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Ticagrelor reversal agent looks promising
NEW ORLEANS – A novel targeted ticagrelor reversal agent demonstrated rapid and sustained reversal of the potent antiplatelet agent in a phase 1 proof-of-concept study, Deepak L. Bhatt, MD, reported at the annual meeting of the American College of Cardiology.
“Hopefully the FDA will view this as something that really is a breakthrough,” commented Dr. Bhatt, executive director of interventional cardiology programs at Brigham and Women’s Hospital and professor of medicine at Harvard University, both in Boston.
Why a breakthrough? Because despite recent major advances in the ability to reverse the action of the direct-acting oral anticoagulants and thereby greatly improve their safety margin, there have been no parallel developments with regard to the potent antiplatelet agents ticagrelor (Brilinta), prasugrel (Effient), and clopidogrel. The effects of these antiplatelet drugs take 3-5 days to dissipate after they’ve been stopped, which is highly problematic when they’ve induced catastrophic bleeding or a patient requires emergent or urgent surgery, the cardiologist explained.
“The ability to reverse tigracelor’s antiplatelet effects rapidly could distinguish it from other antiplatelet agents such as prasugrel or even generic clopidogrel and, for that matter, even aspirin,” Dr. Bhatt said.
The ticagrelor reversal agent, known for now as PB2452, is an intravenously administered recombinant human immunoglobulin G1 monoclonal antibody antigen-binding fragment. It binds specifically and with high affinity to ticagrelor and its active metabolite. In the phase 1, placebo-controlled, double-blind study conducted in 64 healthy volunteers pretreated with ticagrelor for 48 hours, it reversed oral ticagrelor’s antiplatelet effects within 5 minutes and, with prolonged infusion, showed sustained effect for at least 20 hours.
The only adverse events observed in blinded assessment were minor injection site issues.
PB2452 is specific to ticagrelor and will not reverse the activity of other potent antiplatelet agents. Indeed, because of their chemical structure, neither prasugrel nor clopidogrel is reversible, according to Dr. Bhatt.
He said the developmental game plan for the ticagrelor reversal agent is initially to get it approved by the Food and Drug Administration for ticagrelor-related catastrophic bleeding, such as intracranial hemorrhage, since there is a recognized major unmet need in such situations. But as shown in the phase 1 study, BP2452 is potentially titratable by varying the size of the initial bolus dose and the dosing and duration of the subsequent infusion. So after initial approval for catastrophic bleeding, it makes sense to branch out and conduct further studies establishing the reversal agent’s value for prevention of bleeding complications caused by ticagrelor. An example might be a patient on ticagrelor because she recently received a stent in her left main coronary artery who falls and breaks her hip, and her surgeon says she needs surgery right away.
“If someone on ticagrelor came in with an intracranial hemorrhage, you’d want rapid reversal and have it sustained for as many days as the neurologist advises, whereas maybe if someone came in on ticagrelor after placement of a left main stent and you needed to do a lumbar puncture, you’d want to reverse the antiplatelet effect for the LP, and then if things go smoothly you’d want to get the ticagrelor back on board so the stent doesn’t thrombose. But that type of more precise dosing will require further work,” according to the cardiologist.
Discussant Barbara S. Wiggins, PharmD, commented, “We’ve been fortunate to have reversal agents come out for oral anticoagulants, but in terms of antiplatelet activity we’ve not been able to be successful with platelet transfusions. So having a reversal agent added to our armamentarium certainly is something that’s desirable.”
The phase 1 study of PB2452 indicates the monoclonal antibody checks the key boxes one looks for in a reversal agent: quick onset, long duration of effect, lack of a rebound in platelet activity after drug cessation, and potential for tailored titration. Of course, data on efficacy outcomes will also be necessary, noted Dr. Wiggins, a clinical pharmacologist at the Medical University of South Carolina, Charleston.
She added that she was favorably impressed that Dr. Bhatt and his coinvestigators went to the trouble of convincingly demonstrating reversal of ticagrelor’s antiplatelet effects using three different assays: light transmission aggregometry, which is considered the standard, as well as the point-of-care VerifyNow P2Y12 assay and the modified CY-QUANT assay.
The phase 1 study was funded by PhaseBio Pharmaceuticals. Dr. Bhatt reported the company provided a research grant directly to Brigham and Women’s Hospital.
Simultaneous with Dr. Bhatt’s presentation, the study results were published online (N Engl J Med. 2019 Mar 17. doi: 10.1056/NEJMoa1901778).
NEW ORLEANS – A novel targeted ticagrelor reversal agent demonstrated rapid and sustained reversal of the potent antiplatelet agent in a phase 1 proof-of-concept study, Deepak L. Bhatt, MD, reported at the annual meeting of the American College of Cardiology.
“Hopefully the FDA will view this as something that really is a breakthrough,” commented Dr. Bhatt, executive director of interventional cardiology programs at Brigham and Women’s Hospital and professor of medicine at Harvard University, both in Boston.
Why a breakthrough? Because despite recent major advances in the ability to reverse the action of the direct-acting oral anticoagulants and thereby greatly improve their safety margin, there have been no parallel developments with regard to the potent antiplatelet agents ticagrelor (Brilinta), prasugrel (Effient), and clopidogrel. The effects of these antiplatelet drugs take 3-5 days to dissipate after they’ve been stopped, which is highly problematic when they’ve induced catastrophic bleeding or a patient requires emergent or urgent surgery, the cardiologist explained.
“The ability to reverse tigracelor’s antiplatelet effects rapidly could distinguish it from other antiplatelet agents such as prasugrel or even generic clopidogrel and, for that matter, even aspirin,” Dr. Bhatt said.
The ticagrelor reversal agent, known for now as PB2452, is an intravenously administered recombinant human immunoglobulin G1 monoclonal antibody antigen-binding fragment. It binds specifically and with high affinity to ticagrelor and its active metabolite. In the phase 1, placebo-controlled, double-blind study conducted in 64 healthy volunteers pretreated with ticagrelor for 48 hours, it reversed oral ticagrelor’s antiplatelet effects within 5 minutes and, with prolonged infusion, showed sustained effect for at least 20 hours.
The only adverse events observed in blinded assessment were minor injection site issues.
PB2452 is specific to ticagrelor and will not reverse the activity of other potent antiplatelet agents. Indeed, because of their chemical structure, neither prasugrel nor clopidogrel is reversible, according to Dr. Bhatt.
He said the developmental game plan for the ticagrelor reversal agent is initially to get it approved by the Food and Drug Administration for ticagrelor-related catastrophic bleeding, such as intracranial hemorrhage, since there is a recognized major unmet need in such situations. But as shown in the phase 1 study, BP2452 is potentially titratable by varying the size of the initial bolus dose and the dosing and duration of the subsequent infusion. So after initial approval for catastrophic bleeding, it makes sense to branch out and conduct further studies establishing the reversal agent’s value for prevention of bleeding complications caused by ticagrelor. An example might be a patient on ticagrelor because she recently received a stent in her left main coronary artery who falls and breaks her hip, and her surgeon says she needs surgery right away.
“If someone on ticagrelor came in with an intracranial hemorrhage, you’d want rapid reversal and have it sustained for as many days as the neurologist advises, whereas maybe if someone came in on ticagrelor after placement of a left main stent and you needed to do a lumbar puncture, you’d want to reverse the antiplatelet effect for the LP, and then if things go smoothly you’d want to get the ticagrelor back on board so the stent doesn’t thrombose. But that type of more precise dosing will require further work,” according to the cardiologist.
Discussant Barbara S. Wiggins, PharmD, commented, “We’ve been fortunate to have reversal agents come out for oral anticoagulants, but in terms of antiplatelet activity we’ve not been able to be successful with platelet transfusions. So having a reversal agent added to our armamentarium certainly is something that’s desirable.”
The phase 1 study of PB2452 indicates the monoclonal antibody checks the key boxes one looks for in a reversal agent: quick onset, long duration of effect, lack of a rebound in platelet activity after drug cessation, and potential for tailored titration. Of course, data on efficacy outcomes will also be necessary, noted Dr. Wiggins, a clinical pharmacologist at the Medical University of South Carolina, Charleston.
She added that she was favorably impressed that Dr. Bhatt and his coinvestigators went to the trouble of convincingly demonstrating reversal of ticagrelor’s antiplatelet effects using three different assays: light transmission aggregometry, which is considered the standard, as well as the point-of-care VerifyNow P2Y12 assay and the modified CY-QUANT assay.
The phase 1 study was funded by PhaseBio Pharmaceuticals. Dr. Bhatt reported the company provided a research grant directly to Brigham and Women’s Hospital.
Simultaneous with Dr. Bhatt’s presentation, the study results were published online (N Engl J Med. 2019 Mar 17. doi: 10.1056/NEJMoa1901778).
NEW ORLEANS – A novel targeted ticagrelor reversal agent demonstrated rapid and sustained reversal of the potent antiplatelet agent in a phase 1 proof-of-concept study, Deepak L. Bhatt, MD, reported at the annual meeting of the American College of Cardiology.
“Hopefully the FDA will view this as something that really is a breakthrough,” commented Dr. Bhatt, executive director of interventional cardiology programs at Brigham and Women’s Hospital and professor of medicine at Harvard University, both in Boston.
Why a breakthrough? Because despite recent major advances in the ability to reverse the action of the direct-acting oral anticoagulants and thereby greatly improve their safety margin, there have been no parallel developments with regard to the potent antiplatelet agents ticagrelor (Brilinta), prasugrel (Effient), and clopidogrel. The effects of these antiplatelet drugs take 3-5 days to dissipate after they’ve been stopped, which is highly problematic when they’ve induced catastrophic bleeding or a patient requires emergent or urgent surgery, the cardiologist explained.
“The ability to reverse tigracelor’s antiplatelet effects rapidly could distinguish it from other antiplatelet agents such as prasugrel or even generic clopidogrel and, for that matter, even aspirin,” Dr. Bhatt said.
The ticagrelor reversal agent, known for now as PB2452, is an intravenously administered recombinant human immunoglobulin G1 monoclonal antibody antigen-binding fragment. It binds specifically and with high affinity to ticagrelor and its active metabolite. In the phase 1, placebo-controlled, double-blind study conducted in 64 healthy volunteers pretreated with ticagrelor for 48 hours, it reversed oral ticagrelor’s antiplatelet effects within 5 minutes and, with prolonged infusion, showed sustained effect for at least 20 hours.
The only adverse events observed in blinded assessment were minor injection site issues.
PB2452 is specific to ticagrelor and will not reverse the activity of other potent antiplatelet agents. Indeed, because of their chemical structure, neither prasugrel nor clopidogrel is reversible, according to Dr. Bhatt.
He said the developmental game plan for the ticagrelor reversal agent is initially to get it approved by the Food and Drug Administration for ticagrelor-related catastrophic bleeding, such as intracranial hemorrhage, since there is a recognized major unmet need in such situations. But as shown in the phase 1 study, BP2452 is potentially titratable by varying the size of the initial bolus dose and the dosing and duration of the subsequent infusion. So after initial approval for catastrophic bleeding, it makes sense to branch out and conduct further studies establishing the reversal agent’s value for prevention of bleeding complications caused by ticagrelor. An example might be a patient on ticagrelor because she recently received a stent in her left main coronary artery who falls and breaks her hip, and her surgeon says she needs surgery right away.
“If someone on ticagrelor came in with an intracranial hemorrhage, you’d want rapid reversal and have it sustained for as many days as the neurologist advises, whereas maybe if someone came in on ticagrelor after placement of a left main stent and you needed to do a lumbar puncture, you’d want to reverse the antiplatelet effect for the LP, and then if things go smoothly you’d want to get the ticagrelor back on board so the stent doesn’t thrombose. But that type of more precise dosing will require further work,” according to the cardiologist.
