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Colchicine pre-PCI improves biomarkers, not injury risk
PHILADELPHIA – Giving patients a single shot of colchicine before percutaneous coronary intervention was found to favorably impact inflammatory biomarkers linked to vascular injury, but not to lower the risk of procedure-related myocardial injury, according to results of the COLCHICINE-PCI randomized trial reported at the American Heart Association scientific sessions.
This is the first study to evaluate pre-PCI colchicine versus placebo on markers of myocardial injury and inflammation, said Binita Shah, MD, of Veterans Affairs New York Harbor Healthcare System and New York University.
“More work is needed to determine the optimal dosing and timing regimen of colchicine administration in patients undergoing PCI,” Dr. Shah said in an interview. “In this study, we saw inflammatory markers decrease around the 24-hour time point post PCI, so an earlier start to preprocedural colchicine regimen warrants further investigation.” The study found that pre-PCI colchicine attenuated increases in interleukin-6 and high-sensitivity C-reactive protein (CRP) concentrations at 24 hours post PCI, Dr. Shah said.
The results followed by a day the presentation of results from the COLCOT trial (Colchicine Cardiovascular Outcomes Trial) that showed a 23% reduction in cardiovascular events in patients with coronary disease on colchicine 0.5 mg daily vs. placebo (N Engl J Med. 2019 Nov 16. doi: 10.1056/NEJMoa1912388), as Subodh Verma, MD, PhD, of the University of Toronto noted in his discussant comments. COLCHICINE-PCI “has important implications, since patients with acute coronary syndrome often have variable biomarker responses, as biomarkers often function as acute-phase reactants in that setting.”
The COLCHICINE-PCI study of 400 patients investigated oral 1.8 mg colchicine given 1-2 hours before the patient went to the cath lab. The drug was given in a 1.2-mg dose followed an hour later by an 0.6-mg dose. Patients received placebo at the same intervals. An inflammatory biomarker substudy of 280 patients evaluated differences in plasma interleukin-6 levels at baseline and 1 hour post PCI, as well as other key biomarkers at longer intervals.
The primary outcome of PCI-related myocardial injury showed no statistically significant difference between the two groups, Dr. Shah said: 57.3% for colchicine and 64.2% for placebo (P = 0.19). The same was true of 30-day major adverse cardiovascular events, she said: 11.7% and 12.9% for the treatment and placebo groups, respectively (P = 0.82). Rates of PCI-related MI were also similar between the two groups.
However, the biomarker substudy told a different story. IL-6 levels in the treatment group were stable at 1 and 6-8 hours post PCI. “However, at 22-24 hours we see a significant attenuation in the rise of IL-6 with colchicine,” she said.
While IL-beta levels showed no deviation after PCI, the colchicine group showed a noticeable attenuation in the rise of high-sensitivity CRP levels at 22-24 hours.
“This is the first study to demonstrate that an oral load of colchicine prevents a rise of inflammatory markers in an acute-injury setting,” Dr. Shah said.
While results of the COLCOT trial affirmed a “resounding yes” for the use of colchicine in patients who’ve had a recent MI, Dr. Verma said the COLCHICINE-PCI results did not give as clear an answer.
“What about pre- or peri-PCI?” he said. “I don’t think we’re there yet, but I do think that more studies are needed that target residual inflammatory risk and potentially couple an acute loading dose with a chronic, ongoing treatment.” Results from higher-risk primary prevention studies, such as the CLEAR SYNERGY (OASIS 9) of a colchicine-spironolactone combination in patients with STEMI having PCI, are needed, he said.
Dr. Shah disclosed financial relationships with Phillips Volcano and Radux. The VA Office of Research and Development and AHA provided grant funding and Takeda Pharmaceuticals provided the drug.
SOURCE: Shah B. AHA 2019, Late Breaking Science session IV.
PHILADELPHIA – Giving patients a single shot of colchicine before percutaneous coronary intervention was found to favorably impact inflammatory biomarkers linked to vascular injury, but not to lower the risk of procedure-related myocardial injury, according to results of the COLCHICINE-PCI randomized trial reported at the American Heart Association scientific sessions.
This is the first study to evaluate pre-PCI colchicine versus placebo on markers of myocardial injury and inflammation, said Binita Shah, MD, of Veterans Affairs New York Harbor Healthcare System and New York University.
“More work is needed to determine the optimal dosing and timing regimen of colchicine administration in patients undergoing PCI,” Dr. Shah said in an interview. “In this study, we saw inflammatory markers decrease around the 24-hour time point post PCI, so an earlier start to preprocedural colchicine regimen warrants further investigation.” The study found that pre-PCI colchicine attenuated increases in interleukin-6 and high-sensitivity C-reactive protein (CRP) concentrations at 24 hours post PCI, Dr. Shah said.
The results followed by a day the presentation of results from the COLCOT trial (Colchicine Cardiovascular Outcomes Trial) that showed a 23% reduction in cardiovascular events in patients with coronary disease on colchicine 0.5 mg daily vs. placebo (N Engl J Med. 2019 Nov 16. doi: 10.1056/NEJMoa1912388), as Subodh Verma, MD, PhD, of the University of Toronto noted in his discussant comments. COLCHICINE-PCI “has important implications, since patients with acute coronary syndrome often have variable biomarker responses, as biomarkers often function as acute-phase reactants in that setting.”
The COLCHICINE-PCI study of 400 patients investigated oral 1.8 mg colchicine given 1-2 hours before the patient went to the cath lab. The drug was given in a 1.2-mg dose followed an hour later by an 0.6-mg dose. Patients received placebo at the same intervals. An inflammatory biomarker substudy of 280 patients evaluated differences in plasma interleukin-6 levels at baseline and 1 hour post PCI, as well as other key biomarkers at longer intervals.
The primary outcome of PCI-related myocardial injury showed no statistically significant difference between the two groups, Dr. Shah said: 57.3% for colchicine and 64.2% for placebo (P = 0.19). The same was true of 30-day major adverse cardiovascular events, she said: 11.7% and 12.9% for the treatment and placebo groups, respectively (P = 0.82). Rates of PCI-related MI were also similar between the two groups.
However, the biomarker substudy told a different story. IL-6 levels in the treatment group were stable at 1 and 6-8 hours post PCI. “However, at 22-24 hours we see a significant attenuation in the rise of IL-6 with colchicine,” she said.
While IL-beta levels showed no deviation after PCI, the colchicine group showed a noticeable attenuation in the rise of high-sensitivity CRP levels at 22-24 hours.
“This is the first study to demonstrate that an oral load of colchicine prevents a rise of inflammatory markers in an acute-injury setting,” Dr. Shah said.
While results of the COLCOT trial affirmed a “resounding yes” for the use of colchicine in patients who’ve had a recent MI, Dr. Verma said the COLCHICINE-PCI results did not give as clear an answer.
“What about pre- or peri-PCI?” he said. “I don’t think we’re there yet, but I do think that more studies are needed that target residual inflammatory risk and potentially couple an acute loading dose with a chronic, ongoing treatment.” Results from higher-risk primary prevention studies, such as the CLEAR SYNERGY (OASIS 9) of a colchicine-spironolactone combination in patients with STEMI having PCI, are needed, he said.
Dr. Shah disclosed financial relationships with Phillips Volcano and Radux. The VA Office of Research and Development and AHA provided grant funding and Takeda Pharmaceuticals provided the drug.
SOURCE: Shah B. AHA 2019, Late Breaking Science session IV.
PHILADELPHIA – Giving patients a single shot of colchicine before percutaneous coronary intervention was found to favorably impact inflammatory biomarkers linked to vascular injury, but not to lower the risk of procedure-related myocardial injury, according to results of the COLCHICINE-PCI randomized trial reported at the American Heart Association scientific sessions.
This is the first study to evaluate pre-PCI colchicine versus placebo on markers of myocardial injury and inflammation, said Binita Shah, MD, of Veterans Affairs New York Harbor Healthcare System and New York University.
“More work is needed to determine the optimal dosing and timing regimen of colchicine administration in patients undergoing PCI,” Dr. Shah said in an interview. “In this study, we saw inflammatory markers decrease around the 24-hour time point post PCI, so an earlier start to preprocedural colchicine regimen warrants further investigation.” The study found that pre-PCI colchicine attenuated increases in interleukin-6 and high-sensitivity C-reactive protein (CRP) concentrations at 24 hours post PCI, Dr. Shah said.
The results followed by a day the presentation of results from the COLCOT trial (Colchicine Cardiovascular Outcomes Trial) that showed a 23% reduction in cardiovascular events in patients with coronary disease on colchicine 0.5 mg daily vs. placebo (N Engl J Med. 2019 Nov 16. doi: 10.1056/NEJMoa1912388), as Subodh Verma, MD, PhD, of the University of Toronto noted in his discussant comments. COLCHICINE-PCI “has important implications, since patients with acute coronary syndrome often have variable biomarker responses, as biomarkers often function as acute-phase reactants in that setting.”
The COLCHICINE-PCI study of 400 patients investigated oral 1.8 mg colchicine given 1-2 hours before the patient went to the cath lab. The drug was given in a 1.2-mg dose followed an hour later by an 0.6-mg dose. Patients received placebo at the same intervals. An inflammatory biomarker substudy of 280 patients evaluated differences in plasma interleukin-6 levels at baseline and 1 hour post PCI, as well as other key biomarkers at longer intervals.
The primary outcome of PCI-related myocardial injury showed no statistically significant difference between the two groups, Dr. Shah said: 57.3% for colchicine and 64.2% for placebo (P = 0.19). The same was true of 30-day major adverse cardiovascular events, she said: 11.7% and 12.9% for the treatment and placebo groups, respectively (P = 0.82). Rates of PCI-related MI were also similar between the two groups.
However, the biomarker substudy told a different story. IL-6 levels in the treatment group were stable at 1 and 6-8 hours post PCI. “However, at 22-24 hours we see a significant attenuation in the rise of IL-6 with colchicine,” she said.
While IL-beta levels showed no deviation after PCI, the colchicine group showed a noticeable attenuation in the rise of high-sensitivity CRP levels at 22-24 hours.
“This is the first study to demonstrate that an oral load of colchicine prevents a rise of inflammatory markers in an acute-injury setting,” Dr. Shah said.
While results of the COLCOT trial affirmed a “resounding yes” for the use of colchicine in patients who’ve had a recent MI, Dr. Verma said the COLCHICINE-PCI results did not give as clear an answer.
“What about pre- or peri-PCI?” he said. “I don’t think we’re there yet, but I do think that more studies are needed that target residual inflammatory risk and potentially couple an acute loading dose with a chronic, ongoing treatment.” Results from higher-risk primary prevention studies, such as the CLEAR SYNERGY (OASIS 9) of a colchicine-spironolactone combination in patients with STEMI having PCI, are needed, he said.
Dr. Shah disclosed financial relationships with Phillips Volcano and Radux. The VA Office of Research and Development and AHA provided grant funding and Takeda Pharmaceuticals provided the drug.
SOURCE: Shah B. AHA 2019, Late Breaking Science session IV.
REPORTING FROM AHA 2019
Cardiac arrests peak with pollution in Japan
PHILADELPHIA – Out-of-hospital cardiac arrests spike with daily counts of emissions-related particulate matter – a key contributor to urban smog – and particularly affect men and people older than age 75, according to results of a nationwide Japanese study presented at the American Heart Association scientific sessions.
“Short-term exposure to particulate pollutants is a potential trigger for cardiac-origin, out-of-hospital cardiac arrest [OHCA] onset in Japan,” said Sunao Kojima, MD, a professor at Kawasaki Medical School in Kurashiki, Japan.
The study used the All-Japan Utstein Registry of OHCA throughout all 47 prefectures in Japan. The analysis then applied prefecture-specific estimates of PM2.5 – particulate matter that measures 2.5 mcm in average diameter – using a time-stratified, case-crossover design. By comparison, PM2.5 is about 1/40th the diameter of human hair (approximately 100 mcm) and about 1/12th that of cedar pollen (30 mcm).
“Increased OHCAs incidence correlated with the average increase in PM2.5 concentrations over those observed 1 day before cardiac arrest,” Dr. Kojima said.
What’s noteworthy about the Utstein registry, Dr. Kojima said, is that emergency medical service personnel in Japan are not authorized to terminate resuscitation efforts, so most OHCA patients are transported to the nearest hospital and are thus counted in the registry.
From a total count of 1.4 million EMS-assessed OHCAs from 2005 through 2016, the study focused on 103,189 bystander-witnessed events from April 2011 through 2016. The analysis further divided that population into three groups: those presenting with initial ventricular fibrillation/pulseless ventricular tachycardia (20,848); those without initial VF/pulseless VT (80,110); and those with initial cardiac rhythm of unknown origin (2,231).
“The pathways linking PM2.5 exposure with OHCA remain unknown, but several mechanisms have been suspected,” Dr. Kojima said. “A major mechanism is thought to be associated with oxidative stress and systemic inflammation.”
The average daily concentration for PM2.5 was 13.9/m3 across all of Japan, Dr. Kojima said, with the highest concentrations in western Japan (16.3/m3). A 10-mcg/m3 increase in the average PM2.5 concentrations on the day of OHCA from the previous day (lag 0-1) was associated with a 1.6% increase in OHCAs (95% confidence interval, 0.1-3.1%), he said.
“Increased PM2.5 concentrations were closely associated with OHCA incidence, even when adjusted for other pollutants, such as ozone, nitrogen dioxide, sulfur dioxide, and lag 0-1,” Dr. Kojima said.
The incidence for PM2.5-related OHCA was higher for people age 75 and older and for men, during the warm season and in the central region. In the central region, the incidence increased around 6% for every 10-mcg/m3 day-to-day increase in the average PM2.5 compared to less than 1% increases in the eastern and western regions, Dr. Kojima said.
PM2.5 levels also seemed to influence outcomes depending on the origin of the OHCA, he said. Patients with VF/pulseless VT and pulseless electrical activity had better outcomes than did those with asystole. Increased PM2.5 levels were linked with lower rates of restoration of spontaneous circulation, 1-month survival, and 1-month survival with minimal neurological impairment, he said. Patients who had chest-compression-only CPR seemed to do significantly better than did those who had chest compression with rescue breathing, he said.
“There may be room for further discussion regarding the impact of performing rescue breathing in CPR and the consequent effects of short-term PM2.5 exposure on patients with cardiac origin,” he said.
Dr. Kojima has no financial relationships to disclose. The study received funding from the Japan Ministry of the Environment, Japan Society for the Promotion of Science, and Foundation for Total Health Promotion, Japan.
SOURCE: Kojima S. AHA 2019, Session FS.AOS.F1.
PHILADELPHIA – Out-of-hospital cardiac arrests spike with daily counts of emissions-related particulate matter – a key contributor to urban smog – and particularly affect men and people older than age 75, according to results of a nationwide Japanese study presented at the American Heart Association scientific sessions.
“Short-term exposure to particulate pollutants is a potential trigger for cardiac-origin, out-of-hospital cardiac arrest [OHCA] onset in Japan,” said Sunao Kojima, MD, a professor at Kawasaki Medical School in Kurashiki, Japan.
The study used the All-Japan Utstein Registry of OHCA throughout all 47 prefectures in Japan. The analysis then applied prefecture-specific estimates of PM2.5 – particulate matter that measures 2.5 mcm in average diameter – using a time-stratified, case-crossover design. By comparison, PM2.5 is about 1/40th the diameter of human hair (approximately 100 mcm) and about 1/12th that of cedar pollen (30 mcm).
“Increased OHCAs incidence correlated with the average increase in PM2.5 concentrations over those observed 1 day before cardiac arrest,” Dr. Kojima said.
