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Anticoagulation Hub contains news and clinical review articles for physicians seeking the most up-to-date information on the rapidly evolving treatment options for preventing stroke, acute coronary events, deep vein thrombosis, and pulmonary embolism in at-risk patients. The Anticoagulation Hub is powered by Frontline Medical Communications.
How to identify DVT faster in pediatric osteomyelitis
MALMO, SWEDEN – Early identification of deep vein thrombosis in children with acute hematogenous osteomyelitis is critical given the need to plan anticoagulation management around the high likelihood that such patients will undergo multiple surgeries, Lawson A.B. Copley, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.
He and his coinvestigators have identified a handful of risk factors helpful in expediting recognition of deep vein thrombosis (DVT) in children with suspected invasive infection of the musculoskeletal system.
“To improve the rate and timing of identification of DVT, we recommend performing early screening ultrasound on all children with these risk factors who are suspected of having acute hematogenous osteomyelitis,” declared Dr. Copley, professor of orthopaedic surgery and pediatrics at the University of Texas, Dallas.
Delayed diagnosis of DVT in the setting of acute hematogenous osteomyelitis (AHO) is common. Indeed, in a review of the experience at Children’s Medical Center Dallas during 2012-2014, the average time delay from ICU admission in patients suspected of having AHO to identification of DVT by ultrasound was 6.3 days.
“We’ve changed some things on the basis of that study in order to accelerate that timeline,” he explained.
Their major change was to identify actionable risk factors for DVT. This was accomplished by conducting a retrospective study of the EHR of nearly 902,000 Texas children during 2008-2016.
The study demonstrated that children with AHO complicated by DVT are, from the get-go, very different from AHO patients without DVT. They have higher illness severity of illness, are more likely to be admitted to the ICU, are prone to methicillin-resistant Staphylococcus aureus infection with prolonged bacteremia, and are much more likely to undergo multiple surgeries. Moreover, children with AHO and DVT differed substantially from other children with DVT: The dual diagnosis children lacked comorbid conditions, were prone to septic pulmonary emboli, didn’t develop postthrombotic syndrome marked by chronic venous stasis and ulcerations, and had invariably negative coagulopathy workups.
“There is no need, we feel, to perform a hypercoagulopathy workup in children with AHO complicated by DVT,” Dr. Copley said.
Drilling deeper into the data, he and his coinvestigators identified 224 new cases of DVT in the study population, for a prevalence of 2.5 per 10,000 children, along with 466 children with AHO. A total of 6% of children with AHO had DVT, and 12.1% of all children with DVT had AHO. The researchers then compared the demographics, laboratory parameters, and treatment in three cohorts: the 196 children with DVT without AHO, 28 with both AHO and DVT, and 438 with AHO without DVT.
Through this analysis, they came up with a list of risk factors warranting early screening ultrasound in children suspected of having AHO:
- An initial C-reactive protein level above 8 mg/dL, which was present in all 28 dual diagnosis children.
- ICU admission, which occurred in 19 of 28 (68%) children.
- A severity of illness score of at least 7 on a 10-point scale during the first several days in the hospital, present in 27 of the 28 children. The severity of illness scale was developed and validated by Dr. Copley and coworkers (J Pediatr Orthop. 2016 Oct 12. doi: 10.1097/BPO.0000000000000879).
- Bacteremia in the initial blood culture, present in 23 of 28 patients (82%).
- Just under 90% of the children with AHO and DVT had methicillin-resistant S. aureus, compared with 20% of those with AHO without DVT.
- Septic pulmonary emboli visualized on chest x-ray, a complication that occurred in 64% of the dual diagnosis group versus just 1% of patients with DVT without AHO.
- A band percentage of white blood cells greater than 1.5%, present in 86% of children with AHO and DVT.
More than 90% of children with AHO and DVT underwent surgery, with a mean of 2.7 surgeries per child, in contrast to the group with AHO without DVT, 55% of whom had surgery, with a mean of 0.7 surgeries per child.
Of note, there was no significant difference in the occurrence of pulmonary embolism between children with DVT without AHO versus those with DVT and AHO, with a rate of about 10% in both groups.
Dr. Copley reported having no relevant financial conflicts.
MALMO, SWEDEN – Early identification of deep vein thrombosis in children with acute hematogenous osteomyelitis is critical given the need to plan anticoagulation management around the high likelihood that such patients will undergo multiple surgeries, Lawson A.B. Copley, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.
He and his coinvestigators have identified a handful of risk factors helpful in expediting recognition of deep vein thrombosis (DVT) in children with suspected invasive infection of the musculoskeletal system.
“To improve the rate and timing of identification of DVT, we recommend performing early screening ultrasound on all children with these risk factors who are suspected of having acute hematogenous osteomyelitis,” declared Dr. Copley, professor of orthopaedic surgery and pediatrics at the University of Texas, Dallas.
Delayed diagnosis of DVT in the setting of acute hematogenous osteomyelitis (AHO) is common. Indeed, in a review of the experience at Children’s Medical Center Dallas during 2012-2014, the average time delay from ICU admission in patients suspected of having AHO to identification of DVT by ultrasound was 6.3 days.
“We’ve changed some things on the basis of that study in order to accelerate that timeline,” he explained.
Their major change was to identify actionable risk factors for DVT. This was accomplished by conducting a retrospective study of the EHR of nearly 902,000 Texas children during 2008-2016.
The study demonstrated that children with AHO complicated by DVT are, from the get-go, very different from AHO patients without DVT. They have higher illness severity of illness, are more likely to be admitted to the ICU, are prone to methicillin-resistant Staphylococcus aureus infection with prolonged bacteremia, and are much more likely to undergo multiple surgeries. Moreover, children with AHO and DVT differed substantially from other children with DVT: The dual diagnosis children lacked comorbid conditions, were prone to septic pulmonary emboli, didn’t develop postthrombotic syndrome marked by chronic venous stasis and ulcerations, and had invariably negative coagulopathy workups.
“There is no need, we feel, to perform a hypercoagulopathy workup in children with AHO complicated by DVT,” Dr. Copley said.
Drilling deeper into the data, he and his coinvestigators identified 224 new cases of DVT in the study population, for a prevalence of 2.5 per 10,000 children, along with 466 children with AHO. A total of 6% of children with AHO had DVT, and 12.1% of all children with DVT had AHO. The researchers then compared the demographics, laboratory parameters, and treatment in three cohorts: the 196 children with DVT without AHO, 28 with both AHO and DVT, and 438 with AHO without DVT.
Through this analysis, they came up with a list of risk factors warranting early screening ultrasound in children suspected of having AHO:
- An initial C-reactive protein level above 8 mg/dL, which was present in all 28 dual diagnosis children.
- ICU admission, which occurred in 19 of 28 (68%) children.
- A severity of illness score of at least 7 on a 10-point scale during the first several days in the hospital, present in 27 of the 28 children. The severity of illness scale was developed and validated by Dr. Copley and coworkers (J Pediatr Orthop. 2016 Oct 12. doi: 10.1097/BPO.0000000000000879).
- Bacteremia in the initial blood culture, present in 23 of 28 patients (82%).
- Just under 90% of the children with AHO and DVT had methicillin-resistant S. aureus, compared with 20% of those with AHO without DVT.
- Septic pulmonary emboli visualized on chest x-ray, a complication that occurred in 64% of the dual diagnosis group versus just 1% of patients with DVT without AHO.
- A band percentage of white blood cells greater than 1.5%, present in 86% of children with AHO and DVT.
More than 90% of children with AHO and DVT underwent surgery, with a mean of 2.7 surgeries per child, in contrast to the group with AHO without DVT, 55% of whom had surgery, with a mean of 0.7 surgeries per child.
Of note, there was no significant difference in the occurrence of pulmonary embolism between children with DVT without AHO versus those with DVT and AHO, with a rate of about 10% in both groups.
Dr. Copley reported having no relevant financial conflicts.
MALMO, SWEDEN – Early identification of deep vein thrombosis in children with acute hematogenous osteomyelitis is critical given the need to plan anticoagulation management around the high likelihood that such patients will undergo multiple surgeries, Lawson A.B. Copley, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.
He and his coinvestigators have identified a handful of risk factors helpful in expediting recognition of deep vein thrombosis (DVT) in children with suspected invasive infection of the musculoskeletal system.
“To improve the rate and timing of identification of DVT, we recommend performing early screening ultrasound on all children with these risk factors who are suspected of having acute hematogenous osteomyelitis,” declared Dr. Copley, professor of orthopaedic surgery and pediatrics at the University of Texas, Dallas.
Delayed diagnosis of DVT in the setting of acute hematogenous osteomyelitis (AHO) is common. Indeed, in a review of the experience at Children’s Medical Center Dallas during 2012-2014, the average time delay from ICU admission in patients suspected of having AHO to identification of DVT by ultrasound was 6.3 days.
“We’ve changed some things on the basis of that study in order to accelerate that timeline,” he explained.
Their major change was to identify actionable risk factors for DVT. This was accomplished by conducting a retrospective study of the EHR of nearly 902,000 Texas children during 2008-2016.
The study demonstrated that children with AHO complicated by DVT are, from the get-go, very different from AHO patients without DVT. They have higher illness severity of illness, are more likely to be admitted to the ICU, are prone to methicillin-resistant Staphylococcus aureus infection with prolonged bacteremia, and are much more likely to undergo multiple surgeries. Moreover, children with AHO and DVT differed substantially from other children with DVT: The dual diagnosis children lacked comorbid conditions, were prone to septic pulmonary emboli, didn’t develop postthrombotic syndrome marked by chronic venous stasis and ulcerations, and had invariably negative coagulopathy workups.
“There is no need, we feel, to perform a hypercoagulopathy workup in children with AHO complicated by DVT,” Dr. Copley said.
Drilling deeper into the data, he and his coinvestigators identified 224 new cases of DVT in the study population, for a prevalence of 2.5 per 10,000 children, along with 466 children with AHO. A total of 6% of children with AHO had DVT, and 12.1% of all children with DVT had AHO. The researchers then compared the demographics, laboratory parameters, and treatment in three cohorts: the 196 children with DVT without AHO, 28 with both AHO and DVT, and 438 with AHO without DVT.
Through this analysis, they came up with a list of risk factors warranting early screening ultrasound in children suspected of having AHO:
- An initial C-reactive protein level above 8 mg/dL, which was present in all 28 dual diagnosis children.
- ICU admission, which occurred in 19 of 28 (68%) children.
- A severity of illness score of at least 7 on a 10-point scale during the first several days in the hospital, present in 27 of the 28 children. The severity of illness scale was developed and validated by Dr. Copley and coworkers (J Pediatr Orthop. 2016 Oct 12. doi: 10.1097/BPO.0000000000000879).
- Bacteremia in the initial blood culture, present in 23 of 28 patients (82%).
- Just under 90% of the children with AHO and DVT had methicillin-resistant S. aureus, compared with 20% of those with AHO without DVT.
- Septic pulmonary emboli visualized on chest x-ray, a complication that occurred in 64% of the dual diagnosis group versus just 1% of patients with DVT without AHO.
- A band percentage of white blood cells greater than 1.5%, present in 86% of children with AHO and DVT.
More than 90% of children with AHO and DVT underwent surgery, with a mean of 2.7 surgeries per child, in contrast to the group with AHO without DVT, 55% of whom had surgery, with a mean of 0.7 surgeries per child.
Of note, there was no significant difference in the occurrence of pulmonary embolism between children with DVT without AHO versus those with DVT and AHO, with a rate of about 10% in both groups.
Dr. Copley reported having no relevant financial conflicts.
REPORTING FROM ESPID 2018
Key clinical point: Osteomyelitis patients with deep vein thrombosis are much sicker than those without DVT.
Major finding:
Study details: This was a retrospective study of the medical records of more than 900,000 Texas children.
Disclosures: Dr. Copley reported having no relevant financial conflicts.
Obesity triples post-MI sudden cardiac death risk
Obesity is associated with an increased risk of sudden cardiac death after myocardial infarction, although the so-called “obesity paradox” is still evident in a lower risk of all-cause mortality, a new analysis suggests.
Researchers reported the results of an observational cohort study using data from two Japanese cohort studies involving a total of 6,216 patients discharged alive after acute myocardial infarction. The study was published in the Journal of the American Heart Association.
They found that obese patients – those with a body mass index of at least 27.5 kg/m2 – had a nearly threefold higher risk of sudden cardiac death within 3 years, compared with patients who had a normal BMI, even after adjustment for age, sex, and risk factors such as multivessel disease, left ventricular ejection fraction, and medications.
However, the obese group also showed lower 3-year all-cause mortality, compared with the reference group, whose BMI was 18.5-22.9 kg/m2, while individuals with a BMI below 18.5 kg/m2 had a 61% higher risk of mortality.
The overall all-cause mortality in the cohort was 10.1%, and the incidence of sudden cardiac death was 1.2%.
“For the primary prevention of [coronary artery disease], obesity is recognized as a potent risk factor and an opportunity for therapeutic intervention to prevent cardiovascular disease,” wrote Tsuyoshi Shiga, MD, of Tokyo Women’s Medical University, and coauthors. “However, recent reports have shown that obesity (high BMI) itself does not present a mortality risk but is associated with a better prognosis (obesity paradox) in CAD patients receiving secondary care; these patients received appropriate therapy, including percutaneous coronary intervention and guideline-based medications such as aspirin, beta-blockers, and statins.”
The increased risk of sudden cardiac death in obese patients after MI was harder to explain.
The authors suggested that obesity itself may increase the risk of ventricular arrhythmias developing, and it is also linked with left ventricular hypertrophy, which can lead to cardiac remodeling. Other reports have found evidence in obese individuals of QT prolongation or an increased late potential, and autonomic disturbances that could trigger arrhythmias.
Although reduced left ventricular ejection fraction is the best available predictor of sudden cardiac death, the authors noted that their study found high BMI to be a risk factor independent of left ventricular ejection fraction.
The authors also raised the question of whether intentional weight loss might be effective in reducing the risk of sudden cardiac death in obese patients after MI, but suggested more research was needed to answer this.
The two cohort studies included in the analysis were funded by the Japan Heart Foundation, and the Japan Research Promotion Society for Cardiovascular Diseases. No conflicts of interest were declared.
SOURCE: Shiga T et al. J Am Heart Assoc, 2018; July 7. doi: 10.1161/JAHA.118.008633.
