high 5- and 10-year mortality in community practice settings despite excellent rates of evidence-based medications being prescribed at discharge, Ajar Kochar, MD, reported at the annual meeting of the American College of Cardiology.
This observation is based upon more than 22,000 patients aged 65 years or older treated for an acute MI during 2004-2006 at 344 U.S. hospitals participating in the CRUSADE registry. Their median age at the time of MI was 77 years. But 10-year all-cause mortality remained high even among relatively younger patients aged 65-74 whom one would expect to have a favorable long-term prognosis because they had additional survival-enhancing factors working in their favor, including having undergone coronary revascularization during their index hospitalization and surviving their first year post-MI, observed Dr. Kochar of the Duke Clinical Research Institute in Durham, N.C.
This unmet need will increasingly clamor for attention as the aging of the American population accelerates like a runaway freight train. By 2030, an estimated 20% of Americans will be aged 65 or older. That’s more than 71 million people. And more than half of all MIs occur in individuals above age 65, he noted.
Dr. Kochar presented a CRUSADE analysis which included 19,755 older Americans with a non–ST elevation MI (NSTEMI) and 2,540 with a STEMI. The overall group’s 1-year mortality was 24%, with a 5-year cumulative mortality of 51% and a whopping 10-year mortality of 72%.
According to the Centers for Disease Control and Prevention, the expected additional lifespan of someone who was 65 years old in 2015 is 19 years. In contrast, the median survival of patients in the CRUSADE registry who were 65-69 at the time of their MI was less than half of that, at 8.3 years.
Among the key findings from the CRUSADE analysis:
• Unadjusted 10-year all-cause mortality was significantly greater in patients with NSTEMI than STEMI, by a margin of 73% versus 60%. Notably, however, NSTEMI patients were far less likely to undergo coronary revascularization: 32% of them had percutaneous coronary intervention during their index hospitalization, and 8.7% underwent coronary artery bypass grafting, in contrast to rates of 65.5% for PCI and 8.0% for CABG in the STEMI patients. After adjustment for these and other differences in care, NSTEMI patients actually had a 7% lower risk of long-term mortality than the STEMI group.
• Even after limiting the analysis to the youngest elderly – patients aged 65-74 when their MI occurred – 10-year mortality remained high, at 53%.
• After excluding the 24% of patients who died within 1 year after MI, 10-year mortality was still quite high, at 63%. Dr. Kochar and his coinvestigators chose to reanalyze the data in this way because the 1-year mark is an important time point clinically, since it’s when decisions regarding extended dual-antiplatelet therapy are made.
Patients who underwent coronary revascularization during their index hospitalization had a much-improved long-term prognosis, compared with those with medical management only. The 10-year cumulative mortality rate was 57% in patients who had PCI, identical at 57% in those who received CABG, and 84% in medically managed patients.
Ninety-five percent of patients were discharged on aspirin, 94% on a beta blocker, 81% on a statin, and 73% on clopidogrel. Discharge prescriptions for statins and clopidogrel were more common for the STEMI group. Unfortunately, the CRUSADE registry doesn’t include data on long-term medication adherence or prescription refill rates.
Dr. Kochar named several potential strategies aimed at reducing the high long-term mortality rates in older patients with MI as documented in this study. These include structured efforts to improve adherence to evidence-based medications for secondary prevention, as well as making percutaneous revascularization more widely available for older patients with NSTEMI. He noted that while in 2004-2006, 32% of CRUSADE participants with NSTEMI underwent PCI during their index hospitalization, by 2011-2012 that rate had inched upward only to 36%.
Several physicians commented that the high long-term all-cause mortality rates in older CRUSADE participants may paint a grim picture, in part because the aged face growing risks of cancer and other noncardiovascular competing causes of death. But Dr. Kochar replied that while the lack of information on specific causes of death is a study limitation, he and his coinvestigators are convinced based upon data from other studies that most of the deaths in CRUSADE were cardiovascular in nature.
He reported having no financial conflicts regarding his study.
AT ACC 17
Key clinical point:
Major finding: The 10-year cumulative mortality rate in patients who had an MI at age 65-74 is 53%.
Data source: This was an analysis of 10-year cumulative mortality in more than 22,000 patients aged 65 or older treated for an acute MI during 2004-2006 at 344 U.S. community hospitals participating in the prospective CRUSADE registry.
Disclosures: The study presenter reported having no financial conflicts.
Marijuana abuse linked to increased MI risk
Washington – Marijuana abuse was independently associated with an eye-opening doubled risk of acute MI in a large, retrospective, age-matched cohort study, Ahmad Tarek Chami, MD, reported at the annual meeting of the American College of Cardiology.
The link was strongest by far in young adult marijuana abusers, with an adjusted 3.2-fold increased risk of MI in 25- to 29-year-olds with marijuana abuse noted in their medical records, compared with age-matched controls and a 4.56-fold greater risk among the 30- to 34-year-old cannabis abusers, according to Dr. Chami of Case Western Reserve University in Cleveland.
These data constitute a signal warranting further research. Public opinion regarding potheads has undergone a huge shift. Medical and/or recreational marijuana is now legal in 28 states and the District of Columbia. Surveys indicate that, in 2015, 8.3% of Americans aged 12 years and older had used marijuana during the previous month, and 13.5% had used it within the past year.
“Cardiologists and other physicians are more likely than ever before to encounter patients who use marijuana or even ask them to prescribe it,” Dr. Chami said.
The cannabis plant contains more than 60 cannabinoids. Although marijuana is widely prescribed for treatment of nausea, anorexia, neuropathic pain, glaucoma, seizure disorders, and other conditions, the long-term effects of marijuana on the cardiovascular system are largely unknown, he continued.
This ambiguity was the impetus for Dr. Chami’s study. In it, he utilized a database incorporating 26 health care systems across the United States with nearly 50 million patients, which is maintained by Explorys, an 8-year-old Cleveland-based company.
Dr. Chami identified 210,700 patients with cannabis abuse noted in their medical records, covering provider/patient encounters between October 2011 and September 2016. Their mean age was 36.8 years. The abusers were age-matched to 10,395,060 non–marijuana abuser controls.
The 5-year cumulative incidence of MI in this skewed–young patient population was significantly higher than in the marijuana abuser group: 1.28%, compared with 0.89%, for a 44% increase in relative risk.
However, the marijuana abusers also had a significantly higher burden of cardiovascular risk factors than did their non–cannabis abusing counterparts. They were 2.85 times more likely to have hypertension, 1.59 times more likely to be dyslipidemic, and 7.2 times more likely to be cigarette smokers, and they had a 2.8 times greater prevalence of diabetes. Of note, they were also 17.6 times more likely to have been diagnosed with alcohol abuse, and 61 times more likely to abuse cocaine.
In a multivariate analysis adjusted for these and other potential confounders, marijuana abuse remained independently associated with a 1.73-fold increased risk of acute MI. Moreover, after eliminating patients with known coronary artery disease, the strongest risk factor for MI, from the analysis, marijuana abuse was independently associated with a twofold increased risk of MI.
This was a retrospective study, one limitation of which was the standard caveat regarding the possibility of unrecognized confounders that couldn’t be taken into account.
Another study limitation is the uncertainty regarding the diagnosis of “cannabis abuser” in patients’ charts. The Explorys cloud-based database relies on ICD codes to capture data. It doesn’t include specific information on how much marijuana a patient who was labeled as an abuser was actually using. This limitation raises an unanswered question: Were young adults who abused marijuana at highest risk for MI because of heavier use, or are younger patients’ coronary arteries somehow more vulnerable to marijuana’s potential adverse cardiovascular effects?
Several audience members called Dr. Chami’s study “very provocative.” Aaron D. Kugelmass, MD, said that the fundamental question in his mind is whether the cardiovascular hazard of marijuana identified in this study is the result of the practice of smoking the raw product, usually associated with illicit marijuana abusers.
Today, legalized marijuana is often consumed in the form of edible products, tinctures, and other derivatives that don’t involve inhalation of smoke. Whether these alternative forms of consumption pose any cardiovascular risk is an important unresolved issue in this era of widespread decriminalization of cannabis, noted Dr. Kugelmass, chief of cardiology and medical director of the Heart and Vascular Center at Baystate Medical Center in Springfield, Mass.
Dr. Chami reported having no financial conflicts regarding his study.
Washington – Marijuana abuse was independently associated with an eye-opening doubled risk of acute MI in a large, retrospective, age-matched cohort study, Ahmad Tarek Chami, MD, reported at the annual meeting of the American College of Cardiology.
The link was strongest by far in young adult marijuana abusers, with an adjusted 3.2-fold increased risk of MI in 25- to 29-year-olds with marijuana abuse noted in their medical records, compared with age-matched controls and a 4.56-fold greater risk among the 30- to 34-year-old cannabis abusers, according to Dr. Chami of Case Western Reserve University in Cleveland.
These data constitute a signal warranting further research. Public opinion regarding potheads has undergone a huge shift. Medical and/or recreational marijuana is now legal in 28 states and the District of Columbia. Surveys indicate that, in 2015, 8.3% of Americans aged 12 years and older had used marijuana during the previous month, and 13.5% had used it within the past year.
“Cardiologists and other physicians are more likely than ever before to encounter patients who use marijuana or even ask them to prescribe it,” Dr. Chami said.
The cannabis plant contains more than 60 cannabinoids. Although marijuana is widely prescribed for treatment of nausea, anorexia, neuropathic pain, glaucoma, seizure disorders, and other conditions, the long-term effects of marijuana on the cardiovascular system are largely unknown, he continued.
This ambiguity was the impetus for Dr. Chami’s study. In it, he utilized a database incorporating 26 health care systems across the United States with nearly 50 million patients, which is maintained by Explorys, an 8-year-old Cleveland-based company.
Dr. Chami identified 210,700 patients with cannabis abuse noted in their medical records, covering provider/patient encounters between October 2011 and September 2016. Their mean age was 36.8 years. The abusers were age-matched to 10,395,060 non–marijuana abuser controls.
The 5-year cumulative incidence of MI in this skewed–young patient population was significantly higher than in the marijuana abuser group: 1.28%, compared with 0.89%, for a 44% increase in relative risk.
However, the marijuana abusers also had a significantly higher burden of cardiovascular risk factors than did their non–cannabis abusing counterparts. They were 2.85 times more likely to have hypertension, 1.59 times more likely to be dyslipidemic, and 7.2 times more likely to be cigarette smokers, and they had a 2.8 times greater prevalence of diabetes. Of note, they were also 17.6 times more likely to have been diagnosed with alcohol abuse, and 61 times more likely to abuse cocaine.
In a multivariate analysis adjusted for these and other potential confounders, marijuana abuse remained independently associated with a 1.73-fold increased risk of acute MI. Moreover, after eliminating patients with known coronary artery disease, the strongest risk factor for MI, from the analysis, marijuana abuse was independently associated with a twofold increased risk of MI.
This was a retrospective study, one limitation of which was the standard caveat regarding the possibility of unrecognized confounders that couldn’t be taken into account.
Another study limitation is the uncertainty regarding the diagnosis of “cannabis abuser” in patients’ charts. The Explorys cloud-based database relies on ICD codes to capture data. It doesn’t include specific information on how much marijuana a patient who was labeled as an abuser was actually using. This limitation raises an unanswered question: Were young adults who abused marijuana at highest risk for MI because of heavier use, or are younger patients’ coronary arteries somehow more vulnerable to marijuana’s potential adverse cardiovascular effects?
Several audience members called Dr. Chami’s study “very provocative.” Aaron D. Kugelmass, MD, said that the fundamental question in his mind is whether the cardiovascular hazard of marijuana identified in this study is the result of the practice of smoking the raw product, usually associated with illicit marijuana abusers.
Today, legalized marijuana is often consumed in the form of edible products, tinctures, and other derivatives that don’t involve inhalation of smoke. Whether these alternative forms of consumption pose any cardiovascular risk is an important unresolved issue in this era of widespread decriminalization of cannabis, noted Dr. Kugelmass, chief of cardiology and medical director of the Heart and Vascular Center at Baystate Medical Center in Springfield, Mass.
Dr. Chami reported having no financial conflicts regarding his study.
Washington – Marijuana abuse was independently associated with an eye-opening doubled risk of acute MI in a large, retrospective, age-matched cohort study, Ahmad Tarek Chami, MD, reported at the annual meeting of the American College of Cardiology.
The link was strongest by far in young adult marijuana abusers, with an adjusted 3.2-fold increased risk of MI in 25- to 29-year-olds with marijuana abuse noted in their medical records, compared with age-matched controls and a 4.56-fold greater risk among the 30- to 34-year-old cannabis abusers, according to Dr. Chami of Case Western Reserve University in Cleveland.
These data constitute a signal warranting further research. Public opinion regarding potheads has undergone a huge shift. Medical and/or recreational marijuana is now legal in 28 states and the District of Columbia. Surveys indicate that, in 2015, 8.3% of Americans aged 12 years and older had used marijuana during the previous month, and 13.5% had used it within the past year.