What’s noteworthy about the Utstein registry, Dr. Kojima said, is that emergency medical service personnel in Japan are not authorized to terminate resuscitation efforts, so most OHCA patients are transported to the nearest hospital and are thus counted in the registry.
From a total count of 1.4 million EMS-assessed OHCAs from 2005 through 2016, the study focused on 103,189 bystander-witnessed events from April 2011 through 2016. The analysis further divided that population into three groups: those presenting with initial ventricular fibrillation/pulseless ventricular tachycardia (20,848); those without initial VF/pulseless VT (80,110); and those with initial cardiac rhythm of unknown origin (2,231).
“The pathways linking PM2.5 exposure with OHCA remain unknown, but several mechanisms have been suspected,” Dr. Kojima said. “A major mechanism is thought to be associated with oxidative stress and systemic inflammation.”
The average daily concentration for PM2.5 was 13.9/m3 across all of Japan, Dr. Kojima said, with the highest concentrations in western Japan (16.3/m3). A 10-mcg/m3 increase in the average PM2.5 concentrations on the day of OHCA from the previous day (lag 0-1) was associated with a 1.6% increase in OHCAs (95% confidence interval, 0.1-3.1%), he said.
“Increased PM2.5 concentrations were closely associated with OHCA incidence, even when adjusted for other pollutants, such as ozone, nitrogen dioxide, sulfur dioxide, and lag 0-1,” Dr. Kojima said.
The incidence for PM2.5-related OHCA was higher for people age 75 and older and for men, during the warm season and in the central region. In the central region, the incidence increased around 6% for every 10-mcg/m3 day-to-day increase in the average PM2.5 compared to less than 1% increases in the eastern and western regions, Dr. Kojima said.
PM2.5 levels also seemed to influence outcomes depending on the origin of the OHCA, he said. Patients with VF/pulseless VT and pulseless electrical activity had better outcomes than did those with asystole. Increased PM2.5 levels were linked with lower rates of restoration of spontaneous circulation, 1-month survival, and 1-month survival with minimal neurological impairment, he said. Patients who had chest-compression-only CPR seemed to do significantly better than did those who had chest compression with rescue breathing, he said.
“There may be room for further discussion regarding the impact of performing rescue breathing in CPR and the consequent effects of short-term PM2.5 exposure on patients with cardiac origin,” he said.
Dr. Kojima has no financial relationships to disclose. The study received funding from the Japan Ministry of the Environment, Japan Society for the Promotion of Science, and Foundation for Total Health Promotion, Japan.
SOURCE: Kojima S. AHA 2019, Session FS.AOS.F1.
PHILADELPHIA – Out-of-hospital cardiac arrests spike with daily counts of emissions-related particulate matter – a key contributor to urban smog – and particularly affect men and people older than age 75, according to results of a nationwide Japanese study presented at the American Heart Association scientific sessions.
“Short-term exposure to particulate pollutants is a potential trigger for cardiac-origin, out-of-hospital cardiac arrest [OHCA] onset in Japan,” said Sunao Kojima, MD, a professor at Kawasaki Medical School in Kurashiki, Japan.
The study used the All-Japan Utstein Registry of OHCA throughout all 47 prefectures in Japan. The analysis then applied prefecture-specific estimates of PM2.5 – particulate matter that measures 2.5 mcm in average diameter – using a time-stratified, case-crossover design. By comparison, PM2.5 is about 1/40th the diameter of human hair (approximately 100 mcm) and about 1/12th that of cedar pollen (30 mcm).
“Increased OHCAs incidence correlated with the average increase in PM2.5 concentrations over those observed 1 day before cardiac arrest,” Dr. Kojima said.
What’s noteworthy about the Utstein registry, Dr. Kojima said, is that emergency medical service personnel in Japan are not authorized to terminate resuscitation efforts, so most OHCA patients are transported to the nearest hospital and are thus counted in the registry.
From a total count of 1.4 million EMS-assessed OHCAs from 2005 through 2016, the study focused on 103,189 bystander-witnessed events from April 2011 through 2016. The analysis further divided that population into three groups: those presenting with initial ventricular fibrillation/pulseless ventricular tachycardia (20,848); those without initial VF/pulseless VT (80,110); and those with initial cardiac rhythm of unknown origin (2,231).
“The pathways linking PM2.5 exposure with OHCA remain unknown, but several mechanisms have been suspected,” Dr. Kojima said. “A major mechanism is thought to be associated with oxidative stress and systemic inflammation.”
The average daily concentration for PM2.5 was 13.9/m3 across all of Japan, Dr. Kojima said, with the highest concentrations in western Japan (16.3/m3). A 10-mcg/m3 increase in the average PM2.5 concentrations on the day of OHCA from the previous day (lag 0-1) was associated with a 1.6% increase in OHCAs (95% confidence interval, 0.1-3.1%), he said.
“Increased PM2.5 concentrations were closely associated with OHCA incidence, even when adjusted for other pollutants, such as ozone, nitrogen dioxide, sulfur dioxide, and lag 0-1,” Dr. Kojima said.
The incidence for PM2.5-related OHCA was higher for people age 75 and older and for men, during the warm season and in the central region. In the central region, the incidence increased around 6% for every 10-mcg/m3 day-to-day increase in the average PM2.5 compared to less than 1% increases in the eastern and western regions, Dr. Kojima said.
PM2.5 levels also seemed to influence outcomes depending on the origin of the OHCA, he said. Patients with VF/pulseless VT and pulseless electrical activity had better outcomes than did those with asystole. Increased PM2.5 levels were linked with lower rates of restoration of spontaneous circulation, 1-month survival, and 1-month survival with minimal neurological impairment, he said. Patients who had chest-compression-only CPR seemed to do significantly better than did those who had chest compression with rescue breathing, he said.
“There may be room for further discussion regarding the impact of performing rescue breathing in CPR and the consequent effects of short-term PM2.5 exposure on patients with cardiac origin,” he said.
Dr. Kojima has no financial relationships to disclose. The study received funding from the Japan Ministry of the Environment, Japan Society for the Promotion of Science, and Foundation for Total Health Promotion, Japan.
SOURCE: Kojima S. AHA 2019, Session FS.AOS.F1.
REPORTING FROM AHA 2019
Icosapent ethyl cost effective in REDUCE-IT analysis
PHILADELPHIA – The overall costs of icosapent ethyl were less than placebo, and the medication reduced cardiovascular events by 30% at a cost that fits well within acceptable quality-adjusted life-year (QALY) parameters, according to a cost-effectiveness analysis of the REDUCE-IT trial.
Days before the presentation of the analysis at the American Heart Association scientific sessions, a Food and Drug Administration advisory panel unanimously recommended approval of icosapent ethyl (Vascepa) for a new indication for reducing CV event risk. Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid derived from fish oil, received FDA approval in 2012 for treatment of triglyceride levels of at least 500 mg/dL.
“What we found here is that icosapent ethyl is a dominant strategy,” said William S. Weintraub, MD, director of outcomes research at MedStar Heart & Vascular Institute in Washington, in reporting preliminary cost-analysis findings from REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl – Intervention Trial). “It’s offering better outcomes at a lower cost.”
The dominant strategy was demonstrated by cost savings in 70% of simulations the cost-effectiveness analysis ran, Dr. Weintraub said.
“These are very impressive results,” said session moderator Seth S. Martin, MD, an internist and cardiologist at Johns Hopkins University, Baltimore. “We don’t often see dominant strategies for new drugs. This is very exciting.”
“Almost never,” Dr. Weintraub responded.
REDUCE-IT randomized 8,179 patients with a diagnosis of CVD or with diabetes and other risk factors who had been on statins and had triglycerides of 135-499 mg/dL to either 4 g of icosapent ethyl daily or placebo (N Engl J Med. 2019;380:11-22). Trial results showed the treatment group had an absolute risk reduction of 4.8% and a relative risk reduction of 25% of first CV events and a 30% relative risk reduction for total events, Dr. Weintraub said.
The analysis determined that the QALYs for icosapent ethyl versus those for placebo were 3.34 and 3.27, respectively, during the trial period and 11.61 and 11.35 over a lifetime. The mean costs for the two treatments were $27,576 and $28,205 during the trial period and $235,352 and $236,636 lifetime, respectively, Dr. Weintraub said.
An analysis of cost effectiveness showed that almost all of the estimates fell below the willingness-to-pay (WTP) threshold of $50,000 per QALY gained, Dr. Weintraub said. “In fact, some 70% plus are in what’s called quadrant two; that is, decreased cost and increased efficacy.”
The analysis also calculated the value of icosapent ethyl at three different WTP thresholds: up to $6 a day at a WTP of $50,000, up to $12 a day at $100,000, and up to $18 a day at $150,000. The analysis used the actual net pricing of $4.16 a day, Dr. Weintraub said. “That’s why we showed we have the dominant strategy,” he said.
Further cost-effectiveness analyses of the REDUCE-IT data will focus on subgroups, such as U.S. and non–U.S. patients and people with diabetes. He also emphasized the data he reported were preliminary. “We have a lot more work to do,” Dr. Weintraub said.
Dr. Weintraub reported having financial relationships with Amarin Pharma, which markets Vascepa, and AstraZeneca.
SOURCE: Weintraub WS. AHA 2019, Session FS.AOS.F1.
PHILADELPHIA – The overall costs of icosapent ethyl were less than placebo, and the medication reduced cardiovascular events by 30% at a cost that fits well within acceptable quality-adjusted life-year (QALY) parameters, according to a cost-effectiveness analysis of the REDUCE-IT trial.
Days before the presentation of the analysis at the American Heart Association scientific sessions, a Food and Drug Administration advisory panel unanimously recommended approval of icosapent ethyl (Vascepa) for a new indication for reducing CV event risk. Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid derived from fish oil, received FDA approval in 2012 for treatment of triglyceride levels of at least 500 mg/dL.
“What we found here is that icosapent ethyl is a dominant strategy,” said William S. Weintraub, MD, director of outcomes research at MedStar Heart & Vascular Institute in Washington, in reporting preliminary cost-analysis findings from REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl – Intervention Trial). “It’s offering better outcomes at a lower cost.”
The dominant strategy was demonstrated by cost savings in 70% of simulations the cost-effectiveness analysis ran, Dr. Weintraub said.
“These are very impressive results,” said session moderator Seth S. Martin, MD, an internist and cardiologist at Johns Hopkins University, Baltimore. “We don’t often see dominant strategies for new drugs. This is very exciting.”
“Almost never,” Dr. Weintraub responded.
REDUCE-IT randomized 8,179 patients with a diagnosis of CVD or with diabetes and other risk factors who had been on statins and had triglycerides of 135-499 mg/dL to either 4 g of icosapent ethyl daily or placebo (N Engl J Med. 2019;380:11-22). Trial results showed the treatment group had an absolute risk reduction of 4.8% and a relative risk reduction of 25% of first CV events and a 30% relative risk reduction for total events, Dr. Weintraub said.
The analysis determined that the QALYs for icosapent ethyl versus those for placebo were 3.34 and 3.27, respectively, during the trial period and 11.61 and 11.35 over a lifetime. The mean costs for the two treatments were $27,576 and $28,205 during the trial period and $235,352 and $236,636 lifetime, respectively, Dr. Weintraub said.
An analysis of cost effectiveness showed that almost all of the estimates fell below the willingness-to-pay (WTP) threshold of $50,000 per QALY gained, Dr. Weintraub said. “In fact, some 70% plus are in what’s called quadrant two; that is, decreased cost and increased efficacy.”
The analysis also calculated the value of icosapent ethyl at three different WTP thresholds: up to $6 a day at a WTP of $50,000, up to $12 a day at $100,000, and up to $18 a day at $150,000. The analysis used the actual net pricing of $4.16 a day, Dr. Weintraub said. “That’s why we showed we have the dominant strategy,” he said.
Further cost-effectiveness analyses of the REDUCE-IT data will focus on subgroups, such as U.S. and non–U.S. patients and people with diabetes. He also emphasized the data he reported were preliminary. “We have a lot more work to do,” Dr. Weintraub said.
Dr. Weintraub reported having financial relationships with Amarin Pharma, which markets Vascepa, and AstraZeneca.
SOURCE: Weintraub WS. AHA 2019, Session FS.AOS.F1.
PHILADELPHIA – The overall costs of icosapent ethyl were less than placebo, and the medication reduced cardiovascular events by 30% at a cost that fits well within acceptable quality-adjusted life-year (QALY) parameters, according to a cost-effectiveness analysis of the REDUCE-IT trial.
Days before the presentation of the analysis at the American Heart Association scientific sessions, a Food and Drug Administration advisory panel unanimously recommended approval of icosapent ethyl (Vascepa) for a new indication for reducing CV event risk. Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid derived from fish oil, received FDA approval in 2012 for treatment of triglyceride levels of at least 500 mg/dL.
“What we found here is that icosapent ethyl is a dominant strategy,” said William S. Weintraub, MD, director of outcomes research at MedStar Heart & Vascular Institute in Washington, in reporting preliminary cost-analysis findings from REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl – Intervention Trial). “It’s offering better outcomes at a lower cost.”
The dominant strategy was demonstrated by cost savings in 70% of simulations the cost-effectiveness analysis ran, Dr. Weintraub said.
“These are very impressive results,” said session moderator Seth S. Martin, MD, an internist and cardiologist at Johns Hopkins University, Baltimore. “We don’t often see dominant strategies for new drugs. This is very exciting.”
“Almost never,” Dr. Weintraub responded.
REDUCE-IT randomized 8,179 patients with a diagnosis of CVD or with diabetes and other risk factors who had been on statins and had triglycerides of 135-499 mg/dL to either 4 g of icosapent ethyl daily or placebo (N Engl J Med. 2019;380:11-22). Trial results showed the treatment group had an absolute risk reduction of 4.8% and a relative risk reduction of 25% of first CV events and a 30% relative risk reduction for total events, Dr. Weintraub said.
The analysis determined that the QALYs for icosapent ethyl versus those for placebo were 3.34 and 3.27, respectively, during the trial period and 11.61 and 11.35 over a lifetime. The mean costs for the two treatments were $27,576 and $28,205 during the trial period and $235,352 and $236,636 lifetime, respectively, Dr. Weintraub said.
An analysis of cost effectiveness showed that almost all of the estimates fell below the willingness-to-pay (WTP) threshold of $50,000 per QALY gained, Dr. Weintraub said. “In fact, some 70% plus are in what’s called quadrant two; that is, decreased cost and increased efficacy.”
The analysis also calculated the value of icosapent ethyl at three different WTP thresholds: up to $6 a day at a WTP of $50,000, up to $12 a day at $100,000, and up to $18 a day at $150,000. The analysis used the actual net pricing of $4.16 a day, Dr. Weintraub said. “That’s why we showed we have the dominant strategy,” he said.
Further cost-effectiveness analyses of the REDUCE-IT data will focus on subgroups, such as U.S. and non–U.S. patients and people with diabetes. He also emphasized the data he reported were preliminary. “We have a lot more work to do,” Dr. Weintraub said.
Dr. Weintraub reported having financial relationships with Amarin Pharma, which markets Vascepa, and AstraZeneca.
SOURCE: Weintraub WS. AHA 2019, Session FS.AOS.F1.
REPORTING FROM AHA 2019
DAPA-HF: Dapagliflozin benefits regardless of age, HF severity
PHILADELPHIA – The substantial benefits from adding dapagliflozin to guideline-directed medical therapy for patients with heart failure with reduced ejection fraction enrolled in the DAPA-HF trial applied to patients regardless of their age or baseline health status, a pair of new post hoc analyses suggest.