Discussant Barbara S. Wiggins, PharmD, commented, “We’ve been fortunate to have reversal agents come out for oral anticoagulants, but in terms of antiplatelet activity we’ve not been able to be successful with platelet transfusions. So having a reversal agent added to our armamentarium certainly is something that’s desirable.”
The phase 1 study of PB2452 indicates the monoclonal antibody checks the key boxes one looks for in a reversal agent: quick onset, long duration of effect, lack of a rebound in platelet activity after drug cessation, and potential for tailored titration. Of course, data on efficacy outcomes will also be necessary, noted Dr. Wiggins, a clinical pharmacologist at the Medical University of South Carolina, Charleston.
She added that she was favorably impressed that Dr. Bhatt and his coinvestigators went to the trouble of convincingly demonstrating reversal of ticagrelor’s antiplatelet effects using three different assays: light transmission aggregometry, which is considered the standard, as well as the point-of-care VerifyNow P2Y12 assay and the modified CY-QUANT assay.
The phase 1 study was funded by PhaseBio Pharmaceuticals. Dr. Bhatt reported the company provided a research grant directly to Brigham and Women’s Hospital.
Simultaneous with Dr. Bhatt’s presentation, the study results were published online (N Engl J Med. 2019 Mar 17. doi: 10.1056/NEJMoa1901778).
REPORTING FROM ACC 19
Key clinical point: Oral ticagrelor’s antiplatelet effect was reversed within 5 minutes by a novel targeted monoclonal antibody.
Major finding: A novel targeted monoclonal antibody reversed oral ticagrelor’s antiplatelet effects within 5 minutes and, with prolonged infusion, showed sustained effect for at least 20 hours.
Study details: This phase 1 study included 64 healthy subjects pretreated with 48 hours of ticagrelor before receiving various doses of the reversal agent or placebo.
Disclosures: The study was funded by PhaseBio Pharmaceuticals, which provided a research grant directly to Brigham and Women’s Hospital.
Premature death from heart disease hits Asian subgroups hard
Among Asian American subgroups, Asian Indian, Filipino, and Vietnamese populations showed significantly higher premature death rates from ischemic heart disease, compared with other Asian subgroups, based on data from the National Center for Health Statistics for the years 2003 to 2012.
Previous studies have described death rates from cardiovascular disease in Asian subgroups, but premature death in particular has not been well studied, wrote Latha Palaniappan, MD, of the division of primary care and population health at the Stanford (Calif.) University, and her colleagues.
To examine premature mortality from cardiovascular disease in Asian subgroups, the researchers used years of potential life lost (YPLL) to measure premature mortality. “[Years of potential life lost ] compares age at death with average life expectancy to estimate the average time an individual would have lived had he/she not died prematurely from a specific disease,” they explained.
The study population included 354,256 Asian American decedents aged 25 years or older. Of that total, 59,936 died of ischemic heart disease and 28,489 died of cerebrovascular disease.
Overall, Asian men lost 779 years/100,000 people in 2003 and 574 years/100,000 in 2012. However, in 2003, Asian Indian men in particular lost 1,216 years/100,000, more than other Asian male subgroups and non-Hispanic white men.
“Use of race-specific life expectancy revealed greater heterogeneity in YPLL across all Asian subgroups,” the researchers wrote. Similarly, Asian Indian women had the highest years of potential life lost throughout the study period, with a high of 818 years/100,000 people in 2003 and 477 years/100,00 in 2012, compared with 577/100,000 and 426/100,000, respectively, among non-Hispanic white women.
All Asian male subgroups also lost more years of life to cerebrovascular disease, compared with non-Hispanic white men, and women in each Asian subgroup had a higher years of potential life lost, compared with non-Hispanic white women. Filipino men had the highest YPLL values for the period, followed by Vietnamese men, and the patterns were similar for Filipino and Vietnamese women.
Possible explanations for the high rate of premature death from ischemic heart disease in Asian Indians include greater prevalence of risk factors at younger age (including elevated apolipoprotein B100/apolipoprotein A-1 ratios), type 2 diabetes, and cardiometabolic abnormalities in people of normal weight that might go unnoticed in a clinical exam, the researchers said. In the case of cerebrovascular disease, possible risk factors for high years of potential life lost in certain subgroups include hypertension in Filipino populations, limited health literacy about stroke in Vietnamese populations, and high rates of smoking in Vietnamese men.
The study findings were limited by several factors, including the small amount of data on mortality in Asian Americans from census reports, the researchers noted. However, the use of years of potential life lost as a measure of the impact of cardiovascular disease provided a useful model of the impact of cardiovascular disease on life expectancy and total disease burden of cerebrovascular disease on Asian ethnic subgroups, they said.
“Our study also provides evidence that evaluating the Asian population together as one group underestimates the burden of [cerebrovascular disease],” they noted.
The National Institute of Minority Health and Health Disparities Research Project and the National Heart, Lung, and Blood Institute supported the study in part by grants to researchers. The researchers had no financial conflicts to disclose.
SOURCE: Iyer DG et al. J Am Heart Assoc. 2019 Mar 20. doi: 10.1161/JAHA.118.010744.
Among Asian American subgroups, Asian Indian, Filipino, and Vietnamese populations showed significantly higher premature death rates from ischemic heart disease, compared with other Asian subgroups, based on data from the National Center for Health Statistics for the years 2003 to 2012.
Previous studies have described death rates from cardiovascular disease in Asian subgroups, but premature death in particular has not been well studied, wrote Latha Palaniappan, MD, of the division of primary care and population health at the Stanford (Calif.) University, and her colleagues.
To examine premature mortality from cardiovascular disease in Asian subgroups, the researchers used years of potential life lost (YPLL) to measure premature mortality. “[Years of potential life lost ] compares age at death with average life expectancy to estimate the average time an individual would have lived had he/she not died prematurely from a specific disease,” they explained.
The study population included 354,256 Asian American decedents aged 25 years or older. Of that total, 59,936 died of ischemic heart disease and 28,489 died of cerebrovascular disease.
Overall, Asian men lost 779 years/100,000 people in 2003 and 574 years/100,000 in 2012. However, in 2003, Asian Indian men in particular lost 1,216 years/100,000, more than other Asian male subgroups and non-Hispanic white men.
“Use of race-specific life expectancy revealed greater heterogeneity in YPLL across all Asian subgroups,” the researchers wrote. Similarly, Asian Indian women had the highest years of potential life lost throughout the study period, with a high of 818 years/100,000 people in 2003 and 477 years/100,00 in 2012, compared with 577/100,000 and 426/100,000, respectively, among non-Hispanic white women.
All Asian male subgroups also lost more years of life to cerebrovascular disease, compared with non-Hispanic white men, and women in each Asian subgroup had a higher years of potential life lost, compared with non-Hispanic white women. Filipino men had the highest YPLL values for the period, followed by Vietnamese men, and the patterns were similar for Filipino and Vietnamese women.
Possible explanations for the high rate of premature death from ischemic heart disease in Asian Indians include greater prevalence of risk factors at younger age (including elevated apolipoprotein B100/apolipoprotein A-1 ratios), type 2 diabetes, and cardiometabolic abnormalities in people of normal weight that might go unnoticed in a clinical exam, the researchers said. In the case of cerebrovascular disease, possible risk factors for high years of potential life lost in certain subgroups include hypertension in Filipino populations, limited health literacy about stroke in Vietnamese populations, and high rates of smoking in Vietnamese men.
The study findings were limited by several factors, including the small amount of data on mortality in Asian Americans from census reports, the researchers noted. However, the use of years of potential life lost as a measure of the impact of cardiovascular disease provided a useful model of the impact of cardiovascular disease on life expectancy and total disease burden of cerebrovascular disease on Asian ethnic subgroups, they said.
“Our study also provides evidence that evaluating the Asian population together as one group underestimates the burden of [cerebrovascular disease],” they noted.
The National Institute of Minority Health and Health Disparities Research Project and the National Heart, Lung, and Blood Institute supported the study in part by grants to researchers. The researchers had no financial conflicts to disclose.
SOURCE: Iyer DG et al. J Am Heart Assoc. 2019 Mar 20. doi: 10.1161/JAHA.118.010744.
Among Asian American subgroups, Asian Indian, Filipino, and Vietnamese populations showed significantly higher premature death rates from ischemic heart disease, compared with other Asian subgroups, based on data from the National Center for Health Statistics for the years 2003 to 2012.
Previous studies have described death rates from cardiovascular disease in Asian subgroups, but premature death in particular has not been well studied, wrote Latha Palaniappan, MD, of the division of primary care and population health at the Stanford (Calif.) University, and her colleagues.
To examine premature mortality from cardiovascular disease in Asian subgroups, the researchers used years of potential life lost (YPLL) to measure premature mortality. “[Years of potential life lost ] compares age at death with average life expectancy to estimate the average time an individual would have lived had he/she not died prematurely from a specific disease,” they explained.
The study population included 354,256 Asian American decedents aged 25 years or older. Of that total, 59,936 died of ischemic heart disease and 28,489 died of cerebrovascular disease.
Overall, Asian men lost 779 years/100,000 people in 2003 and 574 years/100,000 in 2012. However, in 2003, Asian Indian men in particular lost 1,216 years/100,000, more than other Asian male subgroups and non-Hispanic white men.
“Use of race-specific life expectancy revealed greater heterogeneity in YPLL across all Asian subgroups,” the researchers wrote. Similarly, Asian Indian women had the highest years of potential life lost throughout the study period, with a high of 818 years/100,000 people in 2003 and 477 years/100,00 in 2012, compared with 577/100,000 and 426/100,000, respectively, among non-Hispanic white women.
All Asian male subgroups also lost more years of life to cerebrovascular disease, compared with non-Hispanic white men, and women in each Asian subgroup had a higher years of potential life lost, compared with non-Hispanic white women. Filipino men had the highest YPLL values for the period, followed by Vietnamese men, and the patterns were similar for Filipino and Vietnamese women.
Possible explanations for the high rate of premature death from ischemic heart disease in Asian Indians include greater prevalence of risk factors at younger age (including elevated apolipoprotein B100/apolipoprotein A-1 ratios), type 2 diabetes, and cardiometabolic abnormalities in people of normal weight that might go unnoticed in a clinical exam, the researchers said. In the case of cerebrovascular disease, possible risk factors for high years of potential life lost in certain subgroups include hypertension in Filipino populations, limited health literacy about stroke in Vietnamese populations, and high rates of smoking in Vietnamese men.
The study findings were limited by several factors, including the small amount of data on mortality in Asian Americans from census reports, the researchers noted. However, the use of years of potential life lost as a measure of the impact of cardiovascular disease provided a useful model of the impact of cardiovascular disease on life expectancy and total disease burden of cerebrovascular disease on Asian ethnic subgroups, they said.
“Our study also provides evidence that evaluating the Asian population together as one group underestimates the burden of [cerebrovascular disease],” they noted.
The National Institute of Minority Health and Health Disparities Research Project and the National Heart, Lung, and Blood Institute supported the study in part by grants to researchers. The researchers had no financial conflicts to disclose.
SOURCE: Iyer DG et al. J Am Heart Assoc. 2019 Mar 20. doi: 10.1161/JAHA.118.010744.
FROM THE JOURNAL OF THE AMERICAN HEART ASSOCIATION
Key clinical point: Asian Indian, Filipino, and Vietnamese populations had the greatest loss of life from heart attacks and strokes among Asian population subgroups.