“Cardiologists and other physicians are more likely than ever before to encounter patients who use marijuana or even ask them to prescribe it,” Dr. Chami said.
The cannabis plant contains more than 60 cannabinoids. Although marijuana is widely prescribed for treatment of nausea, anorexia, neuropathic pain, glaucoma, seizure disorders, and other conditions, the long-term effects of marijuana on the cardiovascular system are largely unknown, he continued.
This ambiguity was the impetus for Dr. Chami’s study. In it, he utilized a database incorporating 26 health care systems across the United States with nearly 50 million patients, which is maintained by Explorys, an 8-year-old Cleveland-based company.
Dr. Chami identified 210,700 patients with cannabis abuse noted in their medical records, covering provider/patient encounters between October 2011 and September 2016. Their mean age was 36.8 years. The abusers were age-matched to 10,395,060 non–marijuana abuser controls.
The 5-year cumulative incidence of MI in this skewed–young patient population was significantly higher than in the marijuana abuser group: 1.28%, compared with 0.89%, for a 44% increase in relative risk.
However, the marijuana abusers also had a significantly higher burden of cardiovascular risk factors than did their non–cannabis abusing counterparts. They were 2.85 times more likely to have hypertension, 1.59 times more likely to be dyslipidemic, and 7.2 times more likely to be cigarette smokers, and they had a 2.8 times greater prevalence of diabetes. Of note, they were also 17.6 times more likely to have been diagnosed with alcohol abuse, and 61 times more likely to abuse cocaine.
In a multivariate analysis adjusted for these and other potential confounders, marijuana abuse remained independently associated with a 1.73-fold increased risk of acute MI. Moreover, after eliminating patients with known coronary artery disease, the strongest risk factor for MI, from the analysis, marijuana abuse was independently associated with a twofold increased risk of MI.
This was a retrospective study, one limitation of which was the standard caveat regarding the possibility of unrecognized confounders that couldn’t be taken into account.
Another study limitation is the uncertainty regarding the diagnosis of “cannabis abuser” in patients’ charts. The Explorys cloud-based database relies on ICD codes to capture data. It doesn’t include specific information on how much marijuana a patient who was labeled as an abuser was actually using. This limitation raises an unanswered question: Were young adults who abused marijuana at highest risk for MI because of heavier use, or are younger patients’ coronary arteries somehow more vulnerable to marijuana’s potential adverse cardiovascular effects?
Several audience members called Dr. Chami’s study “very provocative.” Aaron D. Kugelmass, MD, said that the fundamental question in his mind is whether the cardiovascular hazard of marijuana identified in this study is the result of the practice of smoking the raw product, usually associated with illicit marijuana abusers.
Today, legalized marijuana is often consumed in the form of edible products, tinctures, and other derivatives that don’t involve inhalation of smoke. Whether these alternative forms of consumption pose any cardiovascular risk is an important unresolved issue in this era of widespread decriminalization of cannabis, noted Dr. Kugelmass, chief of cardiology and medical director of the Heart and Vascular Center at Baystate Medical Center in Springfield, Mass.
Dr. Chami reported having no financial conflicts regarding his study.
At ACC 17
Key clinical point:
Major finding: Marijuana abuse was associated with a twofold increased risk of acute MI independent of cardiovascular risk factor levels.
Data source: A retrospective cohort study including 210,700 patients with cannabis abuse noted in their medical record and 10,395,060 age-matched controls.
Disclosures: The study presenter reported having no financial conflicts.
VIDEO: Internet-based intervention shows antihypertensive efficacy
WASHINGTON – Patients who regularly accessed 30 minute, Internet-based behavioral counseling videos cut their systolic blood pressure, compared with baseline over 1 year by an average 4 mm Hg more than control patients in a randomized, phase II study with 264 patients.
Electronic counseling (e-counseling) “enhanced the efficacy of usual care for hypertension,” Robert P. Nolan, Ph.D., said at the annual meeting of the American College of Cardiology.
“We hope to optimize the efficacy of medical treatments with a behavioral intervention,” said Dr. Nolan, who added that the magnitude of the added benefit from the e-counseling program was “like adding an additional antihypertensive medication.”
“We know antihypertensive treatments work, but compliance is a huge challenge” for health care providers, commented E. Magnus Ohman, MBBS, a professor and cardiologist at Duke University in Durham, N.C. “Having a new way to enhance compliance would be fantastic,” he said.
The Internet-based counseling program devised by Dr. Nolan and his associates consisted of a year-long series of 28 videos, each about 30 minutes long, that participants in the active arm accessed over the Internet. During the study, participants received a series of emailed messages that sent links to the videos on a set schedule over 12 months: During the first 4 months they received an emailed link weekly, during the next 4 months they received an emailed link to a new video every other week, and during the final 4 months of the intervention participants received emailed links once a month. Patients could access each video more than once if they wished, and they were free to share the links with any family members or friends who helped the patients with lifestyle management of their hypertension.
Patients in the e-counseling intervention arm received links to videos that focused on motivational messages and teaching cognitive behavioral skills. Patients in the control arm received emails with generic messages on blood pressure management and without links to videos.
The REACH (E-Counseling Promotes Blood Pressure Reduction and Therapeutic Lifestyle Change in Hypertension) study ran at four Canadian sites. It sent invitations to participate to 609 patients with stage 1 or 2 hypertension, with a blood pressure prior to treatment of 140/90-180/110 mm Hg. Among the invited patients, 264 elected to participate; 100 patients in the e-counseling arm and 97 control patients completed the 1-year program. Participants averaged 58 years of age, their average body mass index was 31 kg/m2, and 9% smoked. Their blood pressure at entry averaged 141/87 mm Hg, their average pulse pressure was about 54 mm Hg, and their average 10-year risk for a cardiovascular disease event, measured by the Framingham Risk Score, was about 16%. At entry, patients in the study received an average of 1.5 antihypertensive drugs each.
At the end of the 1-year program, systolic blood pressure fell by an average of 6 mm Hg from baseline among patients who completed the control program, and by an average of 10.1 mm Hg among the patients who completed the e-counseling arm, a statistically significant difference for one of the study’s primary endpoints. Change in pulse pressure from baseline showed an average 1.5–mm Hg drop in the control patients and an average 4.3–mm Hg decline in the e-counseling patients, another statistically significant difference for a second primary endpoint, reported Dr. Nolan, a clinical psychologist and director of the cardiac eHealth program at the University of Toronto.
A third primary endpoint was change in the Framingham Risk Score, which fell by an average of 1.9% after 12 months in the e-counseling patients and rose by an average of 0.2% among the controls.
The final primary endpoint was the change in diastolic blood pressure from baseline, which showed a better than 4–mm Hg incremental decline in the men who received e-counseling, compared with controls, but among women in the study, the drop in diastolic blood pressure from baseline was nearly the same – about 6 mm Hg – in both the controls and e-counseling patients.
“This tells us that we need to better tailor the [e-counseling] intervention to men and to women,” Dr. Nolan said in a video interview. He also envisions better tailoring of the e-counseling videos to various socioeconomic and ethnic groups. He plans to continue testing of a revised version of the e-counseling intervention in a larger, phase III study, but he also hopes that the intervention videos can soon be available at no charge for use in routine practice.
REACH received no commercial funding. Dr. Nolan had no disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
I love the REACH study. Hypertension is incredibly prevalent among the patients I see, and they often need three different antihypertensive drugs to control their blood pressure. Lifestyle interventions can be very effective at helping to lower blood pressure, but during the 10-minute visits I have with most of my patients, it’s hard for me to have much impact on their behavior.
What I especially like about the Internet-based counseling used in this study was its application of evidence-based approaches to change patient behavior. This was a well-designed and exciting trial.
Sandra J. Lewis, MD, chief of cardiology at Legacy Good Samaritan Hospital in Portland, Ore., made these comments during a press conference. She had no disclosures.
I love the REACH study. Hypertension is incredibly prevalent among the patients I see, and they often need three different antihypertensive drugs to control their blood pressure. Lifestyle interventions can be very effective at helping to lower blood pressure, but during the 10-minute visits I have with most of my patients, it’s hard for me to have much impact on their behavior.
What I especially like about the Internet-based counseling used in this study was its application of evidence-based approaches to change patient behavior. This was a well-designed and exciting trial.
Sandra J. Lewis, MD, chief of cardiology at Legacy Good Samaritan Hospital in Portland, Ore., made these comments during a press conference. She had no disclosures.
I love the REACH study. Hypertension is incredibly prevalent among the patients I see, and they often need three different antihypertensive drugs to control their blood pressure. Lifestyle interventions can be very effective at helping to lower blood pressure, but during the 10-minute visits I have with most of my patients, it’s hard for me to have much impact on their behavior.
What I especially like about the Internet-based counseling used in this study was its application of evidence-based approaches to change patient behavior. This was a well-designed and exciting trial.
Sandra J. Lewis, MD, chief of cardiology at Legacy Good Samaritan Hospital in Portland, Ore., made these comments during a press conference. She had no disclosures.
WASHINGTON – Patients who regularly accessed 30 minute, Internet-based behavioral counseling videos cut their systolic blood pressure, compared with baseline over 1 year by an average 4 mm Hg more than control patients in a randomized, phase II study with 264 patients.
Electronic counseling (e-counseling) “enhanced the efficacy of usual care for hypertension,” Robert P. Nolan, Ph.D., said at the annual meeting of the American College of Cardiology.
“We hope to optimize the efficacy of medical treatments with a behavioral intervention,” said Dr. Nolan, who added that the magnitude of the added benefit from the e-counseling program was “like adding an additional antihypertensive medication.”
“We know antihypertensive treatments work, but compliance is a huge challenge” for health care providers, commented E. Magnus Ohman, MBBS, a professor and cardiologist at Duke University in Durham, N.C. “Having a new way to enhance compliance would be fantastic,” he said.
The Internet-based counseling program devised by Dr. Nolan and his associates consisted of a year-long series of 28 videos, each about 30 minutes long, that participants in the active arm accessed over the Internet. During the study, participants received a series of emailed messages that sent links to the videos on a set schedule over 12 months: During the first 4 months they received an emailed link weekly, during the next 4 months they received an emailed link to a new video every other week, and during the final 4 months of the intervention participants received emailed links once a month. Patients could access each video more than once if they wished, and they were free to share the links with any family members or friends who helped the patients with lifestyle management of their hypertension.
Patients in the e-counseling intervention arm received links to videos that focused on motivational messages and teaching cognitive behavioral skills. Patients in the control arm received emails with generic messages on blood pressure management and without links to videos.
The REACH (E-Counseling Promotes Blood Pressure Reduction and Therapeutic Lifestyle Change in Hypertension) study ran at four Canadian sites. It sent invitations to participate to 609 patients with stage 1 or 2 hypertension, with a blood pressure prior to treatment of 140/90-180/110 mm Hg. Among the invited patients, 264 elected to participate; 100 patients in the e-counseling arm and 97 control patients completed the 1-year program. Participants averaged 58 years of age, their average body mass index was 31 kg/m2, and 9% smoked. Their blood pressure at entry averaged 141/87 mm Hg, their average pulse pressure was about 54 mm Hg, and their average 10-year risk for a cardiovascular disease event, measured by the Framingham Risk Score, was about 16%. At entry, patients in the study received an average of 1.5 antihypertensive drugs each.
At the end of the 1-year program, systolic blood pressure fell by an average of 6 mm Hg from baseline among patients who completed the control program, and by an average of 10.1 mm Hg among the patients who completed the e-counseling arm, a statistically significant difference for one of the study’s primary endpoints. Change in pulse pressure from baseline showed an average 1.5–mm Hg drop in the control patients and an average 4.3–mm Hg decline in the e-counseling patients, another statistically significant difference for a second primary endpoint, reported Dr. Nolan, a clinical psychologist and director of the cardiac eHealth program at the University of Toronto.
A third primary endpoint was change in the Framingham Risk Score, which fell by an average of 1.9% after 12 months in the e-counseling patients and rose by an average of 0.2% among the controls.
The final primary endpoint was the change in diastolic blood pressure from baseline, which showed a better than 4–mm Hg incremental decline in the men who received e-counseling, compared with controls, but among women in the study, the drop in diastolic blood pressure from baseline was nearly the same – about 6 mm Hg – in both the controls and e-counseling patients.
“This tells us that we need to better tailor the [e-counseling] intervention to men and to women,” Dr. Nolan said in a video interview. He also envisions better tailoring of the e-counseling videos to various socioeconomic and ethnic groups. He plans to continue testing of a revised version of the e-counseling intervention in a larger, phase III study, but he also hopes that the intervention videos can soon be available at no charge for use in routine practice.
REACH received no commercial funding. Dr. Nolan had no disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
WASHINGTON – Patients who regularly accessed 30 minute, Internet-based behavioral counseling videos cut their systolic blood pressure, compared with baseline over 1 year by an average 4 mm Hg more than control patients in a randomized, phase II study with 264 patients.
