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Chinese herbal medicine may offer benefits in STEMI: CTS-AMI
CHICAGO – , the CTS-AMI study suggests.
Compared with those assigned to placebo, Chinese patients assigned to tongxinluo had lower rates of 30-day and 1-year major adverse cardiovascular and cerebrovascular events (MACCE), driven by fewer cardiac deaths. Severe STEMI complications were also lower.
Tongxinluo, which contains 10 or more potential active herbs and insects, did not result in severe adverse effects, including major bleeding.
The results were presented at the American Heart Association scientific sessions by Yuejin Yang, MD, PhD, a professor of cardiology at Fuwai Hospital, National Center for CV Disease, Beijing.
He noted that despite reperfusion and optimal medical therapy, patients with STEMI still face high in-hospital mortality, myocardial no-flow, and reperfusion injury, which have no targeted drugs so far worldwide. In addition, “inadequate implementation of timely revascularization for STEMI in China (50-70%) and other developing countries leaves a substantial infarct size in many patients.”
Tongxinluo has been approved for angina and stroke since 1996 in China. Previous preclinical studies and the investigators’ proof-of-concept ENLEAT trial in STEMI suggested tongxinluo could reduce myocardial no-flow and infarction size and protect the cardiomyocytes, Dr. Yang said.
The CTS-AMI trial was conducted at 124 hospitals in mainland China and evenly randomly assigned 3,797 patients with STEMI or new left bundle-branch block within 24 hours of symptom onset to eight capsules of tongxinluo, 2.08 g, or to placebo plus dual antiplatelet therapy before percutaneous coronary intervention (PCI), thrombolysis, or medical management alone, followed by four capsules thrice daily plus guideline-directed therapy for 12 months.
In the modified intention-to-treat cohort of 1,889 tongxinluo- and 1,888 placebo-treated patients, primary PCI was performed in 94.2% and 92.3%, respectively.
The relative risk of 30-day MACCE was reduced 36% in the tongxinluo group, compared with the placebo group (3.39% vs. 5.24%; RR, 0.64; 95% confidence interval, 0.47-0.88).
Among the primary endpoint components, the relative risk of cardiac death was reduced 30% (2.97% vs. 4.24%; RR, 0.70; 95% CI, 0.50-0.99) and MI reinfarction 65% (0 vs. 9 events; RR, 0.35; 95% CI, 0.13-0.99).
Strokes were similar in the tongxinluo and control groups (4 vs. 9; RR, 0.44; 95% CI, 0.14-1.43) and no patient had emergent coronary revascularization at 30 days.
The benefit of the traditional Chinese compound on the primary endpoint was consistent across subgroups, Dr. Yang reported.
At 30 days, severe STEMI complications (11.79% vs. 14.80%; P = .008) and malignant arrhythmias (7.84% vs. 10.20%; P = .011) were lower in the tongxinluo group, whereas mechanical complications (10 vs. 13; P = .526) and cardiogenic shock (2.37% vs. 3.31%; P =.082) were similar.
At 1 year, hazard ratios favored tongxinluo for MACCE (0.64; 95% CI, 0.49-0.82), cardiac death (0.73; 95% CI, 0.55-0.97), MI reinfarction (0.26; 95% CI, 0.10-0.67), and stroke (0.44; 95% CI, 0.21-0.92).
In terms of safety issues, 41 patients receiving tongxinluo and 52 patients receiving placebo had a serious adverse event (2.17% vs. 2.75%; P = .25).
Except for fewer renal injuries with tongxinluo (3.81% vs. 5.30%; P = .029), there were no significant between-group differences in adverse effects including allergic rash, hepatic injury, prolonged activated partial thromboplastin time or prothrombin time, digestive tract hemorrhage, nausea, diarrhea, and headache or dizziness.
“These findings support the use of tongxinluo as an adjunctive therapy in treating STEMI, at least in China and other developing countries,” Dr. Yang concluded.
Invited discussant Kenneth Mahaffey, MD, associate dean, Stanford (Calif.) University, and director of the Stanford Center for Clinical Research, said the results “likely will support use of tongxinluo in China” but that “more studies are needed in other populations and treatment paradigms.”
Asked for further comment by this news organization, Dr. Mahaffey said, “The surprising thing is where are all the MIs? Where are all the revascularization procedures?”
Usually one would expect MIs in about 1% of patients, or about 40 MIs among the 4,000 patients but, he noted, there were zero MIs in the treatment group and 9 among controls.
“We haven’t seen a 30% reduction in cardiovascular death or overall mortality with a therapy in ages with good background therapy,” Dr. Mahaffey said. “We need to see how they ascertained all those events.”
He noted that the results were based on the modified intention-to-treat cohort, which did not include data on 20 patients allocated to treatment, and showed no difference in ST-segment resolution at 2 hours and only a slight difference at 24 hours.
“So even in this trial, for at least some of the data we’ve gotten already that supports the proposed mechanism, it doesn’t show the benefit on that mechanistic substudy. And that’s why we need to see these echoes, the biomarkers, and probably the angios to see: Did it have any effect on the proposed mechanism?” Dr. Mahaffey said.
Finally, information on background therapy is critical for putting the treatment effect into context for other health systems and populations, he said. “Unfortunately, we need to see some additional information to really understand how this will fit in, even in Chinese therapy for STEMI patients, but definitely not outside of China, particularly in the United States, because I don’t know what their background therapy was.”
The study was funded by the National Key Research and Development Program of China. Tongxinluo and placebo were provided by Yiling Pharmacological. The study was designed, conducted, and analyzed independent of the sponsors. Dr. Yang reports no relevant financial conflicts of interest. Dr. Mahaffey reports research funding from the AHA, Apple, Bayer, CIRM, Eidos, Ferring, Gilead, Idorsia, Johnson & Johnson, Luitpold, PAC-12, Precordior, Sanifit, and Verily; consultancy fees from Amgen, Applied Therapeutics, AstraZeneca, CLS Behring, Elsevier, Fibrogen, Inova, Johnson & Johnson, Lexicon, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, Sanofi, and Theravance; and equity in Precordior.
A version of this article first appeared on Medscape.com.
CHICAGO – , the CTS-AMI study suggests.
Compared with those assigned to placebo, Chinese patients assigned to tongxinluo had lower rates of 30-day and 1-year major adverse cardiovascular and cerebrovascular events (MACCE), driven by fewer cardiac deaths. Severe STEMI complications were also lower.
Tongxinluo, which contains 10 or more potential active herbs and insects, did not result in severe adverse effects, including major bleeding.
The results were presented at the American Heart Association scientific sessions by Yuejin Yang, MD, PhD, a professor of cardiology at Fuwai Hospital, National Center for CV Disease, Beijing.
He noted that despite reperfusion and optimal medical therapy, patients with STEMI still face high in-hospital mortality, myocardial no-flow, and reperfusion injury, which have no targeted drugs so far worldwide. In addition, “inadequate implementation of timely revascularization for STEMI in China (50-70%) and other developing countries leaves a substantial infarct size in many patients.”
Tongxinluo has been approved for angina and stroke since 1996 in China. Previous preclinical studies and the investigators’ proof-of-concept ENLEAT trial in STEMI suggested tongxinluo could reduce myocardial no-flow and infarction size and protect the cardiomyocytes, Dr. Yang said.
The CTS-AMI trial was conducted at 124 hospitals in mainland China and evenly randomly assigned 3,797 patients with STEMI or new left bundle-branch block within 24 hours of symptom onset to eight capsules of tongxinluo, 2.08 g, or to placebo plus dual antiplatelet therapy before percutaneous coronary intervention (PCI), thrombolysis, or medical management alone, followed by four capsules thrice daily plus guideline-directed therapy for 12 months.
In the modified intention-to-treat cohort of 1,889 tongxinluo- and 1,888 placebo-treated patients, primary PCI was performed in 94.2% and 92.3%, respectively.
The relative risk of 30-day MACCE was reduced 36% in the tongxinluo group, compared with the placebo group (3.39% vs. 5.24%; RR, 0.64; 95% confidence interval, 0.47-0.88).
Among the primary endpoint components, the relative risk of cardiac death was reduced 30% (2.97% vs. 4.24%; RR, 0.70; 95% CI, 0.50-0.99) and MI reinfarction 65% (0 vs. 9 events; RR, 0.35; 95% CI, 0.13-0.99).
Strokes were similar in the tongxinluo and control groups (4 vs. 9; RR, 0.44; 95% CI, 0.14-1.43) and no patient had emergent coronary revascularization at 30 days.
The benefit of the traditional Chinese compound on the primary endpoint was consistent across subgroups, Dr. Yang reported.
At 30 days, severe STEMI complications (11.79% vs. 14.80%; P = .008) and malignant arrhythmias (7.84% vs. 10.20%; P = .011) were lower in the tongxinluo group, whereas mechanical complications (10 vs. 13; P = .526) and cardiogenic shock (2.37% vs. 3.31%; P =.082) were similar.
At 1 year, hazard ratios favored tongxinluo for MACCE (0.64; 95% CI, 0.49-0.82), cardiac death (0.73; 95% CI, 0.55-0.97), MI reinfarction (0.26; 95% CI, 0.10-0.67), and stroke (0.44; 95% CI, 0.21-0.92).
In terms of safety issues, 41 patients receiving tongxinluo and 52 patients receiving placebo had a serious adverse event (2.17% vs. 2.75%; P = .25).
Except for fewer renal injuries with tongxinluo (3.81% vs. 5.30%; P = .029), there were no significant between-group differences in adverse effects including allergic rash, hepatic injury, prolonged activated partial thromboplastin time or prothrombin time, digestive tract hemorrhage, nausea, diarrhea, and headache or dizziness.
“These findings support the use of tongxinluo as an adjunctive therapy in treating STEMI, at least in China and other developing countries,” Dr. Yang concluded.
Invited discussant Kenneth Mahaffey, MD, associate dean, Stanford (Calif.) University, and director of the Stanford Center for Clinical Research, said the results “likely will support use of tongxinluo in China” but that “more studies are needed in other populations and treatment paradigms.”
Asked for further comment by this news organization, Dr. Mahaffey said, “The surprising thing is where are all the MIs? Where are all the revascularization procedures?”
Usually one would expect MIs in about 1% of patients, or about 40 MIs among the 4,000 patients but, he noted, there were zero MIs in the treatment group and 9 among controls.
“We haven’t seen a 30% reduction in cardiovascular death or overall mortality with a therapy in ages with good background therapy,” Dr. Mahaffey said. “We need to see how they ascertained all those events.”
He noted that the results were based on the modified intention-to-treat cohort, which did not include data on 20 patients allocated to treatment, and showed no difference in ST-segment resolution at 2 hours and only a slight difference at 24 hours.
“So even in this trial, for at least some of the data we’ve gotten already that supports the proposed mechanism, it doesn’t show the benefit on that mechanistic substudy. And that’s why we need to see these echoes, the biomarkers, and probably the angios to see: Did it have any effect on the proposed mechanism?” Dr. Mahaffey said.
Finally, information on background therapy is critical for putting the treatment effect into context for other health systems and populations, he said. “Unfortunately, we need to see some additional information to really understand how this will fit in, even in Chinese therapy for STEMI patients, but definitely not outside of China, particularly in the United States, because I don’t know what their background therapy was.”
The study was funded by the National Key Research and Development Program of China. Tongxinluo and placebo were provided by Yiling Pharmacological. The study was designed, conducted, and analyzed independent of the sponsors. Dr. Yang reports no relevant financial conflicts of interest. Dr. Mahaffey reports research funding from the AHA, Apple, Bayer, CIRM, Eidos, Ferring, Gilead, Idorsia, Johnson & Johnson, Luitpold, PAC-12, Precordior, Sanifit, and Verily; consultancy fees from Amgen, Applied Therapeutics, AstraZeneca, CLS Behring, Elsevier, Fibrogen, Inova, Johnson & Johnson, Lexicon, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, Sanofi, and Theravance; and equity in Precordior.
A version of this article first appeared on Medscape.com.
CHICAGO – , the CTS-AMI study suggests.
Compared with those assigned to placebo, Chinese patients assigned to tongxinluo had lower rates of 30-day and 1-year major adverse cardiovascular and cerebrovascular events (MACCE), driven by fewer cardiac deaths. Severe STEMI complications were also lower.
Tongxinluo, which contains 10 or more potential active herbs and insects, did not result in severe adverse effects, including major bleeding.
The results were presented at the American Heart Association scientific sessions by Yuejin Yang, MD, PhD, a professor of cardiology at Fuwai Hospital, National Center for CV Disease, Beijing.
He noted that despite reperfusion and optimal medical therapy, patients with STEMI still face high in-hospital mortality, myocardial no-flow, and reperfusion injury, which have no targeted drugs so far worldwide. In addition, “inadequate implementation of timely revascularization for STEMI in China (50-70%) and other developing countries leaves a substantial infarct size in many patients.”
Tongxinluo has been approved for angina and stroke since 1996 in China. Previous preclinical studies and the investigators’ proof-of-concept ENLEAT trial in STEMI suggested tongxinluo could reduce myocardial no-flow and infarction size and protect the cardiomyocytes, Dr. Yang said.
The CTS-AMI trial was conducted at 124 hospitals in mainland China and evenly randomly assigned 3,797 patients with STEMI or new left bundle-branch block within 24 hours of symptom onset to eight capsules of tongxinluo, 2.08 g, or to placebo plus dual antiplatelet therapy before percutaneous coronary intervention (PCI), thrombolysis, or medical management alone, followed by four capsules thrice daily plus guideline-directed therapy for 12 months.
In the modified intention-to-treat cohort of 1,889 tongxinluo- and 1,888 placebo-treated patients, primary PCI was performed in 94.2% and 92.3%, respectively.
The relative risk of 30-day MACCE was reduced 36% in the tongxinluo group, compared with the placebo group (3.39% vs. 5.24%; RR, 0.64; 95% confidence interval, 0.47-0.88).
Among the primary endpoint components, the relative risk of cardiac death was reduced 30% (2.97% vs. 4.24%; RR, 0.70; 95% CI, 0.50-0.99) and MI reinfarction 65% (0 vs. 9 events; RR, 0.35; 95% CI, 0.13-0.99).
Strokes were similar in the tongxinluo and control groups (4 vs. 9; RR, 0.44; 95% CI, 0.14-1.43) and no patient had emergent coronary revascularization at 30 days.
The benefit of the traditional Chinese compound on the primary endpoint was consistent across subgroups, Dr. Yang reported.
At 30 days, severe STEMI complications (11.79% vs. 14.80%; P = .008) and malignant arrhythmias (7.84% vs. 10.20%; P = .011) were lower in the tongxinluo group, whereas mechanical complications (10 vs. 13; P = .526) and cardiogenic shock (2.37% vs. 3.31%; P =.082) were similar.
At 1 year, hazard ratios favored tongxinluo for MACCE (0.64; 95% CI, 0.49-0.82), cardiac death (0.73; 95% CI, 0.55-0.97), MI reinfarction (0.26; 95% CI, 0.10-0.67), and stroke (0.44; 95% CI, 0.21-0.92).
In terms of safety issues, 41 patients receiving tongxinluo and 52 patients receiving placebo had a serious adverse event (2.17% vs. 2.75%; P = .25).
Except for fewer renal injuries with tongxinluo (3.81% vs. 5.30%; P = .029), there were no significant between-group differences in adverse effects including allergic rash, hepatic injury, prolonged activated partial thromboplastin time or prothrombin time, digestive tract hemorrhage, nausea, diarrhea, and headache or dizziness.
“These findings support the use of tongxinluo as an adjunctive therapy in treating STEMI, at least in China and other developing countries,” Dr. Yang concluded.
Invited discussant Kenneth Mahaffey, MD, associate dean, Stanford (Calif.) University, and director of the Stanford Center for Clinical Research, said the results “likely will support use of tongxinluo in China” but that “more studies are needed in other populations and treatment paradigms.”
Asked for further comment by this news organization, Dr. Mahaffey said, “The surprising thing is where are all the MIs? Where are all the revascularization procedures?”
Usually one would expect MIs in about 1% of patients, or about 40 MIs among the 4,000 patients but, he noted, there were zero MIs in the treatment group and 9 among controls.
“We haven’t seen a 30% reduction in cardiovascular death or overall mortality with a therapy in ages with good background therapy,” Dr. Mahaffey said. “We need to see how they ascertained all those events.”
He noted that the results were based on the modified intention-to-treat cohort, which did not include data on 20 patients allocated to treatment, and showed no difference in ST-segment resolution at 2 hours and only a slight difference at 24 hours.
“So even in this trial, for at least some of the data we’ve gotten already that supports the proposed mechanism, it doesn’t show the benefit on that mechanistic substudy. And that’s why we need to see these echoes, the biomarkers, and probably the angios to see: Did it have any effect on the proposed mechanism?” Dr. Mahaffey said.
Finally, information on background therapy is critical for putting the treatment effect into context for other health systems and populations, he said. “Unfortunately, we need to see some additional information to really understand how this will fit in, even in Chinese therapy for STEMI patients, but definitely not outside of China, particularly in the United States, because I don’t know what their background therapy was.”