Major finding: Asian Indian men lost an average of 17 years of life to ischemic heart disease.
Study details: The data come from the National Center for Health Statistics Multiple Causes of Death mortality files from 2003 to 2012.
Disclosures: The National Institute of Minority Health and Health Disparities Research Project and the National Heart, Lung, and Blood Institute supported the study in part by grants to researchers. The researchers had no financial conflicts to disclose.
Source: Iyer DG et al. J Am Heart Assoc. 2019 Mar 20. doi: 10.1161/JAHA.118.010744.
Immediate angiography after non-STEMI cardiac arrest confers no survival benefit
Immediate angiography after resuscitation from out-of-hospital cardiac arrest does not improve survival compared to delaying angiography until neurologic recovery in patients with no evidence of ST-segment elevation myocardial infarction, according to data presented at the annual meeting of the American College of Cardiology.
The Coronary Angiography after Cardiac Arrest (COACT) trial involved 552 patients who had been successfully resuscitated after out-of-hospital cardiac arrest, without signs of ST-segment elevation myocardial infarction. The study also excluded patients with shock and severe renal dysfunction, and was not blinded, so this may have influenced treatment decisions.
Patients were randomized either to immediate coronary angiography after resuscitation, while still unconscious, or delayed coronary angiography until they had recovered neurologically, which was generally after discharge from intensive care.
Overall, 97.1% of patients in the immediate angiography group and 64.9% of the delayed angiography group underwent coronary angiography, with the median time until angiography being 0.8 hours in the immediate group and 119.9 hours in the delayed group.
In the immediate angiography group, 3.4% of patients were found to have an acute coronary occlusion, while in the delayed group that figure was 7.6%. Percutaneous coronary intervention was performed in 33% of the immediate angiography group and 24.2% of the delayed angiography group.
Survival rates at 90 days were not significantly different between the two groups; 64.5% of the immediate angiography group and 67.2% of the delayed angiography group survived to 90 days (OR 0.89, P = 0.51). The two groups also did not significantly differ in the secondary endpoints of survival with good cerebral performance or mild-to-moderate disability (62.9% vs. 64.4%).
“Our findings do not corroborate findings of previous observational studies, which showed a survival benefit with immediate coronary angiography in patients who had cardiac arrest without STEMI,” wrote Dr. Jorrit S. Lemkes, from the department of cardiology at Amsterdam University Medical Center VUmc, and co-authors. “This difference could be related to the observational nature of the previous studies, which may have resulted in selection bias that favored treating patients who had a presumed better prognosis with a strategy of immediate angiography.”
They also suggested the lack of benefit from early coronary angiography could relate to the fact that majority of those who died did so as a result of neurological complications, as has been seen in other studies of resuscitation.
The authors did note that the vast majority of patients in the study had stable coronary artery lesions, and only 5% showed thrombotic occlusions. They suggested this could explain their results, as percutaneous coronary intervention was not associated with improved outcomes in patients with stable coronary artery lesions – only in patients with acute thrombotic coronary occlusions.
However, they did see the suggestion of a treatment effect in patients over 70 years old and those with a history of coronary artery disease.
The study also revealed differences in subsequent treatment between patients who underwent immediate coronary angiography and those who had delayed angiography. Those in the delayed group were significantly more likely to be treated with salicylates or a P2Y12 inhibitor than those in the immediate angiography group.
“This observation illustrates how the result of immediate coronary angiography can influence treatment, since patients who did not have evidence of coronary artery disease on angiography do not require antiplatelet therapy,” the authors wrote.
Conversely, patients in the immediate angiography were more likely to receive a glycoprotein IIb/IIIa inhibitor. However the authors said these different strategies did not translate to any significant difference in major bleeding.
The COACT trial results were published in the New England Journal of Medicine simultaneously with Dr.Lemkes's presentation.
COACT was supported by the Netherlands Heart Institute, Biotronik and AstraZeneca. Two authors declared grants and support from the study supporters, both in and outside the context of the study. One author declared grants from private industry outside the study. No other conflicts of interest were declared.
SOURCE: Lemkes J et al. NEJM, 2019, March 18. DOI: 10.1056/NEJMoa1816897
The results of the COACT trial are consistent with other studies in patients with acute coronary syndromes but without evidence of STEMI or cardiac arrest, showing that immediate coronary angiography is not associated with improved outcomes.
However, less than 20% of the COACT cohort had unstable coronary lesions and less than 40% underwent coronary interventions, so relatively few patients would have been affected by the timing of coronary angiography or the procedure itself. In this trial, more than 60% of deaths were due to neurologic injury rather than cardiac complications.
Enriching the study population with patients with probable coronary disease might have led to a different result. A substudy analysis of patients over age 70 with a history of coronary disease showed they were more likely to benefit from immediate coronary angiography than were younger patients without a history of coronary disease.
Prioritizing interventions also had an impact on targeted temperature managemen, which also may have played into the results. The median time to achieve target temperature was 5.4 hours in the immediate angiography group and 4.7 hours in the delayed angiography group.
Additional insights may come from two ongoing clinical trials, ACCESS and DISCO (Direct or Subacute Coronary Angiography in Out-of-hospital Cardiac Arrest), may shed additional light on how interventions after out-of-hospital cardiac arrest affect patient outcomes.
Dr. Benjamin S. Abella is from the Center for Resuscitation Science and Department of Emergency Medicine at the University of Pennsylvania Perelman School of Medicine and Dr. David F. Gaieski is from the Department of Emergency Medicine at Jefferson Medical College. These comments are adapted from an accompanying editorial (NEJM 2019, March 18. DOI: 10.1056/NEJMe1901651). Both authors declared grants, personal support and other support from private industry outside the submitted work.
The results of the COACT trial are consistent with other studies in patients with acute coronary syndromes but without evidence of STEMI or cardiac arrest, showing that immediate coronary angiography is not associated with improved outcomes.
However, less than 20% of the COACT cohort had unstable coronary lesions and less than 40% underwent coronary interventions, so relatively few patients would have been affected by the timing of coronary angiography or the procedure itself. In this trial, more than 60% of deaths were due to neurologic injury rather than cardiac complications.
Enriching the study population with patients with probable coronary disease might have led to a different result. A substudy analysis of patients over age 70 with a history of coronary disease showed they were more likely to benefit from immediate coronary angiography than were younger patients without a history of coronary disease.
Prioritizing interventions also had an impact on targeted temperature managemen, which also may have played into the results. The median time to achieve target temperature was 5.4 hours in the immediate angiography group and 4.7 hours in the delayed angiography group.
Additional insights may come from two ongoing clinical trials, ACCESS and DISCO (Direct or Subacute Coronary Angiography in Out-of-hospital Cardiac Arrest), may shed additional light on how interventions after out-of-hospital cardiac arrest affect patient outcomes.
Dr. Benjamin S. Abella is from the Center for Resuscitation Science and Department of Emergency Medicine at the University of Pennsylvania Perelman School of Medicine and Dr. David F. Gaieski is from the Department of Emergency Medicine at Jefferson Medical College. These comments are adapted from an accompanying editorial (NEJM 2019, March 18. DOI: 10.1056/NEJMe1901651). Both authors declared grants, personal support and other support from private industry outside the submitted work.
The results of the COACT trial are consistent with other studies in patients with acute coronary syndromes but without evidence of STEMI or cardiac arrest, showing that immediate coronary angiography is not associated with improved outcomes.
However, less than 20% of the COACT cohort had unstable coronary lesions and less than 40% underwent coronary interventions, so relatively few patients would have been affected by the timing of coronary angiography or the procedure itself. In this trial, more than 60% of deaths were due to neurologic injury rather than cardiac complications.
Enriching the study population with patients with probable coronary disease might have led to a different result. A substudy analysis of patients over age 70 with a history of coronary disease showed they were more likely to benefit from immediate coronary angiography than were younger patients without a history of coronary disease.
Prioritizing interventions also had an impact on targeted temperature managemen, which also may have played into the results. The median time to achieve target temperature was 5.4 hours in the immediate angiography group and 4.7 hours in the delayed angiography group.
Additional insights may come from two ongoing clinical trials, ACCESS and DISCO (Direct or Subacute Coronary Angiography in Out-of-hospital Cardiac Arrest), may shed additional light on how interventions after out-of-hospital cardiac arrest affect patient outcomes.
Dr. Benjamin S. Abella is from the Center for Resuscitation Science and Department of Emergency Medicine at the University of Pennsylvania Perelman School of Medicine and Dr. David F. Gaieski is from the Department of Emergency Medicine at Jefferson Medical College. These comments are adapted from an accompanying editorial (NEJM 2019, March 18. DOI: 10.1056/NEJMe1901651). Both authors declared grants, personal support and other support from private industry outside the submitted work.
Immediate angiography after resuscitation from out-of-hospital cardiac arrest does not improve survival compared to delaying angiography until neurologic recovery in patients with no evidence of ST-segment elevation myocardial infarction, according to data presented at the annual meeting of the American College of Cardiology.
The Coronary Angiography after Cardiac Arrest (COACT) trial involved 552 patients who had been successfully resuscitated after out-of-hospital cardiac arrest, without signs of ST-segment elevation myocardial infarction. The study also excluded patients with shock and severe renal dysfunction, and was not blinded, so this may have influenced treatment decisions.
Patients were randomized either to immediate coronary angiography after resuscitation, while still unconscious, or delayed coronary angiography until they had recovered neurologically, which was generally after discharge from intensive care.
Overall, 97.1% of patients in the immediate angiography group and 64.9% of the delayed angiography group underwent coronary angiography, with the median time until angiography being 0.8 hours in the immediate group and 119.9 hours in the delayed group.
In the immediate angiography group, 3.4% of patients were found to have an acute coronary occlusion, while in the delayed group that figure was 7.6%. Percutaneous coronary intervention was performed in 33% of the immediate angiography group and 24.2% of the delayed angiography group.
Survival rates at 90 days were not significantly different between the two groups; 64.5% of the immediate angiography group and 67.2% of the delayed angiography group survived to 90 days (OR 0.89, P = 0.51). The two groups also did not significantly differ in the secondary endpoints of survival with good cerebral performance or mild-to-moderate disability (62.9% vs. 64.4%).
“Our findings do not corroborate findings of previous observational studies, which showed a survival benefit with immediate coronary angiography in patients who had cardiac arrest without STEMI,” wrote Dr. Jorrit S. Lemkes, from the department of cardiology at Amsterdam University Medical Center VUmc, and co-authors. “This difference could be related to the observational nature of the previous studies, which may have resulted in selection bias that favored treating patients who had a presumed better prognosis with a strategy of immediate angiography.”
They also suggested the lack of benefit from early coronary angiography could relate to the fact that majority of those who died did so as a result of neurological complications, as has been seen in other studies of resuscitation.
The authors did note that the vast majority of patients in the study had stable coronary artery lesions, and only 5% showed thrombotic occlusions. They suggested this could explain their results, as percutaneous coronary intervention was not associated with improved outcomes in patients with stable coronary artery lesions – only in patients with acute thrombotic coronary occlusions.
However, they did see the suggestion of a treatment effect in patients over 70 years old and those with a history of coronary artery disease.
The study also revealed differences in subsequent treatment between patients who underwent immediate coronary angiography and those who had delayed angiography. Those in the delayed group were significantly more likely to be treated with salicylates or a P2Y12 inhibitor than those in the immediate angiography group.
“This observation illustrates how the result of immediate coronary angiography can influence treatment, since patients who did not have evidence of coronary artery disease on angiography do not require antiplatelet therapy,” the authors wrote.
Conversely, patients in the immediate angiography were more likely to receive a glycoprotein IIb/IIIa inhibitor. However the authors said these different strategies did not translate to any significant difference in major bleeding.