These findings emerged a day after a report that more fully delineated dapagliflozin’s consistent safety and efficacy in patients with heart failure with reduced ejection fraction (HFrEF) regardless of whether they also had type 2 diabetes. One of the new, post hoc analyses reported at the American Heart Association scientific sessions suggested that even the most elderly enrolled patients, 75 years and older, had a similar cut in mortality and acute heart failure exacerbations, compared with younger patients. A second post hoc analysis indicated that patients with severe heart failure symptoms at entry into the trial received about as much benefit from the addition of dapagliflozin as did patients with mild baseline symptoms, measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ).
The primary results from the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, first reported in August 2019, showed that among more than 4,700 patients with HFrEF randomized to receive the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) on top of standard HFrEF medications or placebo, those who received dapagliflozin had a statistically significant, 26% decrease in their incidence of the primary study endpoint over a median 18 months, regardless of diabetes status (N Engl J Med. 2019 Nov 21;381[21]:1995-2008).
“These benefits were entirely consistent across the range of ages studied,” extending from patients younger than 55 years to those older than 75 years, John McMurray, MD, said at the meeting. “In many parts of the world, particularly North America and Western Europe, we have an increasingly elderly population. Many patients with heart failure are much older than in clinical trials,” he said. 
“The thing of concern is whether elderly patients get as much benefit and tolerate treatment as well as younger patients,” said Dr. McMurray, professor of medical cardiology at the University of Glasgow.
“Dapagliflozin worked across all ages, including some very elderly patients enrolled in the trial,” said Mary Norine Walsh, MD, medical director of the heart failure and transplant program at St. Vincent Heart Center of Indiana in Indianapolis. “Many trials have not looked at age like this. I hope this is a new way to analyze trials to produce more information that can help patients,” she said in an interview.
Quality-of-life outcomes
The other new, post hoc analysis showed that patients with severe HF symptoms at entry into the trial received about as much benefit from the addition of dapagliflozin as did patients with milder baseline symptoms and less impaired function, measured by the KCCQ. Dapagliflozin treatment “improved cardiovascular death and worsening heart failure to a similar extent across the entire range of KCCQ at baseline,” Mikhail N. Kosiborod, MD, said in a separate talk at the meeting. In addition, dapagliflozin treatment increased the rate of small, moderate, and large clinically meaningful improvements in patients’ KCCQ scores across all key domains of the metric, which scores symptom frequency and severity, physical and social limitations, and quality of life, said Dr. Kosiborod, a cardiologist and professor of medicine at the University of Missouri–Kansas City.
After the first 8 months of treatment in the DAPA-HF trial, 58% of the 2,373 patients who received dapagliflozin had a clinically meaningful improvement in their total KCCQ symptom score of at least 5 points, compared with a 51% rate in the 2,371 patients in the control arm, a statistically significant difference. This meant that the number needed to treat with dapagliflozin was 14 patients to produce one additional patient with at least a 5-point KCCQ improvement compared with controls, a “very small” number needed to treat, Dr. Kosiborod said in an interview.
Addition of the KCCQ to the panel of assessments that patients underwent during DAPA-HF reflected an evolved approach to measuring efficacy outcomes in clinical trials by including patient-reported outcomes. Earlier in 2019, the Food and Drug Administration released draft guidance for heart failure drug development that explicitly called for efficacy endpoints in pivotal studies that measure how patients feel and function, and stating that these endpoints can be the basis for new drug approvals.
“To many patients, how they feel matters as much if not more than how long they live,” Dr. Kosiborod noted. The goals of heart failure treatments are not only to extend survival and reduced hospitalizations, but also to improve symptoms, function, and quality of life, he said.
“There is a lot of interest now in having outcomes in heart failure trials that are more meaningful to patients, like feeling better and being able to do more,” noted Dr. Walsh.
The DAPA-HF results also showed that patients had similar rates of reduction in death, heart failure hospitalization, or urgent clinical visits, regardless of how severely they were affected by their heart failure when they began dapagliflozin treatment. The researchers ran an analysis that divided the entire trial population into tertiles based on their KCCQ score on entering the study. Patients in the most severely-affected tertile had a 30% cut in their rate of death or acute heart failure exacerbation on dapagliflozin compared with placebo, while patients in the tertile with the mildest symptoms at baseline had a 38% reduction in their primary outcome incidence compared with controls who received placebo. Concurrently with Dr. Kosiborod’s report, the results appeared in an article online (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044138).
Outcomes by age
Not surprisingly in DAPA-HF, the older patients were, the sicker, Dr. McMurray observed. Of the study’s 1,149 patients (24% of the study cohort) who were at least 75 years old, 62% had chronic kidney disease, compared with a 14% prevalence among the 636 patients younger than age 55. The 75-and-older group showed a steeper, 32% decline in incidence of the primary endpoint – a composite of cardiovascular (CV) death, HF hospitalization, or urgent HF visit requiring intravenous therapy – than in the other studied age groups: a 24% decline in those 65-74 years old, a 29% cut in those 55-64 years old, and a 13% drop in patients younger than 55 years old.
In addition, patients aged 75 years or greater were just as likely as the overall group to show at least a 5-point improvement in their KCCQ Total Symptom Score on dapagliflozin, as well as about the same reduced rate of deterioration compared with placebo as tracked with the KCCQ.
Patients “got as much benefit in terms of symptoms as well as morbidity and mortality,” Dr. McMurray concluded. Concurrently with the meeting report the results appeared in an article online (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044133).
“These data are of critical importance, as improving patient-reported outcomes in heart failure, especially in highly symptomatic patients, is an important goal in drug development,” G. Michael Felker, MD, wrote in an editorial accompanying the two published analyses (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044578). These new analyses also highlight another attractive feature of dapagliflozin and, apparently, the entire class of SGLT2 inhibitors: They “ ‘play well with others’ when it comes to overlapping intolerances that often limit (either in reality or in perception) optimization of GDMT [guideline-directed medical therapy]. Although SGLT2 inhibitor therapy may lead to volume depletion and require adjustment of diuretics, the SGLT2 inhibitors generally lack some of the other dose-limiting adverse effects (such as renal dysfunction, hyperkalemia, and hypotension) that can make aggressive up-titration of GDMT problematic, particularly in older patients or those with more advanced disease,“ wrote Dr. Felker, professor of medicine at Duke University in Durham, N.C. “We stand at the beginning of a new era of ‘quadruple therapy’ for HFrEF with beta-blockers, an angiotensin receptor neprilysin inhibitor, mineralocorticoid receptor antagonists, and SGLT2 inhibitors,” he concluded.
A version of this article also appears on Medscape.com
In DAPA-HF, treatment with dapagliflozin met the three critical goals of heart failure management. When used on top of current guideline-directed medical therapy, the treatment reduced mortality, cut hospitalizations, and improved heart failure–related health status – all to a similar extent regardless of patients’ age or symptom severity at entry. These new, post hoc findings provide important, additional data supporting inhibition of sodium-glucose cotransporter (SGLT) 2 with dapagliflozin as the newest foundational pillar of treatment for heart failure with reduced ejection fraction (HFrEF).
The results of the analysis by baseline symptoms severity as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) showed similar treatment effects from dapagliflozin regardless of a patient’s baseline KCCQ score, suggesting that the prior report of a blunted effect of dapagliflozin in patients classified at baseline as being in New York Heart Association functional class III or IV compared with class I and II patients was likely a chance finding.
Both the analyses by age and by KCCQ scores were limited by their post hoc status using data collected in a single study. No evidence addresses whether these are class effects for all drugs in the SGLT2-inhibitor class, whether these findings from DAPA-HF are generalizable to real world practice, or whether treatment with dapagliflozin would have similar effects on outcomes if it had been used more often in combination with sacubitril/valsartan. In DAPA-HF, 11% of patients also received sacubitril/valsartan even though existing management guidelines recommend sacubitril/valsartan as the preferred agent for inhibiting the renin-angiotensin system.
It’s also unclear whether patient-reported outcomes such as those measured by the KCCQ will help in sequencing the introduction of drugs for HFrEF patients, or drug selection by patients, providers, payers, and in guidelines.
Carolyn S.P. Lam, MD, is professor of medicine at Duke-National University of Singapore. She has been a consultant to and has received research funding from AstraZeneca and several other companies. She made these comments as designated discussant for the two reports.
In DAPA-HF, treatment with dapagliflozin met the three critical goals of heart failure management. When used on top of current guideline-directed medical therapy, the treatment reduced mortality, cut hospitalizations, and improved heart failure–related health status – all to a similar extent regardless of patients’ age or symptom severity at entry. These new, post hoc findings provide important, additional data supporting inhibition of sodium-glucose cotransporter (SGLT) 2 with dapagliflozin as the newest foundational pillar of treatment for heart failure with reduced ejection fraction (HFrEF).
The results of the analysis by baseline symptoms severity as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) showed similar treatment effects from dapagliflozin regardless of a patient’s baseline KCCQ score, suggesting that the prior report of a blunted effect of dapagliflozin in patients classified at baseline as being in New York Heart Association functional class III or IV compared with class I and II patients was likely a chance finding.
Both the analyses by age and by KCCQ scores were limited by their post hoc status using data collected in a single study. No evidence addresses whether these are class effects for all drugs in the SGLT2-inhibitor class, whether these findings from DAPA-HF are generalizable to real world practice, or whether treatment with dapagliflozin would have similar effects on outcomes if it had been used more often in combination with sacubitril/valsartan. In DAPA-HF, 11% of patients also received sacubitril/valsartan even though existing management guidelines recommend sacubitril/valsartan as the preferred agent for inhibiting the renin-angiotensin system.
It’s also unclear whether patient-reported outcomes such as those measured by the KCCQ will help in sequencing the introduction of drugs for HFrEF patients, or drug selection by patients, providers, payers, and in guidelines.
Carolyn S.P. Lam, MD, is professor of medicine at Duke-National University of Singapore. She has been a consultant to and has received research funding from AstraZeneca and several other companies. She made these comments as designated discussant for the two reports.
In DAPA-HF, treatment with dapagliflozin met the three critical goals of heart failure management. When used on top of current guideline-directed medical therapy, the treatment reduced mortality, cut hospitalizations, and improved heart failure–related health status – all to a similar extent regardless of patients’ age or symptom severity at entry. These new, post hoc findings provide important, additional data supporting inhibition of sodium-glucose cotransporter (SGLT) 2 with dapagliflozin as the newest foundational pillar of treatment for heart failure with reduced ejection fraction (HFrEF).
The results of the analysis by baseline symptoms severity as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) showed similar treatment effects from dapagliflozin regardless of a patient’s baseline KCCQ score, suggesting that the prior report of a blunted effect of dapagliflozin in patients classified at baseline as being in New York Heart Association functional class III or IV compared with class I and II patients was likely a chance finding.
Both the analyses by age and by KCCQ scores were limited by their post hoc status using data collected in a single study. No evidence addresses whether these are class effects for all drugs in the SGLT2-inhibitor class, whether these findings from DAPA-HF are generalizable to real world practice, or whether treatment with dapagliflozin would have similar effects on outcomes if it had been used more often in combination with sacubitril/valsartan. In DAPA-HF, 11% of patients also received sacubitril/valsartan even though existing management guidelines recommend sacubitril/valsartan as the preferred agent for inhibiting the renin-angiotensin system.
It’s also unclear whether patient-reported outcomes such as those measured by the KCCQ will help in sequencing the introduction of drugs for HFrEF patients, or drug selection by patients, providers, payers, and in guidelines.
Carolyn S.P. Lam, MD, is professor of medicine at Duke-National University of Singapore. She has been a consultant to and has received research funding from AstraZeneca and several other companies. She made these comments as designated discussant for the two reports.
PHILADELPHIA – The substantial benefits from adding dapagliflozin to guideline-directed medical therapy for patients with heart failure with reduced ejection fraction enrolled in the DAPA-HF trial applied to patients regardless of their age or baseline health status, a pair of new post hoc analyses suggest.
These findings emerged a day after a report that more fully delineated dapagliflozin’s consistent safety and efficacy in patients with heart failure with reduced ejection fraction (HFrEF) regardless of whether they also had type 2 diabetes. One of the new, post hoc analyses reported at the American Heart Association scientific sessions suggested that even the most elderly enrolled patients, 75 years and older, had a similar cut in mortality and acute heart failure exacerbations, compared with younger patients. A second post hoc analysis indicated that patients with severe heart failure symptoms at entry into the trial received about as much benefit from the addition of dapagliflozin as did patients with mild baseline symptoms, measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ).
The primary results from the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, first reported in August 2019, showed that among more than 4,700 patients with HFrEF randomized to receive the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) on top of standard HFrEF medications or placebo, those who received dapagliflozin had a statistically significant, 26% decrease in their incidence of the primary study endpoint over a median 18 months, regardless of diabetes status (N Engl J Med. 2019 Nov 21;381[21]:1995-2008).
“These benefits were entirely consistent across the range of ages studied,” extending from patients younger than 55 years to those older than 75 years, John McMurray, MD, said at the meeting. “In many parts of the world, particularly North America and Western Europe, we have an increasingly elderly population. Many patients with heart failure are much older than in clinical trials,” he said.
“The thing of concern is whether elderly patients get as much benefit and tolerate treatment as well as younger patients,” said Dr. McMurray, professor of medical cardiology at the University of Glasgow.
“Dapagliflozin worked across all ages, including some very elderly patients enrolled in the trial,” said Mary Norine Walsh, MD, medical director of the heart failure and transplant program at St. Vincent Heart Center of Indiana in Indianapolis. “Many trials have not looked at age like this. I hope this is a new way to analyze trials to produce more information that can help patients,” she said in an interview.
Quality-of-life outcomes
The other new, post hoc analysis showed that patients with severe HF symptoms at entry into the trial received about as much benefit from the addition of dapagliflozin as did patients with milder baseline symptoms and less impaired function, measured by the KCCQ. Dapagliflozin treatment “improved cardiovascular death and worsening heart failure to a similar extent across the entire range of KCCQ at baseline,” Mikhail N. Kosiborod, MD, said in a separate talk at the meeting. In addition, dapagliflozin treatment increased the rate of small, moderate, and large clinically meaningful improvements in patients’ KCCQ scores across all key domains of the metric, which scores symptom frequency and severity, physical and social limitations, and quality of life, said Dr. Kosiborod, a cardiologist and professor of medicine at the University of Missouri–Kansas City.
After the first 8 months of treatment in the DAPA-HF trial, 58% of the 2,373 patients who received dapagliflozin had a clinically meaningful improvement in their total KCCQ symptom score of at least 5 points, compared with a 51% rate in the 2,371 patients in the control arm, a statistically significant difference. This meant that the number needed to treat with dapagliflozin was 14 patients to produce one additional patient with at least a 5-point KCCQ improvement compared with controls, a “very small” number needed to treat, Dr. Kosiborod said in an interview.
Addition of the KCCQ to the panel of assessments that patients underwent during DAPA-HF reflected an evolved approach to measuring efficacy outcomes in clinical trials by including patient-reported outcomes. Earlier in 2019, the Food and Drug Administration released draft guidance for heart failure drug development that explicitly called for efficacy endpoints in pivotal studies that measure how patients feel and function, and stating that these endpoints can be the basis for new drug approvals.
“To many patients, how they feel matters as much if not more than how long they live,” Dr. Kosiborod noted. The goals of heart failure treatments are not only to extend survival and reduced hospitalizations, but also to improve symptoms, function, and quality of life, he said.