The study was funded by the National Key Research and Development Program of China. Tongxinluo and placebo were provided by Yiling Pharmacological. The study was designed, conducted, and analyzed independent of the sponsors. Dr. Yang reports no relevant financial conflicts of interest. Dr. Mahaffey reports research funding from the AHA, Apple, Bayer, CIRM, Eidos, Ferring, Gilead, Idorsia, Johnson & Johnson, Luitpold, PAC-12, Precordior, Sanifit, and Verily; consultancy fees from Amgen, Applied Therapeutics, AstraZeneca, CLS Behring, Elsevier, Fibrogen, Inova, Johnson & Johnson, Lexicon, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, Sanofi, and Theravance; and equity in Precordior.
A version of this article first appeared on Medscape.com.
AT AHA 2022
Noninvasive tests may provide prognostic value in NAFLD
Fibrosis stages and liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE) through FibroScan were significant predictors of event-free survival, said Ferenc Mozes, DPhil, a postdoctoral research assistant at the University of Oxford, England, who has worked on biomarker evaluation of nonalcoholic steatohepatitis (NASH) as a member of the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) consortium.
“Liver histology is highly prognostic of liver-related outcomes in patients with NAFLD and NASH,” he said. “Not just that, but liver histology is also accepted, and furthermore mandated by the FDA, as a surrogate endpoint in pharmaceutical trials for NASH.”
However, liver histology is disadvantaged by sampling- and observer-dependent errors, he noted, as well as nonzero risk for patients. In recent years, researchers have hypothesized that noninvasive surrogate endpoints could be used as a way to speed up the development of new pharmaceutical treatments.
Dr. Mozes and colleagues evaluated the prognostic performance of histologically assessed liver fibrosis and three noninvasive tests (NITs): LSM-VCTE, Fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS). They conducted an individual participant data meta-analysis, which first established the diagnostic performance of NITs in identifying patients with NAFLD who had advanced fibrosis (stages F3 and F4). The research team then expanded the search by reaching out to authors to ask for outcomes data and including studies with baseline LSM-VCTE and liver histology performed within 6 months, as well as at least 1 year of follow-up data.
The composite endpoint included all-cause mortality or liver-related outcomes such as decompensation of cirrhosis, hepatocellular cancer, liver transplantation, a model of end-stage liver disease (MELD) score higher than 14, or histological progression to cirrhosis. Participants were censored at the last follow-up time or at the occurrence of the first liver-related event.
Based on Kaplan-Meier survival analysis, participants were stratified into groups based on thresholds derived from the literature: fibrosis stage 0-2 (F0-2), F3, F4; LSM less than 10 kPa, LSM equal to or more than 10 kPa and less than 20 kPa, and LSM equal to or more than 20 kPa; FIB4 less than 1.3, FIB equal to or more than 1.3 and less than 2.67, and FIB4 equal to or more than 2.67; and NFS less than –1.455, NFS equal to or more than –1.455 and less than 0.676, and NFS equal to or more than 0.676.
The research team included 13 studies from Europe and Asia with data on 1,796 patients. The median follow-up time was 64 months, both from biopsy and LSM-VCTE. The fibrosis stages were typical of what would be seen in tertiary care.
Overall, 125 patients (7%) reached the composite endpoint. They tended to be older and more likely to have type 2 diabetes, higher fibrosis stages, and cirrhosis. Among those, 80 participants died, including 25 from liver-related mortality. In addition, 23 had ascites, 28 had hepatocellular cancer, and 31 progressed to cirrhosis or a MELD score greater than 14.
On the Kaplan-Meier curves, both the histology and noninvasive tests showed significant differences among the three strata for event-free survival probability.
Based on univariable Cox proportional hazard modeling, fibrosis stages F3 and F4 and continuous LSM-VCTE were significantly predictive of event-free survival probability. In multivariable models, fibrosis stage 4 and the two higher strata of LSM-VCTE were significantly predictive.
The study had several limitations, Dr. Mozes noted, by using cohort studies that weren’t initially designed to evaluate prognostic performance. They also couldn’t account for treatment effects and had no central histology reading. In addition, there may have been geographical variation in practice, as well as changes in practice over time as FibroScan technology improved in recent years.
“It turns out that stratifying patients by NIT score ranges can predict event-free survival probability,” he said. “This could pave the way into considering noninvasive tests as surrogate endpoints in clinical trials.”
In the ongoing study, Dr. Mozes and colleagues plan to look at additional aspects, such as MELD differentiation, histologic progression, and whether the NIT cutoffs differ from the current factors used to define advanced fibrosis. Future research should include longitudinal data and prospective studies, he added.
The study was sponsored by the LITMUS consortium, which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking and the European Union’s Horizon 2020 research and innovation program. Dr. Mozes disclosed no relevant financial relationships.
Fibrosis stages and liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE) through FibroScan were significant predictors of event-free survival, said Ferenc Mozes, DPhil, a postdoctoral research assistant at the University of Oxford, England, who has worked on biomarker evaluation of nonalcoholic steatohepatitis (NASH) as a member of the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) consortium.
“Liver histology is highly prognostic of liver-related outcomes in patients with NAFLD and NASH,” he said. “Not just that, but liver histology is also accepted, and furthermore mandated by the FDA, as a surrogate endpoint in pharmaceutical trials for NASH.”
However, liver histology is disadvantaged by sampling- and observer-dependent errors, he noted, as well as nonzero risk for patients. In recent years, researchers have hypothesized that noninvasive surrogate endpoints could be used as a way to speed up the development of new pharmaceutical treatments.
Dr. Mozes and colleagues evaluated the prognostic performance of histologically assessed liver fibrosis and three noninvasive tests (NITs): LSM-VCTE, Fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS). They conducted an individual participant data meta-analysis, which first established the diagnostic performance of NITs in identifying patients with NAFLD who had advanced fibrosis (stages F3 and F4). The research team then expanded the search by reaching out to authors to ask for outcomes data and including studies with baseline LSM-VCTE and liver histology performed within 6 months, as well as at least 1 year of follow-up data.
The composite endpoint included all-cause mortality or liver-related outcomes such as decompensation of cirrhosis, hepatocellular cancer, liver transplantation, a model of end-stage liver disease (MELD) score higher than 14, or histological progression to cirrhosis. Participants were censored at the last follow-up time or at the occurrence of the first liver-related event.
Based on Kaplan-Meier survival analysis, participants were stratified into groups based on thresholds derived from the literature: fibrosis stage 0-2 (F0-2), F3, F4; LSM less than 10 kPa, LSM equal to or more than 10 kPa and less than 20 kPa, and LSM equal to or more than 20 kPa; FIB4 less than 1.3, FIB equal to or more than 1.3 and less than 2.67, and FIB4 equal to or more than 2.67; and NFS less than –1.455, NFS equal to or more than –1.455 and less than 0.676, and NFS equal to or more than 0.676.
The research team included 13 studies from Europe and Asia with data on 1,796 patients. The median follow-up time was 64 months, both from biopsy and LSM-VCTE. The fibrosis stages were typical of what would be seen in tertiary care.
Overall, 125 patients (7%) reached the composite endpoint. They tended to be older and more likely to have type 2 diabetes, higher fibrosis stages, and cirrhosis. Among those, 80 participants died, including 25 from liver-related mortality. In addition, 23 had ascites, 28 had hepatocellular cancer, and 31 progressed to cirrhosis or a MELD score greater than 14.
On the Kaplan-Meier curves, both the histology and noninvasive tests showed significant differences among the three strata for event-free survival probability.
Based on univariable Cox proportional hazard modeling, fibrosis stages F3 and F4 and continuous LSM-VCTE were significantly predictive of event-free survival probability. In multivariable models, fibrosis stage 4 and the two higher strata of LSM-VCTE were significantly predictive.
The study had several limitations, Dr. Mozes noted, by using cohort studies that weren’t initially designed to evaluate prognostic performance. They also couldn’t account for treatment effects and had no central histology reading. In addition, there may have been geographical variation in practice, as well as changes in practice over time as FibroScan technology improved in recent years.
“It turns out that stratifying patients by NIT score ranges can predict event-free survival probability,” he said. “This could pave the way into considering noninvasive tests as surrogate endpoints in clinical trials.”
In the ongoing study, Dr. Mozes and colleagues plan to look at additional aspects, such as MELD differentiation, histologic progression, and whether the NIT cutoffs differ from the current factors used to define advanced fibrosis. Future research should include longitudinal data and prospective studies, he added.
The study was sponsored by the LITMUS consortium, which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking and the European Union’s Horizon 2020 research and innovation program. Dr. Mozes disclosed no relevant financial relationships.
Fibrosis stages and liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE) through FibroScan were significant predictors of event-free survival, said Ferenc Mozes, DPhil, a postdoctoral research assistant at the University of Oxford, England, who has worked on biomarker evaluation of nonalcoholic steatohepatitis (NASH) as a member of the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) consortium.
“Liver histology is highly prognostic of liver-related outcomes in patients with NAFLD and NASH,” he said. “Not just that, but liver histology is also accepted, and furthermore mandated by the FDA, as a surrogate endpoint in pharmaceutical trials for NASH.”
However, liver histology is disadvantaged by sampling- and observer-dependent errors, he noted, as well as nonzero risk for patients. In recent years, researchers have hypothesized that noninvasive surrogate endpoints could be used as a way to speed up the development of new pharmaceutical treatments.
Dr. Mozes and colleagues evaluated the prognostic performance of histologically assessed liver fibrosis and three noninvasive tests (NITs): LSM-VCTE, Fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS). They conducted an individual participant data meta-analysis, which first established the diagnostic performance of NITs in identifying patients with NAFLD who had advanced fibrosis (stages F3 and F4). The research team then expanded the search by reaching out to authors to ask for outcomes data and including studies with baseline LSM-VCTE and liver histology performed within 6 months, as well as at least 1 year of follow-up data.
The composite endpoint included all-cause mortality or liver-related outcomes such as decompensation of cirrhosis, hepatocellular cancer, liver transplantation, a model of end-stage liver disease (MELD) score higher than 14, or histological progression to cirrhosis. Participants were censored at the last follow-up time or at the occurrence of the first liver-related event.
Based on Kaplan-Meier survival analysis, participants were stratified into groups based on thresholds derived from the literature: fibrosis stage 0-2 (F0-2), F3, F4; LSM less than 10 kPa, LSM equal to or more than 10 kPa and less than 20 kPa, and LSM equal to or more than 20 kPa; FIB4 less than 1.3, FIB equal to or more than 1.3 and less than 2.67, and FIB4 equal to or more than 2.67; and NFS less than –1.455, NFS equal to or more than –1.455 and less than 0.676, and NFS equal to or more than 0.676.
The research team included 13 studies from Europe and Asia with data on 1,796 patients. The median follow-up time was 64 months, both from biopsy and LSM-VCTE. The fibrosis stages were typical of what would be seen in tertiary care.
Overall, 125 patients (7%) reached the composite endpoint. They tended to be older and more likely to have type 2 diabetes, higher fibrosis stages, and cirrhosis. Among those, 80 participants died, including 25 from liver-related mortality. In addition, 23 had ascites, 28 had hepatocellular cancer, and 31 progressed to cirrhosis or a MELD score greater than 14.
On the Kaplan-Meier curves, both the histology and noninvasive tests showed significant differences among the three strata for event-free survival probability.
Based on univariable Cox proportional hazard modeling, fibrosis stages F3 and F4 and continuous LSM-VCTE were significantly predictive of event-free survival probability. In multivariable models, fibrosis stage 4 and the two higher strata of LSM-VCTE were significantly predictive.
The study had several limitations, Dr. Mozes noted, by using cohort studies that weren’t initially designed to evaluate prognostic performance. They also couldn’t account for treatment effects and had no central histology reading. In addition, there may have been geographical variation in practice, as well as changes in practice over time as FibroScan technology improved in recent years.
“It turns out that stratifying patients by NIT score ranges can predict event-free survival probability,” he said. “This could pave the way into considering noninvasive tests as surrogate endpoints in clinical trials.”
In the ongoing study, Dr. Mozes and colleagues plan to look at additional aspects, such as MELD differentiation, histologic progression, and whether the NIT cutoffs differ from the current factors used to define advanced fibrosis. Future research should include longitudinal data and prospective studies, he added.
The study was sponsored by the LITMUS consortium, which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking and the European Union’s Horizon 2020 research and innovation program. Dr. Mozes disclosed no relevant financial relationships.
FROM THE LIVER MEETING
Precision CAD testing shows 70% cut in composite risk at 1 year
Benefits accrue on multiple endpoints
CHICAGO – A stepwise care pathway was associated with a substantial reduction in the number of invasive tests performed and a major improvement in outcomes, relative to usual management, in patients suspected of coronary artery disease (CAD), according to 1-year results of the multinational, randomized PRECISE trial.
The care pathway is appropriate for patients with nonacute chest pain or equivalent complaints that have raised suspicion of CAD, and it is extremely simple, according to the description from the principal investigator, Pamela S. Douglas, MD, given in her presentation at the annual scientific sessions of the American Heart Association.
Unlike the highly complex diagnostic algorithms shunting suspected CAD patients to the vast array of potential evaluations, the newly tested protocol, characterized as a “precision strategy,” divides patients into those who are immediate candidates for invasive testing and those who are not. The discriminator is the PROMISE minimal risk assessment score, a tool already validated.
Those deemed candidates for testing on the basis of an elevated score undergo computed coronary CT angiography (cCTA). In those who are not, testing is deferred.
Strategy is simple but effective
Although simple, this pathway is highly effective, judging by the results of the PRECISE trial, which tested the strategy in 2,103 patients at 65 sites in North America and Europe. The primary outcome was a composite of major adverse cardiovascular events (MACE) that included death, nonfatal MI, and catheterization without observed CAD.
After a median follow-up of 11.8 months, the primary MACE endpoint was reached in about 11.3% of those in the usual-care group, which was more than twofold higher than the 4.2% in the precision strategy group. The unadjusted risk reduction was 65% but rose to more than 70% (hazard ratio, 0.29; P < .001) after adjustment for gender and baseline characteristics.
In the arm randomized to the precision strategy, 16% were characterized as low risk and received no further testing. Almost all the others underwent cCTA alone (48%) or cCTA with fractional flow reserve (FFR) (31%). Stress echocardiography, treadmill electrocardiography, and other functional studies were performed in the small proportion of remaining patients.
cCTA performed in just 15% of usual care
In the usual-care arm, cCTA with or without FFR was only performed in 15%. More than 80% of patients underwent evaluations with one or more of an array of functional tests. For example, one-third were evaluated with single photon emission CT/PET and nearly as many underwent stress echocardiography testing. Only 7% in usual care underwent no testing after referral.
Within the MACE composite endpoint, almost all the relative benefit in the precision strategy arm was derived from the endpoint of angiography performed without evidence of obstructive CAD (2.6% vs. 10.2%). Rates of all-cause mortality and MI were not significantly different.
Important for the safety and utility of the precision strategy, there “were no deaths or MI events among those assigned deferred testing ” in that experimental arm, according to Dr. Douglas, professor of research in cardiovascular diseases at Duke University, Durham, N.C.
Instead, those in the precision strategy arm were far less likely to undergo catheterization without finding CAD (20% vs. 60%) and far less likely to undergo catheterization without revascularization (28% vs. 70%).
In addition, the group randomized to the precision strategy were more likely to be placed on risk reducing therapies following testing. Although the higher proportion of patients placed on antihypertensive therapy did not reach statistical significance (P = .1), the increased proportions placed on lipid therapy (P < .001) and antiplatelet therapy (P < .001) did.
Citing a study in JAMA Cardiology that found that more than 25% of patients presenting with stable chest pain have normal coronary arteries, Dr. Douglas said that the precision strategy as shown in the PRECISE trial addresses several agreed-upon goals in guidelines from the AHA, the European Society of Cardiology and the U.K.’s National Institute for Health and Care Excellence. These goals include reducing unnecessary testing by risk stratification, improving diagnostic yield of the testing that is performed, and avoiding the costs and complications of unneeded invasive testing.
New protocol called preferred approach
On the basis of these results, Dr. Douglas called the precision strategy “a preferred approach in evaluating patients with stable symptoms and suspected coronary disease.”
Julie Indik, MD, PhD, a professor of medicine at the University of Arizona, Tuscon, said that application of this approach in routine care could have “a major impact on care” by avoiding unnecessary tests with no apparent adverse effect on outcomes.
Although not demonstrated in this study, Dr. Indik suggested that the large number of patients tested for CAD each year – she estimated 4 million visits – means that less testing is likely to have a major impact on the costs of care, and she praised “the practical, efficient” approach of the precision strategy.
Ron Blankstein, MD, director of cardiac computed tomography, Brigham and Women’s Hospital, Boston, also said these data “have both economic and safety implications.” As an AHA-invited discussant of this study, he emphasized that this is a strategy that should only be applied to lower risk patients with no prior history of CAD, but, in this group, he believes these data “will inform future guidelines.”
Dr. Douglas declined to speculate on whether the precision strategy will be incorporated into future guidelines, but she did say that the PRECISE data demonstrate that this approach improves quality of care.
In an interview, Dr. Douglas suggested that this care pathway could provide a basis on which to demonstrate improved outcomes with more efficient use of resources, a common definition of quality care delivery.
Dr. Douglas reported financial relationships with Caption Health, Kowa, and Heartflow, which provided funding for the PRECISE trial. Dr. Indik reported no potential conflicts of interest. Dr. Blankstein reported financial relationships with Amgen, Caristo Diagnostics, and Novartis.