Electronic counseling (e-counseling) “enhanced the efficacy of usual care for hypertension,” Robert P. Nolan, Ph.D., said at the annual meeting of the American College of Cardiology.
“We hope to optimize the efficacy of medical treatments with a behavioral intervention,” said Dr. Nolan, who added that the magnitude of the added benefit from the e-counseling program was “like adding an additional antihypertensive medication.”
“We know antihypertensive treatments work, but compliance is a huge challenge” for health care providers, commented E. Magnus Ohman, MBBS, a professor and cardiologist at Duke University in Durham, N.C. “Having a new way to enhance compliance would be fantastic,” he said.
The Internet-based counseling program devised by Dr. Nolan and his associates consisted of a year-long series of 28 videos, each about 30 minutes long, that participants in the active arm accessed over the Internet. During the study, participants received a series of emailed messages that sent links to the videos on a set schedule over 12 months: During the first 4 months they received an emailed link weekly, during the next 4 months they received an emailed link to a new video every other week, and during the final 4 months of the intervention participants received emailed links once a month. Patients could access each video more than once if they wished, and they were free to share the links with any family members or friends who helped the patients with lifestyle management of their hypertension.
Patients in the e-counseling intervention arm received links to videos that focused on motivational messages and teaching cognitive behavioral skills. Patients in the control arm received emails with generic messages on blood pressure management and without links to videos.
The REACH (E-Counseling Promotes Blood Pressure Reduction and Therapeutic Lifestyle Change in Hypertension) study ran at four Canadian sites. It sent invitations to participate to 609 patients with stage 1 or 2 hypertension, with a blood pressure prior to treatment of 140/90-180/110 mm Hg. Among the invited patients, 264 elected to participate; 100 patients in the e-counseling arm and 97 control patients completed the 1-year program. Participants averaged 58 years of age, their average body mass index was 31 kg/m2, and 9% smoked. Their blood pressure at entry averaged 141/87 mm Hg, their average pulse pressure was about 54 mm Hg, and their average 10-year risk for a cardiovascular disease event, measured by the Framingham Risk Score, was about 16%. At entry, patients in the study received an average of 1.5 antihypertensive drugs each.
At the end of the 1-year program, systolic blood pressure fell by an average of 6 mm Hg from baseline among patients who completed the control program, and by an average of 10.1 mm Hg among the patients who completed the e-counseling arm, a statistically significant difference for one of the study’s primary endpoints. Change in pulse pressure from baseline showed an average 1.5–mm Hg drop in the control patients and an average 4.3–mm Hg decline in the e-counseling patients, another statistically significant difference for a second primary endpoint, reported Dr. Nolan, a clinical psychologist and director of the cardiac eHealth program at the University of Toronto.
A third primary endpoint was change in the Framingham Risk Score, which fell by an average of 1.9% after 12 months in the e-counseling patients and rose by an average of 0.2% among the controls.
The final primary endpoint was the change in diastolic blood pressure from baseline, which showed a better than 4–mm Hg incremental decline in the men who received e-counseling, compared with controls, but among women in the study, the drop in diastolic blood pressure from baseline was nearly the same – about 6 mm Hg – in both the controls and e-counseling patients.
“This tells us that we need to better tailor the [e-counseling] intervention to men and to women,” Dr. Nolan said in a video interview. He also envisions better tailoring of the e-counseling videos to various socioeconomic and ethnic groups. He plans to continue testing of a revised version of the e-counseling intervention in a larger, phase III study, but he also hopes that the intervention videos can soon be available at no charge for use in routine practice.
REACH received no commercial funding. Dr. Nolan had no disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT ACC 17
Key clinical point:
Major finding: The Internet-based program reduced systolic blood pressure from baseline by an average additional 4.1 mm Hg, compared with controls.
Data source: REACH, a multicenter, randomized trial with 264 hypertensive patients.
Disclosures: REACH received no commercial funding. Dr. Nolan had no disclosures.
Digoxin definitively dissed for AF
WASHINGTON – In what could prove to be the final word in the clinical controversy over the safety of prescribing digoxin in patients with atrial fibrillation, a secondary analysis of the roughly 18,000-patient ARISTOTLE trial has come down emphatically on the side of avoiding the venerable drug.
“The clinical implications of our analysis are that in the absence of randomized trial data showing its safety and efficacy, digoxin should generally not be prescribed for patients with atrial fibrillation, particularly if symptoms can be alleviated with other treatments. And in patients with atrial fibrillation already taking digoxin, monitoring its serum concentration may be important, targeting blood levels below 1.2 ng/mL,” Renato D. Lopes, MD, PhD, said at the annual meeting of the American College of Cardiology.
A randomized clinical trial of digoxin in AF is extremely unlikely, added Dr. Lopes, professor of medicine at Duke University in Durham, N.C.
ARISTOTLE was a randomized trial of apixaban (Eliquis) versus warfarin for stroke prevention in AF. The results of this landmark study, previously reported (N Engl J Med. 2011 Sep 15;365[11]:981-92), demonstrated that apixaban was the superior oral anticoagulant in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.
ARISTOTLE had some unique features that rendered the study database an exceptional resource for use in a large observational study of digoxin’s safety in patients with AF. It included a detailed serial assessment of concomitant medications as well as measurements of serum digoxin levels, left ventricular ejection fraction, creatinine clearance, and biomarkers including vasoactive intestinal peptide, troponins T and I, N-terminal pro–brain-type natriuretic peptide, and growth differentiation factor 15. These were among the 48 clinical variables included in multivariate adjusted analyses of mortality risk.
One-third of ARISTOTLE participants were on digoxin at study entry, a prevalence typical of what’s seen in clinical practice. Among the 5,824 subjects with AF already on digoxin at the start of the trial, the risk of death during follow-up proved independently related to baseline serum digoxin concentration. Patients with a level from 0.9 ng/mL to less than 1.2 ng/mL had a 16% increased risk of death during study follow-up, compared with digoxin nonusers, a trend that didn’t reach statistical significance. However, the 11% of AF patients with a serum concentration of 1.2 ng/mL or above were at a significant 56% increased risk for death.
When serum digoxin concentration is looked at as a continuous, rather than dichotomous variable, for each 0.5-ng/mL increase in drug concentration, the adjusted risk of all-cause mortality at 1 year of study follow-up climbed by 19%.
Moreover, among 781 AF patients who initiated digoxin during the study, the risk of death was increased by 78%, compared with that of 2,343 extensively matched controls. The most common cause of this excess mortality was sudden death, and in a closer look at that endpoint, the investigators found that the risk of sudden death was increased fourfold in new users of digoxin. This increased risk occurred early: Most sudden deaths occurred within the first 6 months after going on the drug, suggesting a causal relationship, although not providing definitive proof, Dr. Lopes noted.
Forty-three percent of ARISTOTLE participants had heart failure at enrollment. Interestingly, the increased risk of death associated with on-study initiation of digoxin was of similar magnitude, regardless of whether comorbid heart failure was present. The mortality risk was 58% greater in new users with heart failure, compared with matched nonusers with heart failure, and twofold greater in new users without heart failure than in their matched controls.
The benefits of apixaban over warfarin were consistent regardless of whether or not patients were on digoxin.
Discussant Kristen K. Patton, MD, was effusive in her response to the new ARISTOTLE findings.
“This was a really, truly, beautiful observational analysis,” declared Dr. Patton, an electrophysiologist at the University of Washington, Seattle.
“I think in cardiology, where our hearts have been broken before due to flawed observational studies, it’s really important for people to understand that observational data, when analyzed well, with appropriate propensity matching, with new-user analysis and close attention to clinical variables that are important, can really change practice in a good way. I think that’s what we see here,” she said.
A beaming Dr. Lopes responded that it’s likely that some of the past conflicting studies were marred by survival bias – that is, an inability to account for the fact that patients already on digoxin at the outset of a study have already declared themselves to be more tolerant of the drug. Past studies also didn’t adjust for biomarker levels.
“We could adjust for things we know today are associated with death in atrial fibrillation,” he observed.
Dr. Patton added that the most surprising study finding to her involved the new users of digoxin. She suspects that the reported figure of a 78% increased risk of all-cause mortality during study follow-up actually markedly underestimates the true size of that risk during the initial months on the drug. Dr. Lopes agreed.
She also said she found worrisome and disappointing the increased mortality risk reported with initiation of digoxin in AF patients with heart failure. That hasn’t been seen in other studies.
Dr. Lopes said the investigators utilized multiple means of identifying patients with heart failure and are certain they captured the full population of affected patients.
“We feel very confident that, when you have atrial fibrillation together with heart failure, it might be a different story than without atrial fibrillation,” the cardiologist said.
Discussant Jagmeet P. Singh, MD, associate chief of cardiology at Massachusetts General Hospital and professor of medicine at Harvard Medical School, Boston, said the ARISTOTLE analysis carries an eye-opening take-home message: “If you have to initiate digoxin, you have to follow the serum levels more closely than we ever have before. How frequently, I don’t know – maybe monthly instead of at the 6-monthly intervals that we often do. And I think maybe arrhythmia monitoring in the initial stages of putting patients on digoxin will be key to see if there are any additional proarrhythmic effects.”
The original ARISTOTLE trial was sponsored by Bristol-Myers Squibb and Pfizer. However, the ARISTOTLE digoxin analysis was sponsored by the Duke Clinical Research Institute. Dr. Lopes reported serving as a consultant to and/or receiving research grants from Bristol-Myers Squibb, Pfizer, Bayer, Boehringer Ingleheim, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, and Portola.
WASHINGTON – In what could prove to be the final word in the clinical controversy over the safety of prescribing digoxin in patients with atrial fibrillation, a secondary analysis of the roughly 18,000-patient ARISTOTLE trial has come down emphatically on the side of avoiding the venerable drug.
“The clinical implications of our analysis are that in the absence of randomized trial data showing its safety and efficacy, digoxin should generally not be prescribed for patients with atrial fibrillation, particularly if symptoms can be alleviated with other treatments. And in patients with atrial fibrillation already taking digoxin, monitoring its serum concentration may be important, targeting blood levels below 1.2 ng/mL,” Renato D. Lopes, MD, PhD, said at the annual meeting of the American College of Cardiology.
A randomized clinical trial of digoxin in AF is extremely unlikely, added Dr. Lopes, professor of medicine at Duke University in Durham, N.C.
ARISTOTLE was a randomized trial of apixaban (Eliquis) versus warfarin for stroke prevention in AF. The results of this landmark study, previously reported (N Engl J Med. 2011 Sep 15;365[11]:981-92), demonstrated that apixaban was the superior oral anticoagulant in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.
ARISTOTLE had some unique features that rendered the study database an exceptional resource for use in a large observational study of digoxin’s safety in patients with AF. It included a detailed serial assessment of concomitant medications as well as measurements of serum digoxin levels, left ventricular ejection fraction, creatinine clearance, and biomarkers including vasoactive intestinal peptide, troponins T and I, N-terminal pro–brain-type natriuretic peptide, and growth differentiation factor 15. These were among the 48 clinical variables included in multivariate adjusted analyses of mortality risk.
One-third of ARISTOTLE participants were on digoxin at study entry, a prevalence typical of what’s seen in clinical practice. Among the 5,824 subjects with AF already on digoxin at the start of the trial, the risk of death during follow-up proved independently related to baseline serum digoxin concentration. Patients with a level from 0.9 ng/mL to less than 1.2 ng/mL had a 16% increased risk of death during study follow-up, compared with digoxin nonusers, a trend that didn’t reach statistical significance. However, the 11% of AF patients with a serum concentration of 1.2 ng/mL or above were at a significant 56% increased risk for death.
When serum digoxin concentration is looked at as a continuous, rather than dichotomous variable, for each 0.5-ng/mL increase in drug concentration, the adjusted risk of all-cause mortality at 1 year of study follow-up climbed by 19%.
Moreover, among 781 AF patients who initiated digoxin during the study, the risk of death was increased by 78%, compared with that of 2,343 extensively matched controls. The most common cause of this excess mortality was sudden death, and in a closer look at that endpoint, the investigators found that the risk of sudden death was increased fourfold in new users of digoxin. This increased risk occurred early: Most sudden deaths occurred within the first 6 months after going on the drug, suggesting a causal relationship, although not providing definitive proof, Dr. Lopes noted.
Forty-three percent of ARISTOTLE participants had heart failure at enrollment. Interestingly, the increased risk of death associated with on-study initiation of digoxin was of similar magnitude, regardless of whether comorbid heart failure was present. The mortality risk was 58% greater in new users with heart failure, compared with matched nonusers with heart failure, and twofold greater in new users without heart failure than in their matched controls.
The benefits of apixaban over warfarin were consistent regardless of whether or not patients were on digoxin.
Discussant Kristen K. Patton, MD, was effusive in her response to the new ARISTOTLE findings.
“This was a really, truly, beautiful observational analysis,” declared Dr. Patton, an electrophysiologist at the University of Washington, Seattle.