“There is a lot of interest now in having outcomes in heart failure trials that are more meaningful to patients, like feeling better and being able to do more,” noted Dr. Walsh.
The DAPA-HF results also showed that patients had similar rates of reduction in death, heart failure hospitalization, or urgent clinical visits, regardless of how severely they were affected by their heart failure when they began dapagliflozin treatment. The researchers ran an analysis that divided the entire trial population into tertiles based on their KCCQ score on entering the study. Patients in the most severely-affected tertile had a 30% cut in their rate of death or acute heart failure exacerbation on dapagliflozin compared with placebo, while patients in the tertile with the mildest symptoms at baseline had a 38% reduction in their primary outcome incidence compared with controls who received placebo. Concurrently with Dr. Kosiborod’s report, the results appeared in an article online (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044138).
Outcomes by age
Not surprisingly in DAPA-HF, the older patients were, the sicker, Dr. McMurray observed. Of the study’s 1,149 patients (24% of the study cohort) who were at least 75 years old, 62% had chronic kidney disease, compared with a 14% prevalence among the 636 patients younger than age 55. The 75-and-older group showed a steeper, 32% decline in incidence of the primary endpoint – a composite of cardiovascular (CV) death, HF hospitalization, or urgent HF visit requiring intravenous therapy – than in the other studied age groups: a 24% decline in those 65-74 years old, a 29% cut in those 55-64 years old, and a 13% drop in patients younger than 55 years old.
In addition, patients aged 75 years or greater were just as likely as the overall group to show at least a 5-point improvement in their KCCQ Total Symptom Score on dapagliflozin, as well as about the same reduced rate of deterioration compared with placebo as tracked with the KCCQ.
Patients “got as much benefit in terms of symptoms as well as morbidity and mortality,” Dr. McMurray concluded. Concurrently with the meeting report the results appeared in an article online (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044133).
“These data are of critical importance, as improving patient-reported outcomes in heart failure, especially in highly symptomatic patients, is an important goal in drug development,” G. Michael Felker, MD, wrote in an editorial accompanying the two published analyses (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044578). These new analyses also highlight another attractive feature of dapagliflozin and, apparently, the entire class of SGLT2 inhibitors: They “ ‘play well with others’ when it comes to overlapping intolerances that often limit (either in reality or in perception) optimization of GDMT [guideline-directed medical therapy]. Although SGLT2 inhibitor therapy may lead to volume depletion and require adjustment of diuretics, the SGLT2 inhibitors generally lack some of the other dose-limiting adverse effects (such as renal dysfunction, hyperkalemia, and hypotension) that can make aggressive up-titration of GDMT problematic, particularly in older patients or those with more advanced disease,“ wrote Dr. Felker, professor of medicine at Duke University in Durham, N.C. “We stand at the beginning of a new era of ‘quadruple therapy’ for HFrEF with beta-blockers, an angiotensin receptor neprilysin inhibitor, mineralocorticoid receptor antagonists, and SGLT2 inhibitors,” he concluded.
A version of this article also appears on Medscape.com
PHILADELPHIA – The substantial benefits from adding dapagliflozin to guideline-directed medical therapy for patients with heart failure with reduced ejection fraction enrolled in the DAPA-HF trial applied to patients regardless of their age or baseline health status, a pair of new post hoc analyses suggest.
These findings emerged a day after a report that more fully delineated dapagliflozin’s consistent safety and efficacy in patients with heart failure with reduced ejection fraction (HFrEF) regardless of whether they also had type 2 diabetes. One of the new, post hoc analyses reported at the American Heart Association scientific sessions suggested that even the most elderly enrolled patients, 75 years and older, had a similar cut in mortality and acute heart failure exacerbations, compared with younger patients. A second post hoc analysis indicated that patients with severe heart failure symptoms at entry into the trial received about as much benefit from the addition of dapagliflozin as did patients with mild baseline symptoms, measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ).
The primary results from the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, first reported in August 2019, showed that among more than 4,700 patients with HFrEF randomized to receive the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) on top of standard HFrEF medications or placebo, those who received dapagliflozin had a statistically significant, 26% decrease in their incidence of the primary study endpoint over a median 18 months, regardless of diabetes status (N Engl J Med. 2019 Nov 21;381[21]:1995-2008).
“These benefits were entirely consistent across the range of ages studied,” extending from patients younger than 55 years to those older than 75 years, John McMurray, MD, said at the meeting. “In many parts of the world, particularly North America and Western Europe, we have an increasingly elderly population. Many patients with heart failure are much older than in clinical trials,” he said.
“The thing of concern is whether elderly patients get as much benefit and tolerate treatment as well as younger patients,” said Dr. McMurray, professor of medical cardiology at the University of Glasgow.
“Dapagliflozin worked across all ages, including some very elderly patients enrolled in the trial,” said Mary Norine Walsh, MD, medical director of the heart failure and transplant program at St. Vincent Heart Center of Indiana in Indianapolis. “Many trials have not looked at age like this. I hope this is a new way to analyze trials to produce more information that can help patients,” she said in an interview.
Quality-of-life outcomes
The other new, post hoc analysis showed that patients with severe HF symptoms at entry into the trial received about as much benefit from the addition of dapagliflozin as did patients with milder baseline symptoms and less impaired function, measured by the KCCQ. Dapagliflozin treatment “improved cardiovascular death and worsening heart failure to a similar extent across the entire range of KCCQ at baseline,” Mikhail N. Kosiborod, MD, said in a separate talk at the meeting. In addition, dapagliflozin treatment increased the rate of small, moderate, and large clinically meaningful improvements in patients’ KCCQ scores across all key domains of the metric, which scores symptom frequency and severity, physical and social limitations, and quality of life, said Dr. Kosiborod, a cardiologist and professor of medicine at the University of Missouri–Kansas City.
After the first 8 months of treatment in the DAPA-HF trial, 58% of the 2,373 patients who received dapagliflozin had a clinically meaningful improvement in their total KCCQ symptom score of at least 5 points, compared with a 51% rate in the 2,371 patients in the control arm, a statistically significant difference. This meant that the number needed to treat with dapagliflozin was 14 patients to produce one additional patient with at least a 5-point KCCQ improvement compared with controls, a “very small” number needed to treat, Dr. Kosiborod said in an interview.
Addition of the KCCQ to the panel of assessments that patients underwent during DAPA-HF reflected an evolved approach to measuring efficacy outcomes in clinical trials by including patient-reported outcomes. Earlier in 2019, the Food and Drug Administration released draft guidance for heart failure drug development that explicitly called for efficacy endpoints in pivotal studies that measure how patients feel and function, and stating that these endpoints can be the basis for new drug approvals.
“To many patients, how they feel matters as much if not more than how long they live,” Dr. Kosiborod noted. The goals of heart failure treatments are not only to extend survival and reduced hospitalizations, but also to improve symptoms, function, and quality of life, he said.
“There is a lot of interest now in having outcomes in heart failure trials that are more meaningful to patients, like feeling better and being able to do more,” noted Dr. Walsh.
The DAPA-HF results also showed that patients had similar rates of reduction in death, heart failure hospitalization, or urgent clinical visits, regardless of how severely they were affected by their heart failure when they began dapagliflozin treatment. The researchers ran an analysis that divided the entire trial population into tertiles based on their KCCQ score on entering the study. Patients in the most severely-affected tertile had a 30% cut in their rate of death or acute heart failure exacerbation on dapagliflozin compared with placebo, while patients in the tertile with the mildest symptoms at baseline had a 38% reduction in their primary outcome incidence compared with controls who received placebo. Concurrently with Dr. Kosiborod’s report, the results appeared in an article online (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044138).
Outcomes by age
Not surprisingly in DAPA-HF, the older patients were, the sicker, Dr. McMurray observed. Of the study’s 1,149 patients (24% of the study cohort) who were at least 75 years old, 62% had chronic kidney disease, compared with a 14% prevalence among the 636 patients younger than age 55. The 75-and-older group showed a steeper, 32% decline in incidence of the primary endpoint – a composite of cardiovascular (CV) death, HF hospitalization, or urgent HF visit requiring intravenous therapy – than in the other studied age groups: a 24% decline in those 65-74 years old, a 29% cut in those 55-64 years old, and a 13% drop in patients younger than 55 years old.
In addition, patients aged 75 years or greater were just as likely as the overall group to show at least a 5-point improvement in their KCCQ Total Symptom Score on dapagliflozin, as well as about the same reduced rate of deterioration compared with placebo as tracked with the KCCQ.
Patients “got as much benefit in terms of symptoms as well as morbidity and mortality,” Dr. McMurray concluded. Concurrently with the meeting report the results appeared in an article online (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044133).
“These data are of critical importance, as improving patient-reported outcomes in heart failure, especially in highly symptomatic patients, is an important goal in drug development,” G. Michael Felker, MD, wrote in an editorial accompanying the two published analyses (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044578). These new analyses also highlight another attractive feature of dapagliflozin and, apparently, the entire class of SGLT2 inhibitors: They “ ‘play well with others’ when it comes to overlapping intolerances that often limit (either in reality or in perception) optimization of GDMT [guideline-directed medical therapy]. Although SGLT2 inhibitor therapy may lead to volume depletion and require adjustment of diuretics, the SGLT2 inhibitors generally lack some of the other dose-limiting adverse effects (such as renal dysfunction, hyperkalemia, and hypotension) that can make aggressive up-titration of GDMT problematic, particularly in older patients or those with more advanced disease,“ wrote Dr. Felker, professor of medicine at Duke University in Durham, N.C. “We stand at the beginning of a new era of ‘quadruple therapy’ for HFrEF with beta-blockers, an angiotensin receptor neprilysin inhibitor, mineralocorticoid receptor antagonists, and SGLT2 inhibitors,” he concluded.
A version of this article also appears on Medscape.com
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Colchicine cut post-MI CVD events
PHILADELPHIA – The proof of concept shown by the CANTOS study in 2017 that an anti-inflammatory drug could cut the incidence of cardiovascular events has now been replicated in a study with more than 4,700 post-MI patients who received the much more affordable oral anti-inflammatory drug colchicine.
Daily treatment with a single, 0.5-mg/day colchicine tablet cut cardiovascular disease events by a statistically significant 23%, compared with placebo patients during nearly 20 months on treatment when colchicine was added on top of a regimen that included aspirin, a second antiplatelet drug, a statin, and in many patients a beta-blocking drug, Jean-Claude Tardif, MD, said at the American Heart Association scientific sessions.
Adding colchicine to the treatment of patients within 30 days of having a MI led to an absolute reduction in the study’s primary endpoint of 1.6% during a median 19.6 months on treatment. In a secondary analysis that looked at total cardiovascular events and not just first events, adding colchicine to background therapy was associated with a relative 34% decline, said Dr. Tardif, professor of medicine at the University of Montreal and director of the Research Centre at the Montreal Heart Institute. In addition to his report at the meeting, the results also appeared concurrently in an article published online (N Engl J Med. 2019 Nov 16. doi: 10.1056/NEJMoa1912388).
The dramatic efficacy and overall safety shown by colchicine in COLCOT (Colchicine Cardiovascular Outcomes Trial) appeared to replicate the benefit seen with the relatively expensive monoclonal antibody canakinumab (Ilaris) in CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study), where a canakinumab injection every 3 months led to a 15% reduction in the incidence of cardiovascular events, compared with placebo, during a median 3.7 years of follow-up in a study with just over 10,000 post-MI patients (N Engl J Med. 2017 Sep 21;377[12]:1119-31).
“One of the limitations of CANTOS was that canakinumab is a very expensive, injectable drug. We followed in the footsteps of CANTOS with a less expensive, oral drug,” Dr. Tardif explained during a press briefing. “Colchicine is a known, potent anti-inflammatory drug,” and as of November 2019, the average U.S. cost of a 30-day supply of 0.6-mg capsules was $147. The colchicine formulation used in COLCOT delivered a 0.5-mg daily dose to patients, a formulation that’s not currently on the U.S. market.
“Having a safe drug that’s easily available; it will be hard to hold this one back,” commented Donald M. Lloyd-Jones, MD, professor and chairman of preventive medicine at Northwestern University in Chicago. “What the guidelines will need to wrestle with is there are five drugs” already recommended to use after an MI; “is colchicine number six?” The existing guideline-directed drugs for post-MI patients include aspirin, a second antiplatelet agent, a statin, a beta-blocker, and an angiotensin-converting enzyme inhibitor, Dr. Lloyd-Jones noted. The incremental benefit from adding colchicine to background regimen was “modest, but statistically significant,” he said, and “importantly, this was not an industry-sponsored trial.” Dr. Lloyd-Jones said that he has recently heard from a patient of his in the Chicago area who takes colchicine for gout that the monthly cost for the drug has risen to as high as $270. By comparison, the price in Montreal is less than $9/month, Dr. Tardif said.
COLCOT enrolled 4,745 patients at a median of about 13.5 days following an acute MI at 167 centers in 12 countries. The study’s primary endpoint was the combination of death from cardiovascular causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization in a time-to-event analysis. The combined endpoint occurred in 5.5% of the patients on colchicine and 7.1% of those on placebo during a median of nearly 20 months on treatment. The adverse effects data showed generally similarly rates among patients on colchicine and in the control group, including their rates of gastrointestinal effects. The one exception was the rate of serious pneumonias, which were more than double in the colchicine recipients, a statistically significant difference.
COLCOT received no commercial support. Dr. Tardif has received honoraria from Amarin, DalCor, Sanofi, and Servier; he has an ownership interest in DalCor; and he has received research funding from Amarin, AstraZeneca, DalCor, Esperion, Ionis, RegenxBio, Sanofi, and Servier. Dr. Lloyd-Jones had no disclosures.
SOURCE: Tardif J-C et al. AHA 2019, Abstract.
The landmark results from COLCOT confirm that managing inflammation reduces cardiovascular risk, and the results successfully repurpose colchicine, a broadly available and relatively safe branded generic drug for a new application. Colchicine was also generally well tolerated for measured adverse effects, but we do not know whether unmeasured adverse effects may cause discontinuations that would limit long-term adherence. Clinicians should exercise caution using colchicine in patients with chronic kidney disease because of its renal clearance, and the 0.5-mg daily dosage used in COLCOT does not exactly align with the 0.6-mg colchicine formulation that’s available on the U.S. market.
The adverse effect profile of colchicine showed a concerning, statistically significant increased rate of serious pneumonia infections, which occurred at a 0.9% rate among patients on colchicine and a 0.4% rate among patients on placebo. But the patients on colchicine showed no excess of fatal infections or episodes of septic shock. This increase in the rate of serious pneumonias may be the price paid for using an anti-inflammatory drug in these patients.
A similar, earlier study of methotrexate designed to follow on the CANTOS findings with a less expensive and easier to administer drug failed to show significant benefit. CIRT (Cardiovascular inflammation reduction trial) enrolled 4,786 patients with either a prior MI or multivessel coronary disease plus diabetes or metabolic syndrome, and the CIRT results highlight that not all anti-inflammatory drugs work the same way or have similar effects on cardiovascular disease. The COLCOT findings need replication, and three large studies now in progress are also assessing colchicine in patients with cardiovascular disease. Cardiologists will need to learn how to use colchicine, but the COLCOT results are promising and show an overall low level of adverse effects.
The COLCOT findings followed a prior report from a study without a placebo control that showed a rather dramatic, 67% reduction in cardiovascular events with colchicine treatment in 532 patients with stable coronary disease (J Amer Coll Cardiol. 2013 Jan 29;61[4]:404-10).
Aruna D. Pradhan, MD , is a medical epidemiologist at Brigham and Women’s Hospital in Boston. She has received research funding from Kowa. She made these comments as designated discussant for the COLCOT report.