The COACT trial results were published in the New England Journal of Medicine simultaneously with Dr.Lemkes's presentation.
COACT was supported by the Netherlands Heart Institute, Biotronik and AstraZeneca. Two authors declared grants and support from the study supporters, both in and outside the context of the study. One author declared grants from private industry outside the study. No other conflicts of interest were declared.
SOURCE: Lemkes J et al. NEJM, 2019, March 18. DOI: 10.1056/NEJMoa1816897
Immediate angiography after resuscitation from out-of-hospital cardiac arrest does not improve survival compared to delaying angiography until neurologic recovery in patients with no evidence of ST-segment elevation myocardial infarction, according to data presented at the annual meeting of the American College of Cardiology.
The Coronary Angiography after Cardiac Arrest (COACT) trial involved 552 patients who had been successfully resuscitated after out-of-hospital cardiac arrest, without signs of ST-segment elevation myocardial infarction. The study also excluded patients with shock and severe renal dysfunction, and was not blinded, so this may have influenced treatment decisions.
Patients were randomized either to immediate coronary angiography after resuscitation, while still unconscious, or delayed coronary angiography until they had recovered neurologically, which was generally after discharge from intensive care.
Overall, 97.1% of patients in the immediate angiography group and 64.9% of the delayed angiography group underwent coronary angiography, with the median time until angiography being 0.8 hours in the immediate group and 119.9 hours in the delayed group.
In the immediate angiography group, 3.4% of patients were found to have an acute coronary occlusion, while in the delayed group that figure was 7.6%. Percutaneous coronary intervention was performed in 33% of the immediate angiography group and 24.2% of the delayed angiography group.
Survival rates at 90 days were not significantly different between the two groups; 64.5% of the immediate angiography group and 67.2% of the delayed angiography group survived to 90 days (OR 0.89, P = 0.51). The two groups also did not significantly differ in the secondary endpoints of survival with good cerebral performance or mild-to-moderate disability (62.9% vs. 64.4%).
“Our findings do not corroborate findings of previous observational studies, which showed a survival benefit with immediate coronary angiography in patients who had cardiac arrest without STEMI,” wrote Dr. Jorrit S. Lemkes, from the department of cardiology at Amsterdam University Medical Center VUmc, and co-authors. “This difference could be related to the observational nature of the previous studies, which may have resulted in selection bias that favored treating patients who had a presumed better prognosis with a strategy of immediate angiography.”
They also suggested the lack of benefit from early coronary angiography could relate to the fact that majority of those who died did so as a result of neurological complications, as has been seen in other studies of resuscitation.
The authors did note that the vast majority of patients in the study had stable coronary artery lesions, and only 5% showed thrombotic occlusions. They suggested this could explain their results, as percutaneous coronary intervention was not associated with improved outcomes in patients with stable coronary artery lesions – only in patients with acute thrombotic coronary occlusions.
However, they did see the suggestion of a treatment effect in patients over 70 years old and those with a history of coronary artery disease.
The study also revealed differences in subsequent treatment between patients who underwent immediate coronary angiography and those who had delayed angiography. Those in the delayed group were significantly more likely to be treated with salicylates or a P2Y12 inhibitor than those in the immediate angiography group.
“This observation illustrates how the result of immediate coronary angiography can influence treatment, since patients who did not have evidence of coronary artery disease on angiography do not require antiplatelet therapy,” the authors wrote.
Conversely, patients in the immediate angiography were more likely to receive a glycoprotein IIb/IIIa inhibitor. However the authors said these different strategies did not translate to any significant difference in major bleeding.
The COACT trial results were published in the New England Journal of Medicine simultaneously with Dr.Lemkes's presentation.
COACT was supported by the Netherlands Heart Institute, Biotronik and AstraZeneca. Two authors declared grants and support from the study supporters, both in and outside the context of the study. One author declared grants from private industry outside the study. No other conflicts of interest were declared.
SOURCE: Lemkes J et al. NEJM, 2019, March 18. DOI: 10.1056/NEJMoa1816897
FROM ACC 19
Poor COPD management might increase MI risk in HIV
SEATTLE – Chronic obstructive pulmonary disease is independently associated with an increased risk of myocardial infarction in people with HIV, according to a report at the Conference on Retroviruses and Opportunistic Infections.
Chronic obstructive pulmonary disease (COPD) is known to increase the risk of myocardial infarction (MI) in the general population, but hadn’t been shown until now to do the same in HIV. The study raises the question of whether COPD is being managed adequately in patients with the virus, according to study lead Kristina Crothers, MD, associate professor in the division of pulmonary, critical care & sleep medicine at the University of Washington, Seattle.
The investigators reviewed 25,509 HIV patients in the Center for AIDS Research Network of Integrated Clinical Systems cohort, a large electronic database of HIV-infected people. They defined COPD by diagnostic codes and inhaler prescriptions. MIs were adjudicated by review.
The team identified 423 subjects with moderate to severe COPD, and 698 who had MIs, including 339 type 1 MIs (T1MI) from a ruptured plaque (54%), and 294 (46%) type 2 heart attacks (T2MI) from a supply-demand mismatch due to sepsis or some other problem. In general, T2MIs are far more common in people with HIV.
COPD was associated with a greater than twofold increased risk of MI after adjustment for age, sex, viral load, nadir CD4 count, hypertension, and other confounders. The risk dropped slightly when smoking – both current smoking and pack years – was added to the model (adjusted hazard ratio 1.88, 95% confidence interval, 1.34-2.63).
The association was particularly strong for T2MI, especially in the setting of bacteremia and sepsis, and unlike T1MI, it remained significant after adjustment for smoking.
The study establishes a link between COPD and MI in HIV, but it could not answer what’s going on. Chronic inflammation from the virus could be at play, but the team also found hints of inadequate COPD management.
“About 60% of patients were on inhalers ... but only about 25% of them were on long-acting inhalers. 75% were only on short-acting.” That’s a problem because long-acting inhalers are needed to control exacerbations, Dr. Crothers said.
The study didn’t capture exacerbation rates, but increased rates could help explain the MI risk. Increased rates of pneumonia could as well, since pneumonia is a common cause of sepsis.
“We need to better manage complications of COPD in this population. I think optimizing long-term COPD management could have many beneficial effects,” Dr. Crothers said.
The National Institutes of Health funded the work. Dr. Crothers had no disclosures.
SOURCE: Crothers K et al. CROI 2019, Abstract 31.
SEATTLE – Chronic obstructive pulmonary disease is independently associated with an increased risk of myocardial infarction in people with HIV, according to a report at the Conference on Retroviruses and Opportunistic Infections.
Chronic obstructive pulmonary disease (COPD) is known to increase the risk of myocardial infarction (MI) in the general population, but hadn’t been shown until now to do the same in HIV. The study raises the question of whether COPD is being managed adequately in patients with the virus, according to study lead Kristina Crothers, MD, associate professor in the division of pulmonary, critical care & sleep medicine at the University of Washington, Seattle.
The investigators reviewed 25,509 HIV patients in the Center for AIDS Research Network of Integrated Clinical Systems cohort, a large electronic database of HIV-infected people. They defined COPD by diagnostic codes and inhaler prescriptions. MIs were adjudicated by review.
The team identified 423 subjects with moderate to severe COPD, and 698 who had MIs, including 339 type 1 MIs (T1MI) from a ruptured plaque (54%), and 294 (46%) type 2 heart attacks (T2MI) from a supply-demand mismatch due to sepsis or some other problem. In general, T2MIs are far more common in people with HIV.
COPD was associated with a greater than twofold increased risk of MI after adjustment for age, sex, viral load, nadir CD4 count, hypertension, and other confounders. The risk dropped slightly when smoking – both current smoking and pack years – was added to the model (adjusted hazard ratio 1.88, 95% confidence interval, 1.34-2.63).
The association was particularly strong for T2MI, especially in the setting of bacteremia and sepsis, and unlike T1MI, it remained significant after adjustment for smoking.
The study establishes a link between COPD and MI in HIV, but it could not answer what’s going on. Chronic inflammation from the virus could be at play, but the team also found hints of inadequate COPD management.
“About 60% of patients were on inhalers ... but only about 25% of them were on long-acting inhalers. 75% were only on short-acting.” That’s a problem because long-acting inhalers are needed to control exacerbations, Dr. Crothers said.
The study didn’t capture exacerbation rates, but increased rates could help explain the MI risk. Increased rates of pneumonia could as well, since pneumonia is a common cause of sepsis.
“We need to better manage complications of COPD in this population. I think optimizing long-term COPD management could have many beneficial effects,” Dr. Crothers said.
The National Institutes of Health funded the work. Dr. Crothers had no disclosures.
SOURCE: Crothers K et al. CROI 2019, Abstract 31.
SEATTLE – Chronic obstructive pulmonary disease is independently associated with an increased risk of myocardial infarction in people with HIV, according to a report at the Conference on Retroviruses and Opportunistic Infections.
Chronic obstructive pulmonary disease (COPD) is known to increase the risk of myocardial infarction (MI) in the general population, but hadn’t been shown until now to do the same in HIV. The study raises the question of whether COPD is being managed adequately in patients with the virus, according to study lead Kristina Crothers, MD, associate professor in the division of pulmonary, critical care & sleep medicine at the University of Washington, Seattle.
The investigators reviewed 25,509 HIV patients in the Center for AIDS Research Network of Integrated Clinical Systems cohort, a large electronic database of HIV-infected people. They defined COPD by diagnostic codes and inhaler prescriptions. MIs were adjudicated by review.
The team identified 423 subjects with moderate to severe COPD, and 698 who had MIs, including 339 type 1 MIs (T1MI) from a ruptured plaque (54%), and 294 (46%) type 2 heart attacks (T2MI) from a supply-demand mismatch due to sepsis or some other problem. In general, T2MIs are far more common in people with HIV.
COPD was associated with a greater than twofold increased risk of MI after adjustment for age, sex, viral load, nadir CD4 count, hypertension, and other confounders. The risk dropped slightly when smoking – both current smoking and pack years – was added to the model (adjusted hazard ratio 1.88, 95% confidence interval, 1.34-2.63).
The association was particularly strong for T2MI, especially in the setting of bacteremia and sepsis, and unlike T1MI, it remained significant after adjustment for smoking.
The study establishes a link between COPD and MI in HIV, but it could not answer what’s going on. Chronic inflammation from the virus could be at play, but the team also found hints of inadequate COPD management.
“About 60% of patients were on inhalers ... but only about 25% of them were on long-acting inhalers. 75% were only on short-acting.” That’s a problem because long-acting inhalers are needed to control exacerbations, Dr. Crothers said.
The study didn’t capture exacerbation rates, but increased rates could help explain the MI risk. Increased rates of pneumonia could as well, since pneumonia is a common cause of sepsis.
“We need to better manage complications of COPD in this population. I think optimizing long-term COPD management could have many beneficial effects,” Dr. Crothers said.
The National Institutes of Health funded the work. Dr. Crothers had no disclosures.
SOURCE: Crothers K et al. CROI 2019, Abstract 31.
REPORTING FROM CROI 2019
Death data spur black-box warning for gout drug Uloric
, the Food and Drug Administration declared on Feb. 21. The agency is now mandating a black-box warning.
“Health care professionals should reserve Uloric for use only in patients who have failed or do not tolerate allopurinol,” the FDA announced. “Counsel patients about the cardiovascular risk with Uloric,” the agency suggested, and advise them to seek medical attention at once if they have cardiac symptoms such as chest pain, shortness of breath, rapid or irregular heartbeat, or dizziness.