“I think in cardiology, where our hearts have been broken before due to flawed observational studies, it’s really important for people to understand that observational data, when analyzed well, with appropriate propensity matching, with new-user analysis and close attention to clinical variables that are important, can really change practice in a good way. I think that’s what we see here,” she said.
A beaming Dr. Lopes responded that it’s likely that some of the past conflicting studies were marred by survival bias – that is, an inability to account for the fact that patients already on digoxin at the outset of a study have already declared themselves to be more tolerant of the drug. Past studies also didn’t adjust for biomarker levels.
“We could adjust for things we know today are associated with death in atrial fibrillation,” he observed.
Dr. Patton added that the most surprising study finding to her involved the new users of digoxin. She suspects that the reported figure of a 78% increased risk of all-cause mortality during study follow-up actually markedly underestimates the true size of that risk during the initial months on the drug. Dr. Lopes agreed.
She also said she found worrisome and disappointing the increased mortality risk reported with initiation of digoxin in AF patients with heart failure. That hasn’t been seen in other studies.
Dr. Lopes said the investigators utilized multiple means of identifying patients with heart failure and are certain they captured the full population of affected patients.
“We feel very confident that, when you have atrial fibrillation together with heart failure, it might be a different story than without atrial fibrillation,” the cardiologist said.
Discussant Jagmeet P. Singh, MD, associate chief of cardiology at Massachusetts General Hospital and professor of medicine at Harvard Medical School, Boston, said the ARISTOTLE analysis carries an eye-opening take-home message: “If you have to initiate digoxin, you have to follow the serum levels more closely than we ever have before. How frequently, I don’t know – maybe monthly instead of at the 6-monthly intervals that we often do. And I think maybe arrhythmia monitoring in the initial stages of putting patients on digoxin will be key to see if there are any additional proarrhythmic effects.”
The original ARISTOTLE trial was sponsored by Bristol-Myers Squibb and Pfizer. However, the ARISTOTLE digoxin analysis was sponsored by the Duke Clinical Research Institute. Dr. Lopes reported serving as a consultant to and/or receiving research grants from Bristol-Myers Squibb, Pfizer, Bayer, Boehringer Ingleheim, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, and Portola.
WASHINGTON – In what could prove to be the final word in the clinical controversy over the safety of prescribing digoxin in patients with atrial fibrillation, a secondary analysis of the roughly 18,000-patient ARISTOTLE trial has come down emphatically on the side of avoiding the venerable drug.
“The clinical implications of our analysis are that in the absence of randomized trial data showing its safety and efficacy, digoxin should generally not be prescribed for patients with atrial fibrillation, particularly if symptoms can be alleviated with other treatments. And in patients with atrial fibrillation already taking digoxin, monitoring its serum concentration may be important, targeting blood levels below 1.2 ng/mL,” Renato D. Lopes, MD, PhD, said at the annual meeting of the American College of Cardiology.
A randomized clinical trial of digoxin in AF is extremely unlikely, added Dr. Lopes, professor of medicine at Duke University in Durham, N.C.
ARISTOTLE was a randomized trial of apixaban (Eliquis) versus warfarin for stroke prevention in AF. The results of this landmark study, previously reported (N Engl J Med. 2011 Sep 15;365[11]:981-92), demonstrated that apixaban was the superior oral anticoagulant in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.
ARISTOTLE had some unique features that rendered the study database an exceptional resource for use in a large observational study of digoxin’s safety in patients with AF. It included a detailed serial assessment of concomitant medications as well as measurements of serum digoxin levels, left ventricular ejection fraction, creatinine clearance, and biomarkers including vasoactive intestinal peptide, troponins T and I, N-terminal pro–brain-type natriuretic peptide, and growth differentiation factor 15. These were among the 48 clinical variables included in multivariate adjusted analyses of mortality risk.
One-third of ARISTOTLE participants were on digoxin at study entry, a prevalence typical of what’s seen in clinical practice. Among the 5,824 subjects with AF already on digoxin at the start of the trial, the risk of death during follow-up proved independently related to baseline serum digoxin concentration. Patients with a level from 0.9 ng/mL to less than 1.2 ng/mL had a 16% increased risk of death during study follow-up, compared with digoxin nonusers, a trend that didn’t reach statistical significance. However, the 11% of AF patients with a serum concentration of 1.2 ng/mL or above were at a significant 56% increased risk for death.
When serum digoxin concentration is looked at as a continuous, rather than dichotomous variable, for each 0.5-ng/mL increase in drug concentration, the adjusted risk of all-cause mortality at 1 year of study follow-up climbed by 19%.
Moreover, among 781 AF patients who initiated digoxin during the study, the risk of death was increased by 78%, compared with that of 2,343 extensively matched controls. The most common cause of this excess mortality was sudden death, and in a closer look at that endpoint, the investigators found that the risk of sudden death was increased fourfold in new users of digoxin. This increased risk occurred early: Most sudden deaths occurred within the first 6 months after going on the drug, suggesting a causal relationship, although not providing definitive proof, Dr. Lopes noted.
Forty-three percent of ARISTOTLE participants had heart failure at enrollment. Interestingly, the increased risk of death associated with on-study initiation of digoxin was of similar magnitude, regardless of whether comorbid heart failure was present. The mortality risk was 58% greater in new users with heart failure, compared with matched nonusers with heart failure, and twofold greater in new users without heart failure than in their matched controls.
The benefits of apixaban over warfarin were consistent regardless of whether or not patients were on digoxin.
Discussant Kristen K. Patton, MD, was effusive in her response to the new ARISTOTLE findings.
“This was a really, truly, beautiful observational analysis,” declared Dr. Patton, an electrophysiologist at the University of Washington, Seattle.
“I think in cardiology, where our hearts have been broken before due to flawed observational studies, it’s really important for people to understand that observational data, when analyzed well, with appropriate propensity matching, with new-user analysis and close attention to clinical variables that are important, can really change practice in a good way. I think that’s what we see here,” she said.
A beaming Dr. Lopes responded that it’s likely that some of the past conflicting studies were marred by survival bias – that is, an inability to account for the fact that patients already on digoxin at the outset of a study have already declared themselves to be more tolerant of the drug. Past studies also didn’t adjust for biomarker levels.
“We could adjust for things we know today are associated with death in atrial fibrillation,” he observed.
Dr. Patton added that the most surprising study finding to her involved the new users of digoxin. She suspects that the reported figure of a 78% increased risk of all-cause mortality during study follow-up actually markedly underestimates the true size of that risk during the initial months on the drug. Dr. Lopes agreed.
She also said she found worrisome and disappointing the increased mortality risk reported with initiation of digoxin in AF patients with heart failure. That hasn’t been seen in other studies.
Dr. Lopes said the investigators utilized multiple means of identifying patients with heart failure and are certain they captured the full population of affected patients.
“We feel very confident that, when you have atrial fibrillation together with heart failure, it might be a different story than without atrial fibrillation,” the cardiologist said.
Discussant Jagmeet P. Singh, MD, associate chief of cardiology at Massachusetts General Hospital and professor of medicine at Harvard Medical School, Boston, said the ARISTOTLE analysis carries an eye-opening take-home message: “If you have to initiate digoxin, you have to follow the serum levels more closely than we ever have before. How frequently, I don’t know – maybe monthly instead of at the 6-monthly intervals that we often do. And I think maybe arrhythmia monitoring in the initial stages of putting patients on digoxin will be key to see if there are any additional proarrhythmic effects.”
The original ARISTOTLE trial was sponsored by Bristol-Myers Squibb and Pfizer. However, the ARISTOTLE digoxin analysis was sponsored by the Duke Clinical Research Institute. Dr. Lopes reported serving as a consultant to and/or receiving research grants from Bristol-Myers Squibb, Pfizer, Bayer, Boehringer Ingleheim, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, and Portola.
AT ACC 17
Key clinical point:
Major finding: Patients with atrial fibrillation who initiated digoxin therapy had a fourfold increased risk of sudden death, compared with extensively matched controls.
Data source: This was a secondary observational analysis drawn from the roughly 18,000-patient, randomized, multicenter ARISTOTLE trial.
Disclosures: This ARISTOTLE digoxin analysis was sponsored by the Duke Clinical Research Institute. The study presenter reported serving as a consultant to and/or recipient of research grants from numerous companies, including Bristol-Myers Squibb and Pfizer, which cosponsored the original ARISTOTLE trial.
Study boosts surgical left atrial appendage occlusion
WASHINGTON – Surgical left atrial appendage occlusion in older patients with atrial fibrillation already undergoing cardiac surgery was associated with a 38% reduction in thromboembolism and a 15% lower risk of all-cause mortality during the subsequent year in a large observational study.
“Although randomized trial data are needed, our study demonstrates strong support for the benefits of closing the left atrial appendage at the time of cardiac surgery in patients with atrial fibrillation,” Daniel J. Friedman, MD, said at the annual meeting of the American College of Cardiology.
Thirty-seven percent of patients underwent surgical left atrial appendage occlusion (LAAO) at the time of their primary heart operation. They were slightly younger, more often female, in better cardiovascular health, and more likely to have their surgery at an academic medical center than were patients who didn’t have LAAO. Adjustment for all of these factors was made in the statistical analysis.
The primary outcome was rehospitalization for thromboembolism – that is, ischemic stroke, transient ischemic attack, or other systemic arterial embolism – within 1 year. This occurred in 1.6% of the LAAO group and 2.5% of the non-LAAO group, for an unadjusted 37% and an adjusted 38% relative risk reduction, reported Dr. Friedman, a cardiology research fellow at the Duke Clinical Research Institute in Durham, N.C.
Turning to prespecified secondary endpoints, he noted that the all-cause mortality rate at 1 year was 7.0% in the LAAO group and 10.8% in the comparison arm, for a significant adjusted 15% risk reduction in the closure group. The composite endpoint of thromboembolism, hemorrhagic stroke, or death occurred in 8.7% of the LAAO group compared with 13.5% of non-LAAO patients, representing an adjusted 30% reduction in risk.
In an exploratory analysis, Dr. Friedman and his coinvestigators determined that, in patients discharged without oral anticoagulation, LAAO was associated with a 71% reduction in risk of thromboembolism. In contrast, LAAO didn’t significantly affect thromboembolic risk in patients discharged on an oral anticoagulant.
The STS database did not include information on the methods or completeness of LAAO.
Discussant David J. Wilber, MD, urged care in attempting to translate the study findings into clinical practice.
“I must say, given the diversity of surgical occlusion techniques – everything from excision to internal sutures to external clipping and stapling – I’m really a bit surprised to see the relatively strong outcomes, with a very strong signal for reduction in thromboembolism and also an opportunity to decrease mortality. I guess I’d say I’d be a little bit cautious. I’d want to see data assessing the completeness of closure and its success long term before we take this to heart clinically,” said Dr. Wilber, professor of cardiology and pediatrics and codirector of the Cardiovascular Research Institute at Loyola University in Maywood, Ill.
Dr. Friedman shared Dr. Wilber’s reservations about applying these observational data to clinical practice.
“I think what we can say is that this study supports the concept that the left atrial appendage is important as a source of thromboembolism in atrial fibrillation, and that exclusion of the left atrial appendage can be a potentially viable treatment option for patients,” he said. “I think it’s going to be increasingly important to bring this up as a possible treatment option when we’re discussing cardiac surgery with our heart teams – and that means talking to the surgeon, the cardiologist who may be following the patient afterwards, and even the cardiothoracic anesthesiologist who’s going to be manning the transesophageal echo probe and may be able to give us some insight as to the quality of closure before the patient leaves the operating room.”
There is considerable surgical interest in LAAO for stroke prevention in AF in light of the success of the percutaneous Watchman device. However, many cardiothoracic surgeons have refrained from performing the brief occlusion procedure because of what up until now has been a lack of evidence as to safety and efficacy.
Asked if his study findings imply that oral anticoagulation can routinely be stopped after LAAO provided the surgeon believes the appendage has been successfully excluded from the circulation, Dr. Friedman replied that he does not.
Although the left atrial appendage has been implicated as the site of thrombus formation in 90% of thromboembolic events occurring in patients with AF, ligation of the appendage doesn’t address that other 10%. Dr. Friedman said he believes it’s appropriate to await the results of an ongoing prospective randomized trial of LAAO led by investigators at McMaster University in Hamilton, Ont.
Dr. Friedman reported having no financial conflicts regarding his study, funded by the Burroughs Welcome Fund and the Food and Drug Administration.
WASHINGTON – Surgical left atrial appendage occlusion in older patients with atrial fibrillation already undergoing cardiac surgery was associated with a 38% reduction in thromboembolism and a 15% lower risk of all-cause mortality during the subsequent year in a large observational study.
“Although randomized trial data are needed, our study demonstrates strong support for the benefits of closing the left atrial appendage at the time of cardiac surgery in patients with atrial fibrillation,” Daniel J. Friedman, MD, said at the annual meeting of the American College of Cardiology.