Benefits accrue on multiple endpoints
Benefits accrue on multiple endpoints
CHICAGO – A stepwise care pathway was associated with a substantial reduction in the number of invasive tests performed and a major improvement in outcomes, relative to usual management, in patients suspected of coronary artery disease (CAD), according to 1-year results of the multinational, randomized PRECISE trial.
The care pathway is appropriate for patients with nonacute chest pain or equivalent complaints that have raised suspicion of CAD, and it is extremely simple, according to the description from the principal investigator, Pamela S. Douglas, MD, given in her presentation at the annual scientific sessions of the American Heart Association.
Unlike the highly complex diagnostic algorithms shunting suspected CAD patients to the vast array of potential evaluations, the newly tested protocol, characterized as a “precision strategy,” divides patients into those who are immediate candidates for invasive testing and those who are not. The discriminator is the PROMISE minimal risk assessment score, a tool already validated.
Those deemed candidates for testing on the basis of an elevated score undergo computed coronary CT angiography (cCTA). In those who are not, testing is deferred.
Strategy is simple but effective
Although simple, this pathway is highly effective, judging by the results of the PRECISE trial, which tested the strategy in 2,103 patients at 65 sites in North America and Europe. The primary outcome was a composite of major adverse cardiovascular events (MACE) that included death, nonfatal MI, and catheterization without observed CAD.
After a median follow-up of 11.8 months, the primary MACE endpoint was reached in about 11.3% of those in the usual-care group, which was more than twofold higher than the 4.2% in the precision strategy group. The unadjusted risk reduction was 65% but rose to more than 70% (hazard ratio, 0.29; P < .001) after adjustment for gender and baseline characteristics.
In the arm randomized to the precision strategy, 16% were characterized as low risk and received no further testing. Almost all the others underwent cCTA alone (48%) or cCTA with fractional flow reserve (FFR) (31%). Stress echocardiography, treadmill electrocardiography, and other functional studies were performed in the small proportion of remaining patients.
cCTA performed in just 15% of usual care
In the usual-care arm, cCTA with or without FFR was only performed in 15%. More than 80% of patients underwent evaluations with one or more of an array of functional tests. For example, one-third were evaluated with single photon emission CT/PET and nearly as many underwent stress echocardiography testing. Only 7% in usual care underwent no testing after referral.
Within the MACE composite endpoint, almost all the relative benefit in the precision strategy arm was derived from the endpoint of angiography performed without evidence of obstructive CAD (2.6% vs. 10.2%). Rates of all-cause mortality and MI were not significantly different.
Important for the safety and utility of the precision strategy, there “were no deaths or MI events among those assigned deferred testing ” in that experimental arm, according to Dr. Douglas, professor of research in cardiovascular diseases at Duke University, Durham, N.C.
Instead, those in the precision strategy arm were far less likely to undergo catheterization without finding CAD (20% vs. 60%) and far less likely to undergo catheterization without revascularization (28% vs. 70%).
In addition, the group randomized to the precision strategy were more likely to be placed on risk reducing therapies following testing. Although the higher proportion of patients placed on antihypertensive therapy did not reach statistical significance (P = .1), the increased proportions placed on lipid therapy (P < .001) and antiplatelet therapy (P < .001) did.
Citing a study in JAMA Cardiology that found that more than 25% of patients presenting with stable chest pain have normal coronary arteries, Dr. Douglas said that the precision strategy as shown in the PRECISE trial addresses several agreed-upon goals in guidelines from the AHA, the European Society of Cardiology and the U.K.’s National Institute for Health and Care Excellence. These goals include reducing unnecessary testing by risk stratification, improving diagnostic yield of the testing that is performed, and avoiding the costs and complications of unneeded invasive testing.
New protocol called preferred approach
On the basis of these results, Dr. Douglas called the precision strategy “a preferred approach in evaluating patients with stable symptoms and suspected coronary disease.”
Julie Indik, MD, PhD, a professor of medicine at the University of Arizona, Tuscon, said that application of this approach in routine care could have “a major impact on care” by avoiding unnecessary tests with no apparent adverse effect on outcomes.
Although not demonstrated in this study, Dr. Indik suggested that the large number of patients tested for CAD each year – she estimated 4 million visits – means that less testing is likely to have a major impact on the costs of care, and she praised “the practical, efficient” approach of the precision strategy.
Ron Blankstein, MD, director of cardiac computed tomography, Brigham and Women’s Hospital, Boston, also said these data “have both economic and safety implications.” As an AHA-invited discussant of this study, he emphasized that this is a strategy that should only be applied to lower risk patients with no prior history of CAD, but, in this group, he believes these data “will inform future guidelines.”
Dr. Douglas declined to speculate on whether the precision strategy will be incorporated into future guidelines, but she did say that the PRECISE data demonstrate that this approach improves quality of care.
In an interview, Dr. Douglas suggested that this care pathway could provide a basis on which to demonstrate improved outcomes with more efficient use of resources, a common definition of quality care delivery.
Dr. Douglas reported financial relationships with Caption Health, Kowa, and Heartflow, which provided funding for the PRECISE trial. Dr. Indik reported no potential conflicts of interest. Dr. Blankstein reported financial relationships with Amgen, Caristo Diagnostics, and Novartis.
CHICAGO – A stepwise care pathway was associated with a substantial reduction in the number of invasive tests performed and a major improvement in outcomes, relative to usual management, in patients suspected of coronary artery disease (CAD), according to 1-year results of the multinational, randomized PRECISE trial.
The care pathway is appropriate for patients with nonacute chest pain or equivalent complaints that have raised suspicion of CAD, and it is extremely simple, according to the description from the principal investigator, Pamela S. Douglas, MD, given in her presentation at the annual scientific sessions of the American Heart Association.
Unlike the highly complex diagnostic algorithms shunting suspected CAD patients to the vast array of potential evaluations, the newly tested protocol, characterized as a “precision strategy,” divides patients into those who are immediate candidates for invasive testing and those who are not. The discriminator is the PROMISE minimal risk assessment score, a tool already validated.
Those deemed candidates for testing on the basis of an elevated score undergo computed coronary CT angiography (cCTA). In those who are not, testing is deferred.
Strategy is simple but effective
Although simple, this pathway is highly effective, judging by the results of the PRECISE trial, which tested the strategy in 2,103 patients at 65 sites in North America and Europe. The primary outcome was a composite of major adverse cardiovascular events (MACE) that included death, nonfatal MI, and catheterization without observed CAD.
After a median follow-up of 11.8 months, the primary MACE endpoint was reached in about 11.3% of those in the usual-care group, which was more than twofold higher than the 4.2% in the precision strategy group. The unadjusted risk reduction was 65% but rose to more than 70% (hazard ratio, 0.29; P < .001) after adjustment for gender and baseline characteristics.
In the arm randomized to the precision strategy, 16% were characterized as low risk and received no further testing. Almost all the others underwent cCTA alone (48%) or cCTA with fractional flow reserve (FFR) (31%). Stress echocardiography, treadmill electrocardiography, and other functional studies were performed in the small proportion of remaining patients.
cCTA performed in just 15% of usual care
In the usual-care arm, cCTA with or without FFR was only performed in 15%. More than 80% of patients underwent evaluations with one or more of an array of functional tests. For example, one-third were evaluated with single photon emission CT/PET and nearly as many underwent stress echocardiography testing. Only 7% in usual care underwent no testing after referral.
Within the MACE composite endpoint, almost all the relative benefit in the precision strategy arm was derived from the endpoint of angiography performed without evidence of obstructive CAD (2.6% vs. 10.2%). Rates of all-cause mortality and MI were not significantly different.
Important for the safety and utility of the precision strategy, there “were no deaths or MI events among those assigned deferred testing ” in that experimental arm, according to Dr. Douglas, professor of research in cardiovascular diseases at Duke University, Durham, N.C.
Instead, those in the precision strategy arm were far less likely to undergo catheterization without finding CAD (20% vs. 60%) and far less likely to undergo catheterization without revascularization (28% vs. 70%).
In addition, the group randomized to the precision strategy were more likely to be placed on risk reducing therapies following testing. Although the higher proportion of patients placed on antihypertensive therapy did not reach statistical significance (P = .1), the increased proportions placed on lipid therapy (P < .001) and antiplatelet therapy (P < .001) did.
Citing a study in JAMA Cardiology that found that more than 25% of patients presenting with stable chest pain have normal coronary arteries, Dr. Douglas said that the precision strategy as shown in the PRECISE trial addresses several agreed-upon goals in guidelines from the AHA, the European Society of Cardiology and the U.K.’s National Institute for Health and Care Excellence. These goals include reducing unnecessary testing by risk stratification, improving diagnostic yield of the testing that is performed, and avoiding the costs and complications of unneeded invasive testing.
New protocol called preferred approach
On the basis of these results, Dr. Douglas called the precision strategy “a preferred approach in evaluating patients with stable symptoms and suspected coronary disease.”
Julie Indik, MD, PhD, a professor of medicine at the University of Arizona, Tuscon, said that application of this approach in routine care could have “a major impact on care” by avoiding unnecessary tests with no apparent adverse effect on outcomes.
Although not demonstrated in this study, Dr. Indik suggested that the large number of patients tested for CAD each year – she estimated 4 million visits – means that less testing is likely to have a major impact on the costs of care, and she praised “the practical, efficient” approach of the precision strategy.
Ron Blankstein, MD, director of cardiac computed tomography, Brigham and Women’s Hospital, Boston, also said these data “have both economic and safety implications.” As an AHA-invited discussant of this study, he emphasized that this is a strategy that should only be applied to lower risk patients with no prior history of CAD, but, in this group, he believes these data “will inform future guidelines.”
Dr. Douglas declined to speculate on whether the precision strategy will be incorporated into future guidelines, but she did say that the PRECISE data demonstrate that this approach improves quality of care.
In an interview, Dr. Douglas suggested that this care pathway could provide a basis on which to demonstrate improved outcomes with more efficient use of resources, a common definition of quality care delivery.
Dr. Douglas reported financial relationships with Caption Health, Kowa, and Heartflow, which provided funding for the PRECISE trial. Dr. Indik reported no potential conflicts of interest. Dr. Blankstein reported financial relationships with Amgen, Caristo Diagnostics, and Novartis.
AT AHA 2022
Avoid routine early ECMO in severe cardiogenic shock: ECMO-CS
CHICAGO – Routine early, expeditious use of extracorporeal membrane oxygenation (ECMO) is a common strategy in patients with severe cardiogenic shock, but a less aggressive initial approach may be just as effective, a randomized trial suggests.
In the study that assigned patients with “rapidly deteriorating or severe” cardiogenic shock to one or the other approach, clinical outcomes were no better for those who received immediate ECMO than for those initially managed with inotropes and vasopressors, researchers said.
The conservative strategy, importantly, allowed for downstream ECMO in the event of hemodynamic deterioration, which occurred in a substantial 39% of cases, observed Petr Ostadal, MD, PhD, when presenting the results at the American Heart Association scientific sessions.
Dr. Ostadal of Na Homolce Hospital, Prague, is also first author on the published report of the study, called Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock (ECMO-CS), which was published the same day in Circulation.
The trial makes a firm case for preferring the conservative initial approach over routine early ECMO in the kind of patients it entered, Larry A. Allen, MD, MHS, University of Coloradoat Denver, Aurora, told this news organization.
More than 60% of the trial’s 117 patients had shock secondary to an acute coronary syndrome; another 23% were in heart failure decompensation.
A preference for the conservative initial approach would be welcome, he said. The early aggressive ECMO approach is resource intensive and carries some important risks, such as stroke or coagulopathy, said Dr. Allen, who is not connected with ECMO-CS. Yet it is increasingly the go-to approach in such patients, based primarily on observational data.
Although early ECMO apparently didn’t benefit patients in this study in their specific stage of cardiogenic shock, Dr. Allen observed, it would presumably help some, but identifying them in practice presents challenges. “Defining where people are in the spectrum of early versus middle versus late cardiogenic shock is actually very tricky.”
It will therefore be important, he said, to identify ways to predict which conservatively managed patients do well with the strategy, and which are most at risk for hemodynamic deterioration and for whom ECMO should be readily available.
“I think part of what ECMO-CS tells us is that, if a patient is stable on intravenous inotropic and vasopressor support, you can defer ECMO while you’re thinking about the patient – about their larger context and the right medical decision-making for them.”
The trial randomly assigned 122 patients with rapidly deteriorating or severe cardiogenic shock to the immediate-ECMO or the conservative strategy at four centers in the Czech Republic. The 117 patients for whom informed consent could be obtained were included in the analysis, 58 and 59 patients, respectively. Their mean age was about 65 years and three-fourths were male.
The primary endpoint, the only endpoint for which the study was powered, consisted of death from any cause, resuscitated circulatory arrest, or use of a different form of mechanical circulatory support (MCS) by 30 days.
It occurred in 63.8% of patients assigned to immediate ECMO and 71.2% of those in the conservative strategy group, for a hazard ratio of 0.72 (95% confidence interval, 0.46-1.12; P = .21).
As individual endpoints, rates of death from any cause and resuscitated arrest did not significantly differ between the groups, but conservatively managed patients more often used another form of MCS. The HRs were 1.11 (95% CI, 0.66-1.87) for death from any cause, 0.79 (95% CI, 0.27-2.28) for resuscitated cardiac arrest, and 0.38 (95% CI, 0.18-0.79) for use of another MCS device.
The rates for serious adverse events – including bleeding, ischemia, stroke, pneumonia, or sepsis – were similar at 60.3% in the early-ECMO group and 61% in group with conservative initial management, Dr. Ostadal reported.
Other than the 23 patients in the conservative initial strategy group who went on to receive ECMO (1.9 days after randomization, on average), 1 went on to undergo implantation with a HeartMate (Abbott) ventricular assist device and 3 received an Impella pump (Abiomed).
Six patients in the early-ECMO group were already receiving intra-aortic balloon pump (IABP) support at randomization, two underwent temporary implantation with a Centrimag device (Abbott), and three went on to receive a HeartMate device, the published report notes.
ECMO is the optimal first choice for MCS in such patients with cardiogenic shock who need a circulatory support device, especially because it also oxygenates the blood, Dr. Ostadal told this news organization.
But ECMO doesn’t help with ventricular unloading. Indeed, it can sometimes reduce ventricular preload, especially if right-heart pressures are low. So MCS devices that unload the ventricle, typically an IABP, can complement ECMO.
Dr. Ostadal speculates, however, that there may be a better pairing option. “Impella plus ECMO, I think, is the combination which has a future,” he said, for patients in cardiogenic shock who need a short-term percutaneous hemodynamic support device. Impella “supports the whole circulation” and unloads the left ventricle.
“A balloon pump in combination with ECMO is still not a bad choice. It’s very cheap in comparison with Impella.” But in his opinion, Dr. Ostadal said, “The combination of Impella plus ECMO is more efficient from a hemodynamic point of view.”
As the published report notes, ongoing randomized trials looking at ECMO plus other MCS devices in cardiogenic shock include ECLS-SHOCK, with a projected enrollment of 420 patients, and EURO-SHOCK, aiming for a similar number of patients; both compare routine ECMO to conservative management.
In addition, ANCHOR, in which ECMO is combined with IABP, and DanShock, which looks at early use of Impella rather than ECMO, are enrolling patients with shock secondary to acute coronary syndromes.
Dr. Ostadal disclosed consulting for Getinge, Edwards, Medtronic, Biomedica, and Xenios/Fresenius, and receiving research support from Xenios/Fresenius. Dr. Allen disclosed modest or significant relationships with ACI Clinical, Novartis, UpToDate, Boston Scientific, and Cytokinetics.
A version of this article first appeared on Medscape.com.
CHICAGO – Routine early, expeditious use of extracorporeal membrane oxygenation (ECMO) is a common strategy in patients with severe cardiogenic shock, but a less aggressive initial approach may be just as effective, a randomized trial suggests.
In the study that assigned patients with “rapidly deteriorating or severe” cardiogenic shock to one or the other approach, clinical outcomes were no better for those who received immediate ECMO than for those initially managed with inotropes and vasopressors, researchers said.
The conservative strategy, importantly, allowed for downstream ECMO in the event of hemodynamic deterioration, which occurred in a substantial 39% of cases, observed Petr Ostadal, MD, PhD, when presenting the results at the American Heart Association scientific sessions.
Dr. Ostadal of Na Homolce Hospital, Prague, is also first author on the published report of the study, called Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock (ECMO-CS), which was published the same day in Circulation.
The trial makes a firm case for preferring the conservative initial approach over routine early ECMO in the kind of patients it entered, Larry A. Allen, MD, MHS, University of Coloradoat Denver, Aurora, told this news organization.
More than 60% of the trial’s 117 patients had shock secondary to an acute coronary syndrome; another 23% were in heart failure decompensation.
A preference for the conservative initial approach would be welcome, he said. The early aggressive ECMO approach is resource intensive and carries some important risks, such as stroke or coagulopathy, said Dr. Allen, who is not connected with ECMO-CS. Yet it is increasingly the go-to approach in such patients, based primarily on observational data.
Although early ECMO apparently didn’t benefit patients in this study in their specific stage of cardiogenic shock, Dr. Allen observed, it would presumably help some, but identifying them in practice presents challenges. “Defining where people are in the spectrum of early versus middle versus late cardiogenic shock is actually very tricky.”
It will therefore be important, he said, to identify ways to predict which conservatively managed patients do well with the strategy, and which are most at risk for hemodynamic deterioration and for whom ECMO should be readily available.