Obesity is associated with an increased risk of sudden cardiac death after myocardial infarction, although the so-called “obesity paradox” is still evident in a lower risk of all-cause mortality, a new analysis suggests.
Researchers reported the results of an observational cohort study using data from two Japanese cohort studies involving a total of 6,216 patients discharged alive after acute myocardial infarction. The study was published in the Journal of the American Heart Association.
They found that obese patients – those with a body mass index of at least 27.5 kg/m2 – had a nearly threefold higher risk of sudden cardiac death within 3 years, compared with patients who had a normal BMI, even after adjustment for age, sex, and risk factors such as multivessel disease, left ventricular ejection fraction, and medications.
However, the obese group also showed lower 3-year all-cause mortality, compared with the reference group, whose BMI was 18.5-22.9 kg/m2, while individuals with a BMI below 18.5 kg/m2 had a 61% higher risk of mortality.
The overall all-cause mortality in the cohort was 10.1%, and the incidence of sudden cardiac death was 1.2%.
“For the primary prevention of [coronary artery disease], obesity is recognized as a potent risk factor and an opportunity for therapeutic intervention to prevent cardiovascular disease,” wrote Tsuyoshi Shiga, MD, of Tokyo Women’s Medical University, and coauthors. “However, recent reports have shown that obesity (high BMI) itself does not present a mortality risk but is associated with a better prognosis (obesity paradox) in CAD patients receiving secondary care; these patients received appropriate therapy, including percutaneous coronary intervention and guideline-based medications such as aspirin, beta-blockers, and statins.”
The increased risk of sudden cardiac death in obese patients after MI was harder to explain.
The authors suggested that obesity itself may increase the risk of ventricular arrhythmias developing, and it is also linked with left ventricular hypertrophy, which can lead to cardiac remodeling. Other reports have found evidence in obese individuals of QT prolongation or an increased late potential, and autonomic disturbances that could trigger arrhythmias.
Although reduced left ventricular ejection fraction is the best available predictor of sudden cardiac death, the authors noted that their study found high BMI to be a risk factor independent of left ventricular ejection fraction.
The authors also raised the question of whether intentional weight loss might be effective in reducing the risk of sudden cardiac death in obese patients after MI, but suggested more research was needed to answer this.
The two cohort studies included in the analysis were funded by the Japan Heart Foundation, and the Japan Research Promotion Society for Cardiovascular Diseases. No conflicts of interest were declared.
SOURCE: Shiga T et al. J Am Heart Assoc, 2018; July 7. doi: 10.1161/JAHA.118.008633.
Obesity is associated with an increased risk of sudden cardiac death after myocardial infarction, although the so-called “obesity paradox” is still evident in a lower risk of all-cause mortality, a new analysis suggests.
Researchers reported the results of an observational cohort study using data from two Japanese cohort studies involving a total of 6,216 patients discharged alive after acute myocardial infarction. The study was published in the Journal of the American Heart Association.
They found that obese patients – those with a body mass index of at least 27.5 kg/m2 – had a nearly threefold higher risk of sudden cardiac death within 3 years, compared with patients who had a normal BMI, even after adjustment for age, sex, and risk factors such as multivessel disease, left ventricular ejection fraction, and medications.
However, the obese group also showed lower 3-year all-cause mortality, compared with the reference group, whose BMI was 18.5-22.9 kg/m2, while individuals with a BMI below 18.5 kg/m2 had a 61% higher risk of mortality.
The overall all-cause mortality in the cohort was 10.1%, and the incidence of sudden cardiac death was 1.2%.
“For the primary prevention of [coronary artery disease], obesity is recognized as a potent risk factor and an opportunity for therapeutic intervention to prevent cardiovascular disease,” wrote Tsuyoshi Shiga, MD, of Tokyo Women’s Medical University, and coauthors. “However, recent reports have shown that obesity (high BMI) itself does not present a mortality risk but is associated with a better prognosis (obesity paradox) in CAD patients receiving secondary care; these patients received appropriate therapy, including percutaneous coronary intervention and guideline-based medications such as aspirin, beta-blockers, and statins.”
The increased risk of sudden cardiac death in obese patients after MI was harder to explain.
The authors suggested that obesity itself may increase the risk of ventricular arrhythmias developing, and it is also linked with left ventricular hypertrophy, which can lead to cardiac remodeling. Other reports have found evidence in obese individuals of QT prolongation or an increased late potential, and autonomic disturbances that could trigger arrhythmias.
Although reduced left ventricular ejection fraction is the best available predictor of sudden cardiac death, the authors noted that their study found high BMI to be a risk factor independent of left ventricular ejection fraction.
The authors also raised the question of whether intentional weight loss might be effective in reducing the risk of sudden cardiac death in obese patients after MI, but suggested more research was needed to answer this.
The two cohort studies included in the analysis were funded by the Japan Heart Foundation, and the Japan Research Promotion Society for Cardiovascular Diseases. No conflicts of interest were declared.
SOURCE: Shiga T et al. J Am Heart Assoc, 2018; July 7. doi: 10.1161/JAHA.118.008633.
FROM JOURNAL OF THE AMERICAN HEART ASSOCIATION
Key clinical point: Obese MI patients have a significantly elevated risk of sudden cardiac death.
Major finding:
Study details: An Japanese observational cohort study of 6,216 patients with acute myocardial infarction.
Disclosures: The two cohort studies included in the analysis were funded by the Japan Heart Foundation, and the Japan Research Promotion Society for Cardiovascular Diseases. No conflicts of interest were declared.
Source: Shiga T et al. J Am Heart Assoc. 2018; July 7. doi: 10.1161/JAHA.118.008633.
Alteplase, aspirin provide similar functional outcomes after nondisabling stroke
Treatment with alteplase vs. aspirin did not improve functional outcomes at 90 days in patients with minor nondisabling acute ischemic stroke in the randomized phase 3b PRISMS trial.
At 90 days following a minor stroke judged to be nondisabling, a favorable functional outcome – defined as modified Rankin Scale (mRS) score of 0 or 1 – occurred in 122 (78.2%) of 156 patients who received alteplase and in 128 (81.5%) of 157 who received aspirin (adjusted risk difference, –1.1%), wrote Pooja Khatri, MD, of the University of Cincinnati, and her colleagues. The report was published in the July 10 issue of JAMA.
The PRISMS (Potential of rtPA for Ischemic Strokes with Mild Symptoms) trial was intended as a 948-patient, double-blind, placebo-controlled U.S. trial comparing alteplase and aspirin for emergent stroke in patients with National Institutes of Health Stroke Scale (NIHSS) scores of 0-5 at presentation whose stroke-related neurologic deficits were not clearly disabling and in whom the study treatment could be initiated within 3 hours. However, the trial was terminated early by the sponsor – prior to unblinding or interim analyses – because of below-target enrollment. An original plan to measure the difference in favorable functional outcome in the treatment and placebo groups by Cochran-Mantel-Haenszel hypothesis test with stratification by pretreatment NIHSS score, age, and time from onset to treatment was therefore revised to examine the risk difference of the primary outcome by a linear model adjusted for those factors, the authors explained.
Patients in the study had a mean age of 62 years and mean NIHSS score of 2, and were enrolled between May 30, 2014, and Dec. 20, 2016. They received either intravenous alteplase at a standard dose of 0.9 mg/kg with oral placebo, or oral aspirin at a dose of 325 mg with intravenous placebo, and were followed until March 22, 2017.
The primary safety endpoint of the analysis was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous alteplase; this occurred in 5 (3.2%) of the alteplase-treated patients and in none of aspirin-treated patients (risk difference, 3.3%).
“Secondary outcomes, including the ordinal analysis of mRS scores (odds ratio, 0.81) and global favorable recovery (OR, 0.86), did not significantly favor either group,” the investigators added.
The findings are noteworthy because more than half of all patients with acute ischemic stroke have minor neurologic deficits, the investigators said, and while prior studies of alteplase included patients with low NIHSS score, few included patients who had no clearly disabling deficits. They added that while “alteplase is the standard of care for patients with ischemic stroke and disabling deficits regardless of severity judged by NIHSS scores, the optimal management of patients with not clearly disabling deficits is unclear.
“The study results raise the hypothesis that even a 6% treatment effect might be unlikely. However, the very early study termination precludes any definitive conclusions,” they wrote, noting that the study has several other limitations, including possible selection bias, relatively high loss to follow-up, and the subjective nature of the definition of “not clearly disabling.”
Additional research may be warranted, they said.
In an editorial, William J. Powers, MD, of the University of North Carolina at Chapel Hill, wrote that despite the limitations of the PRISMS trial, the findings help define the role for intravenous alteplase in the management of acute ischemic stroke.
“Even with early study termination and resultant wide 95% confidence intervals, the excellent outcome in the aspirin group and the numerically similar outcomes between the two groups render it unlikely that intravenous alteplase treatment meaningfully improves functional outcome in patients with initial NIHSS scores of 5 or lower with nondisabling deficits,” he wrote.
He noted, however – as did the study authors – that these conclusions do not apply to all patients with mild stroke. Rather, the findings provide “more certain, but not definitive, evidence” of a lack of benefit with alteplase over aspirin in this patient population (JAMA. 2018;320[2]:141-3).
The findings do suggest that “for these patients, treatment with aspirin along with close monitoring may be an appropriate course of action.”
The PRISMS trial was sponsored by Genentech. Dr. Khatri and many of her colleagues reported receiving personal fees from Genentech, some of which were for serving on the steering committee of the trial. Many investigators reported various financial ties to companies involved in cerebrovascular disease treatment.
Dr. Powers reported having no disclosures.
SOURCE: Khatri P et al. JAMA. 2018;320[2]:156-66.
Treatment with alteplase vs. aspirin did not improve functional outcomes at 90 days in patients with minor nondisabling acute ischemic stroke in the randomized phase 3b PRISMS trial.
At 90 days following a minor stroke judged to be nondisabling, a favorable functional outcome – defined as modified Rankin Scale (mRS) score of 0 or 1 – occurred in 122 (78.2%) of 156 patients who received alteplase and in 128 (81.5%) of 157 who received aspirin (adjusted risk difference, –1.1%), wrote Pooja Khatri, MD, of the University of Cincinnati, and her colleagues. The report was published in the July 10 issue of JAMA.
The PRISMS (Potential of rtPA for Ischemic Strokes with Mild Symptoms) trial was intended as a 948-patient, double-blind, placebo-controlled U.S. trial comparing alteplase and aspirin for emergent stroke in patients with National Institutes of Health Stroke Scale (NIHSS) scores of 0-5 at presentation whose stroke-related neurologic deficits were not clearly disabling and in whom the study treatment could be initiated within 3 hours. However, the trial was terminated early by the sponsor – prior to unblinding or interim analyses – because of below-target enrollment. An original plan to measure the difference in favorable functional outcome in the treatment and placebo groups by Cochran-Mantel-Haenszel hypothesis test with stratification by pretreatment NIHSS score, age, and time from onset to treatment was therefore revised to examine the risk difference of the primary outcome by a linear model adjusted for those factors, the authors explained.
Patients in the study had a mean age of 62 years and mean NIHSS score of 2, and were enrolled between May 30, 2014, and Dec. 20, 2016. They received either intravenous alteplase at a standard dose of 0.9 mg/kg with oral placebo, or oral aspirin at a dose of 325 mg with intravenous placebo, and were followed until March 22, 2017.
The primary safety endpoint of the analysis was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous alteplase; this occurred in 5 (3.2%) of the alteplase-treated patients and in none of aspirin-treated patients (risk difference, 3.3%).
“Secondary outcomes, including the ordinal analysis of mRS scores (odds ratio, 0.81) and global favorable recovery (OR, 0.86), did not significantly favor either group,” the investigators added.
The findings are noteworthy because more than half of all patients with acute ischemic stroke have minor neurologic deficits, the investigators said, and while prior studies of alteplase included patients with low NIHSS score, few included patients who had no clearly disabling deficits. They added that while “alteplase is the standard of care for patients with ischemic stroke and disabling deficits regardless of severity judged by NIHSS scores, the optimal management of patients with not clearly disabling deficits is unclear.
“The study results raise the hypothesis that even a 6% treatment effect might be unlikely. However, the very early study termination precludes any definitive conclusions,” they wrote, noting that the study has several other limitations, including possible selection bias, relatively high loss to follow-up, and the subjective nature of the definition of “not clearly disabling.”
Additional research may be warranted, they said.
In an editorial, William J. Powers, MD, of the University of North Carolina at Chapel Hill, wrote that despite the limitations of the PRISMS trial, the findings help define the role for intravenous alteplase in the management of acute ischemic stroke.
“Even with early study termination and resultant wide 95% confidence intervals, the excellent outcome in the aspirin group and the numerically similar outcomes between the two groups render it unlikely that intravenous alteplase treatment meaningfully improves functional outcome in patients with initial NIHSS scores of 5 or lower with nondisabling deficits,” he wrote.
He noted, however – as did the study authors – that these conclusions do not apply to all patients with mild stroke. Rather, the findings provide “more certain, but not definitive, evidence” of a lack of benefit with alteplase over aspirin in this patient population (JAMA. 2018;320[2]:141-3).
The findings do suggest that “for these patients, treatment with aspirin along with close monitoring may be an appropriate course of action.”
The PRISMS trial was sponsored by Genentech. Dr. Khatri and many of her colleagues reported receiving personal fees from Genentech, some of which were for serving on the steering committee of the trial. Many investigators reported various financial ties to companies involved in cerebrovascular disease treatment.
Dr. Powers reported having no disclosures.
SOURCE: Khatri P et al. JAMA. 2018;320[2]:156-66.
Treatment with alteplase vs. aspirin did not improve functional outcomes at 90 days in patients with minor nondisabling acute ischemic stroke in the randomized phase 3b PRISMS trial.
At 90 days following a minor stroke judged to be nondisabling, a favorable functional outcome – defined as modified Rankin Scale (mRS) score of 0 or 1 – occurred in 122 (78.2%) of 156 patients who received alteplase and in 128 (81.5%) of 157 who received aspirin (adjusted risk difference, –1.1%), wrote Pooja Khatri, MD, of the University of Cincinnati, and her colleagues. The report was published in the July 10 issue of JAMA.