Thirty-seven percent of patients underwent surgical left atrial appendage occlusion (LAAO) at the time of their primary heart operation. They were slightly younger, more often female, in better cardiovascular health, and more likely to have their surgery at an academic medical center than were patients who didn’t have LAAO. Adjustment for all of these factors was made in the statistical analysis.
The primary outcome was rehospitalization for thromboembolism – that is, ischemic stroke, transient ischemic attack, or other systemic arterial embolism – within 1 year. This occurred in 1.6% of the LAAO group and 2.5% of the non-LAAO group, for an unadjusted 37% and an adjusted 38% relative risk reduction, reported Dr. Friedman, a cardiology research fellow at the Duke Clinical Research Institute in Durham, N.C.
Turning to prespecified secondary endpoints, he noted that the all-cause mortality rate at 1 year was 7.0% in the LAAO group and 10.8% in the comparison arm, for a significant adjusted 15% risk reduction in the closure group. The composite endpoint of thromboembolism, hemorrhagic stroke, or death occurred in 8.7% of the LAAO group compared with 13.5% of non-LAAO patients, representing an adjusted 30% reduction in risk.
In an exploratory analysis, Dr. Friedman and his coinvestigators determined that, in patients discharged without oral anticoagulation, LAAO was associated with a 71% reduction in risk of thromboembolism. In contrast, LAAO didn’t significantly affect thromboembolic risk in patients discharged on an oral anticoagulant.
The STS database did not include information on the methods or completeness of LAAO.
Discussant David J. Wilber, MD, urged care in attempting to translate the study findings into clinical practice.
“I must say, given the diversity of surgical occlusion techniques – everything from excision to internal sutures to external clipping and stapling – I’m really a bit surprised to see the relatively strong outcomes, with a very strong signal for reduction in thromboembolism and also an opportunity to decrease mortality. I guess I’d say I’d be a little bit cautious. I’d want to see data assessing the completeness of closure and its success long term before we take this to heart clinically,” said Dr. Wilber, professor of cardiology and pediatrics and codirector of the Cardiovascular Research Institute at Loyola University in Maywood, Ill.
Dr. Friedman shared Dr. Wilber’s reservations about applying these observational data to clinical practice.
“I think what we can say is that this study supports the concept that the left atrial appendage is important as a source of thromboembolism in atrial fibrillation, and that exclusion of the left atrial appendage can be a potentially viable treatment option for patients,” he said. “I think it’s going to be increasingly important to bring this up as a possible treatment option when we’re discussing cardiac surgery with our heart teams – and that means talking to the surgeon, the cardiologist who may be following the patient afterwards, and even the cardiothoracic anesthesiologist who’s going to be manning the transesophageal echo probe and may be able to give us some insight as to the quality of closure before the patient leaves the operating room.”
There is considerable surgical interest in LAAO for stroke prevention in AF in light of the success of the percutaneous Watchman device. However, many cardiothoracic surgeons have refrained from performing the brief occlusion procedure because of what up until now has been a lack of evidence as to safety and efficacy.
Asked if his study findings imply that oral anticoagulation can routinely be stopped after LAAO provided the surgeon believes the appendage has been successfully excluded from the circulation, Dr. Friedman replied that he does not.
Although the left atrial appendage has been implicated as the site of thrombus formation in 90% of thromboembolic events occurring in patients with AF, ligation of the appendage doesn’t address that other 10%. Dr. Friedman said he believes it’s appropriate to await the results of an ongoing prospective randomized trial of LAAO led by investigators at McMaster University in Hamilton, Ont.
Dr. Friedman reported having no financial conflicts regarding his study, funded by the Burroughs Welcome Fund and the Food and Drug Administration.
WASHINGTON – Surgical left atrial appendage occlusion in older patients with atrial fibrillation already undergoing cardiac surgery was associated with a 38% reduction in thromboembolism and a 15% lower risk of all-cause mortality during the subsequent year in a large observational study.
“Although randomized trial data are needed, our study demonstrates strong support for the benefits of closing the left atrial appendage at the time of cardiac surgery in patients with atrial fibrillation,” Daniel J. Friedman, MD, said at the annual meeting of the American College of Cardiology.
Thirty-seven percent of patients underwent surgical left atrial appendage occlusion (LAAO) at the time of their primary heart operation. They were slightly younger, more often female, in better cardiovascular health, and more likely to have their surgery at an academic medical center than were patients who didn’t have LAAO. Adjustment for all of these factors was made in the statistical analysis.
The primary outcome was rehospitalization for thromboembolism – that is, ischemic stroke, transient ischemic attack, or other systemic arterial embolism – within 1 year. This occurred in 1.6% of the LAAO group and 2.5% of the non-LAAO group, for an unadjusted 37% and an adjusted 38% relative risk reduction, reported Dr. Friedman, a cardiology research fellow at the Duke Clinical Research Institute in Durham, N.C.
Turning to prespecified secondary endpoints, he noted that the all-cause mortality rate at 1 year was 7.0% in the LAAO group and 10.8% in the comparison arm, for a significant adjusted 15% risk reduction in the closure group. The composite endpoint of thromboembolism, hemorrhagic stroke, or death occurred in 8.7% of the LAAO group compared with 13.5% of non-LAAO patients, representing an adjusted 30% reduction in risk.
In an exploratory analysis, Dr. Friedman and his coinvestigators determined that, in patients discharged without oral anticoagulation, LAAO was associated with a 71% reduction in risk of thromboembolism. In contrast, LAAO didn’t significantly affect thromboembolic risk in patients discharged on an oral anticoagulant.
The STS database did not include information on the methods or completeness of LAAO.
Discussant David J. Wilber, MD, urged care in attempting to translate the study findings into clinical practice.
“I must say, given the diversity of surgical occlusion techniques – everything from excision to internal sutures to external clipping and stapling – I’m really a bit surprised to see the relatively strong outcomes, with a very strong signal for reduction in thromboembolism and also an opportunity to decrease mortality. I guess I’d say I’d be a little bit cautious. I’d want to see data assessing the completeness of closure and its success long term before we take this to heart clinically,” said Dr. Wilber, professor of cardiology and pediatrics and codirector of the Cardiovascular Research Institute at Loyola University in Maywood, Ill.
Dr. Friedman shared Dr. Wilber’s reservations about applying these observational data to clinical practice.
“I think what we can say is that this study supports the concept that the left atrial appendage is important as a source of thromboembolism in atrial fibrillation, and that exclusion of the left atrial appendage can be a potentially viable treatment option for patients,” he said. “I think it’s going to be increasingly important to bring this up as a possible treatment option when we’re discussing cardiac surgery with our heart teams – and that means talking to the surgeon, the cardiologist who may be following the patient afterwards, and even the cardiothoracic anesthesiologist who’s going to be manning the transesophageal echo probe and may be able to give us some insight as to the quality of closure before the patient leaves the operating room.”
There is considerable surgical interest in LAAO for stroke prevention in AF in light of the success of the percutaneous Watchman device. However, many cardiothoracic surgeons have refrained from performing the brief occlusion procedure because of what up until now has been a lack of evidence as to safety and efficacy.
Asked if his study findings imply that oral anticoagulation can routinely be stopped after LAAO provided the surgeon believes the appendage has been successfully excluded from the circulation, Dr. Friedman replied that he does not.
Although the left atrial appendage has been implicated as the site of thrombus formation in 90% of thromboembolic events occurring in patients with AF, ligation of the appendage doesn’t address that other 10%. Dr. Friedman said he believes it’s appropriate to await the results of an ongoing prospective randomized trial of LAAO led by investigators at McMaster University in Hamilton, Ont.
Dr. Friedman reported having no financial conflicts regarding his study, funded by the Burroughs Welcome Fund and the Food and Drug Administration.
At ACC 17
Key clinical point:
Major finding: The ancillary surgical procedure was associated with a 38% reduction in thromboembolism and a 15% lower risk of all-cause mortality at 1 year, compared with no appendage closure.
Data source: A retrospective comparative effectiveness study using the Society of Thoracic Surgeons database of more than 10,000 Medicare recipients with atrial fibrillation who underwent cardiac surgery, 37% of whom underwent surgical left atrial appendage occlusion during their primary operation.
Disclosures: The presenter reported having no financial conflicts. The Burroughs Welcome Fund and the Food and Drug Administration funded the study.
Dabigatran crushes warfarin for AF ablation
Washington – Uninterrupted dabigatran for periprocedural anticoagulation in patients undergoing catheter ablation for atrial fibrillation proved far superior to uninterrupted warfarin – the current standard – in the randomized multicenter RE-CIRCUIT trial, Hugh Calkins, MD, reported at the annual meeting of the American College of Cardiology.
The primary study endpoint – the incidence of major bleeding events from the time of the first femoral puncture at the procedure’s start through the subsequent 8 weeks – occurred in 1.6% of the dabigatran (Pradaxa) group and 6.9% of the warfarin group, for an absolute 5.9% reduction in risk and a 77% relative risk reduction favoring the novel anticoagulant.
“This trial will definitely affect my own practice, and I think it will quickly affect the practices of electrophysiologists around the world,” declared Dr. Calkins, professor of cardiology and medicine and director of the clinical electrophysiology laboratory and the arrhythmia service at Johns Hopkins University, Baltimore.
RE-CIRCUIT (Randomized Evaluation of Dabigatran Etexilate Compared to Warfarin in Pulmonary Vein Ablation: Assessment of an Uninterrupted Periprocedural Anticoagulation Strategy) was a multicenter, prospective, international trial conducted in 635 atrial fibrillation (AF) patients who underwent catheter ablation at 104 sites. The trial was of necessity open label because of the need for frequent adjustments of warfarin dosing; however, outcome assessment was carried out by a blinded panel of six cardiologists and three neurologists.
Standard practice among AF ablationists is to continue oral anticoagulation periprocedurally because prior studies have convincingly shown that periprocedural interruption of warfarin in an effort to reduce bleeding results in a sharply increased risk of periprocedural stroke. So participants in RE-CIRCUIT were randomized to 4-8 weeks of uninterrupted anticoagulation with either dabigatran at 150 mg b.i.d. or warfarin with a target international normalized ratio (INR) of 2.0-3.0 prior to the ablation procedure, during it, and for 8 weeks afterward, at which time an individualized decision was made as to whether to stop or continue the drug.
Major bleeding events were defined by the International Society on Thrombosis and Hemostatis criteria. Most of these bleeds occurred within the first day or two after the procedure. Pericardial tamponades and groin hematomas were significantly less common with dabigatran.
The incidence of minor bleeding events was similar, at around 18% in the two treatment arms. No strokes or systemic embolisms occurred in the study. One patient on warfarin experienced a transient ischemic attack.
Dr. Calkins elaborated on why RE-CIRCUIT will change clinical practice: “A stroke is a terrible thing during an AF procedure and cardiac tamponade is the most common cause of death from the procedure. And now we have high-quality data showing that if you perform this procedure on uninterrupted dabigatran, the risk of stroke and other systemic embolic events is extremely low, and the rate of major bleeding was 77% less.
“Plus, the logistics of warfarin are a pain,” he continued. “If the patient presents on the day of ablation with an INR that’s too high, the procedure is canceled, and if they present with an INR that’s too low and the procedure is carried out, it’s done so with an increased stroke risk.”
Dr. Calkins said he suspects the sharp reduction in major bleeding events during and after AF catheter ablation is a class effect shared by the other NOACs. Studies with those agents are ongoing. But for now, the unique availability of an immediate reversal agent in the form of idarucizumab (Praxbind) for dabigatran in the event of uncontrolled major bleeding is a source of reassurance for operators and patients alike. The antidote was never required in RE-CIRCUIT, though, the cardiologist noted.
Discussant William G. Stevenson, MD, called the trial “informative and helpful.”
“Something we’ve all been struggling with was that some concern was earlier raised that dabigatran might be associated with more thromboembolic events in this scenario. This study clearly refutes that concern,” observed Dr. Stevenson, director of the clinical cardiac electrophysiology program at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston.
Dr. Stevenson wondered whether the outcome differences between the two study groups could be explained by differences in operator techniques and tools. That’s highly unlikely, Dr. Calkins replied. Randomization was done patient by patient, not center by center.
Then why the big difference in major bleeding complications? Dr. Stevenson asked.
“It may be that, if you poke a hole when a patient is on a more forgiving anticoagulant like dabigatran, the bleeding doesn’t persist and turn into a tamponade, whereas if you poke a hole on warfarin it turns into a bigger problem,” Dr. Calkins responded. “When you think about it, warfarin really impacts the whole coagulation cascade through factors VII, IX, and X, so multiple coagulation factors are rendered impotent, whereas dabigatran is a direct thrombin inhibitor, so you’re selectively knocking out just one component of the coagulation cascade. It provides more leeway in preventing a small hole from turning into a big effusion,” he said.
The RE-CIRCUIT trial was funded by Boehringer Ingelheim. Dr. Calkins reported receiving lecture fees from that company and from Medtronic, and serving as a consultant to Medtronic, Abbott Medical, and AtriCure.