“I think part of what ECMO-CS tells us is that, if a patient is stable on intravenous inotropic and vasopressor support, you can defer ECMO while you’re thinking about the patient – about their larger context and the right medical decision-making for them.”
The trial randomly assigned 122 patients with rapidly deteriorating or severe cardiogenic shock to the immediate-ECMO or the conservative strategy at four centers in the Czech Republic. The 117 patients for whom informed consent could be obtained were included in the analysis, 58 and 59 patients, respectively. Their mean age was about 65 years and three-fourths were male.
The primary endpoint, the only endpoint for which the study was powered, consisted of death from any cause, resuscitated circulatory arrest, or use of a different form of mechanical circulatory support (MCS) by 30 days.
It occurred in 63.8% of patients assigned to immediate ECMO and 71.2% of those in the conservative strategy group, for a hazard ratio of 0.72 (95% confidence interval, 0.46-1.12; P = .21).
As individual endpoints, rates of death from any cause and resuscitated arrest did not significantly differ between the groups, but conservatively managed patients more often used another form of MCS. The HRs were 1.11 (95% CI, 0.66-1.87) for death from any cause, 0.79 (95% CI, 0.27-2.28) for resuscitated cardiac arrest, and 0.38 (95% CI, 0.18-0.79) for use of another MCS device.
The rates for serious adverse events – including bleeding, ischemia, stroke, pneumonia, or sepsis – were similar at 60.3% in the early-ECMO group and 61% in group with conservative initial management, Dr. Ostadal reported.
Other than the 23 patients in the conservative initial strategy group who went on to receive ECMO (1.9 days after randomization, on average), 1 went on to undergo implantation with a HeartMate (Abbott) ventricular assist device and 3 received an Impella pump (Abiomed).
Six patients in the early-ECMO group were already receiving intra-aortic balloon pump (IABP) support at randomization, two underwent temporary implantation with a Centrimag device (Abbott), and three went on to receive a HeartMate device, the published report notes.
ECMO is the optimal first choice for MCS in such patients with cardiogenic shock who need a circulatory support device, especially because it also oxygenates the blood, Dr. Ostadal told this news organization.
But ECMO doesn’t help with ventricular unloading. Indeed, it can sometimes reduce ventricular preload, especially if right-heart pressures are low. So MCS devices that unload the ventricle, typically an IABP, can complement ECMO.
Dr. Ostadal speculates, however, that there may be a better pairing option. “Impella plus ECMO, I think, is the combination which has a future,” he said, for patients in cardiogenic shock who need a short-term percutaneous hemodynamic support device. Impella “supports the whole circulation” and unloads the left ventricle.
“A balloon pump in combination with ECMO is still not a bad choice. It’s very cheap in comparison with Impella.” But in his opinion, Dr. Ostadal said, “The combination of Impella plus ECMO is more efficient from a hemodynamic point of view.”
As the published report notes, ongoing randomized trials looking at ECMO plus other MCS devices in cardiogenic shock include ECLS-SHOCK, with a projected enrollment of 420 patients, and EURO-SHOCK, aiming for a similar number of patients; both compare routine ECMO to conservative management.
In addition, ANCHOR, in which ECMO is combined with IABP, and DanShock, which looks at early use of Impella rather than ECMO, are enrolling patients with shock secondary to acute coronary syndromes.
Dr. Ostadal disclosed consulting for Getinge, Edwards, Medtronic, Biomedica, and Xenios/Fresenius, and receiving research support from Xenios/Fresenius. Dr. Allen disclosed modest or significant relationships with ACI Clinical, Novartis, UpToDate, Boston Scientific, and Cytokinetics.
A version of this article first appeared on Medscape.com.
CHICAGO – Routine early, expeditious use of extracorporeal membrane oxygenation (ECMO) is a common strategy in patients with severe cardiogenic shock, but a less aggressive initial approach may be just as effective, a randomized trial suggests.
In the study that assigned patients with “rapidly deteriorating or severe” cardiogenic shock to one or the other approach, clinical outcomes were no better for those who received immediate ECMO than for those initially managed with inotropes and vasopressors, researchers said.
The conservative strategy, importantly, allowed for downstream ECMO in the event of hemodynamic deterioration, which occurred in a substantial 39% of cases, observed Petr Ostadal, MD, PhD, when presenting the results at the American Heart Association scientific sessions.
Dr. Ostadal of Na Homolce Hospital, Prague, is also first author on the published report of the study, called Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock (ECMO-CS), which was published the same day in Circulation.
The trial makes a firm case for preferring the conservative initial approach over routine early ECMO in the kind of patients it entered, Larry A. Allen, MD, MHS, University of Coloradoat Denver, Aurora, told this news organization.
More than 60% of the trial’s 117 patients had shock secondary to an acute coronary syndrome; another 23% were in heart failure decompensation.
A preference for the conservative initial approach would be welcome, he said. The early aggressive ECMO approach is resource intensive and carries some important risks, such as stroke or coagulopathy, said Dr. Allen, who is not connected with ECMO-CS. Yet it is increasingly the go-to approach in such patients, based primarily on observational data.
Although early ECMO apparently didn’t benefit patients in this study in their specific stage of cardiogenic shock, Dr. Allen observed, it would presumably help some, but identifying them in practice presents challenges. “Defining where people are in the spectrum of early versus middle versus late cardiogenic shock is actually very tricky.”
It will therefore be important, he said, to identify ways to predict which conservatively managed patients do well with the strategy, and which are most at risk for hemodynamic deterioration and for whom ECMO should be readily available.
“I think part of what ECMO-CS tells us is that, if a patient is stable on intravenous inotropic and vasopressor support, you can defer ECMO while you’re thinking about the patient – about their larger context and the right medical decision-making for them.”
The trial randomly assigned 122 patients with rapidly deteriorating or severe cardiogenic shock to the immediate-ECMO or the conservative strategy at four centers in the Czech Republic. The 117 patients for whom informed consent could be obtained were included in the analysis, 58 and 59 patients, respectively. Their mean age was about 65 years and three-fourths were male.
The primary endpoint, the only endpoint for which the study was powered, consisted of death from any cause, resuscitated circulatory arrest, or use of a different form of mechanical circulatory support (MCS) by 30 days.
It occurred in 63.8% of patients assigned to immediate ECMO and 71.2% of those in the conservative strategy group, for a hazard ratio of 0.72 (95% confidence interval, 0.46-1.12; P = .21).
As individual endpoints, rates of death from any cause and resuscitated arrest did not significantly differ between the groups, but conservatively managed patients more often used another form of MCS. The HRs were 1.11 (95% CI, 0.66-1.87) for death from any cause, 0.79 (95% CI, 0.27-2.28) for resuscitated cardiac arrest, and 0.38 (95% CI, 0.18-0.79) for use of another MCS device.
The rates for serious adverse events – including bleeding, ischemia, stroke, pneumonia, or sepsis – were similar at 60.3% in the early-ECMO group and 61% in group with conservative initial management, Dr. Ostadal reported.
Other than the 23 patients in the conservative initial strategy group who went on to receive ECMO (1.9 days after randomization, on average), 1 went on to undergo implantation with a HeartMate (Abbott) ventricular assist device and 3 received an Impella pump (Abiomed).
Six patients in the early-ECMO group were already receiving intra-aortic balloon pump (IABP) support at randomization, two underwent temporary implantation with a Centrimag device (Abbott), and three went on to receive a HeartMate device, the published report notes.
ECMO is the optimal first choice for MCS in such patients with cardiogenic shock who need a circulatory support device, especially because it also oxygenates the blood, Dr. Ostadal told this news organization.
But ECMO doesn’t help with ventricular unloading. Indeed, it can sometimes reduce ventricular preload, especially if right-heart pressures are low. So MCS devices that unload the ventricle, typically an IABP, can complement ECMO.
Dr. Ostadal speculates, however, that there may be a better pairing option. “Impella plus ECMO, I think, is the combination which has a future,” he said, for patients in cardiogenic shock who need a short-term percutaneous hemodynamic support device. Impella “supports the whole circulation” and unloads the left ventricle.
“A balloon pump in combination with ECMO is still not a bad choice. It’s very cheap in comparison with Impella.” But in his opinion, Dr. Ostadal said, “The combination of Impella plus ECMO is more efficient from a hemodynamic point of view.”
As the published report notes, ongoing randomized trials looking at ECMO plus other MCS devices in cardiogenic shock include ECLS-SHOCK, with a projected enrollment of 420 patients, and EURO-SHOCK, aiming for a similar number of patients; both compare routine ECMO to conservative management.
In addition, ANCHOR, in which ECMO is combined with IABP, and DanShock, which looks at early use of Impella rather than ECMO, are enrolling patients with shock secondary to acute coronary syndromes.
Dr. Ostadal disclosed consulting for Getinge, Edwards, Medtronic, Biomedica, and Xenios/Fresenius, and receiving research support from Xenios/Fresenius. Dr. Allen disclosed modest or significant relationships with ACI Clinical, Novartis, UpToDate, Boston Scientific, and Cytokinetics.
A version of this article first appeared on Medscape.com.
AT AHA 2022
ISCHEMIA-EXTEND: Conservative stable CAD management holds up
CHICAGO – The case for survival equipoise between an invasive or conservative strategy for managing patients with stable coronary disease and moderate or severe cardiac ischemia grew stronger with an additional 2.5 years of median follow-up of the landmark ISCHEMIA trial.
During a median follow-up of 5.7 years in ISCHEMIA-EXTEND – and as long as 7 years – patients randomized to an upfront invasive strategy regardless of their symptoms had an all-cause mortality rate of 12.7%, compared with a 13.4% rate in the patients randomized to the conservative, medication-based management strategy that employed revascularization only when the medical approach failed to resolve their angina. This survival difference fell far short of significance (adjusted hazard ratio, 1.00; 95% confidence interval, 0.85-1.18), solidifying a finding first seen in the main ISCHEMIA results when they came out 3 years before, in late 2019, Judith S. Hochman, MD, said at the American Heart Association scientific sessions.
The new results “provide evidence for patients with chronic coronary disease and their physicians as they decide whether to add invasive management to guideline-directed medical therapy,” concluded Dr. Hochman, professor and senior associate dean for clinical sciences at New York University Langone Health. Simultaneous with her report, the extended follow-up results also appeared in an article published online in Circulation.
Nil probability of a survival benefit
“The probability over 5.7 years that a patient’s risk of dying is lower with the invasive strategy is nil, which means: Go with the patient’s preference. Not undergoing revascularization is a reasonable strategy because there is no excess mortality,” Dr. Hochman said in an interview. The trial’s extended follow-up provides “much more robust evidence” for the neutral effect on survival. The investigators plan to further follow-up out to a maximum of 10 years to continue to monitor for a signal of a mortality difference.
“These findings might help physicians in shared decision-making as to whether to add invasive management to guideline-directed medical management in selected patients with chronic coronary artery disease and moderate or severe ischemia,” commented M. Cecilia Bahit, MD, designated discussant for the report and chief of cardiology for INECO Neurosciences in Rosario, Argentina.
The original ISCHEMIA results had also shown that invasive intervention can improve the quality of life in patients who have angina as a result of their coronary disease, but also showed “minimal benefits” from an invasive approach in asymptomatic patients, who comprised 35% of the study cohort of 5,179 patients.
While ISCHEMIA enrolled patients with moderate to severe coronary ischemia identified with noninvasive testing, it excluded certain patients for whom an invasive strategy is recommended, including those with unprotected left main coronary stenoses of at least 50%, a recent acute coronary syndrome event, a left ventricular ejection fraction of less than 35%, more advanced functional limitations from heart failure, or advanced chronic kidney disease.
Follow-up without adjudication
The extended follow-up included 4,825 patients from the initial cohort, with data collected from 4,540 patients. One limitation of the follow-up was that the cause of death was not adjudicated as it had been during the initial follow-up phase. It instead relied on unconfirmed information collected either from patients’ families or national databases. The demographics and clinical profiles of the study participants available for extended follow-up closely matched the entire original study cohort.
The additional follow-up also revealed a significant survival benefit from the invasive approach for cardiovascular deaths, with an incidence of 8.6% in the conservative arm and 6.4% in the invasive group, an adjusted 22% relative reduction in this outcome favoring the invasive strategy (95% CI, 0.63-0.96). This difference had appeared as a nonsignificant signal in the initial 3.2-year median follow-up.
However, this significant benefit from the invasive strategy was counterbalanced by a surprising and inexplicable increase in deaths from noncardiovascular causes in those managed with the invasive strategy. Noncardiovascular deaths occurred in 5.5% of those in the invasive arm and in 4.4% of those in the conservative arm, a significant adjusted 44% relative increase in this outcome associated with invasive management. Again, this difference was not as clearly apparent after the initial follow-up phase.
“The increase in noncardiovascular deaths with the invasive strategy surprisingly persisted over time and offset” the cardiovascular survival benefit from upfront invasive treatment, explained Dr. Hochman. A prior report from the investigators looked in depth at the noncardiovascular deaths during the initial follow-up phase and found that most of the excess was caused by malignancies, although why this happened in the invasively treated patients remains a mystery.
Staying alive is what patients care about
“I think that interventional cardiologists who favor an invasive strategy will be excited to see this significant reduction in cardiovascular deaths, but patients don’t care what they die from. What patients care about is whether they are dead or alive,” Dr. Hochman noted.
But B. Hadley Wilson, MD, an interventional cardiologist and vice president of the American College of Cardiology, had a somewhat different take on these findings.
“We need to consider the significant decrease in cardiovascular mortality, as we sort out the conundrum” of the increase in noncardiovascular deaths,” he said in an interview. “Hopefully, the 10-year outcomes will help answer this.”
But until more information is available, the ISCHEMIA and ISCHEMIA-EXTEND results have already helped advance the conversation that patients with stable coronary disease and their families have with clinicians about management decisions.
“I love that ISCHEMIA highlighted the importance of shared decision making and a heart team approach,” said Dr. Wilson, executive vice chair of the Sanger Heart & Vascular Institute of Atrium Health in Charlotte, N.C.
Anecdotally, ISCHEMIA reduced invasive management
After the initial ISCHEMIA results were published nearly 3 years ago, “I think use of invasive treatment for these patients has decreased, although I have seen no numbers” that document this, said Dr. Wilson. “I think most interventional cardiologists would say that ISCHEMIA has had an impact,” with fewer patients who match the trial’s enrollment criteria undergoing invasive management.
“Anecdotally, cardiologists are reviewing the ISCHEMIA data with their patients,” agreed Dr. Hochman, who added that no actual data have yet appeared to document this, nor do data yet document a change in the use of invasive management. “It takes time to measure the impact.”
To expedite the shared decision-making process for these patients, the ISCHEMIA researchers are planning to make available an app that will allow patients and physicians to enter clinical and demographic data and see a calculated estimate of their future cardiovascular disease risk and how amenable it may be to modification by invasive management, Dr. Hochman said. The app would be available on the ISCHEMIA study website in 2023.
ISCHEMIA and ISCHEMIA EXTEND received no commercial funding. Dr. Hochman and Dr. Wilson had no disclosures. Dr. Bahit has received honoraria from Behring, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, MSD, and Pfizer.
CHICAGO – The case for survival equipoise between an invasive or conservative strategy for managing patients with stable coronary disease and moderate or severe cardiac ischemia grew stronger with an additional 2.5 years of median follow-up of the landmark ISCHEMIA trial.
During a median follow-up of 5.7 years in ISCHEMIA-EXTEND – and as long as 7 years – patients randomized to an upfront invasive strategy regardless of their symptoms had an all-cause mortality rate of 12.7%, compared with a 13.4% rate in the patients randomized to the conservative, medication-based management strategy that employed revascularization only when the medical approach failed to resolve their angina. This survival difference fell far short of significance (adjusted hazard ratio, 1.00; 95% confidence interval, 0.85-1.18), solidifying a finding first seen in the main ISCHEMIA results when they came out 3 years before, in late 2019, Judith S. Hochman, MD, said at the American Heart Association scientific sessions.
The new results “provide evidence for patients with chronic coronary disease and their physicians as they decide whether to add invasive management to guideline-directed medical therapy,” concluded Dr. Hochman, professor and senior associate dean for clinical sciences at New York University Langone Health. Simultaneous with her report, the extended follow-up results also appeared in an article published online in Circulation.
Nil probability of a survival benefit
“The probability over 5.7 years that a patient’s risk of dying is lower with the invasive strategy is nil, which means: Go with the patient’s preference. Not undergoing revascularization is a reasonable strategy because there is no excess mortality,” Dr. Hochman said in an interview. The trial’s extended follow-up provides “much more robust evidence” for the neutral effect on survival. The investigators plan to further follow-up out to a maximum of 10 years to continue to monitor for a signal of a mortality difference.
“These findings might help physicians in shared decision-making as to whether to add invasive management to guideline-directed medical management in selected patients with chronic coronary artery disease and moderate or severe ischemia,” commented M. Cecilia Bahit, MD, designated discussant for the report and chief of cardiology for INECO Neurosciences in Rosario, Argentina.
The original ISCHEMIA results had also shown that invasive intervention can improve the quality of life in patients who have angina as a result of their coronary disease, but also showed “minimal benefits” from an invasive approach in asymptomatic patients, who comprised 35% of the study cohort of 5,179 patients.