The landmark results from COLCOT confirm that managing inflammation reduces cardiovascular risk, and the results successfully repurpose colchicine, a broadly available and relatively safe branded generic drug for a new application. Colchicine was also generally well tolerated for measured adverse effects, but we do not know whether unmeasured adverse effects may cause discontinuations that would limit long-term adherence. Clinicians should exercise caution using colchicine in patients with chronic kidney disease because of its renal clearance, and the 0.5-mg daily dosage used in COLCOT does not exactly align with the 0.6-mg colchicine formulation that’s available on the U.S. market.
The adverse effect profile of colchicine showed a concerning, statistically significant increased rate of serious pneumonia infections, which occurred at a 0.9% rate among patients on colchicine and a 0.4% rate among patients on placebo. But the patients on colchicine showed no excess of fatal infections or episodes of septic shock. This increase in the rate of serious pneumonias may be the price paid for using an anti-inflammatory drug in these patients.
A similar, earlier study of methotrexate designed to follow on the CANTOS findings with a less expensive and easier to administer drug failed to show significant benefit. CIRT (Cardiovascular inflammation reduction trial) enrolled 4,786 patients with either a prior MI or multivessel coronary disease plus diabetes or metabolic syndrome, and the CIRT results highlight that not all anti-inflammatory drugs work the same way or have similar effects on cardiovascular disease. The COLCOT findings need replication, and three large studies now in progress are also assessing colchicine in patients with cardiovascular disease. Cardiologists will need to learn how to use colchicine, but the COLCOT results are promising and show an overall low level of adverse effects.
The COLCOT findings followed a prior report from a study without a placebo control that showed a rather dramatic, 67% reduction in cardiovascular events with colchicine treatment in 532 patients with stable coronary disease (J Amer Coll Cardiol. 2013 Jan 29;61[4]:404-10).
Aruna D. Pradhan, MD , is a medical epidemiologist at Brigham and Women’s Hospital in Boston. She has received research funding from Kowa. She made these comments as designated discussant for the COLCOT report.
The landmark results from COLCOT confirm that managing inflammation reduces cardiovascular risk, and the results successfully repurpose colchicine, a broadly available and relatively safe branded generic drug for a new application. Colchicine was also generally well tolerated for measured adverse effects, but we do not know whether unmeasured adverse effects may cause discontinuations that would limit long-term adherence. Clinicians should exercise caution using colchicine in patients with chronic kidney disease because of its renal clearance, and the 0.5-mg daily dosage used in COLCOT does not exactly align with the 0.6-mg colchicine formulation that’s available on the U.S. market.
The adverse effect profile of colchicine showed a concerning, statistically significant increased rate of serious pneumonia infections, which occurred at a 0.9% rate among patients on colchicine and a 0.4% rate among patients on placebo. But the patients on colchicine showed no excess of fatal infections or episodes of septic shock. This increase in the rate of serious pneumonias may be the price paid for using an anti-inflammatory drug in these patients.
A similar, earlier study of methotrexate designed to follow on the CANTOS findings with a less expensive and easier to administer drug failed to show significant benefit. CIRT (Cardiovascular inflammation reduction trial) enrolled 4,786 patients with either a prior MI or multivessel coronary disease plus diabetes or metabolic syndrome, and the CIRT results highlight that not all anti-inflammatory drugs work the same way or have similar effects on cardiovascular disease. The COLCOT findings need replication, and three large studies now in progress are also assessing colchicine in patients with cardiovascular disease. Cardiologists will need to learn how to use colchicine, but the COLCOT results are promising and show an overall low level of adverse effects.
The COLCOT findings followed a prior report from a study without a placebo control that showed a rather dramatic, 67% reduction in cardiovascular events with colchicine treatment in 532 patients with stable coronary disease (J Amer Coll Cardiol. 2013 Jan 29;61[4]:404-10).
Aruna D. Pradhan, MD , is a medical epidemiologist at Brigham and Women’s Hospital in Boston. She has received research funding from Kowa. She made these comments as designated discussant for the COLCOT report.
PHILADELPHIA – The proof of concept shown by the CANTOS study in 2017 that an anti-inflammatory drug could cut the incidence of cardiovascular events has now been replicated in a study with more than 4,700 post-MI patients who received the much more affordable oral anti-inflammatory drug colchicine.
Daily treatment with a single, 0.5-mg/day colchicine tablet cut cardiovascular disease events by a statistically significant 23%, compared with placebo patients during nearly 20 months on treatment when colchicine was added on top of a regimen that included aspirin, a second antiplatelet drug, a statin, and in many patients a beta-blocking drug, Jean-Claude Tardif, MD, said at the American Heart Association scientific sessions.
Adding colchicine to the treatment of patients within 30 days of having a MI led to an absolute reduction in the study’s primary endpoint of 1.6% during a median 19.6 months on treatment. In a secondary analysis that looked at total cardiovascular events and not just first events, adding colchicine to background therapy was associated with a relative 34% decline, said Dr. Tardif, professor of medicine at the University of Montreal and director of the Research Centre at the Montreal Heart Institute. In addition to his report at the meeting, the results also appeared concurrently in an article published online (N Engl J Med. 2019 Nov 16. doi: 10.1056/NEJMoa1912388).
The dramatic efficacy and overall safety shown by colchicine in COLCOT (Colchicine Cardiovascular Outcomes Trial) appeared to replicate the benefit seen with the relatively expensive monoclonal antibody canakinumab (Ilaris) in CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study), where a canakinumab injection every 3 months led to a 15% reduction in the incidence of cardiovascular events, compared with placebo, during a median 3.7 years of follow-up in a study with just over 10,000 post-MI patients (N Engl J Med. 2017 Sep 21;377[12]:1119-31).
“One of the limitations of CANTOS was that canakinumab is a very expensive, injectable drug. We followed in the footsteps of CANTOS with a less expensive, oral drug,” Dr. Tardif explained during a press briefing. “Colchicine is a known, potent anti-inflammatory drug,” and as of November 2019, the average U.S. cost of a 30-day supply of 0.6-mg capsules was $147. The colchicine formulation used in COLCOT delivered a 0.5-mg daily dose to patients, a formulation that’s not currently on the U.S. market.
“Having a safe drug that’s easily available; it will be hard to hold this one back,” commented Donald M. Lloyd-Jones, MD, professor and chairman of preventive medicine at Northwestern University in Chicago. “What the guidelines will need to wrestle with is there are five drugs” already recommended to use after an MI; “is colchicine number six?” The existing guideline-directed drugs for post-MI patients include aspirin, a second antiplatelet agent, a statin, a beta-blocker, and an angiotensin-converting enzyme inhibitor, Dr. Lloyd-Jones noted. The incremental benefit from adding colchicine to background regimen was “modest, but statistically significant,” he said, and “importantly, this was not an industry-sponsored trial.” Dr. Lloyd-Jones said that he has recently heard from a patient of his in the Chicago area who takes colchicine for gout that the monthly cost for the drug has risen to as high as $270. By comparison, the price in Montreal is less than $9/month, Dr. Tardif said.
COLCOT enrolled 4,745 patients at a median of about 13.5 days following an acute MI at 167 centers in 12 countries. The study’s primary endpoint was the combination of death from cardiovascular causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization in a time-to-event analysis. The combined endpoint occurred in 5.5% of the patients on colchicine and 7.1% of those on placebo during a median of nearly 20 months on treatment. The adverse effects data showed generally similarly rates among patients on colchicine and in the control group, including their rates of gastrointestinal effects. The one exception was the rate of serious pneumonias, which were more than double in the colchicine recipients, a statistically significant difference.
COLCOT received no commercial support. Dr. Tardif has received honoraria from Amarin, DalCor, Sanofi, and Servier; he has an ownership interest in DalCor; and he has received research funding from Amarin, AstraZeneca, DalCor, Esperion, Ionis, RegenxBio, Sanofi, and Servier. Dr. Lloyd-Jones had no disclosures.
SOURCE: Tardif J-C et al. AHA 2019, Abstract.
PHILADELPHIA – The proof of concept shown by the CANTOS study in 2017 that an anti-inflammatory drug could cut the incidence of cardiovascular events has now been replicated in a study with more than 4,700 post-MI patients who received the much more affordable oral anti-inflammatory drug colchicine.
Daily treatment with a single, 0.5-mg/day colchicine tablet cut cardiovascular disease events by a statistically significant 23%, compared with placebo patients during nearly 20 months on treatment when colchicine was added on top of a regimen that included aspirin, a second antiplatelet drug, a statin, and in many patients a beta-blocking drug, Jean-Claude Tardif, MD, said at the American Heart Association scientific sessions.
Adding colchicine to the treatment of patients within 30 days of having a MI led to an absolute reduction in the study’s primary endpoint of 1.6% during a median 19.6 months on treatment. In a secondary analysis that looked at total cardiovascular events and not just first events, adding colchicine to background therapy was associated with a relative 34% decline, said Dr. Tardif, professor of medicine at the University of Montreal and director of the Research Centre at the Montreal Heart Institute. In addition to his report at the meeting, the results also appeared concurrently in an article published online (N Engl J Med. 2019 Nov 16. doi: 10.1056/NEJMoa1912388).
The dramatic efficacy and overall safety shown by colchicine in COLCOT (Colchicine Cardiovascular Outcomes Trial) appeared to replicate the benefit seen with the relatively expensive monoclonal antibody canakinumab (Ilaris) in CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study), where a canakinumab injection every 3 months led to a 15% reduction in the incidence of cardiovascular events, compared with placebo, during a median 3.7 years of follow-up in a study with just over 10,000 post-MI patients (N Engl J Med. 2017 Sep 21;377[12]:1119-31).
“One of the limitations of CANTOS was that canakinumab is a very expensive, injectable drug. We followed in the footsteps of CANTOS with a less expensive, oral drug,” Dr. Tardif explained during a press briefing. “Colchicine is a known, potent anti-inflammatory drug,” and as of November 2019, the average U.S. cost of a 30-day supply of 0.6-mg capsules was $147. The colchicine formulation used in COLCOT delivered a 0.5-mg daily dose to patients, a formulation that’s not currently on the U.S. market.
“Having a safe drug that’s easily available; it will be hard to hold this one back,” commented Donald M. Lloyd-Jones, MD, professor and chairman of preventive medicine at Northwestern University in Chicago. “What the guidelines will need to wrestle with is there are five drugs” already recommended to use after an MI; “is colchicine number six?” The existing guideline-directed drugs for post-MI patients include aspirin, a second antiplatelet agent, a statin, a beta-blocker, and an angiotensin-converting enzyme inhibitor, Dr. Lloyd-Jones noted. The incremental benefit from adding colchicine to background regimen was “modest, but statistically significant,” he said, and “importantly, this was not an industry-sponsored trial.” Dr. Lloyd-Jones said that he has recently heard from a patient of his in the Chicago area who takes colchicine for gout that the monthly cost for the drug has risen to as high as $270. By comparison, the price in Montreal is less than $9/month, Dr. Tardif said.
COLCOT enrolled 4,745 patients at a median of about 13.5 days following an acute MI at 167 centers in 12 countries. The study’s primary endpoint was the combination of death from cardiovascular causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization in a time-to-event analysis. The combined endpoint occurred in 5.5% of the patients on colchicine and 7.1% of those on placebo during a median of nearly 20 months on treatment. The adverse effects data showed generally similarly rates among patients on colchicine and in the control group, including their rates of gastrointestinal effects. The one exception was the rate of serious pneumonias, which were more than double in the colchicine recipients, a statistically significant difference.
COLCOT received no commercial support. Dr. Tardif has received honoraria from Amarin, DalCor, Sanofi, and Servier; he has an ownership interest in DalCor; and he has received research funding from Amarin, AstraZeneca, DalCor, Esperion, Ionis, RegenxBio, Sanofi, and Servier. Dr. Lloyd-Jones had no disclosures.
SOURCE: Tardif J-C et al. AHA 2019, Abstract.
REPORTING FROM AHA 2019
Treating LDL to below 70 reduces recurrent stroke
PHILADELPHIA – Treating patients to a lower LDL target after an ischemic stroke of atherosclerotic origin resulted in fewer recurrent strokes or major cardiovascular events, compared with a higher LDL goal, even though the international trial was stopped early because of lack of funding.
“In the Treat Stroke to Target [TST] trial we showed that the group of patients with an atherosclerotic stroke achieving an LDL cholesterol of less than 70 mg/dL had 22% less recurrent ischemic stroke or other major vascular events than the group achieving a LDL cholesterol between 90 and 110 mg/dL,” lead author Pierre Amarenco, MD, chairman of the department of neurology and the stroke center at Bichat Hospital in Paris, said in an interview.
“We avoided more than one in recurrence in five,” he added.
The findings of the investigator-initiated trial were reported during a late-breaking research session at the American Heart Association scientific sessions and simultaneously published online Nov. 18 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1910355).
Discussant Mitchell S.V. Elkind, MD, president-elect of the American Heart Association, called the TST findings “practice confirming” of a strategy many cardiologists already follow for stroke patients.
“The TST study is only the second trial that was done in neurology for stroke prevention using statins and lipid-lowering therapy, and that’s what makes it a hopeful and real advance,” he said in an interview.
To achieve the LDL-lowering goal, two-thirds of patients received a high-dose statin therapy while the remainder received both high-dose statin and ezetimibe (Zetia, Merck). There were no significant increases in intracranial hemorrhage observed between lower- and higher-target groups.
“Now guidelines should move to recommending a target LDL cholesterol of less than 70 mg/dL in all patients with a proven ischemic stroke of atherosclerotic origin,” said Dr. Amarenco, who is also a professor of neurology at Denis Diderot Paris University.
Rare lipid study following stroke
American Heart Association/American Stroke Association guidelines recommend intense statin therapy after an atherothrombotic stroke “but no target level is given to the practitioners,” Dr. Amarenco said. “In reality, most patients receive a reduced dose of statin.”
For example, despite 70% of patients receiving a statin, the average LDL cholesterol level was 92 mg/dL in a real-world registry.
The TST trial is the first major study to evaluate treating to target LDL levels in the ischemic stroke population since the SPARCL trial in 2006. SPARCL was the first randomized, controlled clinical trial to evaluate whether daily statin therapy could reduce the risk of stroke in patients who had suffered a stroke or transient ischemic attack (TIA).
SPARCL demonstrated a 16% risk reduction with atorvastatin 80 mg daily versus placebo, and further risk reduction of 33% among those with carotid stenosis, over 5 years. There was some concern about safety for a time; post-hoc analysis showed what appeared to be an increased risk for intracranial hemorrhage with statin treatment. Subsequent analyses seemed to suggest the finding may have been a chance one, however.
For the TST study, Dr. Amarenco and colleagues enrolled participants between March 2010 and December 2018 at one of 61 centers in France. In 2015, the study expanded to include 16 sites in South Korea.
Investigators evaluated participants after an ischemic stroke or a TIA with evidence of atherosclerosis. Blood pressure, smoking cessation, and diabetes were well controlled, he said.
Dr. Amarenco and colleagues randomly assigned 1,430 participants to the low–LDL cholesterol target group, less than 70 mg/dL, and another 1,430 to a high-LDL group with a target of 100 mg/dL.
Assessments were every 6 months and up to 1 year after the last patient joined the study.
Treatment with any available statin on the market was allowed. Ezetimibe could be added on top of statin therapy as necessary. A total of 55% were statin naive at study entry.
Study stopped early
The trial was stopped in May 2019 after allocated funds ran out. At this point, researchers had 277 events to analyze, although their initial goal was to reach 385.