Simultaneously with Dr. Calkins’ presentation at ACC 17, the RE-CIRCUIT study was published online (N Engl J Med. 2017 Mar 19. doi: 10.1056/NEJMoa1701005).
Washington – Uninterrupted dabigatran for periprocedural anticoagulation in patients undergoing catheter ablation for atrial fibrillation proved far superior to uninterrupted warfarin – the current standard – in the randomized multicenter RE-CIRCUIT trial, Hugh Calkins, MD, reported at the annual meeting of the American College of Cardiology.
The primary study endpoint – the incidence of major bleeding events from the time of the first femoral puncture at the procedure’s start through the subsequent 8 weeks – occurred in 1.6% of the dabigatran (Pradaxa) group and 6.9% of the warfarin group, for an absolute 5.9% reduction in risk and a 77% relative risk reduction favoring the novel anticoagulant.
“This trial will definitely affect my own practice, and I think it will quickly affect the practices of electrophysiologists around the world,” declared Dr. Calkins, professor of cardiology and medicine and director of the clinical electrophysiology laboratory and the arrhythmia service at Johns Hopkins University, Baltimore.
RE-CIRCUIT (Randomized Evaluation of Dabigatran Etexilate Compared to Warfarin in Pulmonary Vein Ablation: Assessment of an Uninterrupted Periprocedural Anticoagulation Strategy) was a multicenter, prospective, international trial conducted in 635 atrial fibrillation (AF) patients who underwent catheter ablation at 104 sites. The trial was of necessity open label because of the need for frequent adjustments of warfarin dosing; however, outcome assessment was carried out by a blinded panel of six cardiologists and three neurologists.
Standard practice among AF ablationists is to continue oral anticoagulation periprocedurally because prior studies have convincingly shown that periprocedural interruption of warfarin in an effort to reduce bleeding results in a sharply increased risk of periprocedural stroke. So participants in RE-CIRCUIT were randomized to 4-8 weeks of uninterrupted anticoagulation with either dabigatran at 150 mg b.i.d. or warfarin with a target international normalized ratio (INR) of 2.0-3.0 prior to the ablation procedure, during it, and for 8 weeks afterward, at which time an individualized decision was made as to whether to stop or continue the drug.
Major bleeding events were defined by the International Society on Thrombosis and Hemostatis criteria. Most of these bleeds occurred within the first day or two after the procedure. Pericardial tamponades and groin hematomas were significantly less common with dabigatran.
The incidence of minor bleeding events was similar, at around 18% in the two treatment arms. No strokes or systemic embolisms occurred in the study. One patient on warfarin experienced a transient ischemic attack.
Dr. Calkins elaborated on why RE-CIRCUIT will change clinical practice: “A stroke is a terrible thing during an AF procedure and cardiac tamponade is the most common cause of death from the procedure. And now we have high-quality data showing that if you perform this procedure on uninterrupted dabigatran, the risk of stroke and other systemic embolic events is extremely low, and the rate of major bleeding was 77% less.
“Plus, the logistics of warfarin are a pain,” he continued. “If the patient presents on the day of ablation with an INR that’s too high, the procedure is canceled, and if they present with an INR that’s too low and the procedure is carried out, it’s done so with an increased stroke risk.”
Dr. Calkins said he suspects the sharp reduction in major bleeding events during and after AF catheter ablation is a class effect shared by the other NOACs. Studies with those agents are ongoing. But for now, the unique availability of an immediate reversal agent in the form of idarucizumab (Praxbind) for dabigatran in the event of uncontrolled major bleeding is a source of reassurance for operators and patients alike. The antidote was never required in RE-CIRCUIT, though, the cardiologist noted.
Discussant William G. Stevenson, MD, called the trial “informative and helpful.”
“Something we’ve all been struggling with was that some concern was earlier raised that dabigatran might be associated with more thromboembolic events in this scenario. This study clearly refutes that concern,” observed Dr. Stevenson, director of the clinical cardiac electrophysiology program at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston.
Dr. Stevenson wondered whether the outcome differences between the two study groups could be explained by differences in operator techniques and tools. That’s highly unlikely, Dr. Calkins replied. Randomization was done patient by patient, not center by center.
Then why the big difference in major bleeding complications? Dr. Stevenson asked.
“It may be that, if you poke a hole when a patient is on a more forgiving anticoagulant like dabigatran, the bleeding doesn’t persist and turn into a tamponade, whereas if you poke a hole on warfarin it turns into a bigger problem,” Dr. Calkins responded. “When you think about it, warfarin really impacts the whole coagulation cascade through factors VII, IX, and X, so multiple coagulation factors are rendered impotent, whereas dabigatran is a direct thrombin inhibitor, so you’re selectively knocking out just one component of the coagulation cascade. It provides more leeway in preventing a small hole from turning into a big effusion,” he said.
The RE-CIRCUIT trial was funded by Boehringer Ingelheim. Dr. Calkins reported receiving lecture fees from that company and from Medtronic, and serving as a consultant to Medtronic, Abbott Medical, and AtriCure.
Simultaneously with Dr. Calkins’ presentation at ACC 17, the RE-CIRCUIT study was published online (N Engl J Med. 2017 Mar 19. doi: 10.1056/NEJMoa1701005).
Washington – Uninterrupted dabigatran for periprocedural anticoagulation in patients undergoing catheter ablation for atrial fibrillation proved far superior to uninterrupted warfarin – the current standard – in the randomized multicenter RE-CIRCUIT trial, Hugh Calkins, MD, reported at the annual meeting of the American College of Cardiology.
The primary study endpoint – the incidence of major bleeding events from the time of the first femoral puncture at the procedure’s start through the subsequent 8 weeks – occurred in 1.6% of the dabigatran (Pradaxa) group and 6.9% of the warfarin group, for an absolute 5.9% reduction in risk and a 77% relative risk reduction favoring the novel anticoagulant.
“This trial will definitely affect my own practice, and I think it will quickly affect the practices of electrophysiologists around the world,” declared Dr. Calkins, professor of cardiology and medicine and director of the clinical electrophysiology laboratory and the arrhythmia service at Johns Hopkins University, Baltimore.
RE-CIRCUIT (Randomized Evaluation of Dabigatran Etexilate Compared to Warfarin in Pulmonary Vein Ablation: Assessment of an Uninterrupted Periprocedural Anticoagulation Strategy) was a multicenter, prospective, international trial conducted in 635 atrial fibrillation (AF) patients who underwent catheter ablation at 104 sites. The trial was of necessity open label because of the need for frequent adjustments of warfarin dosing; however, outcome assessment was carried out by a blinded panel of six cardiologists and three neurologists.
Standard practice among AF ablationists is to continue oral anticoagulation periprocedurally because prior studies have convincingly shown that periprocedural interruption of warfarin in an effort to reduce bleeding results in a sharply increased risk of periprocedural stroke. So participants in RE-CIRCUIT were randomized to 4-8 weeks of uninterrupted anticoagulation with either dabigatran at 150 mg b.i.d. or warfarin with a target international normalized ratio (INR) of 2.0-3.0 prior to the ablation procedure, during it, and for 8 weeks afterward, at which time an individualized decision was made as to whether to stop or continue the drug.
Major bleeding events were defined by the International Society on Thrombosis and Hemostatis criteria. Most of these bleeds occurred within the first day or two after the procedure. Pericardial tamponades and groin hematomas were significantly less common with dabigatran.
The incidence of minor bleeding events was similar, at around 18% in the two treatment arms. No strokes or systemic embolisms occurred in the study. One patient on warfarin experienced a transient ischemic attack.
Dr. Calkins elaborated on why RE-CIRCUIT will change clinical practice: “A stroke is a terrible thing during an AF procedure and cardiac tamponade is the most common cause of death from the procedure. And now we have high-quality data showing that if you perform this procedure on uninterrupted dabigatran, the risk of stroke and other systemic embolic events is extremely low, and the rate of major bleeding was 77% less.
“Plus, the logistics of warfarin are a pain,” he continued. “If the patient presents on the day of ablation with an INR that’s too high, the procedure is canceled, and if they present with an INR that’s too low and the procedure is carried out, it’s done so with an increased stroke risk.”
Dr. Calkins said he suspects the sharp reduction in major bleeding events during and after AF catheter ablation is a class effect shared by the other NOACs. Studies with those agents are ongoing. But for now, the unique availability of an immediate reversal agent in the form of idarucizumab (Praxbind) for dabigatran in the event of uncontrolled major bleeding is a source of reassurance for operators and patients alike. The antidote was never required in RE-CIRCUIT, though, the cardiologist noted.
Discussant William G. Stevenson, MD, called the trial “informative and helpful.”
“Something we’ve all been struggling with was that some concern was earlier raised that dabigatran might be associated with more thromboembolic events in this scenario. This study clearly refutes that concern,” observed Dr. Stevenson, director of the clinical cardiac electrophysiology program at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston.
Dr. Stevenson wondered whether the outcome differences between the two study groups could be explained by differences in operator techniques and tools. That’s highly unlikely, Dr. Calkins replied. Randomization was done patient by patient, not center by center.
Then why the big difference in major bleeding complications? Dr. Stevenson asked.
“It may be that, if you poke a hole when a patient is on a more forgiving anticoagulant like dabigatran, the bleeding doesn’t persist and turn into a tamponade, whereas if you poke a hole on warfarin it turns into a bigger problem,” Dr. Calkins responded. “When you think about it, warfarin really impacts the whole coagulation cascade through factors VII, IX, and X, so multiple coagulation factors are rendered impotent, whereas dabigatran is a direct thrombin inhibitor, so you’re selectively knocking out just one component of the coagulation cascade. It provides more leeway in preventing a small hole from turning into a big effusion,” he said.
The RE-CIRCUIT trial was funded by Boehringer Ingelheim. Dr. Calkins reported receiving lecture fees from that company and from Medtronic, and serving as a consultant to Medtronic, Abbott Medical, and AtriCure.
Simultaneously with Dr. Calkins’ presentation at ACC 17, the RE-CIRCUIT study was published online (N Engl J Med. 2017 Mar 19. doi: 10.1056/NEJMoa1701005).
At ACC 17
Key clinical point:
Major finding: The incidence of major bleeding events in conjunction with catheter ablation of atrial fibrillation was reduced by 77% in patients on periprocedural dabigatran compared with those on warfarin.
Data source: A randomized multicenter prospective international trial of 635 patients who underwent catheter ablation for atrial fibrillation supported by uninterrupted oral anticoagulation.
Disclosures: The RE-CIRCUIT trial was funded by Boehringer Ingelheim. Dr. Calkins reported receiving lecture fees from that company and from Medtronic, and serving as a consultant to Medtronic, Abbott Medical, and AtriCure.
Genetically guided warfarin dosing can lower AE risk
WASHINGTON, DC—Using genetic testing to guide warfarin dosing can lower the risk of combined adverse events (AEs) after elective orthopedic surgery, according to the GIFT trial.
In this trial, investigators found that genotype-guided warfarin dosing was associated with a lower risk of combined AEs—confirmed venous thromboembolism (VTE), warfarin overdose, major bleeding, and death—when compared to clinically based warfarin dosing.
There were no deaths during this trial, so the researchers were unable to assess whether genotype-guided dosing actually reduced mortality risk.
However, they believe these findings could have implications for a broad population of patients starting warfarin therapy.
The findings were presented at the American College of Cardiology’s 66th Annual Scientific Session (abstract 411-14).
“The way we dose warfarin clinically is trial-and-error dosing,” said study investigator Brian F. Gage, MD, of Washington University School of Medicine in St. Louis, Missouri.
“We often start patients on 5 mg daily and don’t find out who is very sensitive to warfarin until their INR is 4 or more, indicating an overdose. Based on our results, as compared with optimized clinical dosing, pharmacogenetic dosing did better overall, meaning this group of patients had a lower rate of adverse events.”
Dr Gage also noted that the clinical dosing used in this trial was likely better than standard dosing used in clinical practice.
In this trial, the researchers used a computer-based, real-time interface that estimated the therapeutic dose and provided recommendations for adjusting dose based on a patient’s age, height, weight, interactions with other medications, and other clinical factors.
Trial interventions
GIFT included 1597 patients age 65 and older who were undergoing elective knee or hip replacement surgery. Most patients were female (63.8%) and Caucasian (91.1%).
The patients were genotyped for genetic variants that influence warfarin sensitivity (CYP2C9*2, CYP2C9*3), warfarin metabolism (VKORC1), and vitamin K recycling (CYP4F2).
They were randomized to receive clinical dosing or genotype-guided dosing (in addition to clinical factors being taken into account). The patients were also randomly assigned to a target international normalized ratio (INR) of either 1.8 or 2.5.
For the first 11 days of therapy, warfarin dosing in both arms was guided by a web application that incorporated clinical factors in all patients and genotype in patients randomized to genotype-guided dosing.
Most (94%) of the time, prescribers gave the dose that was recommended. After 11 days of therapy, they were free to continue the current warfarin dose or make adjustments.
Patients were monitored using standard INR testing, and most underwent screening with lower extremity Doppler ultrasound 3 to 7 weeks after arthroplasty to check for clots.