The PRISMS (Potential of rtPA for Ischemic Strokes with Mild Symptoms) trial was intended as a 948-patient, double-blind, placebo-controlled U.S. trial comparing alteplase and aspirin for emergent stroke in patients with National Institutes of Health Stroke Scale (NIHSS) scores of 0-5 at presentation whose stroke-related neurologic deficits were not clearly disabling and in whom the study treatment could be initiated within 3 hours. However, the trial was terminated early by the sponsor – prior to unblinding or interim analyses – because of below-target enrollment. An original plan to measure the difference in favorable functional outcome in the treatment and placebo groups by Cochran-Mantel-Haenszel hypothesis test with stratification by pretreatment NIHSS score, age, and time from onset to treatment was therefore revised to examine the risk difference of the primary outcome by a linear model adjusted for those factors, the authors explained.
Patients in the study had a mean age of 62 years and mean NIHSS score of 2, and were enrolled between May 30, 2014, and Dec. 20, 2016. They received either intravenous alteplase at a standard dose of 0.9 mg/kg with oral placebo, or oral aspirin at a dose of 325 mg with intravenous placebo, and were followed until March 22, 2017.
The primary safety endpoint of the analysis was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous alteplase; this occurred in 5 (3.2%) of the alteplase-treated patients and in none of aspirin-treated patients (risk difference, 3.3%).
“Secondary outcomes, including the ordinal analysis of mRS scores (odds ratio, 0.81) and global favorable recovery (OR, 0.86), did not significantly favor either group,” the investigators added.
The findings are noteworthy because more than half of all patients with acute ischemic stroke have minor neurologic deficits, the investigators said, and while prior studies of alteplase included patients with low NIHSS score, few included patients who had no clearly disabling deficits. They added that while “alteplase is the standard of care for patients with ischemic stroke and disabling deficits regardless of severity judged by NIHSS scores, the optimal management of patients with not clearly disabling deficits is unclear.
“The study results raise the hypothesis that even a 6% treatment effect might be unlikely. However, the very early study termination precludes any definitive conclusions,” they wrote, noting that the study has several other limitations, including possible selection bias, relatively high loss to follow-up, and the subjective nature of the definition of “not clearly disabling.”
Additional research may be warranted, they said.
In an editorial, William J. Powers, MD, of the University of North Carolina at Chapel Hill, wrote that despite the limitations of the PRISMS trial, the findings help define the role for intravenous alteplase in the management of acute ischemic stroke.
“Even with early study termination and resultant wide 95% confidence intervals, the excellent outcome in the aspirin group and the numerically similar outcomes between the two groups render it unlikely that intravenous alteplase treatment meaningfully improves functional outcome in patients with initial NIHSS scores of 5 or lower with nondisabling deficits,” he wrote.
He noted, however – as did the study authors – that these conclusions do not apply to all patients with mild stroke. Rather, the findings provide “more certain, but not definitive, evidence” of a lack of benefit with alteplase over aspirin in this patient population (JAMA. 2018;320[2]:141-3).
The findings do suggest that “for these patients, treatment with aspirin along with close monitoring may be an appropriate course of action.”
The PRISMS trial was sponsored by Genentech. Dr. Khatri and many of her colleagues reported receiving personal fees from Genentech, some of which were for serving on the steering committee of the trial. Many investigators reported various financial ties to companies involved in cerebrovascular disease treatment.
Dr. Powers reported having no disclosures.
SOURCE: Khatri P et al. JAMA. 2018;320[2]:156-66.
FROM JAMA
Key clinical point: Alteplase does not appear to offer benefit over aspirin in terms of functional outcomes after nondisabling acute ischemic stroke.
Major finding: No significant difference was seen in functional outcomes with alteplase vs. aspirin at 90 days (adjusted risk difference, –1.1%).
Study details: The phase 3b PRISMS trial, involving 313 patients.
Disclosures: Genentech sponsored the trial. Dr. Khatri and many of her colleagues reported receiving personal fees from Genentech, some of which were for serving on the steering committee of the trial. Many investigators reported various financial ties to companies involved in cerebrovascular disease treatment. Dr. Powers reported having no disclosures.
Source: Khatri P et al. JAMA. 2018; 320[2]:156-66.
New look at ATLAS suggests rivaroxaban may still have role in ACS
In a new analysis comparing only clinically similar outcomes in patients with acute coronary syndrome, the addition of rivaroxaban to standard antiplatelet therapy resulted in 115 fewer fatal or irreversible ischemic events per 10,000 patient-years than placebo, at the expense of only 10 additional fatal or seriously harmful events.
This new interpretation of the ATLAS ACS 2-TIMI 51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction-51) suggests that the factor Xa inhibitor may still carve out a place for itself in ACS therapy, despite Food and Drug Administration rejections for this indication.
Not only did the survival benefit of rivaroxaban appear early in postevent treatment, it continued to protect patients over time, C. Michael Gibson, MD, and colleagues reported in the Journal of the American College of Cardiology.
“Time-to-event analysis demonstrated that the risk of fatal or irreversible harm remained low and constant over time, whereas reduction in fatal or irreversible ischemic events expanded,” wrote Dr. Gibson, professor of medicine at Beth Israel Deaconess Medical Center, Boston, and his coinvestigators. “By 720 days, a net of 142 fatal or irreversible events would have been prevented by 2.5-mg oral doses twice per day of rivaroxaban. Additional time-to-event sensitivity analyses demonstrated similar results, even when TIMI major bleeding was included as a fatal or irreversible event.”
In conducting the new analysis, Dr. Gibson and his team argued that the original interpretation of the results of ATLAS ACS 2-TIMI 51 lumped both fatal and nonfatal events together in composite endpoints, resulting in an inaccurate real-life picture of rivaroxaban’s therapeutic potential. “All types of events [were] weighted equally; for example, reversible nonintracranial hemorrhage, nonfatal bleeds that can be managed with supportive care, are weighted equally with death and disabling stroke. Second, stroke can be either hemorrhagic or ischemic, and the relative contributions of hemorrhagic or ischemic stroke may not be appropriately assigned to risk-versus-benefit categories in many analyses.”
The net result was that, while rivaroxaban did reduce the risk of the composite endpoint (cardiovascular death, MI, or stroke), the 1.7% absolute difference in cardiovascular mortality was almost completely offset by a 1.3% increase in major bleeding. However, most of those bleeds were reversible and nonfatal, associated with a drop in hemoglobin and/or blood transfusion. The drug did not increase the risk of fatal bleeding.
Giving equal statistical weight to clinically equal events provides a clearer focus, the investigators said.
“In this form of analysis, only fatal or irreversible events were included so that benefit and seriously harmful events of similar clinical impact were compared,” they wrote. “This is particularly important when the endpoints and analyses do not include measurements of subjective clinical impact such as utility measurements or preference weights. This approach also uses risk differences rather than relative measurements such as hazard ratios, so the number of events prevented and caused are clearly distinguished.”
ATLAS comprised more than 15,000 patients with ST-segment elevation MI, non-STEMI, or unstable angina. They were randomized to either rivaroxaban 2.5 mg orally twice per day, 5 mg orally twice per day, or to placebo, in addition to standard of care, which included low-dose aspirin. Patients were stratified by the optional use of clopidogrel/ticlopidine.
Dr. Gibson and his team reanalyzed the data by comparing outcomes they judged as having a similar clinical impact: fatal and irreversible cardiovascular death, MI, and ischemic stroke. They also assessed all bleeding, TIMI life-threatening bleeding, and TIMI major bleeding.
In this analysis, the 2.5-mg dose was associated with 115 fewer fatal or irreversible ischemic deaths per 10,000 patient-years of exposure than placebo (548 vs. 663 nonbleeding cardiovascular deaths, MIs, or ischemic strokes).
However, the same dose was also associated with 10 more excessive, fatal, or irreversibly serious harmful events, compared with placebo per 10,000 patient years (33 fatal bleeds or intracranial hemorrhage vs. 23 for placebo).
“Considered together, there would be 105 fatal or irreversible events prevented per 10,000 patient-years of exposure to 2.5 mg of rivaroxaban taken orally twice a day, compared with placebo. An alternate interpretation of the data is that there would be 11 [10 of 115] fatal or irreversible ischemic events prevented for each fatal or irreversible harmful event caused,” Dr. Gibson and his colleagues wrote.
The benefit held when the outcomes were individually reckoned as well. If periprocedural MIs were excluded, rivaroxaban would still prevent 115 fatal or irreversible ischemic events. If only nonbleeding cardiovascular death or ischemic strokes were included, then 90 fatal or irreversible events would be prevented. And if only nonbleeding cardiovascular death was included, then 95 events would be prevented per 10,000 patient-years of exposure in the group taking rivaroxaban 2.5 mg twice daily.
“In all cases, the fatal or irreversible events prevented are 9-11 times the fatal or irreversible seriously harmful events caused,” the investigators said.
ATLAS ACS 2-TIMI 51 was supported by Johnson & Johnson and Bayer Healthcare. Dr. Gibson has received institutional funding, grants, and honoraria from those companies and from Portola Pharmaceuticals.
SOURCE: Gibson CM et al. J Am Coll Cardiol. 2018;72:129-36.
Balancing the risks and benefits of anticoagulation therapy after an acute coronary event leaves physicians on the horns of a dilemma. How do we choose the most effective and the least harmful antiplatelet and/or antithrombotic strategy?
To support decision making, a careful and thoughtful interpretation of the existing evidence is essential, with an explicit focus on the risk-versus-benefit assessment. Even the most well-designed trial can contain ambiguities, the study investigators noted, and ATLAS was one of these.
The reanalysis of ATLAS by Gibson et al. is an attempt to cut through some of these ambiguities. By comparing only serious or fatal outcomes, the investigators aimed to bring clinically meaningful insight into the picture. Such a way of reporting provides readers with an extra piece of information to assist in deciding whether a treatment should be used.
The analysis isn’t perfect. It doesn’t include less-serious bleeding events, which still may contribute to a poor prognosis. And the analysis didn’t take into about ischemia-driven revascularizations.
Although commonly successful, repeat revascularizations are not free from complications, which may include occurrence of large infarctions, stroke, and serious bleeding.
Nevertheless, the study enhances our understanding of how to best employ low-dose rivaroxaban therapy in addition to antiplatelet agents.
Although we are getting closer to therapy optimization, the final word regarding the use of low-dose rivaroxaban and other agents for secondary prevention of cardiovascular diseases has not yet been said. This is primarily because of substantial variation in the magnitude of the risks and benefits across a population. Comprehensive, individualized profiling of the patients with respect to their ischemic and bleeding risks is crucial to further improve acute coronary syndrome–related outcomes.
Eugenia Nikolsy, MD, PhD, and Freek Verheugt, MD, made these comments in an accompanying editorial (J Am Coll Cardiol. 2018;72:137-40). Dr. Nikolsy is director of clinical research in invasive cardiology at Rambam Academic Hospital, Haifa, Israel. Dr. Verheugt is a professor of cardiology at the Heart-Lung Centre at University Medical Centre, Nijmegen, the Netherlands.
Balancing the risks and benefits of anticoagulation therapy after an acute coronary event leaves physicians on the horns of a dilemma. How do we choose the most effective and the least harmful antiplatelet and/or antithrombotic strategy?
To support decision making, a careful and thoughtful interpretation of the existing evidence is essential, with an explicit focus on the risk-versus-benefit assessment. Even the most well-designed trial can contain ambiguities, the study investigators noted, and ATLAS was one of these.
The reanalysis of ATLAS by Gibson et al. is an attempt to cut through some of these ambiguities. By comparing only serious or fatal outcomes, the investigators aimed to bring clinically meaningful insight into the picture. Such a way of reporting provides readers with an extra piece of information to assist in deciding whether a treatment should be used.
The analysis isn’t perfect. It doesn’t include less-serious bleeding events, which still may contribute to a poor prognosis. And the analysis didn’t take into about ischemia-driven revascularizations.
Although commonly successful, repeat revascularizations are not free from complications, which may include occurrence of large infarctions, stroke, and serious bleeding.
Nevertheless, the study enhances our understanding of how to best employ low-dose rivaroxaban therapy in addition to antiplatelet agents.
Although we are getting closer to therapy optimization, the final word regarding the use of low-dose rivaroxaban and other agents for secondary prevention of cardiovascular diseases has not yet been said. This is primarily because of substantial variation in the magnitude of the risks and benefits across a population. Comprehensive, individualized profiling of the patients with respect to their ischemic and bleeding risks is crucial to further improve acute coronary syndrome–related outcomes.
Eugenia Nikolsy, MD, PhD, and Freek Verheugt, MD, made these comments in an accompanying editorial (J Am Coll Cardiol. 2018;72:137-40). Dr. Nikolsy is director of clinical research in invasive cardiology at Rambam Academic Hospital, Haifa, Israel. Dr. Verheugt is a professor of cardiology at the Heart-Lung Centre at University Medical Centre, Nijmegen, the Netherlands.
Balancing the risks and benefits of anticoagulation therapy after an acute coronary event leaves physicians on the horns of a dilemma. How do we choose the most effective and the least harmful antiplatelet and/or antithrombotic strategy?
To support decision making, a careful and thoughtful interpretation of the existing evidence is essential, with an explicit focus on the risk-versus-benefit assessment. Even the most well-designed trial can contain ambiguities, the study investigators noted, and ATLAS was one of these.
The reanalysis of ATLAS by Gibson et al. is an attempt to cut through some of these ambiguities. By comparing only serious or fatal outcomes, the investigators aimed to bring clinically meaningful insight into the picture. Such a way of reporting provides readers with an extra piece of information to assist in deciding whether a treatment should be used.
The analysis isn’t perfect. It doesn’t include less-serious bleeding events, which still may contribute to a poor prognosis. And the analysis didn’t take into about ischemia-driven revascularizations.
Although commonly successful, repeat revascularizations are not free from complications, which may include occurrence of large infarctions, stroke, and serious bleeding.
Nevertheless, the study enhances our understanding of how to best employ low-dose rivaroxaban therapy in addition to antiplatelet agents.
Although we are getting closer to therapy optimization, the final word regarding the use of low-dose rivaroxaban and other agents for secondary prevention of cardiovascular diseases has not yet been said. This is primarily because of substantial variation in the magnitude of the risks and benefits across a population. Comprehensive, individualized profiling of the patients with respect to their ischemic and bleeding risks is crucial to further improve acute coronary syndrome–related outcomes.