The primary endpoint of this event-driven trial was a composite of nonfatal stroke, nonfatal MI, and unstable angina followed by urgent coronary revascularization; TIA followed by urgent carotid revascularization; or cardiovascular death, including sudden deaths.
The endpoint was experienced by 8.5% of participants in the lower-target group versus 10.9% of those in the higher-target group. This translated to a 22% relative risk reduction (adjusted hazard ratio, 0.78; 95% confidence interval, 0.68-0.98; P =.04).
A total of 86% of participants had an ischemic stroke confirmed by brain MRI or CT scan. In this group, the relative risk reduction was 33% – “meaning that we could avoid one-third of recurrent major vascular events,” Dr. Amarenco said.
Furthermore, targeting the lower LDL levels was associated with a relative risk reduction of 40% among those with diabetes.
Secondary outcomes not significant
The investigators used hierarchical testing to compare two outcomes at a time in a prespecified order. They planned to continue this strategy until a comparison emerged as nonsignificant.
This occurred right away when their first composite secondary endpoint comparison between nonfatal MI and urgent revascularization was found to be not significantly different between groups (P = .12).
The early ending “weakened the results of the trial, and the results should be taken with caution because of that,” Dr. Amarenco said.
In addition, the number of hemorrhagic strokes did not differ significantly between groups. There were 18 of these events in the lower-target group and 13 in the higher-target cohort.
That numerical increase in intracranial hemorrhage was “driven by the Korean patients. … and that is something we will report soon,” Dr. Amarenco said.
Interestingly, the researchers also evaluated how much time participants spent within the target LDL cholesterol range, averaged by study site. They found that 53% of the lower–LDL target group, for example, was in the therapeutic range on average during the study.
When Dr. Amarenco and colleagues looked at participants who managed to spend 50%-100% in the target range, the relative risk reduction was 36%.
“So we can hypothesize that, if we had used a more potent drug like PCSK9 inhibitors to be closer to 100% in the therapeutic range, we may have had a greater effect size,” Dr. Amarenco said.
“Our results suggest that LDL cholesterol is causally related to atherosclerosis and confirm that the lower the LDL cholesterol the better,” Dr. Amarenco said.
“Future trials should explore the efficacy and safety of lowering LDL cholesterol to very low levels such as less than 55 mg/dL or even 30 mg/dL (as obtained in the FOURIER trial) by using PCSK9 inhibitors or equivalent in patients with an ischemic stroke due to atherosclerotic disease,” Dr. Amarenco said.
‘Practice-confirming’ findings
The findings are also in line with secondary analyses of the WASID (Neurology. 1995 Aug;45[8]:1488-93) and SAMMPRIS trials, which should dispel some concerns that persist about taking LDL to such low levels that it increases risk of intracerebral hemorrhage, Dr. Amarenco noted.
However, TST, he said, didn’t provide clear answers on what specific subgroups of patients with a stroke history would benefit from aggressive lipid lowering.
“What is stroke without atherosclerotic disease?” he said. “Some people say small-vessel disease is also a form of atherosclerosis, and most patients with atrial fibrillation, which is increasingly recognized as a cause of stroke, are also going to have atherosclerosis of the heart as well as the brain and blood vessels.
“Many, many stroke patients will fall into this category,” Dr. Elkind said, “and the question is, should they be treated more aggressively with lipid lowering?”
“The results of this study fit pretty nicely into the rubric of the AHA cholesterol guidelines,” said Donald M. Lloyd-Jones, MD, chairman, department of preventive medicine at Northwestern University Feinberg School of Medicine, Chicago, and chair of the AHA’s 2019 Council on Scientific Sessions Programming. Dr. Lloyd-Jones was also a member of the guideline committee.
Stroke patients are not “garden variety coronary patients,” he said. “The concern about intracerebral hemorrhage continues to be something that we wonder about: Should we be driving our stroke patients as low as our coronary patients? I think these data will certainly help us.”
Consideration for future guidelines
The study would have been more helpful if it provided more detail about the treatment regimens used, Jennifer Robinson, MD, director of the prevention intervention center, department of epidemiology, University of Iowa, said in an interview.
“What was the dose intensity of statins the patients were on?” Dr. Robinson said. “Part of our struggle has been to convince people to use high-intensity statins – get the maximum from statins that are generic now and cost saving in even very low-risk primary prevention patients.”
She said that a third of patients in TST also took ezetimibe with the statin “makes sense” because of its generic status.
Nonetheless, Dr. Robinson said, TST adds to the evidence that LDL of 100 mg/dL is not good enough, that high-intensity statin therapy is superior to a moderate regimen and that adding a nonstatin – ezetimibe in TST – can derive added benefit.
The TST findings may give guideline writers direction going forward, she said. “We really need to start thinking about the potential for net benefit from added therapy, whether it’s from intensifying LDL lowering, adding icosapent ethyl (Vascepa, Amarin), which seems to have remarkable benefits, or SGLT2 inhibitor,” she said.
“There are a lot of options,” Dr. Robinson said. “We need to have an outlook beyond just treating to target with what really is the best maximized accepted therapy.”
TST was funded primarily by French Government, but also with grants from Pfizer, Astra Zeneca and Merck. Dr. Amarenco disclosed that he is a consultant or advisor to Modest, Sanofi, Bristol-Myers Squibb, and Amgen; receives honoraria from Modest, Amgen, Kowa, Shing Poon, Kowa, Bayer, GSK, Fibrogen, and AstraZeneca. He also receives research grants from Pfizer, Astra Zeneca, Sanofi, BMS, Merck, Boston Scientific, and the French Government.
This article also appears on Medscape.com.
SOURCE: Amarenco P. ACC 2019, Late Breaking Science 6 session.
PHILADELPHIA – Treating patients to a lower LDL target after an ischemic stroke of atherosclerotic origin resulted in fewer recurrent strokes or major cardiovascular events, compared with a higher LDL goal, even though the international trial was stopped early because of lack of funding.
“In the Treat Stroke to Target [TST] trial we showed that the group of patients with an atherosclerotic stroke achieving an LDL cholesterol of less than 70 mg/dL had 22% less recurrent ischemic stroke or other major vascular events than the group achieving a LDL cholesterol between 90 and 110 mg/dL,” lead author Pierre Amarenco, MD, chairman of the department of neurology and the stroke center at Bichat Hospital in Paris, said in an interview.
“We avoided more than one in recurrence in five,” he added.
The findings of the investigator-initiated trial were reported during a late-breaking research session at the American Heart Association scientific sessions and simultaneously published online Nov. 18 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1910355).
Discussant Mitchell S.V. Elkind, MD, president-elect of the American Heart Association, called the TST findings “practice confirming” of a strategy many cardiologists already follow for stroke patients.
“The TST study is only the second trial that was done in neurology for stroke prevention using statins and lipid-lowering therapy, and that’s what makes it a hopeful and real advance,” he said in an interview.
To achieve the LDL-lowering goal, two-thirds of patients received a high-dose statin therapy while the remainder received both high-dose statin and ezetimibe (Zetia, Merck). There were no significant increases in intracranial hemorrhage observed between lower- and higher-target groups.
“Now guidelines should move to recommending a target LDL cholesterol of less than 70 mg/dL in all patients with a proven ischemic stroke of atherosclerotic origin,” said Dr. Amarenco, who is also a professor of neurology at Denis Diderot Paris University.
Rare lipid study following stroke
American Heart Association/American Stroke Association guidelines recommend intense statin therapy after an atherothrombotic stroke “but no target level is given to the practitioners,” Dr. Amarenco said. “In reality, most patients receive a reduced dose of statin.”
For example, despite 70% of patients receiving a statin, the average LDL cholesterol level was 92 mg/dL in a real-world registry.
The TST trial is the first major study to evaluate treating to target LDL levels in the ischemic stroke population since the SPARCL trial in 2006. SPARCL was the first randomized, controlled clinical trial to evaluate whether daily statin therapy could reduce the risk of stroke in patients who had suffered a stroke or transient ischemic attack (TIA).
SPARCL demonstrated a 16% risk reduction with atorvastatin 80 mg daily versus placebo, and further risk reduction of 33% among those with carotid stenosis, over 5 years. There was some concern about safety for a time; post-hoc analysis showed what appeared to be an increased risk for intracranial hemorrhage with statin treatment. Subsequent analyses seemed to suggest the finding may have been a chance one, however.
For the TST study, Dr. Amarenco and colleagues enrolled participants between March 2010 and December 2018 at one of 61 centers in France. In 2015, the study expanded to include 16 sites in South Korea.
Investigators evaluated participants after an ischemic stroke or a TIA with evidence of atherosclerosis. Blood pressure, smoking cessation, and diabetes were well controlled, he said.
Dr. Amarenco and colleagues randomly assigned 1,430 participants to the low–LDL cholesterol target group, less than 70 mg/dL, and another 1,430 to a high-LDL group with a target of 100 mg/dL.
Assessments were every 6 months and up to 1 year after the last patient joined the study.
Treatment with any available statin on the market was allowed. Ezetimibe could be added on top of statin therapy as necessary. A total of 55% were statin naive at study entry.
Study stopped early
The trial was stopped in May 2019 after allocated funds ran out. At this point, researchers had 277 events to analyze, although their initial goal was to reach 385.
The primary endpoint of this event-driven trial was a composite of nonfatal stroke, nonfatal MI, and unstable angina followed by urgent coronary revascularization; TIA followed by urgent carotid revascularization; or cardiovascular death, including sudden deaths.
The endpoint was experienced by 8.5% of participants in the lower-target group versus 10.9% of those in the higher-target group. This translated to a 22% relative risk reduction (adjusted hazard ratio, 0.78; 95% confidence interval, 0.68-0.98; P =.04).
A total of 86% of participants had an ischemic stroke confirmed by brain MRI or CT scan. In this group, the relative risk reduction was 33% – “meaning that we could avoid one-third of recurrent major vascular events,” Dr. Amarenco said.
Furthermore, targeting the lower LDL levels was associated with a relative risk reduction of 40% among those with diabetes.
Secondary outcomes not significant
The investigators used hierarchical testing to compare two outcomes at a time in a prespecified order. They planned to continue this strategy until a comparison emerged as nonsignificant.
This occurred right away when their first composite secondary endpoint comparison between nonfatal MI and urgent revascularization was found to be not significantly different between groups (P = .12).
The early ending “weakened the results of the trial, and the results should be taken with caution because of that,” Dr. Amarenco said.
In addition, the number of hemorrhagic strokes did not differ significantly between groups. There were 18 of these events in the lower-target group and 13 in the higher-target cohort.
That numerical increase in intracranial hemorrhage was “driven by the Korean patients. … and that is something we will report soon,” Dr. Amarenco said.
Interestingly, the researchers also evaluated how much time participants spent within the target LDL cholesterol range, averaged by study site. They found that 53% of the lower–LDL target group, for example, was in the therapeutic range on average during the study.
When Dr. Amarenco and colleagues looked at participants who managed to spend 50%-100% in the target range, the relative risk reduction was 36%.
“So we can hypothesize that, if we had used a more potent drug like PCSK9 inhibitors to be closer to 100% in the therapeutic range, we may have had a greater effect size,” Dr. Amarenco said.
“Our results suggest that LDL cholesterol is causally related to atherosclerosis and confirm that the lower the LDL cholesterol the better,” Dr. Amarenco said.
“Future trials should explore the efficacy and safety of lowering LDL cholesterol to very low levels such as less than 55 mg/dL or even 30 mg/dL (as obtained in the FOURIER trial) by using PCSK9 inhibitors or equivalent in patients with an ischemic stroke due to atherosclerotic disease,” Dr. Amarenco said.
‘Practice-confirming’ findings
The findings are also in line with secondary analyses of the WASID (Neurology. 1995 Aug;45[8]:1488-93) and SAMMPRIS trials, which should dispel some concerns that persist about taking LDL to such low levels that it increases risk of intracerebral hemorrhage, Dr. Amarenco noted.
However, TST, he said, didn’t provide clear answers on what specific subgroups of patients with a stroke history would benefit from aggressive lipid lowering.
“What is stroke without atherosclerotic disease?” he said. “Some people say small-vessel disease is also a form of atherosclerosis, and most patients with atrial fibrillation, which is increasingly recognized as a cause of stroke, are also going to have atherosclerosis of the heart as well as the brain and blood vessels.
“Many, many stroke patients will fall into this category,” Dr. Elkind said, “and the question is, should they be treated more aggressively with lipid lowering?”
“The results of this study fit pretty nicely into the rubric of the AHA cholesterol guidelines,” said Donald M. Lloyd-Jones, MD, chairman, department of preventive medicine at Northwestern University Feinberg School of Medicine, Chicago, and chair of the AHA’s 2019 Council on Scientific Sessions Programming. Dr. Lloyd-Jones was also a member of the guideline committee.
Stroke patients are not “garden variety coronary patients,” he said. “The concern about intracerebral hemorrhage continues to be something that we wonder about: Should we be driving our stroke patients as low as our coronary patients? I think these data will certainly help us.”
Consideration for future guidelines
The study would have been more helpful if it provided more detail about the treatment regimens used, Jennifer Robinson, MD, director of the prevention intervention center, department of epidemiology, University of Iowa, said in an interview.
“What was the dose intensity of statins the patients were on?” Dr. Robinson said. “Part of our struggle has been to convince people to use high-intensity statins – get the maximum from statins that are generic now and cost saving in even very low-risk primary prevention patients.”
She said that a third of patients in TST also took ezetimibe with the statin “makes sense” because of its generic status.
Nonetheless, Dr. Robinson said, TST adds to the evidence that LDL of 100 mg/dL is not good enough, that high-intensity statin therapy is superior to a moderate regimen and that adding a nonstatin – ezetimibe in TST – can derive added benefit.
The TST findings may give guideline writers direction going forward, she said. “We really need to start thinking about the potential for net benefit from added therapy, whether it’s from intensifying LDL lowering, adding icosapent ethyl (Vascepa, Amarin), which seems to have remarkable benefits, or SGLT2 inhibitor,” she said.
“There are a lot of options,” Dr. Robinson said. “We need to have an outlook beyond just treating to target with what really is the best maximized accepted therapy.”
TST was funded primarily by French Government, but also with grants from Pfizer, Astra Zeneca and Merck. Dr. Amarenco disclosed that he is a consultant or advisor to Modest, Sanofi, Bristol-Myers Squibb, and Amgen; receives honoraria from Modest, Amgen, Kowa, Shing Poon, Kowa, Bayer, GSK, Fibrogen, and AstraZeneca. He also receives research grants from Pfizer, Astra Zeneca, Sanofi, BMS, Merck, Boston Scientific, and the French Government.
This article also appears on Medscape.com.
SOURCE: Amarenco P. ACC 2019, Late Breaking Science 6 session.
PHILADELPHIA – Treating patients to a lower LDL target after an ischemic stroke of atherosclerotic origin resulted in fewer recurrent strokes or major cardiovascular events, compared with a higher LDL goal, even though the international trial was stopped early because of lack of funding.
“In the Treat Stroke to Target [TST] trial we showed that the group of patients with an atherosclerotic stroke achieving an LDL cholesterol of less than 70 mg/dL had 22% less recurrent ischemic stroke or other major vascular events than the group achieving a LDL cholesterol between 90 and 110 mg/dL,” lead author Pierre Amarenco, MD, chairman of the department of neurology and the stroke center at Bichat Hospital in Paris, said in an interview.
“We avoided more than one in recurrence in five,” he added.
The findings of the investigator-initiated trial were reported during a late-breaking research session at the American Heart Association scientific sessions and simultaneously published online Nov. 18 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1910355).