The investigators followed patients for 90 days and assessed the primary outcome through day 30, although VTEs detected through day 60 were also included in the primary outcome.
Results
The primary outcome—a composite of confirmed VTE, warfarin overdose (INR ≥ 4), major bleeding, and death—occurred in 14.7% of patients in the clinical arm and 10.8% in the genotype-guided arm (P=0.018).
The relative rate of the primary outcome was 0.73 (95% CI, 0.56 - 0.95). The relative rate was 0.24 (95% CI, 0.05 - 1.14) for major bleeding, 0.71 (95% CI, 0.51 - 0.99) for INR ≥ 4.0, and 0.85 (95% CI, 0.54 - 1.34) for VTE.
There were no deaths at the 30-day follow-up point, and 1 patient was lost to follow-up.
“Before GIFT, we had a good idea of how these genes and clinical factors affected the dose of warfarin,” Dr Gage said. “What we didn’t know is whether taking genotype into account improved outcomes. It turns out that the genes that regulate warfarin metabolism and sensitivity and vitamin K use are highly variable, so we can’t simply look at patients and predict their therapeutic warfarin dose.”
“The GIFT trial is an example of personalized medicine. If the patient stays in a safe INR range, warfarin is an incredibly effective and safe drug. By getting the dose approximately right from the get-go, we’re less likely to have the patient overdose and can lower the risk of complications.”
Dr Gage said future research could combine GIFT with prior pharmacogenetic trials in a meta-analysis and should determine what other genetic variations predict response to anticoagulants.
Additionally, as clinical and genetic factors affecting warfarin dose requirements vary by race, dosing algorithms tailored to ancestry may be beneficial.
Dr Gage also said he hopes genetic and clinical dosing algorithms will be integrated within electronic medical records.
“The hope is that when a physician starts a prescription of warfarin, electronic medical records will seamlessly give a prudent recommendation to help the doctor come up with the right dose,” he said. 
WASHINGTON, DC—Using genetic testing to guide warfarin dosing can lower the risk of combined adverse events (AEs) after elective orthopedic surgery, according to the GIFT trial.
In this trial, investigators found that genotype-guided warfarin dosing was associated with a lower risk of combined AEs—confirmed venous thromboembolism (VTE), warfarin overdose, major bleeding, and death—when compared to clinically based warfarin dosing.
There were no deaths during this trial, so the researchers were unable to assess whether genotype-guided dosing actually reduced mortality risk.
However, they believe these findings could have implications for a broad population of patients starting warfarin therapy.
The findings were presented at the American College of Cardiology’s 66th Annual Scientific Session (abstract 411-14).
“The way we dose warfarin clinically is trial-and-error dosing,” said study investigator Brian F. Gage, MD, of Washington University School of Medicine in St. Louis, Missouri.
“We often start patients on 5 mg daily and don’t find out who is very sensitive to warfarin until their INR is 4 or more, indicating an overdose. Based on our results, as compared with optimized clinical dosing, pharmacogenetic dosing did better overall, meaning this group of patients had a lower rate of adverse events.”
Dr Gage also noted that the clinical dosing used in this trial was likely better than standard dosing used in clinical practice.
In this trial, the researchers used a computer-based, real-time interface that estimated the therapeutic dose and provided recommendations for adjusting dose based on a patient’s age, height, weight, interactions with other medications, and other clinical factors.
Trial interventions
GIFT included 1597 patients age 65 and older who were undergoing elective knee or hip replacement surgery. Most patients were female (63.8%) and Caucasian (91.1%).
The patients were genotyped for genetic variants that influence warfarin sensitivity (CYP2C9*2, CYP2C9*3), warfarin metabolism (VKORC1), and vitamin K recycling (CYP4F2).
They were randomized to receive clinical dosing or genotype-guided dosing (in addition to clinical factors being taken into account). The patients were also randomly assigned to a target international normalized ratio (INR) of either 1.8 or 2.5.
For the first 11 days of therapy, warfarin dosing in both arms was guided by a web application that incorporated clinical factors in all patients and genotype in patients randomized to genotype-guided dosing.
Most (94%) of the time, prescribers gave the dose that was recommended. After 11 days of therapy, they were free to continue the current warfarin dose or make adjustments.
Patients were monitored using standard INR testing, and most underwent screening with lower extremity Doppler ultrasound 3 to 7 weeks after arthroplasty to check for clots.
The investigators followed patients for 90 days and assessed the primary outcome through day 30, although VTEs detected through day 60 were also included in the primary outcome.
Results
The primary outcome—a composite of confirmed VTE, warfarin overdose (INR ≥ 4), major bleeding, and death—occurred in 14.7% of patients in the clinical arm and 10.8% in the genotype-guided arm (P=0.018).
The relative rate of the primary outcome was 0.73 (95% CI, 0.56 - 0.95). The relative rate was 0.24 (95% CI, 0.05 - 1.14) for major bleeding, 0.71 (95% CI, 0.51 - 0.99) for INR ≥ 4.0, and 0.85 (95% CI, 0.54 - 1.34) for VTE.
There were no deaths at the 30-day follow-up point, and 1 patient was lost to follow-up.
“Before GIFT, we had a good idea of how these genes and clinical factors affected the dose of warfarin,” Dr Gage said. “What we didn’t know is whether taking genotype into account improved outcomes. It turns out that the genes that regulate warfarin metabolism and sensitivity and vitamin K use are highly variable, so we can’t simply look at patients and predict their therapeutic warfarin dose.”
“The GIFT trial is an example of personalized medicine. If the patient stays in a safe INR range, warfarin is an incredibly effective and safe drug. By getting the dose approximately right from the get-go, we’re less likely to have the patient overdose and can lower the risk of complications.”
Dr Gage said future research could combine GIFT with prior pharmacogenetic trials in a meta-analysis and should determine what other genetic variations predict response to anticoagulants.
Additionally, as clinical and genetic factors affecting warfarin dose requirements vary by race, dosing algorithms tailored to ancestry may be beneficial.
Dr Gage also said he hopes genetic and clinical dosing algorithms will be integrated within electronic medical records.
“The hope is that when a physician starts a prescription of warfarin, electronic medical records will seamlessly give a prudent recommendation to help the doctor come up with the right dose,” he said.
WASHINGTON, DC—Using genetic testing to guide warfarin dosing can lower the risk of combined adverse events (AEs) after elective orthopedic surgery, according to the GIFT trial.
In this trial, investigators found that genotype-guided warfarin dosing was associated with a lower risk of combined AEs—confirmed venous thromboembolism (VTE), warfarin overdose, major bleeding, and death—when compared to clinically based warfarin dosing.
There were no deaths during this trial, so the researchers were unable to assess whether genotype-guided dosing actually reduced mortality risk.
However, they believe these findings could have implications for a broad population of patients starting warfarin therapy.
The findings were presented at the American College of Cardiology’s 66th Annual Scientific Session (abstract 411-14).
“The way we dose warfarin clinically is trial-and-error dosing,” said study investigator Brian F. Gage, MD, of Washington University School of Medicine in St. Louis, Missouri.
“We often start patients on 5 mg daily and don’t find out who is very sensitive to warfarin until their INR is 4 or more, indicating an overdose. Based on our results, as compared with optimized clinical dosing, pharmacogenetic dosing did better overall, meaning this group of patients had a lower rate of adverse events.”
Dr Gage also noted that the clinical dosing used in this trial was likely better than standard dosing used in clinical practice.
In this trial, the researchers used a computer-based, real-time interface that estimated the therapeutic dose and provided recommendations for adjusting dose based on a patient’s age, height, weight, interactions with other medications, and other clinical factors.
Trial interventions
GIFT included 1597 patients age 65 and older who were undergoing elective knee or hip replacement surgery. Most patients were female (63.8%) and Caucasian (91.1%).
The patients were genotyped for genetic variants that influence warfarin sensitivity (CYP2C9*2, CYP2C9*3), warfarin metabolism (VKORC1), and vitamin K recycling (CYP4F2).
They were randomized to receive clinical dosing or genotype-guided dosing (in addition to clinical factors being taken into account). The patients were also randomly assigned to a target international normalized ratio (INR) of either 1.8 or 2.5.
For the first 11 days of therapy, warfarin dosing in both arms was guided by a web application that incorporated clinical factors in all patients and genotype in patients randomized to genotype-guided dosing.
Most (94%) of the time, prescribers gave the dose that was recommended. After 11 days of therapy, they were free to continue the current warfarin dose or make adjustments.
Patients were monitored using standard INR testing, and most underwent screening with lower extremity Doppler ultrasound 3 to 7 weeks after arthroplasty to check for clots.
The investigators followed patients for 90 days and assessed the primary outcome through day 30, although VTEs detected through day 60 were also included in the primary outcome.
Results
The primary outcome—a composite of confirmed VTE, warfarin overdose (INR ≥ 4), major bleeding, and death—occurred in 14.7% of patients in the clinical arm and 10.8% in the genotype-guided arm (P=0.018).
The relative rate of the primary outcome was 0.73 (95% CI, 0.56 - 0.95). The relative rate was 0.24 (95% CI, 0.05 - 1.14) for major bleeding, 0.71 (95% CI, 0.51 - 0.99) for INR ≥ 4.0, and 0.85 (95% CI, 0.54 - 1.34) for VTE.
There were no deaths at the 30-day follow-up point, and 1 patient was lost to follow-up.
“Before GIFT, we had a good idea of how these genes and clinical factors affected the dose of warfarin,” Dr Gage said. “What we didn’t know is whether taking genotype into account improved outcomes. It turns out that the genes that regulate warfarin metabolism and sensitivity and vitamin K use are highly variable, so we can’t simply look at patients and predict their therapeutic warfarin dose.”
“The GIFT trial is an example of personalized medicine. If the patient stays in a safe INR range, warfarin is an incredibly effective and safe drug. By getting the dose approximately right from the get-go, we’re less likely to have the patient overdose and can lower the risk of complications.”
Dr Gage said future research could combine GIFT with prior pharmacogenetic trials in a meta-analysis and should determine what other genetic variations predict response to anticoagulants.
Additionally, as clinical and genetic factors affecting warfarin dose requirements vary by race, dosing algorithms tailored to ancestry may be beneficial.
Dr Gage also said he hopes genetic and clinical dosing algorithms will be integrated within electronic medical records.
“The hope is that when a physician starts a prescription of warfarin, electronic medical records will seamlessly give a prudent recommendation to help the doctor come up with the right dose,” he said.
VIDEO: Postop troponin T spike flags high mortality risk
WASHINGTON – A rise in the blood level of troponin T immediately after patients underwent noncardiac surgery identified a high risk group with a 30-day mortality rate nearly fivefold higher than that of patients who did not have a postoperative troponin T spike, according to a prospective study of more than 21,000 patients.
For 93% of the patients who have these perioperative spikes in troponin T, a marker of myocardial ischemia, the increased level was the only indicator of a heart problem, P.J. Devereaux, MD, said at the annual meeting of the American College of Cardiology. The painkillers that patients receive following surgery generally mask the chest discomfort they might otherwise feel from their heart damage, he explained. The clinical condition is called myocardial injury after noncardiac surgery.
“We’re seeing more older patients with a high burden of vascular disease undergoing surgery, and surgery is a very significant stress, so a large proportion of these patients will have [myocardial injury after noncardiac surgery] and that affects 30-day survival,” said Dr. Devereaux, professor and director of cardiology at McMaster University in Hamilton, Ont.
Based on the new findings, he recommended performing a baseline assessment of troponin T levels in patients scheduled for noncardiac surgery if they are at least 65 years of age, or if they are age 45-64 years with known vascular disease, followed by repeat testing 1 and 2 days after surgery to check whether a spike in the measure had occurred. The high sensitivity troponin T (hsTnT) test he used in the study is relatively costly (and received Food and Drug Administration approval for U.S. marketing in January 2017), but Dr. Devereaux believed that, used in this way, the cost for testing would be reasonable, given its powerful ability to identify high-risk patients and relative to the cost of other screening tools routinely used in U.S. medical practice.
“It looks very cost-effective,” he said in a video interview.
If the baseline and two follow-up measures of hsTnT showed a postoperative level of at least 20 ng/L that rose above the baseline level by at least 5 ng/L, or if the postoperative level was at least 65 ng/L, Dr. Devereaux recommended starting daily treatment with aspirin and a statin to try to contain any perioperative myocardial damage the patient may have, and follow with comprehensive assessment of the patient by a cardiologist or other internal medicine physician.
“Given the risks associated with a rise in hsTnT in this study, Dr. Devereaux’s recommendations are very reasonable until we collect more data on this,” said Frank W. Sellke, MD, professor of surgery and chief of cardiothoracic surgery at Brown Medical School and the Lifespan Hospitals in Providence, R.I. “What was surprising was how few patients had symptoms” of myocardial ischemia. “You can’t do hsTnT measurements on every patient who goes in for a hernia operation; it’s not practical. But his findings are fairly compelling, and hopefully the cost of this testing will come down,” Dr. Sellke said in an interview.