Eugenia Nikolsy, MD, PhD, and Freek Verheugt, MD, made these comments in an accompanying editorial (J Am Coll Cardiol. 2018;72:137-40). Dr. Nikolsy is director of clinical research in invasive cardiology at Rambam Academic Hospital, Haifa, Israel. Dr. Verheugt is a professor of cardiology at the Heart-Lung Centre at University Medical Centre, Nijmegen, the Netherlands.
In a new analysis comparing only clinically similar outcomes in patients with acute coronary syndrome, the addition of rivaroxaban to standard antiplatelet therapy resulted in 115 fewer fatal or irreversible ischemic events per 10,000 patient-years than placebo, at the expense of only 10 additional fatal or seriously harmful events.
This new interpretation of the ATLAS ACS 2-TIMI 51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction-51) suggests that the factor Xa inhibitor may still carve out a place for itself in ACS therapy, despite Food and Drug Administration rejections for this indication.
Not only did the survival benefit of rivaroxaban appear early in postevent treatment, it continued to protect patients over time, C. Michael Gibson, MD, and colleagues reported in the Journal of the American College of Cardiology.
“Time-to-event analysis demonstrated that the risk of fatal or irreversible harm remained low and constant over time, whereas reduction in fatal or irreversible ischemic events expanded,” wrote Dr. Gibson, professor of medicine at Beth Israel Deaconess Medical Center, Boston, and his coinvestigators. “By 720 days, a net of 142 fatal or irreversible events would have been prevented by 2.5-mg oral doses twice per day of rivaroxaban. Additional time-to-event sensitivity analyses demonstrated similar results, even when TIMI major bleeding was included as a fatal or irreversible event.”
In conducting the new analysis, Dr. Gibson and his team argued that the original interpretation of the results of ATLAS ACS 2-TIMI 51 lumped both fatal and nonfatal events together in composite endpoints, resulting in an inaccurate real-life picture of rivaroxaban’s therapeutic potential. “All types of events [were] weighted equally; for example, reversible nonintracranial hemorrhage, nonfatal bleeds that can be managed with supportive care, are weighted equally with death and disabling stroke. Second, stroke can be either hemorrhagic or ischemic, and the relative contributions of hemorrhagic or ischemic stroke may not be appropriately assigned to risk-versus-benefit categories in many analyses.”
The net result was that, while rivaroxaban did reduce the risk of the composite endpoint (cardiovascular death, MI, or stroke), the 1.7% absolute difference in cardiovascular mortality was almost completely offset by a 1.3% increase in major bleeding. However, most of those bleeds were reversible and nonfatal, associated with a drop in hemoglobin and/or blood transfusion. The drug did not increase the risk of fatal bleeding.
Giving equal statistical weight to clinically equal events provides a clearer focus, the investigators said.
“In this form of analysis, only fatal or irreversible events were included so that benefit and seriously harmful events of similar clinical impact were compared,” they wrote. “This is particularly important when the endpoints and analyses do not include measurements of subjective clinical impact such as utility measurements or preference weights. This approach also uses risk differences rather than relative measurements such as hazard ratios, so the number of events prevented and caused are clearly distinguished.”
ATLAS comprised more than 15,000 patients with ST-segment elevation MI, non-STEMI, or unstable angina. They were randomized to either rivaroxaban 2.5 mg orally twice per day, 5 mg orally twice per day, or to placebo, in addition to standard of care, which included low-dose aspirin. Patients were stratified by the optional use of clopidogrel/ticlopidine.
Dr. Gibson and his team reanalyzed the data by comparing outcomes they judged as having a similar clinical impact: fatal and irreversible cardiovascular death, MI, and ischemic stroke. They also assessed all bleeding, TIMI life-threatening bleeding, and TIMI major bleeding.
In this analysis, the 2.5-mg dose was associated with 115 fewer fatal or irreversible ischemic deaths per 10,000 patient-years of exposure than placebo (548 vs. 663 nonbleeding cardiovascular deaths, MIs, or ischemic strokes).
However, the same dose was also associated with 10 more excessive, fatal, or irreversibly serious harmful events, compared with placebo per 10,000 patient years (33 fatal bleeds or intracranial hemorrhage vs. 23 for placebo).
“Considered together, there would be 105 fatal or irreversible events prevented per 10,000 patient-years of exposure to 2.5 mg of rivaroxaban taken orally twice a day, compared with placebo. An alternate interpretation of the data is that there would be 11 [10 of 115] fatal or irreversible ischemic events prevented for each fatal or irreversible harmful event caused,” Dr. Gibson and his colleagues wrote.
The benefit held when the outcomes were individually reckoned as well. If periprocedural MIs were excluded, rivaroxaban would still prevent 115 fatal or irreversible ischemic events. If only nonbleeding cardiovascular death or ischemic strokes were included, then 90 fatal or irreversible events would be prevented. And if only nonbleeding cardiovascular death was included, then 95 events would be prevented per 10,000 patient-years of exposure in the group taking rivaroxaban 2.5 mg twice daily.
“In all cases, the fatal or irreversible events prevented are 9-11 times the fatal or irreversible seriously harmful events caused,” the investigators said.
ATLAS ACS 2-TIMI 51 was supported by Johnson & Johnson and Bayer Healthcare. Dr. Gibson has received institutional funding, grants, and honoraria from those companies and from Portola Pharmaceuticals.
SOURCE: Gibson CM et al. J Am Coll Cardiol. 2018;72:129-36.
In a new analysis comparing only clinically similar outcomes in patients with acute coronary syndrome, the addition of rivaroxaban to standard antiplatelet therapy resulted in 115 fewer fatal or irreversible ischemic events per 10,000 patient-years than placebo, at the expense of only 10 additional fatal or seriously harmful events.
This new interpretation of the ATLAS ACS 2-TIMI 51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction-51) suggests that the factor Xa inhibitor may still carve out a place for itself in ACS therapy, despite Food and Drug Administration rejections for this indication.
Not only did the survival benefit of rivaroxaban appear early in postevent treatment, it continued to protect patients over time, C. Michael Gibson, MD, and colleagues reported in the Journal of the American College of Cardiology.
“Time-to-event analysis demonstrated that the risk of fatal or irreversible harm remained low and constant over time, whereas reduction in fatal or irreversible ischemic events expanded,” wrote Dr. Gibson, professor of medicine at Beth Israel Deaconess Medical Center, Boston, and his coinvestigators. “By 720 days, a net of 142 fatal or irreversible events would have been prevented by 2.5-mg oral doses twice per day of rivaroxaban. Additional time-to-event sensitivity analyses demonstrated similar results, even when TIMI major bleeding was included as a fatal or irreversible event.”
In conducting the new analysis, Dr. Gibson and his team argued that the original interpretation of the results of ATLAS ACS 2-TIMI 51 lumped both fatal and nonfatal events together in composite endpoints, resulting in an inaccurate real-life picture of rivaroxaban’s therapeutic potential. “All types of events [were] weighted equally; for example, reversible nonintracranial hemorrhage, nonfatal bleeds that can be managed with supportive care, are weighted equally with death and disabling stroke. Second, stroke can be either hemorrhagic or ischemic, and the relative contributions of hemorrhagic or ischemic stroke may not be appropriately assigned to risk-versus-benefit categories in many analyses.”
The net result was that, while rivaroxaban did reduce the risk of the composite endpoint (cardiovascular death, MI, or stroke), the 1.7% absolute difference in cardiovascular mortality was almost completely offset by a 1.3% increase in major bleeding. However, most of those bleeds were reversible and nonfatal, associated with a drop in hemoglobin and/or blood transfusion. The drug did not increase the risk of fatal bleeding.
Giving equal statistical weight to clinically equal events provides a clearer focus, the investigators said.
“In this form of analysis, only fatal or irreversible events were included so that benefit and seriously harmful events of similar clinical impact were compared,” they wrote. “This is particularly important when the endpoints and analyses do not include measurements of subjective clinical impact such as utility measurements or preference weights. This approach also uses risk differences rather than relative measurements such as hazard ratios, so the number of events prevented and caused are clearly distinguished.”
ATLAS comprised more than 15,000 patients with ST-segment elevation MI, non-STEMI, or unstable angina. They were randomized to either rivaroxaban 2.5 mg orally twice per day, 5 mg orally twice per day, or to placebo, in addition to standard of care, which included low-dose aspirin. Patients were stratified by the optional use of clopidogrel/ticlopidine.
Dr. Gibson and his team reanalyzed the data by comparing outcomes they judged as having a similar clinical impact: fatal and irreversible cardiovascular death, MI, and ischemic stroke. They also assessed all bleeding, TIMI life-threatening bleeding, and TIMI major bleeding.
In this analysis, the 2.5-mg dose was associated with 115 fewer fatal or irreversible ischemic deaths per 10,000 patient-years of exposure than placebo (548 vs. 663 nonbleeding cardiovascular deaths, MIs, or ischemic strokes).
However, the same dose was also associated with 10 more excessive, fatal, or irreversibly serious harmful events, compared with placebo per 10,000 patient years (33 fatal bleeds or intracranial hemorrhage vs. 23 for placebo).
“Considered together, there would be 105 fatal or irreversible events prevented per 10,000 patient-years of exposure to 2.5 mg of rivaroxaban taken orally twice a day, compared with placebo. An alternate interpretation of the data is that there would be 11 [10 of 115] fatal or irreversible ischemic events prevented for each fatal or irreversible harmful event caused,” Dr. Gibson and his colleagues wrote.
The benefit held when the outcomes were individually reckoned as well. If periprocedural MIs were excluded, rivaroxaban would still prevent 115 fatal or irreversible ischemic events. If only nonbleeding cardiovascular death or ischemic strokes were included, then 90 fatal or irreversible events would be prevented. And if only nonbleeding cardiovascular death was included, then 95 events would be prevented per 10,000 patient-years of exposure in the group taking rivaroxaban 2.5 mg twice daily.
“In all cases, the fatal or irreversible events prevented are 9-11 times the fatal or irreversible seriously harmful events caused,” the investigators said.
ATLAS ACS 2-TIMI 51 was supported by Johnson & Johnson and Bayer Healthcare. Dr. Gibson has received institutional funding, grants, and honoraria from those companies and from Portola Pharmaceuticals.
SOURCE: Gibson CM et al. J Am Coll Cardiol. 2018;72:129-36.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Amplatzer Amulet slashes stroke risk in A-fib
PARIS – The Amplatzer Amulet left atrial appendage occlusion device reduced stroke risk by nearly 60% at 1 year in a large, real-world registry of patients with atrial fibrillation at dual high risk for stroke and bleeding, Ulf Landmesser, MD, reported at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions.
One of the most impressive findings was that this feat was accomplished by and large without background oral anticoagulation. Indeed, 83% of the 1,088 patients in this 61-center, 17-country study had contraindications to oral anticoagulation. Only 11% of subjects were discharged on oral anticoagulation after device implantation, while 22.5% were discharged on aspirin or clopidogrel monotherapy. By 1-3 months post implantation, 60% of patients were either on a single antiplatelet agent or no antithrombotic medication at all.
“Antithrombotic therapy was individualized by the patient’s physician. There didn’t seem to be an increased risk of device-related thrombus in these patients on single antiplatelet therapy. Our data suggest that, given the high bleeding risk, single antiplatelet therapy seems to be a good option for these patients,” said Dr. Landmesser, a professor in and the chair of the department of cardiology at Charité Medical School in Berlin.
Participants in the Global Prospective Amulet Study averaged 75 years of age, and 72% had a history of major bleeding. The average CHA2DS2-VASc score was 4.2, with a HAS-BLED score of 3.3, which emphasizes the high-risk nature of study participants.
On the basis of the CHA2DS2-VASc score, the predicted 1-year ischemic stroke rate without oral anticoagulation was 6.7%, so the actual 2.9% rate represented a 57% reduction in risk. Similarly, for the composite endpoint of ischemic stroke, transient ischemic attack, or systemic embolism, the predicted rate was 9.4%, but the achieved rate was 3.8%, which represented a 60% reduction in risk.
The annualized major bleeding rate was 10.3% despite the low usage of oral anticoagulation or dual-antiplatelet therapy. However, the rate of procedure- or device-related major bleeding was only 3.2%; the other 7.1% was unrelated to Amulet and reflected the underlying high risk of the study population.
The 1-year mortality rate was 8.4%. Thirty-five deaths had cardiovascular causes, 35 were noncardiovascular, and in 18 patients, cause of death couldn’t be determined.
The device-related thrombus rate through 1 year was 1.7%; 10 of 18 cases occurred within the first 90 days.
Dr. Landmesser emphasized that this was a particularly rigorously conducted registry. A unique feature was its use of an independent echocardiography core lab to assess procedural success, as well as an independent clinical events committee to adjudicate serious adverse events. Prior studies of other left atrial appendage (LAA) occlusion devices didn’t use these measures.
The Amplatzer Amulet is a second-generation occlusion device designed for easier placement and more complete sealing than its predecessor and comes in eight sizes to address anatomic variations. At implantation, adequate LAA occlusion as defined by the echocardiography core laboratory was achieved in 99.3% of patients; at that time, 89.4% of patients had no residual flow, and another 9.9% had a residual flow of less than 3 mm. At 1-3 months of follow-up, echocardiography showed 98.4% of patients had adequate occlusion.
Session cochair Alberto Cremonesi, MD, pronounced this to be “really important data.”
“I want to stress that these device implantations were transesophageal echocardiography–guided. In my mind this is absolutely essential to your excellent long-term results,” observed Dr. Cremonesi of Maria Cecilia Hospital in Cotignola, Italy.
Asked to speculate on what outcomes might have looked like had patients been treated with an oral anticoagulant rather than the Amulet occlusion device, Dr. Landmesser predicted the major bleeding rate would have been substantially higher than 10.3%. Most of the bleeding events in the study were gastrointestinal, and the novel oral anticoagulants are known to boost the risk of GI bleeding.
But that’s speculation. He noted that two ongoing randomized trials – one in Germany, the other in Scandinavia – are randomizing high-risk patients to a LAA occlusion device or best medical care, including a novel oral anticoagulant when not contraindicated. The Scandinavian study uses the Amulet, while the German trial uses both the Amulet and the Watchman device. The primary endpoint is the ischemic stroke rate.
The Amulet registry, which will continue for a second year of follow-up, was sponsored by Abbott Laboratories, which developed the Amulet device. Dr. Landmesser reported serving as a consultant to Abbott, as well as Biotronik, Rewa, and Bayer.