Discussant Mitchell S.V. Elkind, MD, president-elect of the American Heart Association, called the TST findings “practice confirming” of a strategy many cardiologists already follow for stroke patients.
“The TST study is only the second trial that was done in neurology for stroke prevention using statins and lipid-lowering therapy, and that’s what makes it a hopeful and real advance,” he said in an interview.
To achieve the LDL-lowering goal, two-thirds of patients received a high-dose statin therapy while the remainder received both high-dose statin and ezetimibe (Zetia, Merck). There were no significant increases in intracranial hemorrhage observed between lower- and higher-target groups.
“Now guidelines should move to recommending a target LDL cholesterol of less than 70 mg/dL in all patients with a proven ischemic stroke of atherosclerotic origin,” said Dr. Amarenco, who is also a professor of neurology at Denis Diderot Paris University.
Rare lipid study following stroke
American Heart Association/American Stroke Association guidelines recommend intense statin therapy after an atherothrombotic stroke “but no target level is given to the practitioners,” Dr. Amarenco said. “In reality, most patients receive a reduced dose of statin.”
For example, despite 70% of patients receiving a statin, the average LDL cholesterol level was 92 mg/dL in a real-world registry.
The TST trial is the first major study to evaluate treating to target LDL levels in the ischemic stroke population since the SPARCL trial in 2006. SPARCL was the first randomized, controlled clinical trial to evaluate whether daily statin therapy could reduce the risk of stroke in patients who had suffered a stroke or transient ischemic attack (TIA).
SPARCL demonstrated a 16% risk reduction with atorvastatin 80 mg daily versus placebo, and further risk reduction of 33% among those with carotid stenosis, over 5 years. There was some concern about safety for a time; post-hoc analysis showed what appeared to be an increased risk for intracranial hemorrhage with statin treatment. Subsequent analyses seemed to suggest the finding may have been a chance one, however.
For the TST study, Dr. Amarenco and colleagues enrolled participants between March 2010 and December 2018 at one of 61 centers in France. In 2015, the study expanded to include 16 sites in South Korea.
Investigators evaluated participants after an ischemic stroke or a TIA with evidence of atherosclerosis. Blood pressure, smoking cessation, and diabetes were well controlled, he said.
Dr. Amarenco and colleagues randomly assigned 1,430 participants to the low–LDL cholesterol target group, less than 70 mg/dL, and another 1,430 to a high-LDL group with a target of 100 mg/dL.
Assessments were every 6 months and up to 1 year after the last patient joined the study.
Treatment with any available statin on the market was allowed. Ezetimibe could be added on top of statin therapy as necessary. A total of 55% were statin naive at study entry.
Study stopped early
The trial was stopped in May 2019 after allocated funds ran out. At this point, researchers had 277 events to analyze, although their initial goal was to reach 385.
The primary endpoint of this event-driven trial was a composite of nonfatal stroke, nonfatal MI, and unstable angina followed by urgent coronary revascularization; TIA followed by urgent carotid revascularization; or cardiovascular death, including sudden deaths.
The endpoint was experienced by 8.5% of participants in the lower-target group versus 10.9% of those in the higher-target group. This translated to a 22% relative risk reduction (adjusted hazard ratio, 0.78; 95% confidence interval, 0.68-0.98; P =.04).
A total of 86% of participants had an ischemic stroke confirmed by brain MRI or CT scan. In this group, the relative risk reduction was 33% – “meaning that we could avoid one-third of recurrent major vascular events,” Dr. Amarenco said.
Furthermore, targeting the lower LDL levels was associated with a relative risk reduction of 40% among those with diabetes.
Secondary outcomes not significant
The investigators used hierarchical testing to compare two outcomes at a time in a prespecified order. They planned to continue this strategy until a comparison emerged as nonsignificant.
This occurred right away when their first composite secondary endpoint comparison between nonfatal MI and urgent revascularization was found to be not significantly different between groups (P = .12).
The early ending “weakened the results of the trial, and the results should be taken with caution because of that,” Dr. Amarenco said.
In addition, the number of hemorrhagic strokes did not differ significantly between groups. There were 18 of these events in the lower-target group and 13 in the higher-target cohort.
That numerical increase in intracranial hemorrhage was “driven by the Korean patients. … and that is something we will report soon,” Dr. Amarenco said.
Interestingly, the researchers also evaluated how much time participants spent within the target LDL cholesterol range, averaged by study site. They found that 53% of the lower–LDL target group, for example, was in the therapeutic range on average during the study.
When Dr. Amarenco and colleagues looked at participants who managed to spend 50%-100% in the target range, the relative risk reduction was 36%.
“So we can hypothesize that, if we had used a more potent drug like PCSK9 inhibitors to be closer to 100% in the therapeutic range, we may have had a greater effect size,” Dr. Amarenco said.
“Our results suggest that LDL cholesterol is causally related to atherosclerosis and confirm that the lower the LDL cholesterol the better,” Dr. Amarenco said.
“Future trials should explore the efficacy and safety of lowering LDL cholesterol to very low levels such as less than 55 mg/dL or even 30 mg/dL (as obtained in the FOURIER trial) by using PCSK9 inhibitors or equivalent in patients with an ischemic stroke due to atherosclerotic disease,” Dr. Amarenco said.
‘Practice-confirming’ findings
The findings are also in line with secondary analyses of the WASID (Neurology. 1995 Aug;45[8]:1488-93) and SAMMPRIS trials, which should dispel some concerns that persist about taking LDL to such low levels that it increases risk of intracerebral hemorrhage, Dr. Amarenco noted.
However, TST, he said, didn’t provide clear answers on what specific subgroups of patients with a stroke history would benefit from aggressive lipid lowering.
“What is stroke without atherosclerotic disease?” he said. “Some people say small-vessel disease is also a form of atherosclerosis, and most patients with atrial fibrillation, which is increasingly recognized as a cause of stroke, are also going to have atherosclerosis of the heart as well as the brain and blood vessels.
“Many, many stroke patients will fall into this category,” Dr. Elkind said, “and the question is, should they be treated more aggressively with lipid lowering?”
“The results of this study fit pretty nicely into the rubric of the AHA cholesterol guidelines,” said Donald M. Lloyd-Jones, MD, chairman, department of preventive medicine at Northwestern University Feinberg School of Medicine, Chicago, and chair of the AHA’s 2019 Council on Scientific Sessions Programming. Dr. Lloyd-Jones was also a member of the guideline committee.
Stroke patients are not “garden variety coronary patients,” he said. “The concern about intracerebral hemorrhage continues to be something that we wonder about: Should we be driving our stroke patients as low as our coronary patients? I think these data will certainly help us.”
Consideration for future guidelines
The study would have been more helpful if it provided more detail about the treatment regimens used, Jennifer Robinson, MD, director of the prevention intervention center, department of epidemiology, University of Iowa, said in an interview.
“What was the dose intensity of statins the patients were on?” Dr. Robinson said. “Part of our struggle has been to convince people to use high-intensity statins – get the maximum from statins that are generic now and cost saving in even very low-risk primary prevention patients.”
She said that a third of patients in TST also took ezetimibe with the statin “makes sense” because of its generic status.
Nonetheless, Dr. Robinson said, TST adds to the evidence that LDL of 100 mg/dL is not good enough, that high-intensity statin therapy is superior to a moderate regimen and that adding a nonstatin – ezetimibe in TST – can derive added benefit.
The TST findings may give guideline writers direction going forward, she said. “We really need to start thinking about the potential for net benefit from added therapy, whether it’s from intensifying LDL lowering, adding icosapent ethyl (Vascepa, Amarin), which seems to have remarkable benefits, or SGLT2 inhibitor,” she said.
“There are a lot of options,” Dr. Robinson said. “We need to have an outlook beyond just treating to target with what really is the best maximized accepted therapy.”
TST was funded primarily by French Government, but also with grants from Pfizer, Astra Zeneca and Merck. Dr. Amarenco disclosed that he is a consultant or advisor to Modest, Sanofi, Bristol-Myers Squibb, and Amgen; receives honoraria from Modest, Amgen, Kowa, Shing Poon, Kowa, Bayer, GSK, Fibrogen, and AstraZeneca. He also receives research grants from Pfizer, Astra Zeneca, Sanofi, BMS, Merck, Boston Scientific, and the French Government.
This article also appears on Medscape.com.
SOURCE: Amarenco P. ACC 2019, Late Breaking Science 6 session.
REPORTING FROM AHA 2019
ISCHEMIA-CKD: No benefit for coronary revascularization in advanced CKD with stable angina
PHILADELPHIA – Coronary revascularization in patients with stage 4 or 5 chronic kidney disease (CKD) and stable ischemic heart disease accomplishes nothing constructive, according to clear-cut results of the landmark ISCHEMIA-CKD trial.
In this multinational randomized trial including 777 stable patients with advanced CKD and moderate or severe myocardial ischemia on noninvasive testing, an early invasive strategy didn’t reduce the risks of death or ischemic events, didn’t provide any significant improvement in quality of life metrics, and resulted in an increased risk of stroke, Sripal Bangalore, MD, reported at the American Heart Association scientific sessions.
“ said Dr. Bangalore, professor of medicine and director of complex coronary intervention at New York University.
This was easily the largest-ever trial of an invasive versus conservative coronary artery disease management strategy in this challenging population. For example, in the COURAGE trial of optimal medical therapy with or without percutaneous coronary intervention for stable coronary disease (N Engl J Med. 2007 Apr 12;356[15]:1503-16), only 16 of the 2,287 participants had an estimated glomerular filtration rate below 30 mL/min per 1.73 m2.
Of note, the participating study sites received special training aimed at minimizing the risk of acute kidney injury after cardiac catheterization in this at-risk population. The training included utilization of a customized left ventricular end diastolic volume–based hydration protocol, guidance on how to perform percutaneous coronary intervention with little or no contrast material, and encouragement of a heart/kidney team approach involving a cardiologist, nephrologist, and cardiovascular surgeon. This training really paid off, with roughly a 7% incidence of acute kidney injury after catheterization.
“The expected rate in such patients would be 30%-60%,” according to Dr. Bangalore.
The primary endpoint in ISCHEMIA-CKD was the rates of death or MI during 3 years of prospective follow-up. This occurred in 36.7% of patients randomized to optimal medical therapy alone and 36.4% of those randomized to an early invasive strategy. Similarly, the major secondary endpoint, comprising death, MI, and hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest, was also a virtual dead heat, occurring in about 39% of subjects. More than 27% of study participants had died by the 3-year mark regardless of how their coronary disease was managed.
The adjusted risk of stroke was 3.76-fold higher in the invasive strategy group; however, the most strokes were not procedurally related, and the explanation for the significantly increased risk in the invasively managed group remains unknown, the cardiologist said.
John A. Spertus, MD, who led the quality of life assessment in ISCHEMIA-CKD and in the 5,129-patient parent ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), also presented at the AHA scientific sessions. He reported that, unlike in the parent study, there was no hint of a meaningful long-term quality of life benefit for revascularization plus optimal medical therapy, compared with that of optimal medical therapy alone, in ISCHEMIA-CKD.
“We have greater than 93% confidence that there is more of a quality of life effect in patients without advanced CKD than in patients with advanced CKD,” said Dr. Spertus, director of health outcomes research at the Saint Luke’s Mid America Heart Institute and professor of medicine at the University of Missouri, Kansas City.
Discussant Glenn L. Levine, MD, hailed ISCHEMIA-CKD as “a monumental achievement,” an ambitious, well-powered study with essentially no loss of follow-up during up to 4 years. It helps fill an utter void in the AHA/American College of Cardiology guidelines, which to date offer no recommendations at all regarding revascularization in patients with CKD because of a lack of evidence. And he considers ISCHEMIA-CKD to be unequivocally practice changing and guideline changing.
“Based on the results of ISCHEMIA-CKD, I will generally not go searching for ischemia and [coronary artery disease] in most severe and end-stage CKD patients, absent marked or unacceptable angina, and will treat them with medical therapy alone,” declared Dr. Levine, professor of medicine at Baylor College of Medicine and director of the cardiac care unit at the Michael E. DeBakey VA Medical Center, both in Houston.
He offered a few caveats. Excluded from participation in ISCHEMIA-CKD were patients with acute coronary syndrome, significant heart failure, or unacceptable angina despite optimal medical therapy at baseline, so the study results don’t apply to them. Also, the acute kidney injury rate after intervention was eye-catchingly low.
Dr. Bangalore discussed the ISCHEMIA-CKD trial and outcomes in a video interview with Medscape’s Tricia Ward.
“It seems unlikely that all centers routinely do and will exactly follow the very careful measures to limit contrast and minimize contrast nephropathy used in this study,” Dr. Levine commented.
ISCHEMIA-CKD, like its parent ISCHEMIA trial, was funded by the National Heart, Lung, and Blood Institute. Dr. Bangalore reported having no relevant financial interests. Dr. Spertus holds the copyright for the Seattle Angina Questionnaire, which was used for quality of life measurement in the trials. Dr. Levine disclosed that he has no relations with industry or conflicts of interest.
PHILADELPHIA – Coronary revascularization in patients with stage 4 or 5 chronic kidney disease (CKD) and stable ischemic heart disease accomplishes nothing constructive, according to clear-cut results of the landmark ISCHEMIA-CKD trial.
In this multinational randomized trial including 777 stable patients with advanced CKD and moderate or severe myocardial ischemia on noninvasive testing, an early invasive strategy didn’t reduce the risks of death or ischemic events, didn’t provide any significant improvement in quality of life metrics, and resulted in an increased risk of stroke, Sripal Bangalore, MD, reported at the American Heart Association scientific sessions.
“ said Dr. Bangalore, professor of medicine and director of complex coronary intervention at New York University.
This was easily the largest-ever trial of an invasive versus conservative coronary artery disease management strategy in this challenging population. For example, in the COURAGE trial of optimal medical therapy with or without percutaneous coronary intervention for stable coronary disease (N Engl J Med. 2007 Apr 12;356[15]:1503-16), only 16 of the 2,287 participants had an estimated glomerular filtration rate below 30 mL/min per 1.73 m2.
Of note, the participating study sites received special training aimed at minimizing the risk of acute kidney injury after cardiac catheterization in this at-risk population. The training included utilization of a customized left ventricular end diastolic volume–based hydration protocol, guidance on how to perform percutaneous coronary intervention with little or no contrast material, and encouragement of a heart/kidney team approach involving a cardiologist, nephrologist, and cardiovascular surgeon. This training really paid off, with roughly a 7% incidence of acute kidney injury after catheterization.
“The expected rate in such patients would be 30%-60%,” according to Dr. Bangalore.
The primary endpoint in ISCHEMIA-CKD was the rates of death or MI during 3 years of prospective follow-up. This occurred in 36.7% of patients randomized to optimal medical therapy alone and 36.4% of those randomized to an early invasive strategy. Similarly, the major secondary endpoint, comprising death, MI, and hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest, was also a virtual dead heat, occurring in about 39% of subjects. More than 27% of study participants had died by the 3-year mark regardless of how their coronary disease was managed.
The adjusted risk of stroke was 3.76-fold higher in the invasive strategy group; however, the most strokes were not procedurally related, and the explanation for the significantly increased risk in the invasively managed group remains unknown, the cardiologist said.
John A. Spertus, MD, who led the quality of life assessment in ISCHEMIA-CKD and in the 5,129-patient parent ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), also presented at the AHA scientific sessions. He reported that, unlike in the parent study, there was no hint of a meaningful long-term quality of life benefit for revascularization plus optimal medical therapy, compared with that of optimal medical therapy alone, in ISCHEMIA-CKD.