While ISCHEMIA enrolled patients with moderate to severe coronary ischemia identified with noninvasive testing, it excluded certain patients for whom an invasive strategy is recommended, including those with unprotected left main coronary stenoses of at least 50%, a recent acute coronary syndrome event, a left ventricular ejection fraction of less than 35%, more advanced functional limitations from heart failure, or advanced chronic kidney disease.
Follow-up without adjudication
The extended follow-up included 4,825 patients from the initial cohort, with data collected from 4,540 patients. One limitation of the follow-up was that the cause of death was not adjudicated as it had been during the initial follow-up phase. It instead relied on unconfirmed information collected either from patients’ families or national databases. The demographics and clinical profiles of the study participants available for extended follow-up closely matched the entire original study cohort.
The additional follow-up also revealed a significant survival benefit from the invasive approach for cardiovascular deaths, with an incidence of 8.6% in the conservative arm and 6.4% in the invasive group, an adjusted 22% relative reduction in this outcome favoring the invasive strategy (95% CI, 0.63-0.96). This difference had appeared as a nonsignificant signal in the initial 3.2-year median follow-up.
However, this significant benefit from the invasive strategy was counterbalanced by a surprising and inexplicable increase in deaths from noncardiovascular causes in those managed with the invasive strategy. Noncardiovascular deaths occurred in 5.5% of those in the invasive arm and in 4.4% of those in the conservative arm, a significant adjusted 44% relative increase in this outcome associated with invasive management. Again, this difference was not as clearly apparent after the initial follow-up phase.
“The increase in noncardiovascular deaths with the invasive strategy surprisingly persisted over time and offset” the cardiovascular survival benefit from upfront invasive treatment, explained Dr. Hochman. A prior report from the investigators looked in depth at the noncardiovascular deaths during the initial follow-up phase and found that most of the excess was caused by malignancies, although why this happened in the invasively treated patients remains a mystery.
Staying alive is what patients care about
“I think that interventional cardiologists who favor an invasive strategy will be excited to see this significant reduction in cardiovascular deaths, but patients don’t care what they die from. What patients care about is whether they are dead or alive,” Dr. Hochman noted.
But B. Hadley Wilson, MD, an interventional cardiologist and vice president of the American College of Cardiology, had a somewhat different take on these findings.
“We need to consider the significant decrease in cardiovascular mortality, as we sort out the conundrum” of the increase in noncardiovascular deaths,” he said in an interview. “Hopefully, the 10-year outcomes will help answer this.”
But until more information is available, the ISCHEMIA and ISCHEMIA-EXTEND results have already helped advance the conversation that patients with stable coronary disease and their families have with clinicians about management decisions.
“I love that ISCHEMIA highlighted the importance of shared decision making and a heart team approach,” said Dr. Wilson, executive vice chair of the Sanger Heart & Vascular Institute of Atrium Health in Charlotte, N.C.
Anecdotally, ISCHEMIA reduced invasive management
After the initial ISCHEMIA results were published nearly 3 years ago, “I think use of invasive treatment for these patients has decreased, although I have seen no numbers” that document this, said Dr. Wilson. “I think most interventional cardiologists would say that ISCHEMIA has had an impact,” with fewer patients who match the trial’s enrollment criteria undergoing invasive management.
“Anecdotally, cardiologists are reviewing the ISCHEMIA data with their patients,” agreed Dr. Hochman, who added that no actual data have yet appeared to document this, nor do data yet document a change in the use of invasive management. “It takes time to measure the impact.”
To expedite the shared decision-making process for these patients, the ISCHEMIA researchers are planning to make available an app that will allow patients and physicians to enter clinical and demographic data and see a calculated estimate of their future cardiovascular disease risk and how amenable it may be to modification by invasive management, Dr. Hochman said. The app would be available on the ISCHEMIA study website in 2023.
ISCHEMIA and ISCHEMIA EXTEND received no commercial funding. Dr. Hochman and Dr. Wilson had no disclosures. Dr. Bahit has received honoraria from Behring, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, MSD, and Pfizer.
CHICAGO – The case for survival equipoise between an invasive or conservative strategy for managing patients with stable coronary disease and moderate or severe cardiac ischemia grew stronger with an additional 2.5 years of median follow-up of the landmark ISCHEMIA trial.
During a median follow-up of 5.7 years in ISCHEMIA-EXTEND – and as long as 7 years – patients randomized to an upfront invasive strategy regardless of their symptoms had an all-cause mortality rate of 12.7%, compared with a 13.4% rate in the patients randomized to the conservative, medication-based management strategy that employed revascularization only when the medical approach failed to resolve their angina. This survival difference fell far short of significance (adjusted hazard ratio, 1.00; 95% confidence interval, 0.85-1.18), solidifying a finding first seen in the main ISCHEMIA results when they came out 3 years before, in late 2019, Judith S. Hochman, MD, said at the American Heart Association scientific sessions.
The new results “provide evidence for patients with chronic coronary disease and their physicians as they decide whether to add invasive management to guideline-directed medical therapy,” concluded Dr. Hochman, professor and senior associate dean for clinical sciences at New York University Langone Health. Simultaneous with her report, the extended follow-up results also appeared in an article published online in Circulation.
Nil probability of a survival benefit
“The probability over 5.7 years that a patient’s risk of dying is lower with the invasive strategy is nil, which means: Go with the patient’s preference. Not undergoing revascularization is a reasonable strategy because there is no excess mortality,” Dr. Hochman said in an interview. The trial’s extended follow-up provides “much more robust evidence” for the neutral effect on survival. The investigators plan to further follow-up out to a maximum of 10 years to continue to monitor for a signal of a mortality difference.
“These findings might help physicians in shared decision-making as to whether to add invasive management to guideline-directed medical management in selected patients with chronic coronary artery disease and moderate or severe ischemia,” commented M. Cecilia Bahit, MD, designated discussant for the report and chief of cardiology for INECO Neurosciences in Rosario, Argentina.
The original ISCHEMIA results had also shown that invasive intervention can improve the quality of life in patients who have angina as a result of their coronary disease, but also showed “minimal benefits” from an invasive approach in asymptomatic patients, who comprised 35% of the study cohort of 5,179 patients.
While ISCHEMIA enrolled patients with moderate to severe coronary ischemia identified with noninvasive testing, it excluded certain patients for whom an invasive strategy is recommended, including those with unprotected left main coronary stenoses of at least 50%, a recent acute coronary syndrome event, a left ventricular ejection fraction of less than 35%, more advanced functional limitations from heart failure, or advanced chronic kidney disease.
Follow-up without adjudication
The extended follow-up included 4,825 patients from the initial cohort, with data collected from 4,540 patients. One limitation of the follow-up was that the cause of death was not adjudicated as it had been during the initial follow-up phase. It instead relied on unconfirmed information collected either from patients’ families or national databases. The demographics and clinical profiles of the study participants available for extended follow-up closely matched the entire original study cohort.
The additional follow-up also revealed a significant survival benefit from the invasive approach for cardiovascular deaths, with an incidence of 8.6% in the conservative arm and 6.4% in the invasive group, an adjusted 22% relative reduction in this outcome favoring the invasive strategy (95% CI, 0.63-0.96). This difference had appeared as a nonsignificant signal in the initial 3.2-year median follow-up.
However, this significant benefit from the invasive strategy was counterbalanced by a surprising and inexplicable increase in deaths from noncardiovascular causes in those managed with the invasive strategy. Noncardiovascular deaths occurred in 5.5% of those in the invasive arm and in 4.4% of those in the conservative arm, a significant adjusted 44% relative increase in this outcome associated with invasive management. Again, this difference was not as clearly apparent after the initial follow-up phase.
“The increase in noncardiovascular deaths with the invasive strategy surprisingly persisted over time and offset” the cardiovascular survival benefit from upfront invasive treatment, explained Dr. Hochman. A prior report from the investigators looked in depth at the noncardiovascular deaths during the initial follow-up phase and found that most of the excess was caused by malignancies, although why this happened in the invasively treated patients remains a mystery.
Staying alive is what patients care about
“I think that interventional cardiologists who favor an invasive strategy will be excited to see this significant reduction in cardiovascular deaths, but patients don’t care what they die from. What patients care about is whether they are dead or alive,” Dr. Hochman noted.
But B. Hadley Wilson, MD, an interventional cardiologist and vice president of the American College of Cardiology, had a somewhat different take on these findings.
“We need to consider the significant decrease in cardiovascular mortality, as we sort out the conundrum” of the increase in noncardiovascular deaths,” he said in an interview. “Hopefully, the 10-year outcomes will help answer this.”
But until more information is available, the ISCHEMIA and ISCHEMIA-EXTEND results have already helped advance the conversation that patients with stable coronary disease and their families have with clinicians about management decisions.
“I love that ISCHEMIA highlighted the importance of shared decision making and a heart team approach,” said Dr. Wilson, executive vice chair of the Sanger Heart & Vascular Institute of Atrium Health in Charlotte, N.C.
Anecdotally, ISCHEMIA reduced invasive management
After the initial ISCHEMIA results were published nearly 3 years ago, “I think use of invasive treatment for these patients has decreased, although I have seen no numbers” that document this, said Dr. Wilson. “I think most interventional cardiologists would say that ISCHEMIA has had an impact,” with fewer patients who match the trial’s enrollment criteria undergoing invasive management.
“Anecdotally, cardiologists are reviewing the ISCHEMIA data with their patients,” agreed Dr. Hochman, who added that no actual data have yet appeared to document this, nor do data yet document a change in the use of invasive management. “It takes time to measure the impact.”
To expedite the shared decision-making process for these patients, the ISCHEMIA researchers are planning to make available an app that will allow patients and physicians to enter clinical and demographic data and see a calculated estimate of their future cardiovascular disease risk and how amenable it may be to modification by invasive management, Dr. Hochman said. The app would be available on the ISCHEMIA study website in 2023.
ISCHEMIA and ISCHEMIA EXTEND received no commercial funding. Dr. Hochman and Dr. Wilson had no disclosures. Dr. Bahit has received honoraria from Behring, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, MSD, and Pfizer.
AT AHA 2022
Study sheds new light on RAS inhibitors’ role for advanced CKD
ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m2.
Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, , for 3 years.
People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.
“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.
The results were simultaneously published in the New England Journal of Medicine.
Similar eGFR levels after 3 years
While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.
Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.
“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.
And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.
Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m2 in the discontinuation group and 13.3 mL/min per 1.73 m2 in the 205 patients in the continuation group, a difference that was not significant.
In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).
The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
Participants had an eGFR less than 30 mL/min per 1.73 m2
The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m2 who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m2 during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.
The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.
Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.
People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.
The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m2, and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m2. Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.
Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
Continue RAS inhibitors in advanced CKD for best outcomes
Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.
But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”
“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”
“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.
STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m2.
Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, , for 3 years.
People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.
“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.
The results were simultaneously published in the New England Journal of Medicine.
Similar eGFR levels after 3 years
While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.
Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.
“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.
And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.
Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m2 in the discontinuation group and 13.3 mL/min per 1.73 m2 in the 205 patients in the continuation group, a difference that was not significant.
In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).
The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
Participants had an eGFR less than 30 mL/min per 1.73 m2
The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m2 who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m2 during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.
The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.
Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.
People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.
The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m2, and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m2. Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.
Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
Continue RAS inhibitors in advanced CKD for best outcomes
Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.
But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”
“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”
“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.
STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m2.
Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, , for 3 years.
People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.
“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.
The results were simultaneously published in the New England Journal of Medicine.
Similar eGFR levels after 3 years
While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.
Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.
“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.
And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.
Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m2 in the discontinuation group and 13.3 mL/min per 1.73 m2 in the 205 patients in the continuation group, a difference that was not significant.
In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).
The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
Participants had an eGFR less than 30 mL/min per 1.73 m2
The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m2 who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m2 during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.
The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.
Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.
People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.
The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m2, and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m2. Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.
Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
Continue RAS inhibitors in advanced CKD for best outcomes
Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.
But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”
“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”
“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.
STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT KIDNEY WEEK 2022
Moving the needle: SGLT2 inhibitor role for isolated kidney disease
ORLANDO – in a pivotal trial with more than 6,600 patients.
This confirms the efficacy for this population that was previously seen with dapagliflozin, another agent from the same class, in the DAPA-CKD trial.
In the new trial, EMPA-Kidney, treatment with empagliflozin 10 mg daily for a median of 2.0 years led to a significant 28% relative risk reduction in the primary combined endpoint in comparison with placebo, William G. Herrington, MD, reported at the annual meeting of the American Society of Nephrology.
The results were simultaneously published in the New England Journal of Medicine.
In 2020, a different team of researchers running DAPA-CKD reported that during a median of 2.4 years, treatment of 4,304 patients with dapagliflozin 10 mg daily resulted in a significant 39% relative risk reduction, compared with placebo for an identical combined primary endpoint. Enrollment criteria for the DAPA-CKD trial were mostly similar to that of the current trial.
‘Remarkably similar’ findings
Results from EMPA-Kidney and DAPA-CKD are “remarkably similar,” said Dr. Herrington during a press briefing at the meeting.
He also noted that when the EMPA-Kidney study began – before results from DAPA-CKD were known – “we never imagined such a large effect” on important endpoints in people with CKD.
In addition to cardiovascular death, the combined primary endpoint included the incidence of renal death, incident end-stage kidney disease, a sustained decrease in estimated glomerular filtration rate to less than 10 mL/min per 1.73m2, or a sustained decrease in eGFR of at least 40% from baseline.
Having similar evidence from both trials “will hopefully provide people with the confidence to start to use SGLT2 inhibitors as standard care in people with CKD” who match enrollment criteria of the two trials, added Dr. Herrington, a nephrologist at the University of Oxford (England).
The analyses he reported also showed that empagliflozin had similar efficacy for the primary endpoint regardless of whether patients had type 2 diabetes at the time of enrollment and regardless of their eGFR at entry.
To enter EMPA-Kidney, people needed to have either an eGFR of 20-44 mL/min per 1.73m2 with no minimum level of albuminuria or an eGFR of 45-89 mL/min per 1.73m2 with a urine albumin-to-creatinine ratio (UACR) of at least 200 mg/g.
In contrast, to enroll in DAPA-CKD, patients had to have a UACR of at least 200 mg/g. This means that for the first time, EMPA-Kidney produced data on the relationship between albuminuria severity and the impact of treatment with an SGLT2 inhibitor in the enrolled population.
A signal of greater efficacy with higher UACR
A total of 6,609 patients underwent randomization in EMPA-Kidney. During a median of 2.0 years of follow-up, the primary endpoint – progression of kidney disease or death from cardiovascular causes – occurred in 432 of 3,304 patients (13.1%) in the empagliflozin group and in 558 of 3,305 patients (16.9%) in the placebo group (hazard ratio, 0.72; P < .001).
The results “suggested that the effects [of empagliflozin] are greater in patients with higher levels of albuminuria, with statistically significant heterogeneity between this subgroup and those with a UACR of less than 200 mg/g (P = .02),” Dr. Herrington said.
Of the study population, 54% had no evidence of diabetes at enrollment.
Having data from a second large trial of an SGLT2 inhibitor that included people with isolated CKD who did not have diabetes or heart failure “will start to move the needle” on using this class of drugs in these types of patients, commented F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn.
On the basis of the DAPA-CKD results, in April 2021 the Food and Drug Administration expanded dapagliflozin’s indications to include CKD, yet, “a lot of nephrologists consider SGLT2 inhibitors to be agents for people with diabetes or heart failure, and they defer prescribing them to endocrinologists and cardiologists,” Dr. Wilson said in an interview.
‘Flozinators’ rising
But Pascale H. Lane, MD, a pediatric nephrologist at the University of Oklahoma Health Sciences Center, Oklahoma City, commented that many nephrologists she knows have been prescribing dapagliflozin “widely” to their patients with CKD.
“I know many adult nephrologists who use it almost universally now,” Dr. Lane said. “They call themselves ‘flozinators.’ ”
EMPA-Kidney was sponsored by Boehringer Ingelheim, the company that along with Lilly markets empagliflozin (Jardiance). Dr. Herrington, Dr. Wilson, and Dr. Lane disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ORLANDO – in a pivotal trial with more than 6,600 patients.
This confirms the efficacy for this population that was previously seen with dapagliflozin, another agent from the same class, in the DAPA-CKD trial.
In the new trial, EMPA-Kidney, treatment with empagliflozin 10 mg daily for a median of 2.0 years led to a significant 28% relative risk reduction in the primary combined endpoint in comparison with placebo, William G. Herrington, MD, reported at the annual meeting of the American Society of Nephrology.
The results were simultaneously published in the New England Journal of Medicine.
In 2020, a different team of researchers running DAPA-CKD reported that during a median of 2.4 years, treatment of 4,304 patients with dapagliflozin 10 mg daily resulted in a significant 39% relative risk reduction, compared with placebo for an identical combined primary endpoint. Enrollment criteria for the DAPA-CKD trial were mostly similar to that of the current trial.
‘Remarkably similar’ findings
Results from EMPA-Kidney and DAPA-CKD are “remarkably similar,” said Dr. Herrington during a press briefing at the meeting.
He also noted that when the EMPA-Kidney study began – before results from DAPA-CKD were known – “we never imagined such a large effect” on important endpoints in people with CKD.
In addition to cardiovascular death, the combined primary endpoint included the incidence of renal death, incident end-stage kidney disease, a sustained decrease in estimated glomerular filtration rate to less than 10 mL/min per 1.73m2, or a sustained decrease in eGFR of at least 40% from baseline.