PARIS – The Amplatzer Amulet left atrial appendage occlusion device reduced stroke risk by nearly 60% at 1 year in a large, real-world registry of patients with atrial fibrillation at dual high risk for stroke and bleeding, Ulf Landmesser, MD, reported at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions.
One of the most impressive findings was that this feat was accomplished by and large without background oral anticoagulation. Indeed, 83% of the 1,088 patients in this 61-center, 17-country study had contraindications to oral anticoagulation. Only 11% of subjects were discharged on oral anticoagulation after device implantation, while 22.5% were discharged on aspirin or clopidogrel monotherapy. By 1-3 months post implantation, 60% of patients were either on a single antiplatelet agent or no antithrombotic medication at all.
“Antithrombotic therapy was individualized by the patient’s physician. There didn’t seem to be an increased risk of device-related thrombus in these patients on single antiplatelet therapy. Our data suggest that, given the high bleeding risk, single antiplatelet therapy seems to be a good option for these patients,” said Dr. Landmesser, a professor in and the chair of the department of cardiology at Charité Medical School in Berlin.
Participants in the Global Prospective Amulet Study averaged 75 years of age, and 72% had a history of major bleeding. The average CHA2DS2-VASc score was 4.2, with a HAS-BLED score of 3.3, which emphasizes the high-risk nature of study participants.
On the basis of the CHA2DS2-VASc score, the predicted 1-year ischemic stroke rate without oral anticoagulation was 6.7%, so the actual 2.9% rate represented a 57% reduction in risk. Similarly, for the composite endpoint of ischemic stroke, transient ischemic attack, or systemic embolism, the predicted rate was 9.4%, but the achieved rate was 3.8%, which represented a 60% reduction in risk.
The annualized major bleeding rate was 10.3% despite the low usage of oral anticoagulation or dual-antiplatelet therapy. However, the rate of procedure- or device-related major bleeding was only 3.2%; the other 7.1% was unrelated to Amulet and reflected the underlying high risk of the study population.
The 1-year mortality rate was 8.4%. Thirty-five deaths had cardiovascular causes, 35 were noncardiovascular, and in 18 patients, cause of death couldn’t be determined.
The device-related thrombus rate through 1 year was 1.7%; 10 of 18 cases occurred within the first 90 days.
Dr. Landmesser emphasized that this was a particularly rigorously conducted registry. A unique feature was its use of an independent echocardiography core lab to assess procedural success, as well as an independent clinical events committee to adjudicate serious adverse events. Prior studies of other left atrial appendage (LAA) occlusion devices didn’t use these measures.
The Amplatzer Amulet is a second-generation occlusion device designed for easier placement and more complete sealing than its predecessor and comes in eight sizes to address anatomic variations. At implantation, adequate LAA occlusion as defined by the echocardiography core laboratory was achieved in 99.3% of patients; at that time, 89.4% of patients had no residual flow, and another 9.9% had a residual flow of less than 3 mm. At 1-3 months of follow-up, echocardiography showed 98.4% of patients had adequate occlusion.
Session cochair Alberto Cremonesi, MD, pronounced this to be “really important data.”
“I want to stress that these device implantations were transesophageal echocardiography–guided. In my mind this is absolutely essential to your excellent long-term results,” observed Dr. Cremonesi of Maria Cecilia Hospital in Cotignola, Italy.
Asked to speculate on what outcomes might have looked like had patients been treated with an oral anticoagulant rather than the Amulet occlusion device, Dr. Landmesser predicted the major bleeding rate would have been substantially higher than 10.3%. Most of the bleeding events in the study were gastrointestinal, and the novel oral anticoagulants are known to boost the risk of GI bleeding.
But that’s speculation. He noted that two ongoing randomized trials – one in Germany, the other in Scandinavia – are randomizing high-risk patients to a LAA occlusion device or best medical care, including a novel oral anticoagulant when not contraindicated. The Scandinavian study uses the Amulet, while the German trial uses both the Amulet and the Watchman device. The primary endpoint is the ischemic stroke rate.
The Amulet registry, which will continue for a second year of follow-up, was sponsored by Abbott Laboratories, which developed the Amulet device. Dr. Landmesser reported serving as a consultant to Abbott, as well as Biotronik, Rewa, and Bayer.
PARIS – The Amplatzer Amulet left atrial appendage occlusion device reduced stroke risk by nearly 60% at 1 year in a large, real-world registry of patients with atrial fibrillation at dual high risk for stroke and bleeding, Ulf Landmesser, MD, reported at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions.
One of the most impressive findings was that this feat was accomplished by and large without background oral anticoagulation. Indeed, 83% of the 1,088 patients in this 61-center, 17-country study had contraindications to oral anticoagulation. Only 11% of subjects were discharged on oral anticoagulation after device implantation, while 22.5% were discharged on aspirin or clopidogrel monotherapy. By 1-3 months post implantation, 60% of patients were either on a single antiplatelet agent or no antithrombotic medication at all.
“Antithrombotic therapy was individualized by the patient’s physician. There didn’t seem to be an increased risk of device-related thrombus in these patients on single antiplatelet therapy. Our data suggest that, given the high bleeding risk, single antiplatelet therapy seems to be a good option for these patients,” said Dr. Landmesser, a professor in and the chair of the department of cardiology at Charité Medical School in Berlin.
Participants in the Global Prospective Amulet Study averaged 75 years of age, and 72% had a history of major bleeding. The average CHA2DS2-VASc score was 4.2, with a HAS-BLED score of 3.3, which emphasizes the high-risk nature of study participants.
On the basis of the CHA2DS2-VASc score, the predicted 1-year ischemic stroke rate without oral anticoagulation was 6.7%, so the actual 2.9% rate represented a 57% reduction in risk. Similarly, for the composite endpoint of ischemic stroke, transient ischemic attack, or systemic embolism, the predicted rate was 9.4%, but the achieved rate was 3.8%, which represented a 60% reduction in risk.
The annualized major bleeding rate was 10.3% despite the low usage of oral anticoagulation or dual-antiplatelet therapy. However, the rate of procedure- or device-related major bleeding was only 3.2%; the other 7.1% was unrelated to Amulet and reflected the underlying high risk of the study population.
The 1-year mortality rate was 8.4%. Thirty-five deaths had cardiovascular causes, 35 were noncardiovascular, and in 18 patients, cause of death couldn’t be determined.
The device-related thrombus rate through 1 year was 1.7%; 10 of 18 cases occurred within the first 90 days.
Dr. Landmesser emphasized that this was a particularly rigorously conducted registry. A unique feature was its use of an independent echocardiography core lab to assess procedural success, as well as an independent clinical events committee to adjudicate serious adverse events. Prior studies of other left atrial appendage (LAA) occlusion devices didn’t use these measures.
The Amplatzer Amulet is a second-generation occlusion device designed for easier placement and more complete sealing than its predecessor and comes in eight sizes to address anatomic variations. At implantation, adequate LAA occlusion as defined by the echocardiography core laboratory was achieved in 99.3% of patients; at that time, 89.4% of patients had no residual flow, and another 9.9% had a residual flow of less than 3 mm. At 1-3 months of follow-up, echocardiography showed 98.4% of patients had adequate occlusion.
Session cochair Alberto Cremonesi, MD, pronounced this to be “really important data.”
“I want to stress that these device implantations were transesophageal echocardiography–guided. In my mind this is absolutely essential to your excellent long-term results,” observed Dr. Cremonesi of Maria Cecilia Hospital in Cotignola, Italy.
Asked to speculate on what outcomes might have looked like had patients been treated with an oral anticoagulant rather than the Amulet occlusion device, Dr. Landmesser predicted the major bleeding rate would have been substantially higher than 10.3%. Most of the bleeding events in the study were gastrointestinal, and the novel oral anticoagulants are known to boost the risk of GI bleeding.
But that’s speculation. He noted that two ongoing randomized trials – one in Germany, the other in Scandinavia – are randomizing high-risk patients to a LAA occlusion device or best medical care, including a novel oral anticoagulant when not contraindicated. The Scandinavian study uses the Amulet, while the German trial uses both the Amulet and the Watchman device. The primary endpoint is the ischemic stroke rate.
The Amulet registry, which will continue for a second year of follow-up, was sponsored by Abbott Laboratories, which developed the Amulet device. Dr. Landmesser reported serving as a consultant to Abbott, as well as Biotronik, Rewa, and Bayer.
REPORTING FROM EUROPCR 2018
Key clinical point:
Major finding: The 1-year ischemic stroke rate in Amulet recipients was 2.9%, compared with a predicted rate of 6.7% based on CHA2DS2-VASc score.
Study details: This prospective all-comers registry included 1,088 atrial fibrillation patients who received the Amulet device at 61 centers in 17 countries.
Disclosures: The study was sponsored by Abbott Laboratories, which developed the device. The presenter reported serving as a consultant to the company, as well as Biotronik, Rewa, and Bayer.
Design limitations may have compromised DVT intervention trial
WASHINGTON – On the basis of a large randomized trial called ATTRACT, many clinicians have concluded that pharmacomechanical intervention is ineffective for preventing postthrombotic syndrome (PTS) in patients with deep venous thrombosis (DVT). But weaknesses in the study design challenge this conclusion, according to several experts in a DVT symposium at the 2018 Cardiovascular Research Technologies (CRT) meeting.
“The diagnosis and evaluation of DVT must be performed with IVUS [intravascular ultrasound], not with venography,” said Peter A. Soukas, MD, director of vascular medicine at Miriam Hospital in Providence, R.I. “You cannot know whether you successfully treated the clot if you cannot see it.”
“There were lots of limitations to that study. Here are some,” said Dr. Soukas, who then listed on a list of several considerations, including the fact that venograms – rather than IVUS, which Dr. Soukas labeled the “current gold standard” – were taken to evaluate procedure success. Another was that only half of patients had a moderate to severe DVT based on a Villalta score.
“If you look at the subgroup with a Villalta score of 10 or greater, the benefit [of pharmacomechanical intervention] was statistically significant,” he said.
In addition, the study enrolled a substantial number of patients with femoral-popliteal DVTs even though iliofemoral DVTs pose the greatest risk of postthrombotic syndrome. Dr. Soukas suggested these would have been a more appropriate focus of a study exploring the benefits of an intervention.
The limitations of the ATTRACT trial, which was conceived more than 5 years ago, have arisen primarily from advances in the field rather than problems with the design, Dr. Soukas explained. IVUS was not the preferred method for deep vein thrombosis evaluation then as it is now, and there have been several advances in current models of pharmacomechanical devices, which involve catheter-directed delivery of fibrinolytic therapy into the thrombus along with mechanical destruction of the clot.
Although further steps beyond clot lysis, such as stenting, were encouraged in ATTRACT to maintain venous patency, Dr. Soukas questioned whether these were employed sufficiently. For example, the rate of stenting in the experimental arm was 28%, a rate that “is not what we currently do” for patients at high risk of PTS, Dr. Soukas said.
In ATTRACT, major bleeding events were significantly higher in the experimental group (1.7% vs. 0.3%; P = .049). The authors cited this finding when they concluded that the experimental intervention was ineffective. Dr. Soukas acknowledged that bleeding risk is an important factor to consider, but he also emphasized the serious risks for failing to treat patients at high risk for PTS.
“PTS is devastating for patients, both functionally and economically,” Dr. Soukas said. He called the morbidity of deep vein thrombosis “staggering,” with in-hospital mortality in some series exceeding 10% and a risk of late development of postthrombotic syndrome persisting for up to 5 years. For those with proximal iliofemoral DVT, the PTS rate can reach 90%, about 15% of which can develop claudication with ulcerations, according to Dr. Soukas.
A large trial that was published in a prominent journal, ATTRACT has the potential to dissuade clinicians from considering pharmacomechanical intervention in high-risk patients who could benefit, Dr. Soukas said. Others speaking during the same symposium about advances in this field, such as John Fritz Angle, MD, director of the division of vascular and interventional radiology at the University of Virginia, Charlottesville, agreed with this assessment. Although other studies underway will reexamine this issue, there was consensus from several speakers at the CRT symposium that the results of ATTRACT should not preclude intervention in patients at high risk of PTS.
“I believe there is a role for DVT intervention for symptomatic patients with an extensive [proximal iliofemoral] clot provided they have a low bleeding risk,” Dr. Soukas said.
Dr. Soukas reported no potential conflicts of interest.
WASHINGTON – On the basis of a large randomized trial called ATTRACT, many clinicians have concluded that pharmacomechanical intervention is ineffective for preventing postthrombotic syndrome (PTS) in patients with deep venous thrombosis (DVT). But weaknesses in the study design challenge this conclusion, according to several experts in a DVT symposium at the 2018 Cardiovascular Research Technologies (CRT) meeting.
“The diagnosis and evaluation of DVT must be performed with IVUS [intravascular ultrasound], not with venography,” said Peter A. Soukas, MD, director of vascular medicine at Miriam Hospital in Providence, R.I. “You cannot know whether you successfully treated the clot if you cannot see it.”
“There were lots of limitations to that study. Here are some,” said Dr. Soukas, who then listed on a list of several considerations, including the fact that venograms – rather than IVUS, which Dr. Soukas labeled the “current gold standard” – were taken to evaluate procedure success. Another was that only half of patients had a moderate to severe DVT based on a Villalta score.
“If you look at the subgroup with a Villalta score of 10 or greater, the benefit [of pharmacomechanical intervention] was statistically significant,” he said.
In addition, the study enrolled a substantial number of patients with femoral-popliteal DVTs even though iliofemoral DVTs pose the greatest risk of postthrombotic syndrome. Dr. Soukas suggested these would have been a more appropriate focus of a study exploring the benefits of an intervention.
The limitations of the ATTRACT trial, which was conceived more than 5 years ago, have arisen primarily from advances in the field rather than problems with the design, Dr. Soukas explained. IVUS was not the preferred method for deep vein thrombosis evaluation then as it is now, and there have been several advances in current models of pharmacomechanical devices, which involve catheter-directed delivery of fibrinolytic therapy into the thrombus along with mechanical destruction of the clot.
Although further steps beyond clot lysis, such as stenting, were encouraged in ATTRACT to maintain venous patency, Dr. Soukas questioned whether these were employed sufficiently. For example, the rate of stenting in the experimental arm was 28%, a rate that “is not what we currently do” for patients at high risk of PTS, Dr. Soukas said.