In the multicenter study of 21,842 patients, 24% had a postoperative hsTnT level of 20 ng/L or greater, including 5% with a level of 65 ng/L or greater. The 30-day mortality rate was 3% among those with a perioperative level of 20-64 ng/L, 9% among patients with perioperative hsTnT levels of 65-999 ng/L, and 30% among the 54 patients (0.2% of the study group) with perioperative levels that reached 1,000 ng/L or greater. Dr. Devereaux reported.
This iteration of the Vascular Events In Noncardiac Surgery Patients Cohort Evaluation Study (VISION) enrolled patients who were at least 45 years of age and underwent noncardiac surgery at 23 centers in 13 countries, including the United States and Canada. All patients underwent hsTnT testing 6-12 hours after surgery and 1, 2, and 3 days after surgery, but only 40% also had a baseline measurement before their surgery began. Full 30-day follow-up occurred for 21,050. The patients’ average age was 63 years. The most common surgery was “low-risk,” in 35%, followed by “major” general surgery in 20%, and “major” orthopedic surgery in 16%. At 30 days, 266 patients (1.2%) had died.
These findings “help define a cutoff for hsTnT that will be clinically useful to change practice,” said Athena Poppas, MD, a cardiologist and director of the Cardiovascular Institute at Rhode Island Hospital in Providence. Dr. Poppas was a designated discussant for Dr. Devereaux’s report at the meeting.
In January 2017, the Canadian Cardiovascular Society issued guidelines for perioperative cardiac risk assessment and management for patients undergoing noncardiac surgery (Can J Cardiol. 2017 Jan;33[1]:17-32). Dr. Devereaux was a member of the writing panel for these guidelines. This is what the guidelines said about using troponin T measurements:
“We recommend obtaining daily troponin measurements for 48-72 hours after noncardiac surgery in patients with a baseline risk greater than 5% for cardiovascular death or nonfatal myocardial infarction at 30 days after surgery (i.e., patients with an elevated NT-proBNP/BNP measurement before surgery or, if there is no NT-proBNP/BNP measurement before surgery, in those who have an RCRI [revised cardiac risk index] score of 1 or greater, age 45-64 years with significant cardiovascular disease, or age 65 years or older).”
The VISION study is sponsored by Roche Diagnostics, which markets the high sensitivity troponin T assay used in the study. Dr. Devereaux has received research funding from Roche Diagnostics and from Abbott Diagnostics and Boehringer Ingelheim. Dr. Sellke and Dr. Poppas had no relevant disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
WASHINGTON – A rise in the blood level of troponin T immediately after patients underwent noncardiac surgery identified a high risk group with a 30-day mortality rate nearly fivefold higher than that of patients who did not have a postoperative troponin T spike, according to a prospective study of more than 21,000 patients.
For 93% of the patients who have these perioperative spikes in troponin T, a marker of myocardial ischemia, the increased level was the only indicator of a heart problem, P.J. Devereaux, MD, said at the annual meeting of the American College of Cardiology. The painkillers that patients receive following surgery generally mask the chest discomfort they might otherwise feel from their heart damage, he explained. The clinical condition is called myocardial injury after noncardiac surgery.
“We’re seeing more older patients with a high burden of vascular disease undergoing surgery, and surgery is a very significant stress, so a large proportion of these patients will have [myocardial injury after noncardiac surgery] and that affects 30-day survival,” said Dr. Devereaux, professor and director of cardiology at McMaster University in Hamilton, Ont.
Based on the new findings, he recommended performing a baseline assessment of troponin T levels in patients scheduled for noncardiac surgery if they are at least 65 years of age, or if they are age 45-64 years with known vascular disease, followed by repeat testing 1 and 2 days after surgery to check whether a spike in the measure had occurred. The high sensitivity troponin T (hsTnT) test he used in the study is relatively costly (and received Food and Drug Administration approval for U.S. marketing in January 2017), but Dr. Devereaux believed that, used in this way, the cost for testing would be reasonable, given its powerful ability to identify high-risk patients and relative to the cost of other screening tools routinely used in U.S. medical practice.
“It looks very cost-effective,” he said in a video interview.
If the baseline and two follow-up measures of hsTnT showed a postoperative level of at least 20 ng/L that rose above the baseline level by at least 5 ng/L, or if the postoperative level was at least 65 ng/L, Dr. Devereaux recommended starting daily treatment with aspirin and a statin to try to contain any perioperative myocardial damage the patient may have, and follow with comprehensive assessment of the patient by a cardiologist or other internal medicine physician.
“Given the risks associated with a rise in hsTnT in this study, Dr. Devereaux’s recommendations are very reasonable until we collect more data on this,” said Frank W. Sellke, MD, professor of surgery and chief of cardiothoracic surgery at Brown Medical School and the Lifespan Hospitals in Providence, R.I. “What was surprising was how few patients had symptoms” of myocardial ischemia. “You can’t do hsTnT measurements on every patient who goes in for a hernia operation; it’s not practical. But his findings are fairly compelling, and hopefully the cost of this testing will come down,” Dr. Sellke said in an interview.
In the multicenter study of 21,842 patients, 24% had a postoperative hsTnT level of 20 ng/L or greater, including 5% with a level of 65 ng/L or greater. The 30-day mortality rate was 3% among those with a perioperative level of 20-64 ng/L, 9% among patients with perioperative hsTnT levels of 65-999 ng/L, and 30% among the 54 patients (0.2% of the study group) with perioperative levels that reached 1,000 ng/L or greater. Dr. Devereaux reported.
This iteration of the Vascular Events In Noncardiac Surgery Patients Cohort Evaluation Study (VISION) enrolled patients who were at least 45 years of age and underwent noncardiac surgery at 23 centers in 13 countries, including the United States and Canada. All patients underwent hsTnT testing 6-12 hours after surgery and 1, 2, and 3 days after surgery, but only 40% also had a baseline measurement before their surgery began. Full 30-day follow-up occurred for 21,050. The patients’ average age was 63 years. The most common surgery was “low-risk,” in 35%, followed by “major” general surgery in 20%, and “major” orthopedic surgery in 16%. At 30 days, 266 patients (1.2%) had died.
These findings “help define a cutoff for hsTnT that will be clinically useful to change practice,” said Athena Poppas, MD, a cardiologist and director of the Cardiovascular Institute at Rhode Island Hospital in Providence. Dr. Poppas was a designated discussant for Dr. Devereaux’s report at the meeting.
In January 2017, the Canadian Cardiovascular Society issued guidelines for perioperative cardiac risk assessment and management for patients undergoing noncardiac surgery (Can J Cardiol. 2017 Jan;33[1]:17-32). Dr. Devereaux was a member of the writing panel for these guidelines. This is what the guidelines said about using troponin T measurements:
“We recommend obtaining daily troponin measurements for 48-72 hours after noncardiac surgery in patients with a baseline risk greater than 5% for cardiovascular death or nonfatal myocardial infarction at 30 days after surgery (i.e., patients with an elevated NT-proBNP/BNP measurement before surgery or, if there is no NT-proBNP/BNP measurement before surgery, in those who have an RCRI [revised cardiac risk index] score of 1 or greater, age 45-64 years with significant cardiovascular disease, or age 65 years or older).”
The VISION study is sponsored by Roche Diagnostics, which markets the high sensitivity troponin T assay used in the study. Dr. Devereaux has received research funding from Roche Diagnostics and from Abbott Diagnostics and Boehringer Ingelheim. Dr. Sellke and Dr. Poppas had no relevant disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
WASHINGTON – A rise in the blood level of troponin T immediately after patients underwent noncardiac surgery identified a high risk group with a 30-day mortality rate nearly fivefold higher than that of patients who did not have a postoperative troponin T spike, according to a prospective study of more than 21,000 patients.
For 93% of the patients who have these perioperative spikes in troponin T, a marker of myocardial ischemia, the increased level was the only indicator of a heart problem, P.J. Devereaux, MD, said at the annual meeting of the American College of Cardiology. The painkillers that patients receive following surgery generally mask the chest discomfort they might otherwise feel from their heart damage, he explained. The clinical condition is called myocardial injury after noncardiac surgery.
“We’re seeing more older patients with a high burden of vascular disease undergoing surgery, and surgery is a very significant stress, so a large proportion of these patients will have [myocardial injury after noncardiac surgery] and that affects 30-day survival,” said Dr. Devereaux, professor and director of cardiology at McMaster University in Hamilton, Ont.
Based on the new findings, he recommended performing a baseline assessment of troponin T levels in patients scheduled for noncardiac surgery if they are at least 65 years of age, or if they are age 45-64 years with known vascular disease, followed by repeat testing 1 and 2 days after surgery to check whether a spike in the measure had occurred. The high sensitivity troponin T (hsTnT) test he used in the study is relatively costly (and received Food and Drug Administration approval for U.S. marketing in January 2017), but Dr. Devereaux believed that, used in this way, the cost for testing would be reasonable, given its powerful ability to identify high-risk patients and relative to the cost of other screening tools routinely used in U.S. medical practice.
“It looks very cost-effective,” he said in a video interview.
If the baseline and two follow-up measures of hsTnT showed a postoperative level of at least 20 ng/L that rose above the baseline level by at least 5 ng/L, or if the postoperative level was at least 65 ng/L, Dr. Devereaux recommended starting daily treatment with aspirin and a statin to try to contain any perioperative myocardial damage the patient may have, and follow with comprehensive assessment of the patient by a cardiologist or other internal medicine physician.
“Given the risks associated with a rise in hsTnT in this study, Dr. Devereaux’s recommendations are very reasonable until we collect more data on this,” said Frank W. Sellke, MD, professor of surgery and chief of cardiothoracic surgery at Brown Medical School and the Lifespan Hospitals in Providence, R.I. “What was surprising was how few patients had symptoms” of myocardial ischemia. “You can’t do hsTnT measurements on every patient who goes in for a hernia operation; it’s not practical. But his findings are fairly compelling, and hopefully the cost of this testing will come down,” Dr. Sellke said in an interview.
In the multicenter study of 21,842 patients, 24% had a postoperative hsTnT level of 20 ng/L or greater, including 5% with a level of 65 ng/L or greater. The 30-day mortality rate was 3% among those with a perioperative level of 20-64 ng/L, 9% among patients with perioperative hsTnT levels of 65-999 ng/L, and 30% among the 54 patients (0.2% of the study group) with perioperative levels that reached 1,000 ng/L or greater. Dr. Devereaux reported.
This iteration of the Vascular Events In Noncardiac Surgery Patients Cohort Evaluation Study (VISION) enrolled patients who were at least 45 years of age and underwent noncardiac surgery at 23 centers in 13 countries, including the United States and Canada. All patients underwent hsTnT testing 6-12 hours after surgery and 1, 2, and 3 days after surgery, but only 40% also had a baseline measurement before their surgery began. Full 30-day follow-up occurred for 21,050. The patients’ average age was 63 years. The most common surgery was “low-risk,” in 35%, followed by “major” general surgery in 20%, and “major” orthopedic surgery in 16%. At 30 days, 266 patients (1.2%) had died.
These findings “help define a cutoff for hsTnT that will be clinically useful to change practice,” said Athena Poppas, MD, a cardiologist and director of the Cardiovascular Institute at Rhode Island Hospital in Providence. Dr. Poppas was a designated discussant for Dr. Devereaux’s report at the meeting.
In January 2017, the Canadian Cardiovascular Society issued guidelines for perioperative cardiac risk assessment and management for patients undergoing noncardiac surgery (Can J Cardiol. 2017 Jan;33[1]:17-32). Dr. Devereaux was a member of the writing panel for these guidelines. This is what the guidelines said about using troponin T measurements:
“We recommend obtaining daily troponin measurements for 48-72 hours after noncardiac surgery in patients with a baseline risk greater than 5% for cardiovascular death or nonfatal myocardial infarction at 30 days after surgery (i.e., patients with an elevated NT-proBNP/BNP measurement before surgery or, if there is no NT-proBNP/BNP measurement before surgery, in those who have an RCRI [revised cardiac risk index] score of 1 or greater, age 45-64 years with significant cardiovascular disease, or age 65 years or older).”
The VISION study is sponsored by Roche Diagnostics, which markets the high sensitivity troponin T assay used in the study. Dr. Devereaux has received research funding from Roche Diagnostics and from Abbott Diagnostics and Boehringer Ingelheim. Dr. Sellke and Dr. Poppas had no relevant disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT ACC 17
Key clinical point:
Major finding: A postoperative high sensitivity troponin T rise of 5 ng/L or more linked with a 4.7-fold increase in 30-day mortality.
Data source: VISION, a prospective, multicenter observational study of 21,842 patients undergoing noncardiac surgery.
Disclosures: The VISION study is sponsored by Roche Diagnostics, which markets the high sensitivity troponin T assay used in the study. Dr. Devereaux has received research funding from Roche Diagnostics and from Abbott Diagnostics and Boehringer Ingelheim.