The FDA’s move comes a decade after it approved febuxostat as a gout treatment. As the FDA noted in its announcement, “the number of medicines to treat gout is limited, and there is an unmet need for treatments for this disease.”
Research has suggested that both febuxostat and allopurinol have similar efficacy. Some experts have recommended febuxostat as an alternative for patients who shouldn’t take allopurinol (Semin Arthritis Rheum. 2013 Dec;43[3]:367-75).
However, research has raised concerns about febuxostat’s cardiac risk. In its Feb. 21 statement, the FDA pointed to the findings of a 2010-2017 postmarket clinical trial of 6,190 patients with gout who were treated with febuxostat or allopurinol (N Engl J Med. 2018;378:1200-10).
“In patients treated with Uloric, 15 deaths from heart-related causes were observed for every 1,000 patients treated for a year compared to 11 deaths from heart-related causes per 1,000 patients treated with allopurinol for a year,” the FDA said. “In addition, there were 26 deaths from any cause per 1,000 patients treated for a year with Uloric compared to 22 deaths per 1,000 patients treated for a year with allopurinol.”
, the Food and Drug Administration declared on Feb. 21. The agency is now mandating a black-box warning.
“Health care professionals should reserve Uloric for use only in patients who have failed or do not tolerate allopurinol,” the FDA announced. “Counsel patients about the cardiovascular risk with Uloric,” the agency suggested, and advise them to seek medical attention at once if they have cardiac symptoms such as chest pain, shortness of breath, rapid or irregular heartbeat, or dizziness.
The FDA’s move comes a decade after it approved febuxostat as a gout treatment. As the FDA noted in its announcement, “the number of medicines to treat gout is limited, and there is an unmet need for treatments for this disease.”
Research has suggested that both febuxostat and allopurinol have similar efficacy. Some experts have recommended febuxostat as an alternative for patients who shouldn’t take allopurinol (Semin Arthritis Rheum. 2013 Dec;43[3]:367-75).
However, research has raised concerns about febuxostat’s cardiac risk. In its Feb. 21 statement, the FDA pointed to the findings of a 2010-2017 postmarket clinical trial of 6,190 patients with gout who were treated with febuxostat or allopurinol (N Engl J Med. 2018;378:1200-10).
“In patients treated with Uloric, 15 deaths from heart-related causes were observed for every 1,000 patients treated for a year compared to 11 deaths from heart-related causes per 1,000 patients treated with allopurinol for a year,” the FDA said. “In addition, there were 26 deaths from any cause per 1,000 patients treated for a year with Uloric compared to 22 deaths per 1,000 patients treated for a year with allopurinol.”
, the Food and Drug Administration declared on Feb. 21. The agency is now mandating a black-box warning.
“Health care professionals should reserve Uloric for use only in patients who have failed or do not tolerate allopurinol,” the FDA announced. “Counsel patients about the cardiovascular risk with Uloric,” the agency suggested, and advise them to seek medical attention at once if they have cardiac symptoms such as chest pain, shortness of breath, rapid or irregular heartbeat, or dizziness.
The FDA’s move comes a decade after it approved febuxostat as a gout treatment. As the FDA noted in its announcement, “the number of medicines to treat gout is limited, and there is an unmet need for treatments for this disease.”
Research has suggested that both febuxostat and allopurinol have similar efficacy. Some experts have recommended febuxostat as an alternative for patients who shouldn’t take allopurinol (Semin Arthritis Rheum. 2013 Dec;43[3]:367-75).
However, research has raised concerns about febuxostat’s cardiac risk. In its Feb. 21 statement, the FDA pointed to the findings of a 2010-2017 postmarket clinical trial of 6,190 patients with gout who were treated with febuxostat or allopurinol (N Engl J Med. 2018;378:1200-10).
“In patients treated with Uloric, 15 deaths from heart-related causes were observed for every 1,000 patients treated for a year compared to 11 deaths from heart-related causes per 1,000 patients treated with allopurinol for a year,” the FDA said. “In addition, there were 26 deaths from any cause per 1,000 patients treated for a year with Uloric compared to 22 deaths per 1,000 patients treated for a year with allopurinol.”
Hormone therapy in transgender individuals may up risk of CV events
when compared with the general population, according to a study that analyzed medical records of more than 6,000 patients.
“In light of our results, we urge both physicians and transgender individuals to be aware of this increased cardiovascular risk,” first author Nienke M. Nota, MD, said in a press release for the study, which was published online Feb. 18 in Circulation. “It may be helpful to reduce risk factors by stopping smoking, exercising, eating a healthy diet, and losing weight, if needed, before starting therapy, and clinicians should continue to evaluate patients on an ongoing basis thereafter.”Dr. Nota and her colleagues at the Amsterdam University Medical Center analyzed the risk of cardiovascular events by comparing the medical records of 6,793 individuals, including only patients who received hormone therapy at their center or affiliate. They did not include those who had discontinued hormone therapy for an extended period or had alternated female and male sex hormones.
They defined transmen as indiviuals assigned female sex at birth but who had male gender identity, and transwomen as those assigned male sex at birth but with female gender identity.*
Researchers analyzed 2,517 transwomen (median age 30 years) and 1,358 transmen (median age 23 years) who received hormone therapy (defined as estrogen with and without androgen-suppressors for transwomen and testosterone for transmen) at the center gender’s clinic between 1972 and 2015. These records were compared with those of cisgender women and men (individuals whose gender identity matches their assigned birth gender).
The mean follow-up duration was 9.07 years for transwomen and 8.10 years for transmen. The researchers compared observed cases of stroke, myocardial infarction (MI), and venous thromboembolism (VTE) with expected cases using cisgender reference women and men. There were 29 stroke events, 30 MIs, and 73 VTE events for transwomen and 6 stroke, 11 MIs, and 2 VTE events for transmen.
There was a greater risk of stroke for transwomen, compared with cisgender women (standardized incidence ratio [SIR] = 2.42) and cisgender men (1.80), and a significantly greater risk of VTE, compared with cisgender women (5.52) and cisgender men (4.55).
The rate of MI was also significantly higher in transwomen, compared with cisgender women (2.64) and in transmen compared with cisgender women (3.69).
In a subgroup analysis, the researchers found ethinylestradiol use prior to 2001 did not significantly change the incident rate of cardiovascular events, but noted there was a lower rate of VTE when transwomen who began hormone therapy prior to 2001 were excluded from the analysis.
The researchers noted that hormone therapy may increase the risk of cardiovascular events in transgender individuals, in part, due to hormone therapy’s effect on cardiovascular risk factors such as lipid levels. Although a previous study analyzed the risk of cardiovascular events in transwomen and transmen, the researchers said that study could not conclude there was an increased risk of cardiovascular events for transmen.
The researchers said the results may be limited by study design, and their analysis of medical records could not account for potential confounders such as psychosocial stressors and smoking, as well as the decreasing risk of cardiovascular events over the period of the study, and assessing cardiovascular events differently than reference studies used.
The study had no specific funding, and the authors reported no relevant conflicts of interest.
SOURCE: Nota NM et al. Circulation. 2019 Feb 18. doi: 10.1161/CIRCULATIONAHA.118.038584
*Correction 2/25/2019: An earlier version of this story incorrectly defined transwomen and transmen. The definitions are now accurate.
when compared with the general population, according to a study that analyzed medical records of more than 6,000 patients.
“In light of our results, we urge both physicians and transgender individuals to be aware of this increased cardiovascular risk,” first author Nienke M. Nota, MD, said in a press release for the study, which was published online Feb. 18 in Circulation. “It may be helpful to reduce risk factors by stopping smoking, exercising, eating a healthy diet, and losing weight, if needed, before starting therapy, and clinicians should continue to evaluate patients on an ongoing basis thereafter.”Dr. Nota and her colleagues at the Amsterdam University Medical Center analyzed the risk of cardiovascular events by comparing the medical records of 6,793 individuals, including only patients who received hormone therapy at their center or affiliate. They did not include those who had discontinued hormone therapy for an extended period or had alternated female and male sex hormones.
They defined transmen as indiviuals assigned female sex at birth but who had male gender identity, and transwomen as those assigned male sex at birth but with female gender identity.*
Researchers analyzed 2,517 transwomen (median age 30 years) and 1,358 transmen (median age 23 years) who received hormone therapy (defined as estrogen with and without androgen-suppressors for transwomen and testosterone for transmen) at the center gender’s clinic between 1972 and 2015. These records were compared with those of cisgender women and men (individuals whose gender identity matches their assigned birth gender).
The mean follow-up duration was 9.07 years for transwomen and 8.10 years for transmen. The researchers compared observed cases of stroke, myocardial infarction (MI), and venous thromboembolism (VTE) with expected cases using cisgender reference women and men. There were 29 stroke events, 30 MIs, and 73 VTE events for transwomen and 6 stroke, 11 MIs, and 2 VTE events for transmen.
There was a greater risk of stroke for transwomen, compared with cisgender women (standardized incidence ratio [SIR] = 2.42) and cisgender men (1.80), and a significantly greater risk of VTE, compared with cisgender women (5.52) and cisgender men (4.55).
The rate of MI was also significantly higher in transwomen, compared with cisgender women (2.64) and in transmen compared with cisgender women (3.69).
In a subgroup analysis, the researchers found ethinylestradiol use prior to 2001 did not significantly change the incident rate of cardiovascular events, but noted there was a lower rate of VTE when transwomen who began hormone therapy prior to 2001 were excluded from the analysis.
The researchers noted that hormone therapy may increase the risk of cardiovascular events in transgender individuals, in part, due to hormone therapy’s effect on cardiovascular risk factors such as lipid levels. Although a previous study analyzed the risk of cardiovascular events in transwomen and transmen, the researchers said that study could not conclude there was an increased risk of cardiovascular events for transmen.
The researchers said the results may be limited by study design, and their analysis of medical records could not account for potential confounders such as psychosocial stressors and smoking, as well as the decreasing risk of cardiovascular events over the period of the study, and assessing cardiovascular events differently than reference studies used.
The study had no specific funding, and the authors reported no relevant conflicts of interest.
SOURCE: Nota NM et al. Circulation. 2019 Feb 18. doi: 10.1161/CIRCULATIONAHA.118.038584
*Correction 2/25/2019: An earlier version of this story incorrectly defined transwomen and transmen. The definitions are now accurate.
when compared with the general population, according to a study that analyzed medical records of more than 6,000 patients.
“In light of our results, we urge both physicians and transgender individuals to be aware of this increased cardiovascular risk,” first author Nienke M. Nota, MD, said in a press release for the study, which was published online Feb. 18 in Circulation. “It may be helpful to reduce risk factors by stopping smoking, exercising, eating a healthy diet, and losing weight, if needed, before starting therapy, and clinicians should continue to evaluate patients on an ongoing basis thereafter.”Dr. Nota and her colleagues at the Amsterdam University Medical Center analyzed the risk of cardiovascular events by comparing the medical records of 6,793 individuals, including only patients who received hormone therapy at their center or affiliate. They did not include those who had discontinued hormone therapy for an extended period or had alternated female and male sex hormones.
They defined transmen as indiviuals assigned female sex at birth but who had male gender identity, and transwomen as those assigned male sex at birth but with female gender identity.*
Researchers analyzed 2,517 transwomen (median age 30 years) and 1,358 transmen (median age 23 years) who received hormone therapy (defined as estrogen with and without androgen-suppressors for transwomen and testosterone for transmen) at the center gender’s clinic between 1972 and 2015. These records were compared with those of cisgender women and men (individuals whose gender identity matches their assigned birth gender).