In ATTRACT, major bleeding events were significantly higher in the experimental group (1.7% vs. 0.3%; P = .049). The authors cited this finding when they concluded that the experimental intervention was ineffective. Dr. Soukas acknowledged that bleeding risk is an important factor to consider, but he also emphasized the serious risks for failing to treat patients at high risk for PTS.
“PTS is devastating for patients, both functionally and economically,” Dr. Soukas said. He called the morbidity of deep vein thrombosis “staggering,” with in-hospital mortality in some series exceeding 10% and a risk of late development of postthrombotic syndrome persisting for up to 5 years. For those with proximal iliofemoral DVT, the PTS rate can reach 90%, about 15% of which can develop claudication with ulcerations, according to Dr. Soukas.
A large trial that was published in a prominent journal, ATTRACT has the potential to dissuade clinicians from considering pharmacomechanical intervention in high-risk patients who could benefit, Dr. Soukas said. Others speaking during the same symposium about advances in this field, such as John Fritz Angle, MD, director of the division of vascular and interventional radiology at the University of Virginia, Charlottesville, agreed with this assessment. Although other studies underway will reexamine this issue, there was consensus from several speakers at the CRT symposium that the results of ATTRACT should not preclude intervention in patients at high risk of PTS.
“I believe there is a role for DVT intervention for symptomatic patients with an extensive [proximal iliofemoral] clot provided they have a low bleeding risk,” Dr. Soukas said.
Dr. Soukas reported no potential conflicts of interest.
WASHINGTON – On the basis of a large randomized trial called ATTRACT, many clinicians have concluded that pharmacomechanical intervention is ineffective for preventing postthrombotic syndrome (PTS) in patients with deep venous thrombosis (DVT). But weaknesses in the study design challenge this conclusion, according to several experts in a DVT symposium at the 2018 Cardiovascular Research Technologies (CRT) meeting.
“The diagnosis and evaluation of DVT must be performed with IVUS [intravascular ultrasound], not with venography,” said Peter A. Soukas, MD, director of vascular medicine at Miriam Hospital in Providence, R.I. “You cannot know whether you successfully treated the clot if you cannot see it.”
“There were lots of limitations to that study. Here are some,” said Dr. Soukas, who then listed on a list of several considerations, including the fact that venograms – rather than IVUS, which Dr. Soukas labeled the “current gold standard” – were taken to evaluate procedure success. Another was that only half of patients had a moderate to severe DVT based on a Villalta score.
“If you look at the subgroup with a Villalta score of 10 or greater, the benefit [of pharmacomechanical intervention] was statistically significant,” he said.
In addition, the study enrolled a substantial number of patients with femoral-popliteal DVTs even though iliofemoral DVTs pose the greatest risk of postthrombotic syndrome. Dr. Soukas suggested these would have been a more appropriate focus of a study exploring the benefits of an intervention.
The limitations of the ATTRACT trial, which was conceived more than 5 years ago, have arisen primarily from advances in the field rather than problems with the design, Dr. Soukas explained. IVUS was not the preferred method for deep vein thrombosis evaluation then as it is now, and there have been several advances in current models of pharmacomechanical devices, which involve catheter-directed delivery of fibrinolytic therapy into the thrombus along with mechanical destruction of the clot.
Although further steps beyond clot lysis, such as stenting, were encouraged in ATTRACT to maintain venous patency, Dr. Soukas questioned whether these were employed sufficiently. For example, the rate of stenting in the experimental arm was 28%, a rate that “is not what we currently do” for patients at high risk of PTS, Dr. Soukas said.
In ATTRACT, major bleeding events were significantly higher in the experimental group (1.7% vs. 0.3%; P = .049). The authors cited this finding when they concluded that the experimental intervention was ineffective. Dr. Soukas acknowledged that bleeding risk is an important factor to consider, but he also emphasized the serious risks for failing to treat patients at high risk for PTS.
“PTS is devastating for patients, both functionally and economically,” Dr. Soukas said. He called the morbidity of deep vein thrombosis “staggering,” with in-hospital mortality in some series exceeding 10% and a risk of late development of postthrombotic syndrome persisting for up to 5 years. For those with proximal iliofemoral DVT, the PTS rate can reach 90%, about 15% of which can develop claudication with ulcerations, according to Dr. Soukas.
A large trial that was published in a prominent journal, ATTRACT has the potential to dissuade clinicians from considering pharmacomechanical intervention in high-risk patients who could benefit, Dr. Soukas said. Others speaking during the same symposium about advances in this field, such as John Fritz Angle, MD, director of the division of vascular and interventional radiology at the University of Virginia, Charlottesville, agreed with this assessment. Although other studies underway will reexamine this issue, there was consensus from several speakers at the CRT symposium that the results of ATTRACT should not preclude intervention in patients at high risk of PTS.
“I believe there is a role for DVT intervention for symptomatic patients with an extensive [proximal iliofemoral] clot provided they have a low bleeding risk,” Dr. Soukas said.
Dr. Soukas reported no potential conflicts of interest.
EXPERT ANALYSIS FROM THE 2018 CRT MEETING
First reversal agent for apixaban and rivaroxaban gets fast-track approval
, according to a May 3 statement from Portola Pharmaceuticals.
It is approved for use in patients treated with these factor Xa inhibitors when reversal of anticoagulation is needed because of life-threatening or uncontrolled bleeding, according to the company.
Andexanet alfa (Andexxa, Portola) received both U.S. Orphan Drug and FDA Breakthrough Therapy designations and was approved under the FDA’s Accelerated Approval pathway.
“Today’s approval represents a significant step forward in patient care and one that the medical community has been eagerly anticipating,” said Stuart J. Connolly, MD, professor of medicine and an electrophysiologist at McMaster University in Hamilton, Ont., who is chair of the ANNEXA-4 executive committee. “Andexxa’s rapid reversal of the anticoagulating effects of rivaroxaban and apixaban will help clinicians treat life-threatening bleeds, where every minute counts,” he added in the statement.
The approval was supported by two phase 3 trials in the ANNEXA series, which showed acceptable change from baseline in anti-Factor Xa activity in healthy volunteers. But the strongest data came from interim results from ANNEXA-4, a single-arm cohort study with 227 patients who were receiving a factor Xa inhibitor and were experiencing an acute major bleeding event.
Clinicians administered andexanet alfa as a bolus followed by a 2-hour continuous infusion, with hemostatic efficacy assessed 12 hours after the start of treatment. The results showed that factor Xa inhibition fell by a median 90% for rivaroxaban and 93% for apixaban.
Andexanet alfa is a factor Xa “decoy” molecule that acts by latching onto the inhibitor molecules and thereby preventing them from interacting with actual factor Xa, but andexanet also has a short half life and hence the effect quickly reduces once treatment stops, Dr. Connelly reported at the American College of Cardiology annual meeting in March when presenting ANNEXA-4.
He noted at the time the results placed andexanet in the same ballpark for efficacy and safety as idarucizumab (Praxbind) approved in 2015 for reversing the anticoagulant dabigatran (Pradaxa)
“The expansion of available reversal agents for people prescribed newer oral anticoagulant therapies is crucial,” Randy Fenninger, chief executive officer of the National Blood Clot Alliance, said in the Portola statement. “The availability now of a reversal agent specific to rivaroxaban and apixaban expands choice and enables patients and providers to consider these treatment options with greater confidence.”
The prescribing information for andexanet states that treated patients should be monitored for signs and symptoms of arterial and venous thromboembolic events, ischemic events, and cardiac arrest. Further, anticoagulant therapy should be resumed as soon as medically appropriate following andexanet treatment to reduce thromboembolic risk.
The most common adverse reactions, occurring in at least 5% of patients, were urinary tract infections and pneumonia.
Portola intends to bring Andexxa to limited markets in early June; a broader commercial launch is anticipated in early 2019.*
The FDA is requiring a postmarketing clinical trial that randomizes patients to either andexanet or usual care. The study is scheduled to begin in 2019 and report outcomes in 2023.
*This article was updated on May 7, 2018.
, according to a May 3 statement from Portola Pharmaceuticals.
It is approved for use in patients treated with these factor Xa inhibitors when reversal of anticoagulation is needed because of life-threatening or uncontrolled bleeding, according to the company.
Andexanet alfa (Andexxa, Portola) received both U.S. Orphan Drug and FDA Breakthrough Therapy designations and was approved under the FDA’s Accelerated Approval pathway.
“Today’s approval represents a significant step forward in patient care and one that the medical community has been eagerly anticipating,” said Stuart J. Connolly, MD, professor of medicine and an electrophysiologist at McMaster University in Hamilton, Ont., who is chair of the ANNEXA-4 executive committee. “Andexxa’s rapid reversal of the anticoagulating effects of rivaroxaban and apixaban will help clinicians treat life-threatening bleeds, where every minute counts,” he added in the statement.
The approval was supported by two phase 3 trials in the ANNEXA series, which showed acceptable change from baseline in anti-Factor Xa activity in healthy volunteers. But the strongest data came from interim results from ANNEXA-4, a single-arm cohort study with 227 patients who were receiving a factor Xa inhibitor and were experiencing an acute major bleeding event.
Clinicians administered andexanet alfa as a bolus followed by a 2-hour continuous infusion, with hemostatic efficacy assessed 12 hours after the start of treatment. The results showed that factor Xa inhibition fell by a median 90% for rivaroxaban and 93% for apixaban.
Andexanet alfa is a factor Xa “decoy” molecule that acts by latching onto the inhibitor molecules and thereby preventing them from interacting with actual factor Xa, but andexanet also has a short half life and hence the effect quickly reduces once treatment stops, Dr. Connelly reported at the American College of Cardiology annual meeting in March when presenting ANNEXA-4.
He noted at the time the results placed andexanet in the same ballpark for efficacy and safety as idarucizumab (Praxbind) approved in 2015 for reversing the anticoagulant dabigatran (Pradaxa)
“The expansion of available reversal agents for people prescribed newer oral anticoagulant therapies is crucial,” Randy Fenninger, chief executive officer of the National Blood Clot Alliance, said in the Portola statement. “The availability now of a reversal agent specific to rivaroxaban and apixaban expands choice and enables patients and providers to consider these treatment options with greater confidence.”
The prescribing information for andexanet states that treated patients should be monitored for signs and symptoms of arterial and venous thromboembolic events, ischemic events, and cardiac arrest. Further, anticoagulant therapy should be resumed as soon as medically appropriate following andexanet treatment to reduce thromboembolic risk.
The most common adverse reactions, occurring in at least 5% of patients, were urinary tract infections and pneumonia.
Portola intends to bring Andexxa to limited markets in early June; a broader commercial launch is anticipated in early 2019.*
The FDA is requiring a postmarketing clinical trial that randomizes patients to either andexanet or usual care. The study is scheduled to begin in 2019 and report outcomes in 2023.
*This article was updated on May 7, 2018.
, according to a May 3 statement from Portola Pharmaceuticals.
It is approved for use in patients treated with these factor Xa inhibitors when reversal of anticoagulation is needed because of life-threatening or uncontrolled bleeding, according to the company.
Andexanet alfa (Andexxa, Portola) received both U.S. Orphan Drug and FDA Breakthrough Therapy designations and was approved under the FDA’s Accelerated Approval pathway.
“Today’s approval represents a significant step forward in patient care and one that the medical community has been eagerly anticipating,” said Stuart J. Connolly, MD, professor of medicine and an electrophysiologist at McMaster University in Hamilton, Ont., who is chair of the ANNEXA-4 executive committee. “Andexxa’s rapid reversal of the anticoagulating effects of rivaroxaban and apixaban will help clinicians treat life-threatening bleeds, where every minute counts,” he added in the statement.
The approval was supported by two phase 3 trials in the ANNEXA series, which showed acceptable change from baseline in anti-Factor Xa activity in healthy volunteers. But the strongest data came from interim results from ANNEXA-4, a single-arm cohort study with 227 patients who were receiving a factor Xa inhibitor and were experiencing an acute major bleeding event.
Clinicians administered andexanet alfa as a bolus followed by a 2-hour continuous infusion, with hemostatic efficacy assessed 12 hours after the start of treatment. The results showed that factor Xa inhibition fell by a median 90% for rivaroxaban and 93% for apixaban.
Andexanet alfa is a factor Xa “decoy” molecule that acts by latching onto the inhibitor molecules and thereby preventing them from interacting with actual factor Xa, but andexanet also has a short half life and hence the effect quickly reduces once treatment stops, Dr. Connelly reported at the American College of Cardiology annual meeting in March when presenting ANNEXA-4.
He noted at the time the results placed andexanet in the same ballpark for efficacy and safety as idarucizumab (Praxbind) approved in 2015 for reversing the anticoagulant dabigatran (Pradaxa)
“The expansion of available reversal agents for people prescribed newer oral anticoagulant therapies is crucial,” Randy Fenninger, chief executive officer of the National Blood Clot Alliance, said in the Portola statement. “The availability now of a reversal agent specific to rivaroxaban and apixaban expands choice and enables patients and providers to consider these treatment options with greater confidence.”
The prescribing information for andexanet states that treated patients should be monitored for signs and symptoms of arterial and venous thromboembolic events, ischemic events, and cardiac arrest. Further, anticoagulant therapy should be resumed as soon as medically appropriate following andexanet treatment to reduce thromboembolic risk.
The most common adverse reactions, occurring in at least 5% of patients, were urinary tract infections and pneumonia.
Portola intends to bring Andexxa to limited markets in early June; a broader commercial launch is anticipated in early 2019.*
The FDA is requiring a postmarketing clinical trial that randomizes patients to either andexanet or usual care. The study is scheduled to begin in 2019 and report outcomes in 2023.
*This article was updated on May 7, 2018.
Does warfarin cause acute kidney injury?
SAN DIEGO – Patients with chronic kidney disease (CKD) and those on renin angiotensin system inhibitors and/or diuretics should have their renal function monitored during periods of overanticoagulation, results from a large retrospective study suggest.
“Unfortunately, warfarin-related nephropathy is quite hard to study,” Hugh Traquair, MD, the study’s lead author, said in an interview at the biennial summit of the Thrombosis & Hemostasis Societies of North America. “The best way to establish diagnosis is with a kidney biopsy. No one is very keen to stick a needle into a kidney when someone’s overanticoagulated. It’s been observed previously that acute kidney injury related to over-anticoagulation is more common in people with CKD, but we don’t know more about risk factors.”