Having similar evidence from both trials “will hopefully provide people with the confidence to start to use SGLT2 inhibitors as standard care in people with CKD” who match enrollment criteria of the two trials, added Dr. Herrington, a nephrologist at the University of Oxford (England).
The analyses he reported also showed that empagliflozin had similar efficacy for the primary endpoint regardless of whether patients had type 2 diabetes at the time of enrollment and regardless of their eGFR at entry.
To enter EMPA-Kidney, people needed to have either an eGFR of 20-44 mL/min per 1.73m2 with no minimum level of albuminuria or an eGFR of 45-89 mL/min per 1.73m2 with a urine albumin-to-creatinine ratio (UACR) of at least 200 mg/g.
In contrast, to enroll in DAPA-CKD, patients had to have a UACR of at least 200 mg/g. This means that for the first time, EMPA-Kidney produced data on the relationship between albuminuria severity and the impact of treatment with an SGLT2 inhibitor in the enrolled population.
A signal of greater efficacy with higher UACR
A total of 6,609 patients underwent randomization in EMPA-Kidney. During a median of 2.0 years of follow-up, the primary endpoint – progression of kidney disease or death from cardiovascular causes – occurred in 432 of 3,304 patients (13.1%) in the empagliflozin group and in 558 of 3,305 patients (16.9%) in the placebo group (hazard ratio, 0.72; P < .001).
The results “suggested that the effects [of empagliflozin] are greater in patients with higher levels of albuminuria, with statistically significant heterogeneity between this subgroup and those with a UACR of less than 200 mg/g (P = .02),” Dr. Herrington said.
Of the study population, 54% had no evidence of diabetes at enrollment.
Having data from a second large trial of an SGLT2 inhibitor that included people with isolated CKD who did not have diabetes or heart failure “will start to move the needle” on using this class of drugs in these types of patients, commented F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn.
On the basis of the DAPA-CKD results, in April 2021 the Food and Drug Administration expanded dapagliflozin’s indications to include CKD, yet, “a lot of nephrologists consider SGLT2 inhibitors to be agents for people with diabetes or heart failure, and they defer prescribing them to endocrinologists and cardiologists,” Dr. Wilson said in an interview.
‘Flozinators’ rising
But Pascale H. Lane, MD, a pediatric nephrologist at the University of Oklahoma Health Sciences Center, Oklahoma City, commented that many nephrologists she knows have been prescribing dapagliflozin “widely” to their patients with CKD.
“I know many adult nephrologists who use it almost universally now,” Dr. Lane said. “They call themselves ‘flozinators.’ ”
EMPA-Kidney was sponsored by Boehringer Ingelheim, the company that along with Lilly markets empagliflozin (Jardiance). Dr. Herrington, Dr. Wilson, and Dr. Lane disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ORLANDO – in a pivotal trial with more than 6,600 patients.
This confirms the efficacy for this population that was previously seen with dapagliflozin, another agent from the same class, in the DAPA-CKD trial.
In the new trial, EMPA-Kidney, treatment with empagliflozin 10 mg daily for a median of 2.0 years led to a significant 28% relative risk reduction in the primary combined endpoint in comparison with placebo, William G. Herrington, MD, reported at the annual meeting of the American Society of Nephrology.
The results were simultaneously published in the New England Journal of Medicine.
In 2020, a different team of researchers running DAPA-CKD reported that during a median of 2.4 years, treatment of 4,304 patients with dapagliflozin 10 mg daily resulted in a significant 39% relative risk reduction, compared with placebo for an identical combined primary endpoint. Enrollment criteria for the DAPA-CKD trial were mostly similar to that of the current trial.
‘Remarkably similar’ findings
Results from EMPA-Kidney and DAPA-CKD are “remarkably similar,” said Dr. Herrington during a press briefing at the meeting.
He also noted that when the EMPA-Kidney study began – before results from DAPA-CKD were known – “we never imagined such a large effect” on important endpoints in people with CKD.
In addition to cardiovascular death, the combined primary endpoint included the incidence of renal death, incident end-stage kidney disease, a sustained decrease in estimated glomerular filtration rate to less than 10 mL/min per 1.73m2, or a sustained decrease in eGFR of at least 40% from baseline.
Having similar evidence from both trials “will hopefully provide people with the confidence to start to use SGLT2 inhibitors as standard care in people with CKD” who match enrollment criteria of the two trials, added Dr. Herrington, a nephrologist at the University of Oxford (England).
The analyses he reported also showed that empagliflozin had similar efficacy for the primary endpoint regardless of whether patients had type 2 diabetes at the time of enrollment and regardless of their eGFR at entry.
To enter EMPA-Kidney, people needed to have either an eGFR of 20-44 mL/min per 1.73m2 with no minimum level of albuminuria or an eGFR of 45-89 mL/min per 1.73m2 with a urine albumin-to-creatinine ratio (UACR) of at least 200 mg/g.
In contrast, to enroll in DAPA-CKD, patients had to have a UACR of at least 200 mg/g. This means that for the first time, EMPA-Kidney produced data on the relationship between albuminuria severity and the impact of treatment with an SGLT2 inhibitor in the enrolled population.
A signal of greater efficacy with higher UACR
A total of 6,609 patients underwent randomization in EMPA-Kidney. During a median of 2.0 years of follow-up, the primary endpoint – progression of kidney disease or death from cardiovascular causes – occurred in 432 of 3,304 patients (13.1%) in the empagliflozin group and in 558 of 3,305 patients (16.9%) in the placebo group (hazard ratio, 0.72; P < .001).
The results “suggested that the effects [of empagliflozin] are greater in patients with higher levels of albuminuria, with statistically significant heterogeneity between this subgroup and those with a UACR of less than 200 mg/g (P = .02),” Dr. Herrington said.
Of the study population, 54% had no evidence of diabetes at enrollment.
Having data from a second large trial of an SGLT2 inhibitor that included people with isolated CKD who did not have diabetes or heart failure “will start to move the needle” on using this class of drugs in these types of patients, commented F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn.
On the basis of the DAPA-CKD results, in April 2021 the Food and Drug Administration expanded dapagliflozin’s indications to include CKD, yet, “a lot of nephrologists consider SGLT2 inhibitors to be agents for people with diabetes or heart failure, and they defer prescribing them to endocrinologists and cardiologists,” Dr. Wilson said in an interview.
‘Flozinators’ rising
But Pascale H. Lane, MD, a pediatric nephrologist at the University of Oklahoma Health Sciences Center, Oklahoma City, commented that many nephrologists she knows have been prescribing dapagliflozin “widely” to their patients with CKD.
“I know many adult nephrologists who use it almost universally now,” Dr. Lane said. “They call themselves ‘flozinators.’ ”
EMPA-Kidney was sponsored by Boehringer Ingelheim, the company that along with Lilly markets empagliflozin (Jardiance). Dr. Herrington, Dr. Wilson, and Dr. Lane disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT KIDNEY WEEK 2022
Low-carb diet aids weight loss in liver transplant recipients with obesity
A low-carbohydrate diet appears to be an effective weight-loss intervention in liver transplant recipients with obesity as compared with a calorie-restrictive diet, according to interim findings presented at the annual meeting of the American Association for the Study of Liver Diseases.
In particular, the intervention showed significant improvements in the metabophenotype profile, including visceral adipose tissue and abdominal subcutaneous adipose tissue, said Mohammad Siddiqui, MD, a gastroenterologist and liver transplant specialist at Virginia Commonwealth University, Richmond.
“Weight gain and obesity after liver transplantation is common,” he said. “Posttransplant obesity is associated with increased cardiometabolic risk burden, increased risk of cardiovascular disease and mortality, and overall mortality.”
Previously, Dr. Siddiqui and colleagues have shown that posttransplant weight loss is difficult because of metabolic inflexibility and mitochondrial inefficiency. By specifically targeting carbohydrate utilization, metabolic flexibility could be restored in liver transplant recipients, he noted.
Dr. Siddiqui and colleagues conducted a randomized controlled trial of 27 adult liver transplant recipients with obesity for 24 weeks. The primary endpoint was change in weight, and the secondary endpoints involved metabophenotype, metabolic flexibility, mitochondrial function, and metabolic risk. The research team excluded patients with end-stage disease, terminal disease, use of weight-loss medications, pregnancy, or uncontrolled psychiatric illness that could interfere with adherence.
Among the participants, 13 were randomized to a calorie restrictive diet of less than 1,200-1,500 calories per day, and 14 were randomized to a low-carbohydrate diet of 20 grams or less per day. At enrollment, the participants underwent dietary, activity, skeletal muscle, and body composition assessments, as well as metabophenotype measurements of visceral adipose tissue, abdominal subcutaneous adipose tissue, muscle fat infiltration, fat-free muscle volume, and proton density fat fraction.
All participants were advised to maintain the same level of physical activity, which was measured through 7-day accelerometry. In addition, the patients were contacted every 2 weeks throughout the 24-week study period.
“We wanted to reinforce the dietary advice. We wanted to identify factors that may lead to compliance,” Dr. Siddiqui said. “Multiple studies have documented that the more contact that patients have during weight-loss studies with medical personnel, the more effective those strategies are.”
Overall, the dietary interventions were well tolerated, and neither group showed a significant change in renal function.
The average weight loss was –7.6 kg over 6 months in the low-carbohydrate group, as compared with –0.6 kg in the calorie-restrictive group.
The low carbohydrate diet also positively affected participants’ metabophenotype profile, particularly fat deposits. As compared with the calorie-restrictive group, the low-carbohydrate group showed statistically significant improvements in visceral adipose tissue, abdominal subcutaneous adipose tissue, and muscle fat infiltration.
The liver proton density fat fraction, which is associated with fatty liver disease, decreased by 0.53% in the low-carbohydrate group and increased by 0.46% in the calorie-restrictive group, but the difference didn’t reach statistical significance.
The fat-free muscle volume decreased by about 5% in the low-carbohydrate group. Dr. Siddiqui noted that the researchers don’t know yet whether this translates to a decrease in muscle function.
In terms of metabolic risk, the low-carbohydrate diet did not affect serum lipids (such as triglycerides or cholesterol measures), renal function (such as serum creatinine, glomerular filtration rate, or blood urea nitrogen), or insulin resistance (through glucose or hemoglobin A1c). At the same time, among patients taking insulin at the time of enrollment, about 90% of patients randomized to the low-carbohydrate group were able to reduce insulin to zero during the study.
Upon completion of the current study, Dr. Siddiqui and colleagues hope to provide foundational safety and efficacy data for carbohydrate restriction in liver transplant recipients. In the ongoing study, the researchers are further investigating the dietary intervention impacts on metabolic flexibility, skeletal muscle mitochondrial function, atherogenic lipoproteins, and vascular function.
“Are we actually, on a molecular level, fixing the fundamental problem that liver transplant recipients have to improve outcomes?” he said. “We’re doing very detailed profiling of these patients, so we will have data that shows how this actually affects them.”
Dr. Siddiqui was asked about the sustainability of the low-carbohydrate diet, particularly with a restrictive parameter of 20 grams per day. During the COVID-19 pandemic, Dr. Siddiqui noted, the study was slowed and the research team was able to collect follow-up data.
“Surprisingly, we have a high rate of compliance, even after 6 months of therapy, and I think this has to do with a patient population that’s been through cirrhosis and has almost died,” he said. “They’re far more compliant, and we’re seeing that. We’re also changing the physiology and improving mitochondrial function, which improves the weight loss and weight maintenance, though I don’t know how long that’s going to last.”
The study sponsorship was not disclosed. Dr. Siddiqui reported no relevant conflicts of interest.
A low-carbohydrate diet appears to be an effective weight-loss intervention in liver transplant recipients with obesity as compared with a calorie-restrictive diet, according to interim findings presented at the annual meeting of the American Association for the Study of Liver Diseases.
In particular, the intervention showed significant improvements in the metabophenotype profile, including visceral adipose tissue and abdominal subcutaneous adipose tissue, said Mohammad Siddiqui, MD, a gastroenterologist and liver transplant specialist at Virginia Commonwealth University, Richmond.
“Weight gain and obesity after liver transplantation is common,” he said. “Posttransplant obesity is associated with increased cardiometabolic risk burden, increased risk of cardiovascular disease and mortality, and overall mortality.”
Previously, Dr. Siddiqui and colleagues have shown that posttransplant weight loss is difficult because of metabolic inflexibility and mitochondrial inefficiency. By specifically targeting carbohydrate utilization, metabolic flexibility could be restored in liver transplant recipients, he noted.
Dr. Siddiqui and colleagues conducted a randomized controlled trial of 27 adult liver transplant recipients with obesity for 24 weeks. The primary endpoint was change in weight, and the secondary endpoints involved metabophenotype, metabolic flexibility, mitochondrial function, and metabolic risk. The research team excluded patients with end-stage disease, terminal disease, use of weight-loss medications, pregnancy, or uncontrolled psychiatric illness that could interfere with adherence.
Among the participants, 13 were randomized to a calorie restrictive diet of less than 1,200-1,500 calories per day, and 14 were randomized to a low-carbohydrate diet of 20 grams or less per day. At enrollment, the participants underwent dietary, activity, skeletal muscle, and body composition assessments, as well as metabophenotype measurements of visceral adipose tissue, abdominal subcutaneous adipose tissue, muscle fat infiltration, fat-free muscle volume, and proton density fat fraction.
All participants were advised to maintain the same level of physical activity, which was measured through 7-day accelerometry. In addition, the patients were contacted every 2 weeks throughout the 24-week study period.
“We wanted to reinforce the dietary advice. We wanted to identify factors that may lead to compliance,” Dr. Siddiqui said. “Multiple studies have documented that the more contact that patients have during weight-loss studies with medical personnel, the more effective those strategies are.”
Overall, the dietary interventions were well tolerated, and neither group showed a significant change in renal function.
The average weight loss was –7.6 kg over 6 months in the low-carbohydrate group, as compared with –0.6 kg in the calorie-restrictive group.
The low carbohydrate diet also positively affected participants’ metabophenotype profile, particularly fat deposits. As compared with the calorie-restrictive group, the low-carbohydrate group showed statistically significant improvements in visceral adipose tissue, abdominal subcutaneous adipose tissue, and muscle fat infiltration.
The liver proton density fat fraction, which is associated with fatty liver disease, decreased by 0.53% in the low-carbohydrate group and increased by 0.46% in the calorie-restrictive group, but the difference didn’t reach statistical significance.
The fat-free muscle volume decreased by about 5% in the low-carbohydrate group. Dr. Siddiqui noted that the researchers don’t know yet whether this translates to a decrease in muscle function.
In terms of metabolic risk, the low-carbohydrate diet did not affect serum lipids (such as triglycerides or cholesterol measures), renal function (such as serum creatinine, glomerular filtration rate, or blood urea nitrogen), or insulin resistance (through glucose or hemoglobin A1c). At the same time, among patients taking insulin at the time of enrollment, about 90% of patients randomized to the low-carbohydrate group were able to reduce insulin to zero during the study.
Upon completion of the current study, Dr. Siddiqui and colleagues hope to provide foundational safety and efficacy data for carbohydrate restriction in liver transplant recipients. In the ongoing study, the researchers are further investigating the dietary intervention impacts on metabolic flexibility, skeletal muscle mitochondrial function, atherogenic lipoproteins, and vascular function.
“Are we actually, on a molecular level, fixing the fundamental problem that liver transplant recipients have to improve outcomes?” he said. “We’re doing very detailed profiling of these patients, so we will have data that shows how this actually affects them.”
Dr. Siddiqui was asked about the sustainability of the low-carbohydrate diet, particularly with a restrictive parameter of 20 grams per day. During the COVID-19 pandemic, Dr. Siddiqui noted, the study was slowed and the research team was able to collect follow-up data.
“Surprisingly, we have a high rate of compliance, even after 6 months of therapy, and I think this has to do with a patient population that’s been through cirrhosis and has almost died,” he said. “They’re far more compliant, and we’re seeing that. We’re also changing the physiology and improving mitochondrial function, which improves the weight loss and weight maintenance, though I don’t know how long that’s going to last.”
The study sponsorship was not disclosed. Dr. Siddiqui reported no relevant conflicts of interest.
A low-carbohydrate diet appears to be an effective weight-loss intervention in liver transplant recipients with obesity as compared with a calorie-restrictive diet, according to interim findings presented at the annual meeting of the American Association for the Study of Liver Diseases.
In particular, the intervention showed significant improvements in the metabophenotype profile, including visceral adipose tissue and abdominal subcutaneous adipose tissue, said Mohammad Siddiqui, MD, a gastroenterologist and liver transplant specialist at Virginia Commonwealth University, Richmond.
“Weight gain and obesity after liver transplantation is common,” he said. “Posttransplant obesity is associated with increased cardiometabolic risk burden, increased risk of cardiovascular disease and mortality, and overall mortality.”
Previously, Dr. Siddiqui and colleagues have shown that posttransplant weight loss is difficult because of metabolic inflexibility and mitochondrial inefficiency. By specifically targeting carbohydrate utilization, metabolic flexibility could be restored in liver transplant recipients, he noted.
Dr. Siddiqui and colleagues conducted a randomized controlled trial of 27 adult liver transplant recipients with obesity for 24 weeks. The primary endpoint was change in weight, and the secondary endpoints involved metabophenotype, metabolic flexibility, mitochondrial function, and metabolic risk. The research team excluded patients with end-stage disease, terminal disease, use of weight-loss medications, pregnancy, or uncontrolled psychiatric illness that could interfere with adherence.