The mean follow-up duration was 9.07 years for transwomen and 8.10 years for transmen. The researchers compared observed cases of stroke, myocardial infarction (MI), and venous thromboembolism (VTE) with expected cases using cisgender reference women and men. There were 29 stroke events, 30 MIs, and 73 VTE events for transwomen and 6 stroke, 11 MIs, and 2 VTE events for transmen.
There was a greater risk of stroke for transwomen, compared with cisgender women (standardized incidence ratio [SIR] = 2.42) and cisgender men (1.80), and a significantly greater risk of VTE, compared with cisgender women (5.52) and cisgender men (4.55).
The rate of MI was also significantly higher in transwomen, compared with cisgender women (2.64) and in transmen compared with cisgender women (3.69).
In a subgroup analysis, the researchers found ethinylestradiol use prior to 2001 did not significantly change the incident rate of cardiovascular events, but noted there was a lower rate of VTE when transwomen who began hormone therapy prior to 2001 were excluded from the analysis.
The researchers noted that hormone therapy may increase the risk of cardiovascular events in transgender individuals, in part, due to hormone therapy’s effect on cardiovascular risk factors such as lipid levels. Although a previous study analyzed the risk of cardiovascular events in transwomen and transmen, the researchers said that study could not conclude there was an increased risk of cardiovascular events for transmen.
The researchers said the results may be limited by study design, and their analysis of medical records could not account for potential confounders such as psychosocial stressors and smoking, as well as the decreasing risk of cardiovascular events over the period of the study, and assessing cardiovascular events differently than reference studies used.
The study had no specific funding, and the authors reported no relevant conflicts of interest.
SOURCE: Nota NM et al. Circulation. 2019 Feb 18. doi: 10.1161/CIRCULATIONAHA.118.038584
*Correction 2/25/2019: An earlier version of this story incorrectly defined transwomen and transmen. The definitions are now accurate.
FROM CIRCULATION
Biologics curb coronary artery plaques in severe psoriasis
Treatment with biologic therapy significantly improves coronary plaque profiles in patients with severe psoriasis, based on data from 121 adult patients who completed a year of follow-up.
A previous study showed a reduced rate of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death among individuals treated with biologic therapies, wrote Youssef A. Elnabawi, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Md., and his colleagues.
Psoriasis “provides a reliable model to study inflammatory atherogenesis and the longitudinal impact of modulating specific cytokines on vascular behavior, while treating the primary skin disease with [Food and Drug Administration]–approved biologic therapies,” the researchers said.
In a study published in Cardiovascular Research, patients given biologics showed a 5% reduction in total coronary plaque burden after 1 year, as well as a 64% improvement in Psoriasis Area Severity Index scores. In addition, the decrease in noncalcified plaque burden in the biologics group was significantly greater, compared with the nonbiologics group (P =.03), and remained significant after controlling for standard cardiovascular risk factors.
When broken down by biologic, “we observed the greatest percent reduction of noncalcified plaque burden in patients on [anti-interleukin (IL)–17] therapy with a reduction in necrotic core suggesting a potential role for IL-17 in atherosclerotic pathways,” Dr. Elnabawi and his colleagues wrote.
(from 2.0 mg/dL to 1.4 mg/dL), but no change in the nonbiologics group.
The study population included patients naive to biologic or systemic psoriasis therapies who were assessed via clinical and laboratory data and coronary computed tomography angiography at baseline and after 1 year. A total of 89 participants with moderate to severe psoriasis received biologics, including adalimumab, etanercept, ustekinumab, secukinumab, and ixekizumab; 32 psoriasis patients received no biologics and served as a reference group. The average age of the patients was 50 years, and 58% were male. At baseline, patients had low cardiovascular risk based on Framingham scores, and moderate to severe skin disease.
The findings were limited by several factors, including the observational nature of the study, small study population, and the open-label use of biologics, as well as the use of coronary indices, rather than actual cardiovascular events, to assess cardiovascular disease risk, the researchers noted.
However, the results, combined with results from previous studies in animal models, “support further investigation of IL-17 blockade on coronary disease in humans,” they said.
The study was supported by the National Heart, Lung, and Blood Institute, with additional support from the National Institutes of Health Medical Research Scholars Program, the Doris Duke Charitable Foundation, the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, Elsevier, and other private donors. Dr. Elnabawi had no financial conflicts to disclose.
SOURCE: Elnabawi YA et al. Cardiovasc Res. 2019. doi: 10.1093/cvr/cvz009.
Treatment with biologic therapy significantly improves coronary plaque profiles in patients with severe psoriasis, based on data from 121 adult patients who completed a year of follow-up.
A previous study showed a reduced rate of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death among individuals treated with biologic therapies, wrote Youssef A. Elnabawi, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Md., and his colleagues.
Psoriasis “provides a reliable model to study inflammatory atherogenesis and the longitudinal impact of modulating specific cytokines on vascular behavior, while treating the primary skin disease with [Food and Drug Administration]–approved biologic therapies,” the researchers said.
In a study published in Cardiovascular Research, patients given biologics showed a 5% reduction in total coronary plaque burden after 1 year, as well as a 64% improvement in Psoriasis Area Severity Index scores. In addition, the decrease in noncalcified plaque burden in the biologics group was significantly greater, compared with the nonbiologics group (P =.03), and remained significant after controlling for standard cardiovascular risk factors.
When broken down by biologic, “we observed the greatest percent reduction of noncalcified plaque burden in patients on [anti-interleukin (IL)–17] therapy with a reduction in necrotic core suggesting a potential role for IL-17 in atherosclerotic pathways,” Dr. Elnabawi and his colleagues wrote.
(from 2.0 mg/dL to 1.4 mg/dL), but no change in the nonbiologics group.
The study population included patients naive to biologic or systemic psoriasis therapies who were assessed via clinical and laboratory data and coronary computed tomography angiography at baseline and after 1 year. A total of 89 participants with moderate to severe psoriasis received biologics, including adalimumab, etanercept, ustekinumab, secukinumab, and ixekizumab; 32 psoriasis patients received no biologics and served as a reference group. The average age of the patients was 50 years, and 58% were male. At baseline, patients had low cardiovascular risk based on Framingham scores, and moderate to severe skin disease.
The findings were limited by several factors, including the observational nature of the study, small study population, and the open-label use of biologics, as well as the use of coronary indices, rather than actual cardiovascular events, to assess cardiovascular disease risk, the researchers noted.
However, the results, combined with results from previous studies in animal models, “support further investigation of IL-17 blockade on coronary disease in humans,” they said.
The study was supported by the National Heart, Lung, and Blood Institute, with additional support from the National Institutes of Health Medical Research Scholars Program, the Doris Duke Charitable Foundation, the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, Elsevier, and other private donors. Dr. Elnabawi had no financial conflicts to disclose.
SOURCE: Elnabawi YA et al. Cardiovasc Res. 2019. doi: 10.1093/cvr/cvz009.
Treatment with biologic therapy significantly improves coronary plaque profiles in patients with severe psoriasis, based on data from 121 adult patients who completed a year of follow-up.
A previous study showed a reduced rate of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death among individuals treated with biologic therapies, wrote Youssef A. Elnabawi, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Md., and his colleagues.
Psoriasis “provides a reliable model to study inflammatory atherogenesis and the longitudinal impact of modulating specific cytokines on vascular behavior, while treating the primary skin disease with [Food and Drug Administration]–approved biologic therapies,” the researchers said.
In a study published in Cardiovascular Research, patients given biologics showed a 5% reduction in total coronary plaque burden after 1 year, as well as a 64% improvement in Psoriasis Area Severity Index scores. In addition, the decrease in noncalcified plaque burden in the biologics group was significantly greater, compared with the nonbiologics group (P =.03), and remained significant after controlling for standard cardiovascular risk factors.
When broken down by biologic, “we observed the greatest percent reduction of noncalcified plaque burden in patients on [anti-interleukin (IL)–17] therapy with a reduction in necrotic core suggesting a potential role for IL-17 in atherosclerotic pathways,” Dr. Elnabawi and his colleagues wrote.
(from 2.0 mg/dL to 1.4 mg/dL), but no change in the nonbiologics group.
The study population included patients naive to biologic or systemic psoriasis therapies who were assessed via clinical and laboratory data and coronary computed tomography angiography at baseline and after 1 year. A total of 89 participants with moderate to severe psoriasis received biologics, including adalimumab, etanercept, ustekinumab, secukinumab, and ixekizumab; 32 psoriasis patients received no biologics and served as a reference group. The average age of the patients was 50 years, and 58% were male. At baseline, patients had low cardiovascular risk based on Framingham scores, and moderate to severe skin disease.
The findings were limited by several factors, including the observational nature of the study, small study population, and the open-label use of biologics, as well as the use of coronary indices, rather than actual cardiovascular events, to assess cardiovascular disease risk, the researchers noted.
However, the results, combined with results from previous studies in animal models, “support further investigation of IL-17 blockade on coronary disease in humans,” they said.
The study was supported by the National Heart, Lung, and Blood Institute, with additional support from the National Institutes of Health Medical Research Scholars Program, the Doris Duke Charitable Foundation, the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, Elsevier, and other private donors. Dr. Elnabawi had no financial conflicts to disclose.
SOURCE: Elnabawi YA et al. Cardiovasc Res. 2019. doi: 10.1093/cvr/cvz009.
FROM CARDIOVASCULAR RESEARCH
Key clinical point: Psoriasis patients treated with biologics also showed improvement in coronary artery profiles after 1 year, compared with patients not treated with biologics.
Major finding: Biologic therapy was associated with a 5% reduction in total coronary plaque burden from baseline.
Study details: The data come from 121 psoriasis patients in a prospective, observational study.
Disclosures: The study was supported by the National Heart, Lung, and Blood Institute, with additional support from the National Institutes of Health Medical Research Scholars Program, the Doris Duke Charitable Foundation, the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, Elsevier, and other private donors. Dr. Elnabawi had no financial conflicts to disclose.
Source: Elnabawi YA et al. Cardiovasc Res. 2019. doi: 10.1093/cvr/cvz009.
ADT harms likely limited to men with CV comorbidities
WASHINGTON – The cardiovascular effects of androgen deprivation therapy (ADT) for men with advanced prostate cancer are less severe than once feared, but there is evidence to suggest that men with preexisting heart failure or a history of myocardial infarction could be at excess risk for death from cardiovascular causes when they receive ADT, according to a leading prostate cancer expert.
“I think there are concerns about potential cardiovascular harm of ADT, and I think this has reduced ADT use, despite the fact that we know for most men it improves overall survival,” said Paul Nguyen, MD, a radiation oncologist at the Dana-Farber/Brigham and Women’s Cancer Center in Boston.
“In fact, when we looked recently at men with high-risk prostate cancer, this is a group where overall survival is improved by 50% if they get ADT – so it cuts the risk of death in half – but it turns out that nearly a quarter of those patients are not receiving ADT. I think that the concern about cardiovascular harm and the confusion as to where that data stands is a lot of what’s driving that right now,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Randomized trial data
Dr. Nguyen noted that the evidence suggesting that ADT can increase the risk of death from cardiovascular causes came largely from three major studies:
- A 2006 study of 73,196 Medicare enrollees aged 66 or older, which found that ADT with a gonadotropin-releasing hormone (GnRH) agonist was possibly associated with increased risk of incident diabetes and cardiovascular disease (J Clin Oncol. 2006 Sep 20;24[27]:4448-56.).
- A 2007 analysis of data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CAPSURE) database on 3,262 men treated with radical prostatectomy and 1,630 men treated with radiation or cryotherapy for localized prostate cancer, which found that among those 65 and older the 5-year cumulative incidence of cardiovascular death was 5.5% for patients who received ADT, vs. 2% for those who did not (J Natl Cancer Inst. 2007 Oct 17;99[20]:1516-24).