The primary outcome was AKI, defined as an acute increase in creatinine of greater than 26.5 micromol/L within 7-14 days of an INR 4 or greater. The secondary outcome was creatinine level within 3 months of the abnormal INR. The researchers excluded patients with AKI due to another cause, and those who lacked a creatinine level at baseline, within 7-14 days of an INR of 4 or greater, and/or at 3 months.
The median age of the 292 patients was 79 years, 55% were male, 30% were taking aspirin, and 77% were taking renin angiotensin inhibitors and/or diuretics. The control group consisted of 93 patients with a 12-month time in therapeutic range of 100%. The median age of controls was 68 years, 67% were male, and 9% had CKD. None of the controls had an AKI, said Dr. Traquair, a second-year internal medicine resident in the department of medicine at McMaster University.
Of the 292 patients with an INR of 4 or greater, 13% had an AKI, and the incidence of AKI was significantly higher in the CKD patients, compared with those who had a normal baseline creatinine level (19% vs. 10%; odds ratio, 2.1; P less than .05).
In a binomial logistic regression model, diuretic use was the only significant predictor of AKI (OR 3.4; P less than .05). The researchers also found that of the 52 patients with an INR of 4 or greater who did not use renin angiotensin system inhibitors and/or diuretics and did not have CKD, only 1 had an AKI (2%).
“We don’t know that all of these episodes of AKI are related to warfarin, but we do see a definite increase of AKI after an episode of overanticoagulation (an INR greater than 4),” Dr. Traquair said. “In patients who are at risk for AKI, monitoring their kidney function after an episode of overanticoagulation is probably warranted.”
Dr. Traquair reported having no financial disclosures.
SOURCE: Traquair H et al. THSNA 2018, Poster 79.
SAN DIEGO – Patients with chronic kidney disease (CKD) and those on renin angiotensin system inhibitors and/or diuretics should have their renal function monitored during periods of overanticoagulation, results from a large retrospective study suggest.
“Unfortunately, warfarin-related nephropathy is quite hard to study,” Hugh Traquair, MD, the study’s lead author, said in an interview at the biennial summit of the Thrombosis & Hemostasis Societies of North America. “The best way to establish diagnosis is with a kidney biopsy. No one is very keen to stick a needle into a kidney when someone’s overanticoagulated. It’s been observed previously that acute kidney injury related to over-anticoagulation is more common in people with CKD, but we don’t know more about risk factors.”
The primary outcome was AKI, defined as an acute increase in creatinine of greater than 26.5 micromol/L within 7-14 days of an INR 4 or greater. The secondary outcome was creatinine level within 3 months of the abnormal INR. The researchers excluded patients with AKI due to another cause, and those who lacked a creatinine level at baseline, within 7-14 days of an INR of 4 or greater, and/or at 3 months.
The median age of the 292 patients was 79 years, 55% were male, 30% were taking aspirin, and 77% were taking renin angiotensin inhibitors and/or diuretics. The control group consisted of 93 patients with a 12-month time in therapeutic range of 100%. The median age of controls was 68 years, 67% were male, and 9% had CKD. None of the controls had an AKI, said Dr. Traquair, a second-year internal medicine resident in the department of medicine at McMaster University.
Of the 292 patients with an INR of 4 or greater, 13% had an AKI, and the incidence of AKI was significantly higher in the CKD patients, compared with those who had a normal baseline creatinine level (19% vs. 10%; odds ratio, 2.1; P less than .05).
In a binomial logistic regression model, diuretic use was the only significant predictor of AKI (OR 3.4; P less than .05). The researchers also found that of the 52 patients with an INR of 4 or greater who did not use renin angiotensin system inhibitors and/or diuretics and did not have CKD, only 1 had an AKI (2%).
“We don’t know that all of these episodes of AKI are related to warfarin, but we do see a definite increase of AKI after an episode of overanticoagulation (an INR greater than 4),” Dr. Traquair said. “In patients who are at risk for AKI, monitoring their kidney function after an episode of overanticoagulation is probably warranted.”
Dr. Traquair reported having no financial disclosures.
SOURCE: Traquair H et al. THSNA 2018, Poster 79.
SAN DIEGO – Patients with chronic kidney disease (CKD) and those on renin angiotensin system inhibitors and/or diuretics should have their renal function monitored during periods of overanticoagulation, results from a large retrospective study suggest.
“Unfortunately, warfarin-related nephropathy is quite hard to study,” Hugh Traquair, MD, the study’s lead author, said in an interview at the biennial summit of the Thrombosis & Hemostasis Societies of North America. “The best way to establish diagnosis is with a kidney biopsy. No one is very keen to stick a needle into a kidney when someone’s overanticoagulated. It’s been observed previously that acute kidney injury related to over-anticoagulation is more common in people with CKD, but we don’t know more about risk factors.”
The primary outcome was AKI, defined as an acute increase in creatinine of greater than 26.5 micromol/L within 7-14 days of an INR 4 or greater. The secondary outcome was creatinine level within 3 months of the abnormal INR. The researchers excluded patients with AKI due to another cause, and those who lacked a creatinine level at baseline, within 7-14 days of an INR of 4 or greater, and/or at 3 months.
The median age of the 292 patients was 79 years, 55% were male, 30% were taking aspirin, and 77% were taking renin angiotensin inhibitors and/or diuretics. The control group consisted of 93 patients with a 12-month time in therapeutic range of 100%. The median age of controls was 68 years, 67% were male, and 9% had CKD. None of the controls had an AKI, said Dr. Traquair, a second-year internal medicine resident in the department of medicine at McMaster University.
Of the 292 patients with an INR of 4 or greater, 13% had an AKI, and the incidence of AKI was significantly higher in the CKD patients, compared with those who had a normal baseline creatinine level (19% vs. 10%; odds ratio, 2.1; P less than .05).
In a binomial logistic regression model, diuretic use was the only significant predictor of AKI (OR 3.4; P less than .05). The researchers also found that of the 52 patients with an INR of 4 or greater who did not use renin angiotensin system inhibitors and/or diuretics and did not have CKD, only 1 had an AKI (2%).
“We don’t know that all of these episodes of AKI are related to warfarin, but we do see a definite increase of AKI after an episode of overanticoagulation (an INR greater than 4),” Dr. Traquair said. “In patients who are at risk for AKI, monitoring their kidney function after an episode of overanticoagulation is probably warranted.”
Dr. Traquair reported having no financial disclosures.
SOURCE: Traquair H et al. THSNA 2018, Poster 79.
REPORTING FROM THSNA 2018
Key clinical point:
Major finding: Among patients with warfarin anticoagulation, 13% had an acute kidney injury.
Study details: A retrospective study of 292 patients with an INR of 4.0 or greater who were treated between 2007 and 2017.
Disclosures: Dr. Traquair reported having no financial disclosures.
Source: Traquair H et al. THSNA 2018, Poster 79.
Women’s representation in CV drug trials still lagging
Although women have been well represented recently in certain types of cardiovascular drug trials, they remain underrepresented in studies of heart failure, coronary artery disease, and acute coronary syndrome, a recent study authored by Food and Drug Administration researchers has revealed.
However, representation of women fell below an acceptable participation-to-prevalence ratio in those other trial types that were evaluated, according to researchers, including lead author Pamela E. Scott, PhD, of the FDA’s Office of Women’s Health.
“As we move into the era of precision medicine – that is, assessing the impact of a wide range of patient and disease characteristics on drug effects – it is imperative that clinical trial participants represent the full spectrum of patients for whom the drug will be prescribed,” Dr. Scott and her colleagues said in the report.
To quantify the participation of women in clinical trials, Dr. Scott and coinvestigators reviewed publicly available FDA reviews from 2005 to 2015 supporting the approval of 36 drugs.
They used a metric called the participation-to-prevalence ratio (PPR) to compare representation of women in a study relative to the representation of women in the disease population being studied. The range of PPR of 0.8-1.2 represented similar representation of women in the study and disease population.
Participation of women in drug trials varied widely – from a low of 22% to a high of 81% – with a mean of 46%, they found.
The PPR was within the desirable range for hypertension, at 0.9, and atrial fibrillation trials, at 0.8-1.1, while participation for pulmonary arterial hypertension trials was above the desirable range, at 1.4, according to the report.
However, a PPR of less than 0.8 was found for coronary artery disease trials, at 0.6; acute coronary syndrome/myocardial infarction trials, also at 0.6; and heart failure trials, at 0.5 to 0.6.
Few clinically meaningful gender differences were found in efficacy or safety, they added, noting that such differences were discussed in the prescribing information for four different drugs.
To ensure that representative patient populations are enrolled in drug trials, clinical researchers, patient advocacy groups, federal agencies, and the industry as a whole should work together, Dr. Scott and her colleagues said.
“These steps will move us closer toward the goal of providing the best information possible about the use of drugs for every patient,” they wrote.
Dr. Scott and coauthors reported that they had no relationships relevant to their study.
SOURCE: Scott PE et al. J Am Coll Cardiol. 2018 May 18;71:1960-9.
Any optimism for results of this study by FDA authors are dampened significantly by the continued under-representation of women in heart failure and ischemic heart disease.
Even though progress has been made toward a higher participation of women in pivotal clinical trials, it still is not time to rest on our laurels.
One key contributor to the persistently low representation of women is the eligibility criteria of clinical trials. Those criteria often describe a male pattern of disease, particularly in drug trials for ischemic heart disease and heart failure.
As an example, heart failure trials have included eligibility criteria that consistently exclude women, such as a glomerular filtration rate less than 30 mL/min per 1.73 m2, and an ejection fraction of 40% or less.
The inclusion criteria in randomized, controlled trials impose homogeneous clinical characteristics for men and women and may be responsible for the lack of sex differences in efficacy outcomes.
Thus, the current analysis exposes not only successes but also failings of clinical trial design for FDA approval. We are still far from providing equitable cardiovascular health care for women.
Louise Pilote, MD, MPH, PhD, and Valeria Raparelli, MD, PhD, are both affiliated with McGill University Health Centre, Montreal. These comments are derived from their editorial in the Journal of the American College of Cardiology . Both reported that they had no relationships relevant to the contents of their editorial.
Any optimism for results of this study by FDA authors are dampened significantly by the continued under-representation of women in heart failure and ischemic heart disease.
Even though progress has been made toward a higher participation of women in pivotal clinical trials, it still is not time to rest on our laurels.
One key contributor to the persistently low representation of women is the eligibility criteria of clinical trials. Those criteria often describe a male pattern of disease, particularly in drug trials for ischemic heart disease and heart failure.
As an example, heart failure trials have included eligibility criteria that consistently exclude women, such as a glomerular filtration rate less than 30 mL/min per 1.73 m2, and an ejection fraction of 40% or less.
The inclusion criteria in randomized, controlled trials impose homogeneous clinical characteristics for men and women and may be responsible for the lack of sex differences in efficacy outcomes.
Thus, the current analysis exposes not only successes but also failings of clinical trial design for FDA approval. We are still far from providing equitable cardiovascular health care for women.
Louise Pilote, MD, MPH, PhD, and Valeria Raparelli, MD, PhD, are both affiliated with McGill University Health Centre, Montreal. These comments are derived from their editorial in the Journal of the American College of Cardiology . Both reported that they had no relationships relevant to the contents of their editorial.
Any optimism for results of this study by FDA authors are dampened significantly by the continued under-representation of women in heart failure and ischemic heart disease.
Even though progress has been made toward a higher participation of women in pivotal clinical trials, it still is not time to rest on our laurels.
One key contributor to the persistently low representation of women is the eligibility criteria of clinical trials. Those criteria often describe a male pattern of disease, particularly in drug trials for ischemic heart disease and heart failure.
As an example, heart failure trials have included eligibility criteria that consistently exclude women, such as a glomerular filtration rate less than 30 mL/min per 1.73 m2, and an ejection fraction of 40% or less.
The inclusion criteria in randomized, controlled trials impose homogeneous clinical characteristics for men and women and may be responsible for the lack of sex differences in efficacy outcomes.
Thus, the current analysis exposes not only successes but also failings of clinical trial design for FDA approval. We are still far from providing equitable cardiovascular health care for women.
Louise Pilote, MD, MPH, PhD, and Valeria Raparelli, MD, PhD, are both affiliated with McGill University Health Centre, Montreal. These comments are derived from their editorial in the Journal of the American College of Cardiology . Both reported that they had no relationships relevant to the contents of their editorial.
Although women have been well represented recently in certain types of cardiovascular drug trials, they remain underrepresented in studies of heart failure, coronary artery disease, and acute coronary syndrome, a recent study authored by Food and Drug Administration researchers has revealed.
However, representation of women fell below an acceptable participation-to-prevalence ratio in those other trial types that were evaluated, according to researchers, including lead author Pamela E. Scott, PhD, of the FDA’s Office of Women’s Health.
“As we move into the era of precision medicine – that is, assessing the impact of a wide range of patient and disease characteristics on drug effects – it is imperative that clinical trial participants represent the full spectrum of patients for whom the drug will be prescribed,” Dr. Scott and her colleagues said in the report.
To quantify the participation of women in clinical trials, Dr. Scott and coinvestigators reviewed publicly available FDA reviews from 2005 to 2015 supporting the approval of 36 drugs.
They used a metric called the participation-to-prevalence ratio (PPR) to compare representation of women in a study relative to the representation of women in the disease population being studied. The range of PPR of 0.8-1.2 represented similar representation of women in the study and disease population.
Participation of women in drug trials varied widely – from a low of 22% to a high of 81% – with a mean of 46%, they found.
The PPR was within the desirable range for hypertension, at 0.9, and atrial fibrillation trials, at 0.8-1.1, while participation for pulmonary arterial hypertension trials was above the desirable range, at 1.4, according to the report.
However, a PPR of less than 0.8 was found for coronary artery disease trials, at 0.6; acute coronary syndrome/myocardial infarction trials, also at 0.6; and heart failure trials, at 0.5 to 0.6.
Few clinically meaningful gender differences were found in efficacy or safety, they added, noting that such differences were discussed in the prescribing information for four different drugs.
To ensure that representative patient populations are enrolled in drug trials, clinical researchers, patient advocacy groups, federal agencies, and the industry as a whole should work together, Dr. Scott and her colleagues said.
“These steps will move us closer toward the goal of providing the best information possible about the use of drugs for every patient,” they wrote.
Dr. Scott and coauthors reported that they had no relationships relevant to their study.
SOURCE: Scott PE et al. J Am Coll Cardiol. 2018 May 18;71:1960-9.