Among the participants, 13 were randomized to a calorie restrictive diet of less than 1,200-1,500 calories per day, and 14 were randomized to a low-carbohydrate diet of 20 grams or less per day. At enrollment, the participants underwent dietary, activity, skeletal muscle, and body composition assessments, as well as metabophenotype measurements of visceral adipose tissue, abdominal subcutaneous adipose tissue, muscle fat infiltration, fat-free muscle volume, and proton density fat fraction.
All participants were advised to maintain the same level of physical activity, which was measured through 7-day accelerometry. In addition, the patients were contacted every 2 weeks throughout the 24-week study period.
“We wanted to reinforce the dietary advice. We wanted to identify factors that may lead to compliance,” Dr. Siddiqui said. “Multiple studies have documented that the more contact that patients have during weight-loss studies with medical personnel, the more effective those strategies are.”
Overall, the dietary interventions were well tolerated, and neither group showed a significant change in renal function.
The average weight loss was –7.6 kg over 6 months in the low-carbohydrate group, as compared with –0.6 kg in the calorie-restrictive group.
The low carbohydrate diet also positively affected participants’ metabophenotype profile, particularly fat deposits. As compared with the calorie-restrictive group, the low-carbohydrate group showed statistically significant improvements in visceral adipose tissue, abdominal subcutaneous adipose tissue, and muscle fat infiltration.
The liver proton density fat fraction, which is associated with fatty liver disease, decreased by 0.53% in the low-carbohydrate group and increased by 0.46% in the calorie-restrictive group, but the difference didn’t reach statistical significance.
The fat-free muscle volume decreased by about 5% in the low-carbohydrate group. Dr. Siddiqui noted that the researchers don’t know yet whether this translates to a decrease in muscle function.
In terms of metabolic risk, the low-carbohydrate diet did not affect serum lipids (such as triglycerides or cholesterol measures), renal function (such as serum creatinine, glomerular filtration rate, or blood urea nitrogen), or insulin resistance (through glucose or hemoglobin A1c). At the same time, among patients taking insulin at the time of enrollment, about 90% of patients randomized to the low-carbohydrate group were able to reduce insulin to zero during the study.
Upon completion of the current study, Dr. Siddiqui and colleagues hope to provide foundational safety and efficacy data for carbohydrate restriction in liver transplant recipients. In the ongoing study, the researchers are further investigating the dietary intervention impacts on metabolic flexibility, skeletal muscle mitochondrial function, atherogenic lipoproteins, and vascular function.
“Are we actually, on a molecular level, fixing the fundamental problem that liver transplant recipients have to improve outcomes?” he said. “We’re doing very detailed profiling of these patients, so we will have data that shows how this actually affects them.”
Dr. Siddiqui was asked about the sustainability of the low-carbohydrate diet, particularly with a restrictive parameter of 20 grams per day. During the COVID-19 pandemic, Dr. Siddiqui noted, the study was slowed and the research team was able to collect follow-up data.
“Surprisingly, we have a high rate of compliance, even after 6 months of therapy, and I think this has to do with a patient population that’s been through cirrhosis and has almost died,” he said. “They’re far more compliant, and we’re seeing that. We’re also changing the physiology and improving mitochondrial function, which improves the weight loss and weight maintenance, though I don’t know how long that’s going to last.”
The study sponsorship was not disclosed. Dr. Siddiqui reported no relevant conflicts of interest.
FROM THE LIVER MEETING
Education about OTC tools key for patients with acne and rosacea
LAS VEGAS – , Hilary E. Baldwin, MD, of Rutgers Robert Wood Johnson Medical Center, New Brunswick, N.J., said in a presentation at Medscape Live’s annual Las Vegas Dermatology Seminar.
In some cases, the use of good-quality over-the -counter skin care products can improve acne without prescription treatment, said Dr. Baldwin, who is medical director of the Acne Treatment and Research Center, New York. Good skin care can enhance the effects of prescription medication by decreasing side effects such as inflammation, pain, and erythema, and improving compliance; and use of OTC products has not been shown to interfere with the efficacy of prescription products, she noted.
However, patient education about OTC products is key, she said. In particular, “cleansers are a double-edged sword,” Dr. Baldwin emphasized.
Cleansing is important to preserve barrier function, but “there is a risk of skin damage” if cleansers are too harsh, she said. The goal is to remove dirt, oils, and bacteria without disrupting the lipids, proteins, and normal flora that keep skin healthy, and to avoid altering pH, she added.
Key considerations for OTC cleansers include surfactants, pH, and patient preferences, Dr. Baldwin said.
Surfactants, the main components of OTC cleansers, can do more harm than good in some cases. Surfactants break down impurities on the skin surface, but not all are created equal, and some may cause skin irritation, she explained.
Surfactants fall into four categories: nonionic (no charge), anionic (negative charge), cationic (positive charge), and amphoteric (dual charge). Of these, cationic surfactants have the highest level of antimicrobial activity.
Many patients with acne seek out antibacterial cleansers, but many of these products have a high pH, which can inhibit healthy skin function and promote inflammation, Dr. Baldwin noted.
The right OTC skin care products can normalize pH, which promotes repair of the skin barrier and reduces inflammation, she said. While some products are labeled as “gentle,” they may have a high pH, and many products don’t list a pH, Dr. Baldwin pointed out. Many antibacterial products have pH levels in the 10-12 range, while true soaps fall in the 9-10 range, and hydrating liquid cleansers often land in the 5-7 range, she said.
“Most of our patients don’t know what ingredients to look for” in a cleanser, she noted. However, data show that a majority of patients prefer a foaming cleanser, enjoy the face-washing experience – and wash their faces at least twice a day, with a range of products including bath soap, said Dr. Baldwin. Consequently, “educate your patient about moisturizing,” she advised.
For patients with greasy or oily skin, Dr. Baldwin recommends lipid-free foaming cleansers, such as those with ceramides or glycerin. For patients with dry, irritated acne, she advises once-daily washing only, without cleansing devices, which includes washcloths, she said. Look for hydrating cleansers that are nonfoaming or slightly foaming for these patients, she added.
Another tip for patients is to remind them that “sebum is not a moisturizer,” said Dr. Baldwin. Acne patients may still need moisturizers, especially if they experience dry skin as a side effect of their acne medication, but finding the right fit can be a challenge requiring some trial and error, she noted.
OTC products for rosacea
Dr. Baldwin also addressed the use of OTC products for patients with rosacea. For cleansers, she recommends the same hydrating, nonfoaming categories as for her acne patients, with a once-daily, no-device regimen. She advises rosacea patients to avoid pure humectants for moisturizing and noted that silicone-based products are often the least irritating.
Seek moisturizers with ceramides, hyaluronic acid, glycerin, or niacinamide, she said. Data have shown that effective moisturization improves the ability of patients with rosacea to use and adhere to their prescription medications, Dr. Baldwin emphasized. Moisturizers also can make the medication more effective by enhancing the penetration of products such as azelaic acid, she added.
No acne or rosacea visit is complete until overall skin care has been discussed, Dr. Baldwin said.
Dr. Baldwin disclosed serving as a consultant or adviser for Almirall, EPI Health, Galderma, La Roche Posay, Ortho Dermatologics, Sun, and Vyne; and serving as a speaker or member of the speakers’ bureau for Almirall, Galderma, La Roche Posay, Ortho Dermatologics, and Sun. MedscapeLive and this news organization are owned by the same parent company.
LAS VEGAS – , Hilary E. Baldwin, MD, of Rutgers Robert Wood Johnson Medical Center, New Brunswick, N.J., said in a presentation at Medscape Live’s annual Las Vegas Dermatology Seminar.
In some cases, the use of good-quality over-the -counter skin care products can improve acne without prescription treatment, said Dr. Baldwin, who is medical director of the Acne Treatment and Research Center, New York. Good skin care can enhance the effects of prescription medication by decreasing side effects such as inflammation, pain, and erythema, and improving compliance; and use of OTC products has not been shown to interfere with the efficacy of prescription products, she noted.
However, patient education about OTC products is key, she said. In particular, “cleansers are a double-edged sword,” Dr. Baldwin emphasized.
Cleansing is important to preserve barrier function, but “there is a risk of skin damage” if cleansers are too harsh, she said. The goal is to remove dirt, oils, and bacteria without disrupting the lipids, proteins, and normal flora that keep skin healthy, and to avoid altering pH, she added.
Key considerations for OTC cleansers include surfactants, pH, and patient preferences, Dr. Baldwin said.
Surfactants, the main components of OTC cleansers, can do more harm than good in some cases. Surfactants break down impurities on the skin surface, but not all are created equal, and some may cause skin irritation, she explained.
Surfactants fall into four categories: nonionic (no charge), anionic (negative charge), cationic (positive charge), and amphoteric (dual charge). Of these, cationic surfactants have the highest level of antimicrobial activity.
Many patients with acne seek out antibacterial cleansers, but many of these products have a high pH, which can inhibit healthy skin function and promote inflammation, Dr. Baldwin noted.
The right OTC skin care products can normalize pH, which promotes repair of the skin barrier and reduces inflammation, she said. While some products are labeled as “gentle,” they may have a high pH, and many products don’t list a pH, Dr. Baldwin pointed out. Many antibacterial products have pH levels in the 10-12 range, while true soaps fall in the 9-10 range, and hydrating liquid cleansers often land in the 5-7 range, she said.
“Most of our patients don’t know what ingredients to look for” in a cleanser, she noted. However, data show that a majority of patients prefer a foaming cleanser, enjoy the face-washing experience – and wash their faces at least twice a day, with a range of products including bath soap, said Dr. Baldwin. Consequently, “educate your patient about moisturizing,” she advised.
For patients with greasy or oily skin, Dr. Baldwin recommends lipid-free foaming cleansers, such as those with ceramides or glycerin. For patients with dry, irritated acne, she advises once-daily washing only, without cleansing devices, which includes washcloths, she said. Look for hydrating cleansers that are nonfoaming or slightly foaming for these patients, she added.
Another tip for patients is to remind them that “sebum is not a moisturizer,” said Dr. Baldwin. Acne patients may still need moisturizers, especially if they experience dry skin as a side effect of their acne medication, but finding the right fit can be a challenge requiring some trial and error, she noted.
OTC products for rosacea
Dr. Baldwin also addressed the use of OTC products for patients with rosacea. For cleansers, she recommends the same hydrating, nonfoaming categories as for her acne patients, with a once-daily, no-device regimen. She advises rosacea patients to avoid pure humectants for moisturizing and noted that silicone-based products are often the least irritating.
Seek moisturizers with ceramides, hyaluronic acid, glycerin, or niacinamide, she said. Data have shown that effective moisturization improves the ability of patients with rosacea to use and adhere to their prescription medications, Dr. Baldwin emphasized. Moisturizers also can make the medication more effective by enhancing the penetration of products such as azelaic acid, she added.
No acne or rosacea visit is complete until overall skin care has been discussed, Dr. Baldwin said.
Dr. Baldwin disclosed serving as a consultant or adviser for Almirall, EPI Health, Galderma, La Roche Posay, Ortho Dermatologics, Sun, and Vyne; and serving as a speaker or member of the speakers’ bureau for Almirall, Galderma, La Roche Posay, Ortho Dermatologics, and Sun. MedscapeLive and this news organization are owned by the same parent company.
LAS VEGAS – , Hilary E. Baldwin, MD, of Rutgers Robert Wood Johnson Medical Center, New Brunswick, N.J., said in a presentation at Medscape Live’s annual Las Vegas Dermatology Seminar.
In some cases, the use of good-quality over-the -counter skin care products can improve acne without prescription treatment, said Dr. Baldwin, who is medical director of the Acne Treatment and Research Center, New York. Good skin care can enhance the effects of prescription medication by decreasing side effects such as inflammation, pain, and erythema, and improving compliance; and use of OTC products has not been shown to interfere with the efficacy of prescription products, she noted.
However, patient education about OTC products is key, she said. In particular, “cleansers are a double-edged sword,” Dr. Baldwin emphasized.
Cleansing is important to preserve barrier function, but “there is a risk of skin damage” if cleansers are too harsh, she said. The goal is to remove dirt, oils, and bacteria without disrupting the lipids, proteins, and normal flora that keep skin healthy, and to avoid altering pH, she added.
Key considerations for OTC cleansers include surfactants, pH, and patient preferences, Dr. Baldwin said.
Surfactants, the main components of OTC cleansers, can do more harm than good in some cases. Surfactants break down impurities on the skin surface, but not all are created equal, and some may cause skin irritation, she explained.
Surfactants fall into four categories: nonionic (no charge), anionic (negative charge), cationic (positive charge), and amphoteric (dual charge). Of these, cationic surfactants have the highest level of antimicrobial activity.
Many patients with acne seek out antibacterial cleansers, but many of these products have a high pH, which can inhibit healthy skin function and promote inflammation, Dr. Baldwin noted.
The right OTC skin care products can normalize pH, which promotes repair of the skin barrier and reduces inflammation, she said. While some products are labeled as “gentle,” they may have a high pH, and many products don’t list a pH, Dr. Baldwin pointed out. Many antibacterial products have pH levels in the 10-12 range, while true soaps fall in the 9-10 range, and hydrating liquid cleansers often land in the 5-7 range, she said.
“Most of our patients don’t know what ingredients to look for” in a cleanser, she noted. However, data show that a majority of patients prefer a foaming cleanser, enjoy the face-washing experience – and wash their faces at least twice a day, with a range of products including bath soap, said Dr. Baldwin. Consequently, “educate your patient about moisturizing,” she advised.
For patients with greasy or oily skin, Dr. Baldwin recommends lipid-free foaming cleansers, such as those with ceramides or glycerin. For patients with dry, irritated acne, she advises once-daily washing only, without cleansing devices, which includes washcloths, she said. Look for hydrating cleansers that are nonfoaming or slightly foaming for these patients, she added.
Another tip for patients is to remind them that “sebum is not a moisturizer,” said Dr. Baldwin. Acne patients may still need moisturizers, especially if they experience dry skin as a side effect of their acne medication, but finding the right fit can be a challenge requiring some trial and error, she noted.
OTC products for rosacea
Dr. Baldwin also addressed the use of OTC products for patients with rosacea. For cleansers, she recommends the same hydrating, nonfoaming categories as for her acne patients, with a once-daily, no-device regimen. She advises rosacea patients to avoid pure humectants for moisturizing and noted that silicone-based products are often the least irritating.
Seek moisturizers with ceramides, hyaluronic acid, glycerin, or niacinamide, she said. Data have shown that effective moisturization improves the ability of patients with rosacea to use and adhere to their prescription medications, Dr. Baldwin emphasized. Moisturizers also can make the medication more effective by enhancing the penetration of products such as azelaic acid, she added.
No acne or rosacea visit is complete until overall skin care has been discussed, Dr. Baldwin said.
Dr. Baldwin disclosed serving as a consultant or adviser for Almirall, EPI Health, Galderma, La Roche Posay, Ortho Dermatologics, Sun, and Vyne; and serving as a speaker or member of the speakers’ bureau for Almirall, Galderma, La Roche Posay, Ortho Dermatologics, and Sun. MedscapeLive and this news organization are owned by the same parent company.
AT INNOVATIONS IN DERMATOLOGY
CRISPR gene editing takes next step in TTR amyloidosis
CHICAGO – Treatment with the investigational CRISPR-Cas9 gene-editing therapy, NTLA-2001, led to rapid responses in patients with transthyretin (TTR) amyloidosis with cardiomyopathy (ATTR-CM), interim phase 1 results show.
Serum levels of the disease-causing TTR protein were reduced by at least 90% at day 28 with a single infusion of NTLA-2001 at two different doses, with reductions sustained across 4-6 months’ follow-up.
NTLA-2001 was generally well-tolerated, and the results were similar in patients with New York Heart Association (NYHA) class I-III heart failure.
“These data further support and extend the early findings demonstrating the promise of CRISPR-based in vivo genome editing in humans,” said Julian Gillmore, MD, PhD, MBBS, who is leading the study at University College London.
“More specifically, the deep TTR reductions observed in patients with ATTR amyloidosis in this study provide a real possibility of genuine clinical improvement in a condition that has hitherto been ultimately progressive and invariably fatal,” he said.
The results were reported in a late-breaking session at the American Heart Association scientific sessions.
Mutations in the TTR gene and age-related changes in the stability of the TTR protein can cause misfolding of the TTR protein, resulting in amyloid deposits in skin and myocardial tissues.
An estimated 50,000 people worldwide are thought to have hereditary ATTR and up to 500,000 to have wild-type ATTR amyloidosis. Amyloid cardiomyopathy is underdiagnosed and fatal in 3-10 years without treatment. Current treatment options only slow progression and require lifelong administration, he said.
Results reported last year from the polyneuropathy arm of the study were hailed as a breakthrough and further proof-of-concept that CRISPR could be used to treat other diseases
CRISPR gene editing has shown success, for example, in beta-thalassemia and sickle cell disease but involved stem cells extracted from patients’ bone marrow, edited in the lab, and then replaced.
NTLA-2001 (Intellia Therapeutics/Regeneron) is an in vivo treatment that uses lipid nanoparticles containing messenger RNA for Cas9 and a single-guide RNA targeting TTR in the liver, where it’s almost exclusively produced.