- A 2007 study of 1,372 men in three randomized trials of radiation therapy with or without androgen suppression therapy up to 8 months in duration, which found that men 65 and older who received 6 months of androgen suppression had significantly shorter times to fatal MIs than did men who did not receive the therapy (J Clin Oncol. 2007;25[17]:2420-5).
These studies, combined with observational data, led to a 2010 consensus statement from the American Heart Association, American Cancer Society, and American Urological Association, with endorsement from the American Society for Radiation Oncology, which stated that “there may be a relation between ADT and cardiovascular events and death.”
Also in 2010, the Food and Drug Administration required new labeling on GnRH agonists warning of “increased risk of diabetes and certain cardiovascular diseases (heart attack, sudden cardiac death, stroke).”
Not unanimous
Two other large randomized studies (J Clin Oncol. 2008 Feb 1;26[4]:585-91 and J Clin Oncol. 2009 Jan 1;27[1]:92-9) and two retrospective studies (J Clin Oncol. 2009 Jul 20;27[21]:3452-8 and J Clin Oncol. 2011 Sep 10;29[26]3510-16) found no excess risk of cardiovascular disease from ADT, Dr. Nguyen said, prompting him and his colleagues to see whether they could get a better estimate of the actual risk.
They did so through a 2011 meta-analysis (JAMA. 2011;306[21]:2359-66) of data on 4,141 patients from eight randomized trials. They found that among patients with unfavorable-risk prostate cancer, ADT was not associated with an increased risk of cardiovascular death, but was associated with lower risks for both prostate-specific and all-cause mortality.
Subpopulations may still be at risk
Dr. Nguyen said that the principal finding of the meta-analysis, while reassuring, “doesn’t let ADT off the hook for metabolic events, diabetes which we know happens, and the possibility of nonfatal cardiac events.”
He noted that while ADT was not associated with cardiovascular disease in clinical trials, observational studies showed significantly increased risk for fatal or non-fatal MI.
One possible explanation for the difference is that observational studies included nonfatal MI, while randomized trials looked only at cardiovascular deaths. It’s also possible that ADT causes harm primarily in men with preexisting comorbidities, who are often excluded from or underrepresented in clinical trials.
Evidence from a 2009 study (JAMA. 2009 Aug 26;302[8]:866-73) showed that among men with clinical stage T1 to T3 noninvasive, nonmetastatic prostate cancer, neoadjuvant hormonal therapy with both a luteinizing hormone-releasing hormone (LHRH) agonist and a nonsteroidal antiandrogen was associated with increased risk for all-cause mortality for those with a history of coronary artery disease–induced heart failure, but not for men with either no comorbidities or only a single comorbidity such as hypertension, hypercholesterolemia, or diabetes.
Clinical considerations
The decision to treat men with prostate cancer with ADT is therefore a balancing act, Dr. Nguyen said.
“As the risk of prostate cancer death goes up, the benefit of ADT goes up. However, as the comorbidity level goes up, the potential cardiovascular harm of ADT goes up,” he said.
For patients at the extreme ends of each continuum, such as a patient with high-risk prostate cancer and no cardiovascular comorbidities or a patient with low-risk cancer but multiple CV risk factors, the decision to give or withhold ADT is relatively simple, he said.
But for patients in between, such as a man with intermediate-risk cancer and one risk factor or a man with high risk disease with multiple comorbidities, the decision is far more complex.
“This where I think the dialogue with the cardiologist really needs to come into this decision,” he said.
Evidence to support the decision comes from retrospective studies suggesting that even men with high-risk prostate cancer have poorer overall survival with ADT if they have a history of heart failure or MI.
For patients with low-risk cancer and diabetes, ADT is associated with worse overall survival, but ADT does not cause additional harm to men with intermediate- to high-risk prostate cancer who have concomitant diabetes, Dr. Nguyen said.
“My view is that ADT has not been shown to increase cardiovascular death in randomized trials, so I think that for the vast majority of patients it probably does not increase cardiovascular deaths. But I think there could very well be a vulnerable 5% of patients who might have an excess risk of cardiovascular death, and I think we have to be careful, but we still have to balance it out against their risks for prostate cancer death,” he said.
Dr. Nguyen reported consulting fees/honoraria from Astellas, Augmenix, Blue Earth Diagnostics, Cota, Dendreon, Ferring Pharmaceuticals, GenomeDx, Janssen, and Nanobiotix.
WASHINGTON – The cardiovascular effects of androgen deprivation therapy (ADT) for men with advanced prostate cancer are less severe than once feared, but there is evidence to suggest that men with preexisting heart failure or a history of myocardial infarction could be at excess risk for death from cardiovascular causes when they receive ADT, according to a leading prostate cancer expert.
“I think there are concerns about potential cardiovascular harm of ADT, and I think this has reduced ADT use, despite the fact that we know for most men it improves overall survival,” said Paul Nguyen, MD, a radiation oncologist at the Dana-Farber/Brigham and Women’s Cancer Center in Boston.
“In fact, when we looked recently at men with high-risk prostate cancer, this is a group where overall survival is improved by 50% if they get ADT – so it cuts the risk of death in half – but it turns out that nearly a quarter of those patients are not receiving ADT. I think that the concern about cardiovascular harm and the confusion as to where that data stands is a lot of what’s driving that right now,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Randomized trial data
Dr. Nguyen noted that the evidence suggesting that ADT can increase the risk of death from cardiovascular causes came largely from three major studies:
- A 2006 study of 73,196 Medicare enrollees aged 66 or older, which found that ADT with a gonadotropin-releasing hormone (GnRH) agonist was possibly associated with increased risk of incident diabetes and cardiovascular disease (J Clin Oncol. 2006 Sep 20;24[27]:4448-56.).
- A 2007 analysis of data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CAPSURE) database on 3,262 men treated with radical prostatectomy and 1,630 men treated with radiation or cryotherapy for localized prostate cancer, which found that among those 65 and older the 5-year cumulative incidence of cardiovascular death was 5.5% for patients who received ADT, vs. 2% for those who did not (J Natl Cancer Inst. 2007 Oct 17;99[20]:1516-24).
- A 2007 study of 1,372 men in three randomized trials of radiation therapy with or without androgen suppression therapy up to 8 months in duration, which found that men 65 and older who received 6 months of androgen suppression had significantly shorter times to fatal MIs than did men who did not receive the therapy (J Clin Oncol. 2007;25[17]:2420-5).
These studies, combined with observational data, led to a 2010 consensus statement from the American Heart Association, American Cancer Society, and American Urological Association, with endorsement from the American Society for Radiation Oncology, which stated that “there may be a relation between ADT and cardiovascular events and death.”
Also in 2010, the Food and Drug Administration required new labeling on GnRH agonists warning of “increased risk of diabetes and certain cardiovascular diseases (heart attack, sudden cardiac death, stroke).”
Not unanimous
Two other large randomized studies (J Clin Oncol. 2008 Feb 1;26[4]:585-91 and J Clin Oncol. 2009 Jan 1;27[1]:92-9) and two retrospective studies (J Clin Oncol. 2009 Jul 20;27[21]:3452-8 and J Clin Oncol. 2011 Sep 10;29[26]3510-16) found no excess risk of cardiovascular disease from ADT, Dr. Nguyen said, prompting him and his colleagues to see whether they could get a better estimate of the actual risk.
They did so through a 2011 meta-analysis (JAMA. 2011;306[21]:2359-66) of data on 4,141 patients from eight randomized trials. They found that among patients with unfavorable-risk prostate cancer, ADT was not associated with an increased risk of cardiovascular death, but was associated with lower risks for both prostate-specific and all-cause mortality.
Subpopulations may still be at risk
Dr. Nguyen said that the principal finding of the meta-analysis, while reassuring, “doesn’t let ADT off the hook for metabolic events, diabetes which we know happens, and the possibility of nonfatal cardiac events.”
He noted that while ADT was not associated with cardiovascular disease in clinical trials, observational studies showed significantly increased risk for fatal or non-fatal MI.
One possible explanation for the difference is that observational studies included nonfatal MI, while randomized trials looked only at cardiovascular deaths. It’s also possible that ADT causes harm primarily in men with preexisting comorbidities, who are often excluded from or underrepresented in clinical trials.
Evidence from a 2009 study (JAMA. 2009 Aug 26;302[8]:866-73) showed that among men with clinical stage T1 to T3 noninvasive, nonmetastatic prostate cancer, neoadjuvant hormonal therapy with both a luteinizing hormone-releasing hormone (LHRH) agonist and a nonsteroidal antiandrogen was associated with increased risk for all-cause mortality for those with a history of coronary artery disease–induced heart failure, but not for men with either no comorbidities or only a single comorbidity such as hypertension, hypercholesterolemia, or diabetes.
Clinical considerations
The decision to treat men with prostate cancer with ADT is therefore a balancing act, Dr. Nguyen said.
“As the risk of prostate cancer death goes up, the benefit of ADT goes up. However, as the comorbidity level goes up, the potential cardiovascular harm of ADT goes up,” he said.
For patients at the extreme ends of each continuum, such as a patient with high-risk prostate cancer and no cardiovascular comorbidities or a patient with low-risk cancer but multiple CV risk factors, the decision to give or withhold ADT is relatively simple, he said.
But for patients in between, such as a man with intermediate-risk cancer and one risk factor or a man with high risk disease with multiple comorbidities, the decision is far more complex.
“This where I think the dialogue with the cardiologist really needs to come into this decision,” he said.
Evidence to support the decision comes from retrospective studies suggesting that even men with high-risk prostate cancer have poorer overall survival with ADT if they have a history of heart failure or MI.
For patients with low-risk cancer and diabetes, ADT is associated with worse overall survival, but ADT does not cause additional harm to men with intermediate- to high-risk prostate cancer who have concomitant diabetes, Dr. Nguyen said.
“My view is that ADT has not been shown to increase cardiovascular death in randomized trials, so I think that for the vast majority of patients it probably does not increase cardiovascular deaths. But I think there could very well be a vulnerable 5% of patients who might have an excess risk of cardiovascular death, and I think we have to be careful, but we still have to balance it out against their risks for prostate cancer death,” he said.
Dr. Nguyen reported consulting fees/honoraria from Astellas, Augmenix, Blue Earth Diagnostics, Cota, Dendreon, Ferring Pharmaceuticals, GenomeDx, Janssen, and Nanobiotix.
WASHINGTON – The cardiovascular effects of androgen deprivation therapy (ADT) for men with advanced prostate cancer are less severe than once feared, but there is evidence to suggest that men with preexisting heart failure or a history of myocardial infarction could be at excess risk for death from cardiovascular causes when they receive ADT, according to a leading prostate cancer expert.
“I think there are concerns about potential cardiovascular harm of ADT, and I think this has reduced ADT use, despite the fact that we know for most men it improves overall survival,” said Paul Nguyen, MD, a radiation oncologist at the Dana-Farber/Brigham and Women’s Cancer Center in Boston.
“In fact, when we looked recently at men with high-risk prostate cancer, this is a group where overall survival is improved by 50% if they get ADT – so it cuts the risk of death in half – but it turns out that nearly a quarter of those patients are not receiving ADT. I think that the concern about cardiovascular harm and the confusion as to where that data stands is a lot of what’s driving that right now,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Randomized trial data
Dr. Nguyen noted that the evidence suggesting that ADT can increase the risk of death from cardiovascular causes came largely from three major studies:
- A 2006 study of 73,196 Medicare enrollees aged 66 or older, which found that ADT with a gonadotropin-releasing hormone (GnRH) agonist was possibly associated with increased risk of incident diabetes and cardiovascular disease (J Clin Oncol. 2006 Sep 20;24[27]:4448-56.).