Although women have been well represented recently in certain types of cardiovascular drug trials, they remain underrepresented in studies of heart failure, coronary artery disease, and acute coronary syndrome, a recent study authored by Food and Drug Administration researchers has revealed.
However, representation of women fell below an acceptable participation-to-prevalence ratio in those other trial types that were evaluated, according to researchers, including lead author Pamela E. Scott, PhD, of the FDA’s Office of Women’s Health.
“As we move into the era of precision medicine – that is, assessing the impact of a wide range of patient and disease characteristics on drug effects – it is imperative that clinical trial participants represent the full spectrum of patients for whom the drug will be prescribed,” Dr. Scott and her colleagues said in the report.
To quantify the participation of women in clinical trials, Dr. Scott and coinvestigators reviewed publicly available FDA reviews from 2005 to 2015 supporting the approval of 36 drugs.
They used a metric called the participation-to-prevalence ratio (PPR) to compare representation of women in a study relative to the representation of women in the disease population being studied. The range of PPR of 0.8-1.2 represented similar representation of women in the study and disease population.
Participation of women in drug trials varied widely – from a low of 22% to a high of 81% – with a mean of 46%, they found.
The PPR was within the desirable range for hypertension, at 0.9, and atrial fibrillation trials, at 0.8-1.1, while participation for pulmonary arterial hypertension trials was above the desirable range, at 1.4, according to the report.
However, a PPR of less than 0.8 was found for coronary artery disease trials, at 0.6; acute coronary syndrome/myocardial infarction trials, also at 0.6; and heart failure trials, at 0.5 to 0.6.
Few clinically meaningful gender differences were found in efficacy or safety, they added, noting that such differences were discussed in the prescribing information for four different drugs.
To ensure that representative patient populations are enrolled in drug trials, clinical researchers, patient advocacy groups, federal agencies, and the industry as a whole should work together, Dr. Scott and her colleagues said.
“These steps will move us closer toward the goal of providing the best information possible about the use of drugs for every patient,” they wrote.
Dr. Scott and coauthors reported that they had no relationships relevant to their study.
SOURCE: Scott PE et al. J Am Coll Cardiol. 2018 May 18;71:1960-9.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Key clinical point: Although women are well represented in clinical trials for hypertension, atrial fibrillation, and pulmonary arterial hypertension, they are not well represented in other trial types.
Major finding: The participation-to-prevalence ratio fell below 0.8 (that is, the bottom end of the range reflecting a similar representation of women) for coronary artery disease, acute coronary syndrome, and heart failure.
Study details: An assessment of publicly available FDA data from 2005 to 2015 on enrollment of women in clinical trials representing 36 drug approvals.
Disclosures: Authors reported that they had no relationships relevant to their report.
Source: Scott PE et al. J Am Coll Cardiol. 2018 May 18;71:1960-9.
MI before age 50? Think familial hypercholesterolemia, substance abuse
ORLANDO – Patients with an MI before age 50 commonly have familial hypercholesterolemia or a substance abuse issue, according to presentations at the annual meeting of the American College of Cardiology.
Not only is the prevalence of familial hypercholesterolemia (FH) increased in patients with an MI at a young age, but 1 year post MI, their LDL remains unacceptably high at 100 mg/dL or more in a high percentage of cases. For that matter, the same is true in patients with an MI before age 50 who don’t have FH, reported Ron Blankstein, MD, director of cardiac computed tomography at Brigham and Women’s Hospital and a cardiologist at Harvard Medical School, Boston.
FH patients after early MI
Dr. Blankstein presented a retrospective study of 1,996 adults with a first confirmed type 1 MI before at 50 who presented at Brigham and Women’s Hospital or Massachusetts General Hospital, of whom 9% met Dutch Lipid Clinic Network criteria for probable or definite FH.
Among patients with an MI before age 50 and a family history of premature CAD, the prevalence of FH was enriched, at 22%. Among those with an LDL of 160 mg/dL or more, the prevalence of FH rose further, to 36%. And by combining all three criteria – MI before age 50, a positive family history of early CAD, and an LDL of at least 160 mg/dL – the prevalence of FH shot up to 64%, Dr. Blankstein said.
Only 89% of patients with an MI prior to turning 50 years old were discharged on a statin. “That’s lower than I would have expected,” he said.
One year post MI, LDL levels had dropped by a mean of 79 mg/dL in the FH group and 39 mg/dL in the non-FH patients. This translated into a 45% reduction in the FH patients, a significantly greater decrease than the 34% drop in the non-FH group. Nonetheless, 43% of FH patients had an LDL of 100 mg/dL or greater at 1 year, as did 26% without FH. These are patients who are particularly likely to benefit from more aggressive lipid-lowering after an acute coronary syndrome. Given that almost 90% of patients with FH remain undiagnosed, assessment for the genetic disorder in young patients with MI is an important means of case finding, the cardiologist observed.
Session cochair Carl E. Orringer, MD, director of preventive cardiovascular medicine at the University of Miami, said he and his colleagues have just initiated a program at that medical center whereby patients with an LDL of 190 mg/dL or more are identified through their electronic medical records and referred to a lipid clinic or cardiovascular prevention program.
“I think this is certainly something to think about for other programs because you want to make sure that if you have lipid intervention services, they actually take care of patients who are at the highest risk,” he said.
Substance abuse plays role
Elsewhere at ACC 2018, Ersilia M. Defilippis, MD, reported on an expanded population of 2,097 patients with a first type 1 MI prior to age 50 at the same two hospitals. Their electronic medical records revealed that 6.0% of them used marijuana and 4.7% used cocaine. During a median 11.2 years of follow-up, the group that used cocaine or marijuana had a 2.2-fold increased risk of cardiovascular death and a 2.0-fold increase in all-cause mortality, compared with nonusers, in an analysis adjusted for baseline differences.
Among these differences, 46% of drug users and 61% of nonusers were hyperlipidemic, 70% of users and 49% of nonusers were smokers, 8% of users and 4% of nonusers presented in cardiac arrest, and the median normalized troponin level was 61 interquartile range (IQR) in users versus 39 IQR in nonusers.
“Given these findings, young patients with MI should be screened for substance abuse and counseled about behavioral change to prevent future adverse events,” concluded Dr. Defilippis of Brigham and Women’s Hospital and Harvard University. She and Dr. Blankstein were coinvestigators in this study. She reported having no financial conflicts of interest. Dr. Blankstein reported receiving research grants from Amgen, Astellas, and Sanofi, and serves as a consultant to Amgen.
Source: Blankstein R. Abstracts 1180M-03 and 1262-436/436.
ORLANDO – Patients with an MI before age 50 commonly have familial hypercholesterolemia or a substance abuse issue, according to presentations at the annual meeting of the American College of Cardiology.
Not only is the prevalence of familial hypercholesterolemia (FH) increased in patients with an MI at a young age, but 1 year post MI, their LDL remains unacceptably high at 100 mg/dL or more in a high percentage of cases. For that matter, the same is true in patients with an MI before age 50 who don’t have FH, reported Ron Blankstein, MD, director of cardiac computed tomography at Brigham and Women’s Hospital and a cardiologist at Harvard Medical School, Boston.
FH patients after early MI
Dr. Blankstein presented a retrospective study of 1,996 adults with a first confirmed type 1 MI before at 50 who presented at Brigham and Women’s Hospital or Massachusetts General Hospital, of whom 9% met Dutch Lipid Clinic Network criteria for probable or definite FH.
Among patients with an MI before age 50 and a family history of premature CAD, the prevalence of FH was enriched, at 22%. Among those with an LDL of 160 mg/dL or more, the prevalence of FH rose further, to 36%. And by combining all three criteria – MI before age 50, a positive family history of early CAD, and an LDL of at least 160 mg/dL – the prevalence of FH shot up to 64%, Dr. Blankstein said.
Only 89% of patients with an MI prior to turning 50 years old were discharged on a statin. “That’s lower than I would have expected,” he said.
One year post MI, LDL levels had dropped by a mean of 79 mg/dL in the FH group and 39 mg/dL in the non-FH patients. This translated into a 45% reduction in the FH patients, a significantly greater decrease than the 34% drop in the non-FH group. Nonetheless, 43% of FH patients had an LDL of 100 mg/dL or greater at 1 year, as did 26% without FH. These are patients who are particularly likely to benefit from more aggressive lipid-lowering after an acute coronary syndrome. Given that almost 90% of patients with FH remain undiagnosed, assessment for the genetic disorder in young patients with MI is an important means of case finding, the cardiologist observed.
Session cochair Carl E. Orringer, MD, director of preventive cardiovascular medicine at the University of Miami, said he and his colleagues have just initiated a program at that medical center whereby patients with an LDL of 190 mg/dL or more are identified through their electronic medical records and referred to a lipid clinic or cardiovascular prevention program.
“I think this is certainly something to think about for other programs because you want to make sure that if you have lipid intervention services, they actually take care of patients who are at the highest risk,” he said.
Substance abuse plays role
Elsewhere at ACC 2018, Ersilia M. Defilippis, MD, reported on an expanded population of 2,097 patients with a first type 1 MI prior to age 50 at the same two hospitals. Their electronic medical records revealed that 6.0% of them used marijuana and 4.7% used cocaine. During a median 11.2 years of follow-up, the group that used cocaine or marijuana had a 2.2-fold increased risk of cardiovascular death and a 2.0-fold increase in all-cause mortality, compared with nonusers, in an analysis adjusted for baseline differences.
Among these differences, 46% of drug users and 61% of nonusers were hyperlipidemic, 70% of users and 49% of nonusers were smokers, 8% of users and 4% of nonusers presented in cardiac arrest, and the median normalized troponin level was 61 interquartile range (IQR) in users versus 39 IQR in nonusers.
“Given these findings, young patients with MI should be screened for substance abuse and counseled about behavioral change to prevent future adverse events,” concluded Dr. Defilippis of Brigham and Women’s Hospital and Harvard University. She and Dr. Blankstein were coinvestigators in this study. She reported having no financial conflicts of interest. Dr. Blankstein reported receiving research grants from Amgen, Astellas, and Sanofi, and serves as a consultant to Amgen.
Source: Blankstein R. Abstracts 1180M-03 and 1262-436/436.
ORLANDO – Patients with an MI before age 50 commonly have familial hypercholesterolemia or a substance abuse issue, according to presentations at the annual meeting of the American College of Cardiology.
Not only is the prevalence of familial hypercholesterolemia (FH) increased in patients with an MI at a young age, but 1 year post MI, their LDL remains unacceptably high at 100 mg/dL or more in a high percentage of cases. For that matter, the same is true in patients with an MI before age 50 who don’t have FH, reported Ron Blankstein, MD, director of cardiac computed tomography at Brigham and Women’s Hospital and a cardiologist at Harvard Medical School, Boston.
FH patients after early MI
Dr. Blankstein presented a retrospective study of 1,996 adults with a first confirmed type 1 MI before at 50 who presented at Brigham and Women’s Hospital or Massachusetts General Hospital, of whom 9% met Dutch Lipid Clinic Network criteria for probable or definite FH.
Among patients with an MI before age 50 and a family history of premature CAD, the prevalence of FH was enriched, at 22%. Among those with an LDL of 160 mg/dL or more, the prevalence of FH rose further, to 36%. And by combining all three criteria – MI before age 50, a positive family history of early CAD, and an LDL of at least 160 mg/dL – the prevalence of FH shot up to 64%, Dr. Blankstein said.
Only 89% of patients with an MI prior to turning 50 years old were discharged on a statin. “That’s lower than I would have expected,” he said.
One year post MI, LDL levels had dropped by a mean of 79 mg/dL in the FH group and 39 mg/dL in the non-FH patients. This translated into a 45% reduction in the FH patients, a significantly greater decrease than the 34% drop in the non-FH group. Nonetheless, 43% of FH patients had an LDL of 100 mg/dL or greater at 1 year, as did 26% without FH. These are patients who are particularly likely to benefit from more aggressive lipid-lowering after an acute coronary syndrome. Given that almost 90% of patients with FH remain undiagnosed, assessment for the genetic disorder in young patients with MI is an important means of case finding, the cardiologist observed.
Session cochair Carl E. Orringer, MD, director of preventive cardiovascular medicine at the University of Miami, said he and his colleagues have just initiated a program at that medical center whereby patients with an LDL of 190 mg/dL or more are identified through their electronic medical records and referred to a lipid clinic or cardiovascular prevention program.
“I think this is certainly something to think about for other programs because you want to make sure that if you have lipid intervention services, they actually take care of patients who are at the highest risk,” he said.
Substance abuse plays role
Elsewhere at ACC 2018, Ersilia M. Defilippis, MD, reported on an expanded population of 2,097 patients with a first type 1 MI prior to age 50 at the same two hospitals. Their electronic medical records revealed that 6.0% of them used marijuana and 4.7% used cocaine. During a median 11.2 years of follow-up, the group that used cocaine or marijuana had a 2.2-fold increased risk of cardiovascular death and a 2.0-fold increase in all-cause mortality, compared with nonusers, in an analysis adjusted for baseline differences.
Among these differences, 46% of drug users and 61% of nonusers were hyperlipidemic, 70% of users and 49% of nonusers were smokers, 8% of users and 4% of nonusers presented in cardiac arrest, and the median normalized troponin level was 61 interquartile range (IQR) in users versus 39 IQR in nonusers.
“Given these findings, young patients with MI should be screened for substance abuse and counseled about behavioral change to prevent future adverse events,” concluded Dr. Defilippis of Brigham and Women’s Hospital and Harvard University. She and Dr. Blankstein were coinvestigators in this study. She reported having no financial conflicts of interest. Dr. Blankstein reported receiving research grants from Amgen, Astellas, and Sanofi, and serves as a consultant to Amgen.
Source: Blankstein R. Abstracts 1180M-03 and 1262-436/436.
REPORTING FROM ACC 18
Key clinical point: Familial hypercholesterolemia is common in young adults with MI.
Major finding: Among patients with MI before age 50, a family history of premature CAD, and an LDL of 160 mg/dL or more, the prevalence of familial hypercholesterolemia was 64%.
Study details: This retrospective study involved 1,996 adults diagnosed with a type 1 MI before age 50.
Disclosures: The study presenter reported receiving research grants from Amgen, Astellas, and Sanofi and serving as a consultant to Amgen.
Source: Blankstein R. Abstracts 1180M-03 and 1262-436/436.