The new analysis included 12 patients with heart failure: 3 in NYHA class I-II and 6 in NYHA class III who received a single dose of NTLA-2001 at 0.7 mg/kg, while the remaining 3 patients in NYHA class I-II received a single dose of 1.0 mg/kg.
During follow-up out to 6 months, TTR reductions averaged:
- 93% in the 0.7 mg/kg NYHA I-II group at 6 months.
- 94% in the 0.7 mg/kg NYHA III group at 4 months.
- 92% in the 1.0 mg/kg NYHA I-II group at 4 months.
Eight patients reported mild or moderate adverse events, and two patients experienced transient infusion reactions, including one grade 3 reaction in the 0.7 mg/kg NYHA class III group that resolved without clinical consequence. This group was expanded to six patients per study protocol. No additional treatment-related adverse events higher than grade 1 were reported, and no further dose escalation was undertaken, Dr. Gillmore reported.
There were no clinically relevant laboratory findings; one patient had a transient grade 1 liver enzyme elevation.
One disadvantage of CRISPR is the potential for off-target effects, but Dr. Gillmore said in an interview that the drug developers went through a “very rigorous process when selecting the guide RNA, which is what really targets the specificity of the TTR gene.”
“That’s a really, really important point,” he said. “When they did various studies using, for example, primary human hepatocytes, they found no evidence of off-target editing at concentrations of NTLA-2001 threefold greater than the EC90, the concentration at which one knocks down the protein by 90%. So, what we can say at the moment, is the specificity of NTLA-2001 for the TTR gene seems to be absolute.”
In terms of other challenges going forward, Dr. Gillmore added, “I think that it’s really to see whether the knockdown that is being achieved is going to translate into greater clinical benefit.”
Invited discussant Kevin M. Alexander, MD, of Stanford (Calif.) University, said therapies that stabilize or reduce TTR have recently emerged that have improved ATTR amyloidosis outcomes, including tafamidis and patisiran.
Nevertheless, there has been an unmet need to develop therapies that can halt or reverse disease, are effective in advanced ATTR, and have an improved route or frequency of administration, given that this is a chronic disease, he said.
Dr. Alexander noted that the reductions of greater than 90% were achieved with higher doses than used in the polyneuropathy arm reported last year but were well tolerated in patients that for the most part had wild-type ATTR (83%) and reflect the wild-type ATTR population in practice. “The data support consideration for subsequent efficacy trials for this compound.”
Unanswered questions in ongoing ATTR trials are whether TTR reductions translate into improved clinical outcomes, the long-term safety of TTR lowering, and the efficacy of NTLA-2001, particularly in higher-risk patients, such as those in NYHA class III and those with hereditary ATTR, Dr. Alexander said.
During a media briefing earlier in the day, invited discussant Kiran Musunuru, MD, University of Pennsylvania, Philadelphia, pointed out that, in the recent APOLLO-B trial of patisiran, patients with ATTR amyloidosis with cardiomyopathy had an average 87% TTR reduction but need intravenous infusions every 3 weeks for the rest of their lives.
“In contrast, gene editing is a one-and-done proposition,” he said. “You receive a single treatment that turns off the TTR gene permanently and the effects are durable and likely last a lifetime.”
Dr. Musunuru noted that patients who received patisiran also had significantly and substantially better functional capacity and quality of life, compared with those who received placebo. “Based on today’s results, we can expect future clinical trials for gene editing to have the same beneficial effects and possibly a mortality benefit as well.”
Today’s study is also important because it is part of the first wave of putting CRISPR into the body for an array of diseases, he commented.
“TTR gene editing stands out because it’s the very first CRISPR trial to show unequivocal success – you see that with a greater than 90% reduction in TTR,” Dr. Musunuru said. “So, in my view that makes it a milestone for modern medicine.”
Dosing at 55 mg, corresponding to a fixed 0.7 mg/kg dose, is ongoing in the dose-expansion portion of the trial, with enrollment across both arms expected to be completed by the end of 2022, Intellia Therapeutics reported.
The study was funded by Intellia Therapeutics and Regeneron Pharmaceuticals. Dr. Gillmore reports receiving consultancy fees from Alnylam, Ionis, AstraZeneca, Pfizer, Intellia, ATTRalus, and Novo Nordisk and has received grant support from Alnylam Pharmaceuticals. Dr. Alexander reports serving on advisory boards for Almylam and Arbor Biotechnologies; has consulted for Eidos, Ionis, Novo Nordisk, and Pfizer; and has received grants from AHA, Alnylam, Eidos, and the National Institutes of Health.
A version of this article first appeared on Medscape.com.
CHICAGO – Treatment with the investigational CRISPR-Cas9 gene-editing therapy, NTLA-2001, led to rapid responses in patients with transthyretin (TTR) amyloidosis with cardiomyopathy (ATTR-CM), interim phase 1 results show.
Serum levels of the disease-causing TTR protein were reduced by at least 90% at day 28 with a single infusion of NTLA-2001 at two different doses, with reductions sustained across 4-6 months’ follow-up.
NTLA-2001 was generally well-tolerated, and the results were similar in patients with New York Heart Association (NYHA) class I-III heart failure.
“These data further support and extend the early findings demonstrating the promise of CRISPR-based in vivo genome editing in humans,” said Julian Gillmore, MD, PhD, MBBS, who is leading the study at University College London.
“More specifically, the deep TTR reductions observed in patients with ATTR amyloidosis in this study provide a real possibility of genuine clinical improvement in a condition that has hitherto been ultimately progressive and invariably fatal,” he said.
The results were reported in a late-breaking session at the American Heart Association scientific sessions.
Mutations in the TTR gene and age-related changes in the stability of the TTR protein can cause misfolding of the TTR protein, resulting in amyloid deposits in skin and myocardial tissues.
An estimated 50,000 people worldwide are thought to have hereditary ATTR and up to 500,000 to have wild-type ATTR amyloidosis. Amyloid cardiomyopathy is underdiagnosed and fatal in 3-10 years without treatment. Current treatment options only slow progression and require lifelong administration, he said.
Results reported last year from the polyneuropathy arm of the study were hailed as a breakthrough and further proof-of-concept that CRISPR could be used to treat other diseases
CRISPR gene editing has shown success, for example, in beta-thalassemia and sickle cell disease but involved stem cells extracted from patients’ bone marrow, edited in the lab, and then replaced.
NTLA-2001 (Intellia Therapeutics/Regeneron) is an in vivo treatment that uses lipid nanoparticles containing messenger RNA for Cas9 and a single-guide RNA targeting TTR in the liver, where it’s almost exclusively produced.
The new analysis included 12 patients with heart failure: 3 in NYHA class I-II and 6 in NYHA class III who received a single dose of NTLA-2001 at 0.7 mg/kg, while the remaining 3 patients in NYHA class I-II received a single dose of 1.0 mg/kg.
During follow-up out to 6 months, TTR reductions averaged:
- 93% in the 0.7 mg/kg NYHA I-II group at 6 months.
- 94% in the 0.7 mg/kg NYHA III group at 4 months.
- 92% in the 1.0 mg/kg NYHA I-II group at 4 months.
Eight patients reported mild or moderate adverse events, and two patients experienced transient infusion reactions, including one grade 3 reaction in the 0.7 mg/kg NYHA class III group that resolved without clinical consequence. This group was expanded to six patients per study protocol. No additional treatment-related adverse events higher than grade 1 were reported, and no further dose escalation was undertaken, Dr. Gillmore reported.
There were no clinically relevant laboratory findings; one patient had a transient grade 1 liver enzyme elevation.
One disadvantage of CRISPR is the potential for off-target effects, but Dr. Gillmore said in an interview that the drug developers went through a “very rigorous process when selecting the guide RNA, which is what really targets the specificity of the TTR gene.”
“That’s a really, really important point,” he said. “When they did various studies using, for example, primary human hepatocytes, they found no evidence of off-target editing at concentrations of NTLA-2001 threefold greater than the EC90, the concentration at which one knocks down the protein by 90%. So, what we can say at the moment, is the specificity of NTLA-2001 for the TTR gene seems to be absolute.”
In terms of other challenges going forward, Dr. Gillmore added, “I think that it’s really to see whether the knockdown that is being achieved is going to translate into greater clinical benefit.”
Invited discussant Kevin M. Alexander, MD, of Stanford (Calif.) University, said therapies that stabilize or reduce TTR have recently emerged that have improved ATTR amyloidosis outcomes, including tafamidis and patisiran.
Nevertheless, there has been an unmet need to develop therapies that can halt or reverse disease, are effective in advanced ATTR, and have an improved route or frequency of administration, given that this is a chronic disease, he said.
Dr. Alexander noted that the reductions of greater than 90% were achieved with higher doses than used in the polyneuropathy arm reported last year but were well tolerated in patients that for the most part had wild-type ATTR (83%) and reflect the wild-type ATTR population in practice. “The data support consideration for subsequent efficacy trials for this compound.”
Unanswered questions in ongoing ATTR trials are whether TTR reductions translate into improved clinical outcomes, the long-term safety of TTR lowering, and the efficacy of NTLA-2001, particularly in higher-risk patients, such as those in NYHA class III and those with hereditary ATTR, Dr. Alexander said.
During a media briefing earlier in the day, invited discussant Kiran Musunuru, MD, University of Pennsylvania, Philadelphia, pointed out that, in the recent APOLLO-B trial of patisiran, patients with ATTR amyloidosis with cardiomyopathy had an average 87% TTR reduction but need intravenous infusions every 3 weeks for the rest of their lives.
“In contrast, gene editing is a one-and-done proposition,” he said. “You receive a single treatment that turns off the TTR gene permanently and the effects are durable and likely last a lifetime.”
Dr. Musunuru noted that patients who received patisiran also had significantly and substantially better functional capacity and quality of life, compared with those who received placebo. “Based on today’s results, we can expect future clinical trials for gene editing to have the same beneficial effects and possibly a mortality benefit as well.”
Today’s study is also important because it is part of the first wave of putting CRISPR into the body for an array of diseases, he commented.
“TTR gene editing stands out because it’s the very first CRISPR trial to show unequivocal success – you see that with a greater than 90% reduction in TTR,” Dr. Musunuru said. “So, in my view that makes it a milestone for modern medicine.”
Dosing at 55 mg, corresponding to a fixed 0.7 mg/kg dose, is ongoing in the dose-expansion portion of the trial, with enrollment across both arms expected to be completed by the end of 2022, Intellia Therapeutics reported.
The study was funded by Intellia Therapeutics and Regeneron Pharmaceuticals. Dr. Gillmore reports receiving consultancy fees from Alnylam, Ionis, AstraZeneca, Pfizer, Intellia, ATTRalus, and Novo Nordisk and has received grant support from Alnylam Pharmaceuticals. Dr. Alexander reports serving on advisory boards for Almylam and Arbor Biotechnologies; has consulted for Eidos, Ionis, Novo Nordisk, and Pfizer; and has received grants from AHA, Alnylam, Eidos, and the National Institutes of Health.
A version of this article first appeared on Medscape.com.
CHICAGO – Treatment with the investigational CRISPR-Cas9 gene-editing therapy, NTLA-2001, led to rapid responses in patients with transthyretin (TTR) amyloidosis with cardiomyopathy (ATTR-CM), interim phase 1 results show.
Serum levels of the disease-causing TTR protein were reduced by at least 90% at day 28 with a single infusion of NTLA-2001 at two different doses, with reductions sustained across 4-6 months’ follow-up.
NTLA-2001 was generally well-tolerated, and the results were similar in patients with New York Heart Association (NYHA) class I-III heart failure.
“These data further support and extend the early findings demonstrating the promise of CRISPR-based in vivo genome editing in humans,” said Julian Gillmore, MD, PhD, MBBS, who is leading the study at University College London.
“More specifically, the deep TTR reductions observed in patients with ATTR amyloidosis in this study provide a real possibility of genuine clinical improvement in a condition that has hitherto been ultimately progressive and invariably fatal,” he said.
The results were reported in a late-breaking session at the American Heart Association scientific sessions.
Mutations in the TTR gene and age-related changes in the stability of the TTR protein can cause misfolding of the TTR protein, resulting in amyloid deposits in skin and myocardial tissues.
An estimated 50,000 people worldwide are thought to have hereditary ATTR and up to 500,000 to have wild-type ATTR amyloidosis. Amyloid cardiomyopathy is underdiagnosed and fatal in 3-10 years without treatment. Current treatment options only slow progression and require lifelong administration, he said.
Results reported last year from the polyneuropathy arm of the study were hailed as a breakthrough and further proof-of-concept that CRISPR could be used to treat other diseases
CRISPR gene editing has shown success, for example, in beta-thalassemia and sickle cell disease but involved stem cells extracted from patients’ bone marrow, edited in the lab, and then replaced.
NTLA-2001 (Intellia Therapeutics/Regeneron) is an in vivo treatment that uses lipid nanoparticles containing messenger RNA for Cas9 and a single-guide RNA targeting TTR in the liver, where it’s almost exclusively produced.
The new analysis included 12 patients with heart failure: 3 in NYHA class I-II and 6 in NYHA class III who received a single dose of NTLA-2001 at 0.7 mg/kg, while the remaining 3 patients in NYHA class I-II received a single dose of 1.0 mg/kg.
During follow-up out to 6 months, TTR reductions averaged:
- 93% in the 0.7 mg/kg NYHA I-II group at 6 months.
- 94% in the 0.7 mg/kg NYHA III group at 4 months.
- 92% in the 1.0 mg/kg NYHA I-II group at 4 months.
Eight patients reported mild or moderate adverse events, and two patients experienced transient infusion reactions, including one grade 3 reaction in the 0.7 mg/kg NYHA class III group that resolved without clinical consequence. This group was expanded to six patients per study protocol. No additional treatment-related adverse events higher than grade 1 were reported, and no further dose escalation was undertaken, Dr. Gillmore reported.
There were no clinically relevant laboratory findings; one patient had a transient grade 1 liver enzyme elevation.
One disadvantage of CRISPR is the potential for off-target effects, but Dr. Gillmore said in an interview that the drug developers went through a “very rigorous process when selecting the guide RNA, which is what really targets the specificity of the TTR gene.”
“That’s a really, really important point,” he said. “When they did various studies using, for example, primary human hepatocytes, they found no evidence of off-target editing at concentrations of NTLA-2001 threefold greater than the EC90, the concentration at which one knocks down the protein by 90%. So, what we can say at the moment, is the specificity of NTLA-2001 for the TTR gene seems to be absolute.”
In terms of other challenges going forward, Dr. Gillmore added, “I think that it’s really to see whether the knockdown that is being achieved is going to translate into greater clinical benefit.”
Invited discussant Kevin M. Alexander, MD, of Stanford (Calif.) University, said therapies that stabilize or reduce TTR have recently emerged that have improved ATTR amyloidosis outcomes, including tafamidis and patisiran.
Nevertheless, there has been an unmet need to develop therapies that can halt or reverse disease, are effective in advanced ATTR, and have an improved route or frequency of administration, given that this is a chronic disease, he said.
Dr. Alexander noted that the reductions of greater than 90% were achieved with higher doses than used in the polyneuropathy arm reported last year but were well tolerated in patients that for the most part had wild-type ATTR (83%) and reflect the wild-type ATTR population in practice. “The data support consideration for subsequent efficacy trials for this compound.”
Unanswered questions in ongoing ATTR trials are whether TTR reductions translate into improved clinical outcomes, the long-term safety of TTR lowering, and the efficacy of NTLA-2001, particularly in higher-risk patients, such as those in NYHA class III and those with hereditary ATTR, Dr. Alexander said.
During a media briefing earlier in the day, invited discussant Kiran Musunuru, MD, University of Pennsylvania, Philadelphia, pointed out that, in the recent APOLLO-B trial of patisiran, patients with ATTR amyloidosis with cardiomyopathy had an average 87% TTR reduction but need intravenous infusions every 3 weeks for the rest of their lives.
“In contrast, gene editing is a one-and-done proposition,” he said. “You receive a single treatment that turns off the TTR gene permanently and the effects are durable and likely last a lifetime.”
Dr. Musunuru noted that patients who received patisiran also had significantly and substantially better functional capacity and quality of life, compared with those who received placebo. “Based on today’s results, we can expect future clinical trials for gene editing to have the same beneficial effects and possibly a mortality benefit as well.”
Today’s study is also important because it is part of the first wave of putting CRISPR into the body for an array of diseases, he commented.
“TTR gene editing stands out because it’s the very first CRISPR trial to show unequivocal success – you see that with a greater than 90% reduction in TTR,” Dr. Musunuru said. “So, in my view that makes it a milestone for modern medicine.”
Dosing at 55 mg, corresponding to a fixed 0.7 mg/kg dose, is ongoing in the dose-expansion portion of the trial, with enrollment across both arms expected to be completed by the end of 2022, Intellia Therapeutics reported.
The study was funded by Intellia Therapeutics and Regeneron Pharmaceuticals. Dr. Gillmore reports receiving consultancy fees from Alnylam, Ionis, AstraZeneca, Pfizer, Intellia, ATTRalus, and Novo Nordisk and has received grant support from Alnylam Pharmaceuticals. Dr. Alexander reports serving on advisory boards for Almylam and Arbor Biotechnologies; has consulted for Eidos, Ionis, Novo Nordisk, and Pfizer; and has received grants from AHA, Alnylam, Eidos, and the National Institutes of Health.
A version of this article first appeared on Medscape.com.
AT AHA 2022