- A 2007 analysis of data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CAPSURE) database on 3,262 men treated with radical prostatectomy and 1,630 men treated with radiation or cryotherapy for localized prostate cancer, which found that among those 65 and older the 5-year cumulative incidence of cardiovascular death was 5.5% for patients who received ADT, vs. 2% for those who did not (J Natl Cancer Inst. 2007 Oct 17;99[20]:1516-24).
- A 2007 study of 1,372 men in three randomized trials of radiation therapy with or without androgen suppression therapy up to 8 months in duration, which found that men 65 and older who received 6 months of androgen suppression had significantly shorter times to fatal MIs than did men who did not receive the therapy (J Clin Oncol. 2007;25[17]:2420-5).
These studies, combined with observational data, led to a 2010 consensus statement from the American Heart Association, American Cancer Society, and American Urological Association, with endorsement from the American Society for Radiation Oncology, which stated that “there may be a relation between ADT and cardiovascular events and death.”
Also in 2010, the Food and Drug Administration required new labeling on GnRH agonists warning of “increased risk of diabetes and certain cardiovascular diseases (heart attack, sudden cardiac death, stroke).”
Not unanimous
Two other large randomized studies (J Clin Oncol. 2008 Feb 1;26[4]:585-91 and J Clin Oncol. 2009 Jan 1;27[1]:92-9) and two retrospective studies (J Clin Oncol. 2009 Jul 20;27[21]:3452-8 and J Clin Oncol. 2011 Sep 10;29[26]3510-16) found no excess risk of cardiovascular disease from ADT, Dr. Nguyen said, prompting him and his colleagues to see whether they could get a better estimate of the actual risk.
They did so through a 2011 meta-analysis (JAMA. 2011;306[21]:2359-66) of data on 4,141 patients from eight randomized trials. They found that among patients with unfavorable-risk prostate cancer, ADT was not associated with an increased risk of cardiovascular death, but was associated with lower risks for both prostate-specific and all-cause mortality.
Subpopulations may still be at risk
Dr. Nguyen said that the principal finding of the meta-analysis, while reassuring, “doesn’t let ADT off the hook for metabolic events, diabetes which we know happens, and the possibility of nonfatal cardiac events.”
He noted that while ADT was not associated with cardiovascular disease in clinical trials, observational studies showed significantly increased risk for fatal or non-fatal MI.
One possible explanation for the difference is that observational studies included nonfatal MI, while randomized trials looked only at cardiovascular deaths. It’s also possible that ADT causes harm primarily in men with preexisting comorbidities, who are often excluded from or underrepresented in clinical trials.
Evidence from a 2009 study (JAMA. 2009 Aug 26;302[8]:866-73) showed that among men with clinical stage T1 to T3 noninvasive, nonmetastatic prostate cancer, neoadjuvant hormonal therapy with both a luteinizing hormone-releasing hormone (LHRH) agonist and a nonsteroidal antiandrogen was associated with increased risk for all-cause mortality for those with a history of coronary artery disease–induced heart failure, but not for men with either no comorbidities or only a single comorbidity such as hypertension, hypercholesterolemia, or diabetes.
Clinical considerations
The decision to treat men with prostate cancer with ADT is therefore a balancing act, Dr. Nguyen said.
“As the risk of prostate cancer death goes up, the benefit of ADT goes up. However, as the comorbidity level goes up, the potential cardiovascular harm of ADT goes up,” he said.
For patients at the extreme ends of each continuum, such as a patient with high-risk prostate cancer and no cardiovascular comorbidities or a patient with low-risk cancer but multiple CV risk factors, the decision to give or withhold ADT is relatively simple, he said.
But for patients in between, such as a man with intermediate-risk cancer and one risk factor or a man with high risk disease with multiple comorbidities, the decision is far more complex.
“This where I think the dialogue with the cardiologist really needs to come into this decision,” he said.
Evidence to support the decision comes from retrospective studies suggesting that even men with high-risk prostate cancer have poorer overall survival with ADT if they have a history of heart failure or MI.
For patients with low-risk cancer and diabetes, ADT is associated with worse overall survival, but ADT does not cause additional harm to men with intermediate- to high-risk prostate cancer who have concomitant diabetes, Dr. Nguyen said.
“My view is that ADT has not been shown to increase cardiovascular death in randomized trials, so I think that for the vast majority of patients it probably does not increase cardiovascular deaths. But I think there could very well be a vulnerable 5% of patients who might have an excess risk of cardiovascular death, and I think we have to be careful, but we still have to balance it out against their risks for prostate cancer death,” he said.
Dr. Nguyen reported consulting fees/honoraria from Astellas, Augmenix, Blue Earth Diagnostics, Cota, Dendreon, Ferring Pharmaceuticals, GenomeDx, Janssen, and Nanobiotix.
REPORTING FROM ACC CARDIO-ONCOLOGY
Key clinical point: Risk of cardiovascular death should be weighed against proven ADT benefits.
Major finding: ADT-related cardiovascular events appear limited to men with comorbid cardiovascular disease.
Study details: Review of clinical data on the cardiovascular consequences of ADT.
Disclosures: Dr. Nguyen reported consulting fees/honoraria from Astellas, Augmenix, Blue Earth Diagnostics, Cota, Dendreon, Ferring Pharmaceuticals, GenomeDx, Janssen, and Nanobiotix.
Impella RP shows higher mortality in postapproval study
The Food and Drug Administration issued a letter on Feb. 4, 2019, to health care providers regarding interim results from a postapproval study for Abiomed’s Impella RP System because these results appear to have a higher mortality rate than was seen in premarket clinical studies.
As a condition of its approval, the FDA mandated Abiomed to perform a postapproval study (PAS); this study reflects use in a broader population than the premarket studies, which adhered to stricter inclusion and exclusion criteria.
Earlier in January, Abiomed submitted data to the FDA suggesting that differences in preimplant characteristics between patients in the PAS and those in the premarket clinical studies may explain the difference in mortality. Specifically, 16 of the 23 patients enrolled in the PAS would not have met the enrollment criteria for the premarket clinical studies because they were in cardiogenic shock for longer than 48 hours, experienced an in-hospital cardiac arrest, were treated with an intra-aortic balloon pump, or suffered a preimplant hypoxic or ischemic neurologic event.
“Although the FDA is concerned about the high mortality rate from the interim PAS results,” they wrote in the letter, which is available on the FDA website, “we believe that, when the device is used for the currently approved indication in appropriately selected patients, the benefits of the Impella RP system continue to outweigh the risks.”
The Food and Drug Administration issued a letter on Feb. 4, 2019, to health care providers regarding interim results from a postapproval study for Abiomed’s Impella RP System because these results appear to have a higher mortality rate than was seen in premarket clinical studies.
As a condition of its approval, the FDA mandated Abiomed to perform a postapproval study (PAS); this study reflects use in a broader population than the premarket studies, which adhered to stricter inclusion and exclusion criteria.
Earlier in January, Abiomed submitted data to the FDA suggesting that differences in preimplant characteristics between patients in the PAS and those in the premarket clinical studies may explain the difference in mortality. Specifically, 16 of the 23 patients enrolled in the PAS would not have met the enrollment criteria for the premarket clinical studies because they were in cardiogenic shock for longer than 48 hours, experienced an in-hospital cardiac arrest, were treated with an intra-aortic balloon pump, or suffered a preimplant hypoxic or ischemic neurologic event.
“Although the FDA is concerned about the high mortality rate from the interim PAS results,” they wrote in the letter, which is available on the FDA website, “we believe that, when the device is used for the currently approved indication in appropriately selected patients, the benefits of the Impella RP system continue to outweigh the risks.”
The Food and Drug Administration issued a letter on Feb. 4, 2019, to health care providers regarding interim results from a postapproval study for Abiomed’s Impella RP System because these results appear to have a higher mortality rate than was seen in premarket clinical studies.
As a condition of its approval, the FDA mandated Abiomed to perform a postapproval study (PAS); this study reflects use in a broader population than the premarket studies, which adhered to stricter inclusion and exclusion criteria.
Earlier in January, Abiomed submitted data to the FDA suggesting that differences in preimplant characteristics between patients in the PAS and those in the premarket clinical studies may explain the difference in mortality. Specifically, 16 of the 23 patients enrolled in the PAS would not have met the enrollment criteria for the premarket clinical studies because they were in cardiogenic shock for longer than 48 hours, experienced an in-hospital cardiac arrest, were treated with an intra-aortic balloon pump, or suffered a preimplant hypoxic or ischemic neurologic event.
“Although the FDA is concerned about the high mortality rate from the interim PAS results,” they wrote in the letter, which is available on the FDA website, “we believe that, when the device is used for the currently approved indication in appropriately selected patients, the benefits of the Impella RP system continue to outweigh the risks.”
Stryker issues voluntary field action for Lifepak 15 defibrillators
Stryker has announced a voluntary field action for its Lifepak 15 monitor/defibrillators, according to a safety alert from the Food and Drug Administration.
The company is notifying certain Lifepak 15 customers of an issue causing the device to lock up after a defibrillation shock is delivered. The lockup displays as a blank monitor with the LED lights on, indicating that the power is on, but the keypad and device become nonfunctional, the FDA said. This lockup can delay delivery of therapy, which can cause injury or death.
Since the introduction of the device in 2009, 58 complaints regarding the issue have been reported, including 6 that resulted in death. In all, 13,003 devices are included in the field action.
Customers should continue to use their devices if they have been affected until a correction can be completed. If the lockup occurs, the user should press and hold the “on” button until the LED turns off, then hit the “on” button again. If this does not reset the device, the batteries should be removed and reinserted, or the device should be removed and reconnected to its power adapter, the FDA said.
Find the full press release on the FDA website.
Stryker has announced a voluntary field action for its Lifepak 15 monitor/defibrillators, according to a safety alert from the Food and Drug Administration.
The company is notifying certain Lifepak 15 customers of an issue causing the device to lock up after a defibrillation shock is delivered. The lockup displays as a blank monitor with the LED lights on, indicating that the power is on, but the keypad and device become nonfunctional, the FDA said. This lockup can delay delivery of therapy, which can cause injury or death.
Since the introduction of the device in 2009, 58 complaints regarding the issue have been reported, including 6 that resulted in death. In all, 13,003 devices are included in the field action.
Customers should continue to use their devices if they have been affected until a correction can be completed. If the lockup occurs, the user should press and hold the “on” button until the LED turns off, then hit the “on” button again. If this does not reset the device, the batteries should be removed and reinserted, or the device should be removed and reconnected to its power adapter, the FDA said.
Find the full press release on the FDA website.
Stryker has announced a voluntary field action for its Lifepak 15 monitor/defibrillators, according to a safety alert from the Food and Drug Administration.
The company is notifying certain Lifepak 15 customers of an issue causing the device to lock up after a defibrillation shock is delivered. The lockup displays as a blank monitor with the LED lights on, indicating that the power is on, but the keypad and device become nonfunctional, the FDA said. This lockup can delay delivery of therapy, which can cause injury or death.
Since the introduction of the device in 2009, 58 complaints regarding the issue have been reported, including 6 that resulted in death. In all, 13,003 devices are included in the field action.
Customers should continue to use their devices if they have been affected until a correction can be completed. If the lockup occurs, the user should press and hold the “on” button until the LED turns off, then hit the “on” button again. If this does not reset the device, the batteries should be removed and reinserted, or the device should be removed and reconnected to its power adapter, the FDA said.
Find the full press release on the FDA website.