“We have greater than 93% confidence that there is more of a quality of life effect in patients without advanced CKD than in patients with advanced CKD,” said Dr. Spertus, director of health outcomes research at the Saint Luke’s Mid America Heart Institute and professor of medicine at the University of Missouri, Kansas City.
Discussant Glenn L. Levine, MD, hailed ISCHEMIA-CKD as “a monumental achievement,” an ambitious, well-powered study with essentially no loss of follow-up during up to 4 years. It helps fill an utter void in the AHA/American College of Cardiology guidelines, which to date offer no recommendations at all regarding revascularization in patients with CKD because of a lack of evidence. And he considers ISCHEMIA-CKD to be unequivocally practice changing and guideline changing.
“Based on the results of ISCHEMIA-CKD, I will generally not go searching for ischemia and [coronary artery disease] in most severe and end-stage CKD patients, absent marked or unacceptable angina, and will treat them with medical therapy alone,” declared Dr. Levine, professor of medicine at Baylor College of Medicine and director of the cardiac care unit at the Michael E. DeBakey VA Medical Center, both in Houston.
He offered a few caveats. Excluded from participation in ISCHEMIA-CKD were patients with acute coronary syndrome, significant heart failure, or unacceptable angina despite optimal medical therapy at baseline, so the study results don’t apply to them. Also, the acute kidney injury rate after intervention was eye-catchingly low.
Dr. Bangalore discussed the ISCHEMIA-CKD trial and outcomes in a video interview with Medscape’s Tricia Ward.
“It seems unlikely that all centers routinely do and will exactly follow the very careful measures to limit contrast and minimize contrast nephropathy used in this study,” Dr. Levine commented.
ISCHEMIA-CKD, like its parent ISCHEMIA trial, was funded by the National Heart, Lung, and Blood Institute. Dr. Bangalore reported having no relevant financial interests. Dr. Spertus holds the copyright for the Seattle Angina Questionnaire, which was used for quality of life measurement in the trials. Dr. Levine disclosed that he has no relations with industry or conflicts of interest.
PHILADELPHIA – Coronary revascularization in patients with stage 4 or 5 chronic kidney disease (CKD) and stable ischemic heart disease accomplishes nothing constructive, according to clear-cut results of the landmark ISCHEMIA-CKD trial.
In this multinational randomized trial including 777 stable patients with advanced CKD and moderate or severe myocardial ischemia on noninvasive testing, an early invasive strategy didn’t reduce the risks of death or ischemic events, didn’t provide any significant improvement in quality of life metrics, and resulted in an increased risk of stroke, Sripal Bangalore, MD, reported at the American Heart Association scientific sessions.
“ said Dr. Bangalore, professor of medicine and director of complex coronary intervention at New York University.
This was easily the largest-ever trial of an invasive versus conservative coronary artery disease management strategy in this challenging population. For example, in the COURAGE trial of optimal medical therapy with or without percutaneous coronary intervention for stable coronary disease (N Engl J Med. 2007 Apr 12;356[15]:1503-16), only 16 of the 2,287 participants had an estimated glomerular filtration rate below 30 mL/min per 1.73 m2.
Of note, the participating study sites received special training aimed at minimizing the risk of acute kidney injury after cardiac catheterization in this at-risk population. The training included utilization of a customized left ventricular end diastolic volume–based hydration protocol, guidance on how to perform percutaneous coronary intervention with little or no contrast material, and encouragement of a heart/kidney team approach involving a cardiologist, nephrologist, and cardiovascular surgeon. This training really paid off, with roughly a 7% incidence of acute kidney injury after catheterization.
“The expected rate in such patients would be 30%-60%,” according to Dr. Bangalore.
The primary endpoint in ISCHEMIA-CKD was the rates of death or MI during 3 years of prospective follow-up. This occurred in 36.7% of patients randomized to optimal medical therapy alone and 36.4% of those randomized to an early invasive strategy. Similarly, the major secondary endpoint, comprising death, MI, and hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest, was also a virtual dead heat, occurring in about 39% of subjects. More than 27% of study participants had died by the 3-year mark regardless of how their coronary disease was managed.
The adjusted risk of stroke was 3.76-fold higher in the invasive strategy group; however, the most strokes were not procedurally related, and the explanation for the significantly increased risk in the invasively managed group remains unknown, the cardiologist said.
John A. Spertus, MD, who led the quality of life assessment in ISCHEMIA-CKD and in the 5,129-patient parent ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), also presented at the AHA scientific sessions. He reported that, unlike in the parent study, there was no hint of a meaningful long-term quality of life benefit for revascularization plus optimal medical therapy, compared with that of optimal medical therapy alone, in ISCHEMIA-CKD.
“We have greater than 93% confidence that there is more of a quality of life effect in patients without advanced CKD than in patients with advanced CKD,” said Dr. Spertus, director of health outcomes research at the Saint Luke’s Mid America Heart Institute and professor of medicine at the University of Missouri, Kansas City.
Discussant Glenn L. Levine, MD, hailed ISCHEMIA-CKD as “a monumental achievement,” an ambitious, well-powered study with essentially no loss of follow-up during up to 4 years. It helps fill an utter void in the AHA/American College of Cardiology guidelines, which to date offer no recommendations at all regarding revascularization in patients with CKD because of a lack of evidence. And he considers ISCHEMIA-CKD to be unequivocally practice changing and guideline changing.
“Based on the results of ISCHEMIA-CKD, I will generally not go searching for ischemia and [coronary artery disease] in most severe and end-stage CKD patients, absent marked or unacceptable angina, and will treat them with medical therapy alone,” declared Dr. Levine, professor of medicine at Baylor College of Medicine and director of the cardiac care unit at the Michael E. DeBakey VA Medical Center, both in Houston.
He offered a few caveats. Excluded from participation in ISCHEMIA-CKD were patients with acute coronary syndrome, significant heart failure, or unacceptable angina despite optimal medical therapy at baseline, so the study results don’t apply to them. Also, the acute kidney injury rate after intervention was eye-catchingly low.
Dr. Bangalore discussed the ISCHEMIA-CKD trial and outcomes in a video interview with Medscape’s Tricia Ward.
“It seems unlikely that all centers routinely do and will exactly follow the very careful measures to limit contrast and minimize contrast nephropathy used in this study,” Dr. Levine commented.
ISCHEMIA-CKD, like its parent ISCHEMIA trial, was funded by the National Heart, Lung, and Blood Institute. Dr. Bangalore reported having no relevant financial interests. Dr. Spertus holds the copyright for the Seattle Angina Questionnaire, which was used for quality of life measurement in the trials. Dr. Levine disclosed that he has no relations with industry or conflicts of interest.
REPORTING FROM AHA 2019
RNA inhibitors silence two new targets in dyslipidemia
PHILADELPHIA – A novel treatment strategy tackling hypertriglyceridemia via long-acting agents targeting two specific culprit genes caused a stir based on the highly encouraging early results of two small proof-of-concept studies presented at the American Heart Association scientific sessions.
ARO-APOC3 is a small interfering ribonucleic acid molecule (siRNA) targeting the apolipoprotein C-III gene (APOC3) specifically within hepatocytes, while ARO-ANG3 is an siRNA targeting hepatic angiotensinlike protein 3 (ANG3). ARO-APOC3 is being developed as a potential treatment for familial chylomicronemia syndrome, a rare disorder associated with triglyceride levels in excess of 800 mg/dL, as well as for patients with severe hypertriglyceridemia and associated pancreatitis – a far more common condition – and ultimately, perhaps, for patients with hypertriglyceridemia and heart disease. ARO-ANG3, which lowers very-low-density lipoprotein (VLDL) as well as LDL cholesterol while increasing HDL cholesterol levels, is under development as a treatment for high triglycerides, homozygous familial hypercholesterolemia, nonalcoholic fatty liver disease, and metabolic diseases.
Christie M. Ballantyne, MD, presented the results of the phase 1/2a study of ARO-APOC3, which included 40 healthy subjects who received a single subcutaneous injection of the RNA inhibitor at 10, 25, 50, or 100 mg and were followed for 16 weeks. At the highest dose, it reduced serum APOC3 levels by 94%, triglyceride levels by 64%, LDL cholesterol levels by up to 25%, and VLDL by a maximum of 68%, while boosting HDL cholesterol levels by up to 69%. These substantial changes in lipids remained stable through week 16.
The observed prolonged duration of effect provides a potential opportunity for dosing quarterly or perhaps even twice a year. This would be ideal for patients who have problems with adherence to daily therapy with statins and other oral agents, observed Dr. Ballantyne, professor of medicine and professor of molecular and human genetics at Baylor College of Medicine, Houston.
Gerald F. Watts, MBBS, DM, DSc, PhD, presented a separate phase 1/2a, 16-week study of a single dose of ARO-ANG3 at 35, 100, 200, or 300 mg in 40 dyslipidemic subjects who were not on background lipid-lowering therapy. The impact on lipids was similar to that achieved by silencing apolipoprotein C-III, except that the reduction in LDL cholesterol was larger and ARO-ANG3 reduced HDL cholesterol in dose-dependent fashion by up to 26%. As in the ARO-APOC3 study, the safety profile of the ANG3 RNA inhibitor raised no concerns, with no study dropouts and no serious adverse events, added Dr. Watts, professor of medicine at the University of Western Australia, Perth.
Discussant Daniel J. Rader, MD, noted that there is an unmet need for hypertriglyceridemia-lowering therapies, because elevated triglycerides can cause pancreatitis as well as coronary disease.
“These siRNA molecules are catalytic: They can go around and destroy multiple aspects of the target RNAs in a way that provides substantial longevity of effect, which is quite remarkable,” explained Dr. Rader, professor of molecular medicine and director of the preventive cardiology program at the University of Pennsylvania, Philadelphia.
Hypertriglyceridemia is often a challenge to treat successfully in clinical practice, so the siRNA studies drew considerable attention, not only for the impressive size and durability of the lipid changes, but also because of the way in which the target genes were identified, a process that began by genetic analysis of individuals with inherently low levels of APOC3 and ANG3.
“One of the really interesting parts of this story is the rapidity with which we went from target identification to therapeutics, now moving into phase 1 and 2 trials. It’s happening much more rapidly than we’ve ever seen before,” commented AHA scientific sessions program chair Donald Lloyd-Jones, MD, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.
Still, he was quick to inject a cautionary note. “These genomic studies can show us that having lower levels of these proteins is associated with lower risk. But that doesn’t necessarily mean that lowering levels of these proteins will lower risk, and it certainly doesn’t tell us anything about potential safety concerns.”
In an interview, AHA spokesperson Jennifer Robinson, MD, made a similar point: “We have had lots of fibrate trials in which we’ve lowered triglycerides, and they didn’t really work.”
Yet she, too, was clearly caught up in the thrill of the early evidence of a novel means of treating new targets in dyslipidemia.
“We’re on the cusp of the genetic revolution,” declared Dr. Robinson, professor of epidemiology and director of the preventive and intervention center at the University of Iowa, Iowa City. “For us science nerds, this is so exciting. It’s so cool. The brilliance of these compounds is they have a very focused target in a very focused organ. If you’re just in the liver, you’re limiting off-target effects, so the safety issue should be better than with what we have now.”
Dr. Rader commented that plenty of questions remain to be answered about siRNA therapy for hyperlipidemia. These include which target – APOC3 or ANG3 – is the more effective for treating severe hypertriglyceridemia and/or for preventing major cardiovascular events, how frequently these agents will need to be dosed, whether there’s a clinical downside to the substantial HDL cholesterol lowering seen with silencing of ANG3, and whether the APOC3 that’s produced in the intestine – and which isn’t touched by hepatocentric ARO-APOC3 – will cause problems.
Dr. Ballantyne reported serving as a consultant to Arrowhead Pharmaceutics, which is developing the RNA inhibitors for hypertriglyceridemia, as well as numerous other pharmaceutical companies. Dr. Watts has received research grants from Amgen and Sanofi-Regeneron.
PHILADELPHIA – A novel treatment strategy tackling hypertriglyceridemia via long-acting agents targeting two specific culprit genes caused a stir based on the highly encouraging early results of two small proof-of-concept studies presented at the American Heart Association scientific sessions.
ARO-APOC3 is a small interfering ribonucleic acid molecule (siRNA) targeting the apolipoprotein C-III gene (APOC3) specifically within hepatocytes, while ARO-ANG3 is an siRNA targeting hepatic angiotensinlike protein 3 (ANG3). ARO-APOC3 is being developed as a potential treatment for familial chylomicronemia syndrome, a rare disorder associated with triglyceride levels in excess of 800 mg/dL, as well as for patients with severe hypertriglyceridemia and associated pancreatitis – a far more common condition – and ultimately, perhaps, for patients with hypertriglyceridemia and heart disease. ARO-ANG3, which lowers very-low-density lipoprotein (VLDL) as well as LDL cholesterol while increasing HDL cholesterol levels, is under development as a treatment for high triglycerides, homozygous familial hypercholesterolemia, nonalcoholic fatty liver disease, and metabolic diseases.
Christie M. Ballantyne, MD, presented the results of the phase 1/2a study of ARO-APOC3, which included 40 healthy subjects who received a single subcutaneous injection of the RNA inhibitor at 10, 25, 50, or 100 mg and were followed for 16 weeks. At the highest dose, it reduced serum APOC3 levels by 94%, triglyceride levels by 64%, LDL cholesterol levels by up to 25%, and VLDL by a maximum of 68%, while boosting HDL cholesterol levels by up to 69%. These substantial changes in lipids remained stable through week 16.
The observed prolonged duration of effect provides a potential opportunity for dosing quarterly or perhaps even twice a year. This would be ideal for patients who have problems with adherence to daily therapy with statins and other oral agents, observed Dr. Ballantyne, professor of medicine and professor of molecular and human genetics at Baylor College of Medicine, Houston.
Gerald F. Watts, MBBS, DM, DSc, PhD, presented a separate phase 1/2a, 16-week study of a single dose of ARO-ANG3 at 35, 100, 200, or 300 mg in 40 dyslipidemic subjects who were not on background lipid-lowering therapy. The impact on lipids was similar to that achieved by silencing apolipoprotein C-III, except that the reduction in LDL cholesterol was larger and ARO-ANG3 reduced HDL cholesterol in dose-dependent fashion by up to 26%. As in the ARO-APOC3 study, the safety profile of the ANG3 RNA inhibitor raised no concerns, with no study dropouts and no serious adverse events, added Dr. Watts, professor of medicine at the University of Western Australia, Perth.
Discussant Daniel J. Rader, MD, noted that there is an unmet need for hypertriglyceridemia-lowering therapies, because elevated triglycerides can cause pancreatitis as well as coronary disease.
“These siRNA molecules are catalytic: They can go around and destroy multiple aspects of the target RNAs in a way that provides substantial longevity of effect, which is quite remarkable,” explained Dr. Rader, professor of molecular medicine and director of the preventive cardiology program at the University of Pennsylvania, Philadelphia.
Hypertriglyceridemia is often a challenge to treat successfully in clinical practice, so the siRNA studies drew considerable attention, not only for the impressive size and durability of the lipid changes, but also because of the way in which the target genes were identified, a process that began by genetic analysis of individuals with inherently low levels of APOC3 and ANG3.
“One of the really interesting parts of this story is the rapidity with which we went from target identification to therapeutics, now moving into phase 1 and 2 trials. It’s happening much more rapidly than we’ve ever seen before,” commented AHA scientific sessions program chair Donald Lloyd-Jones, MD, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.
Still, he was quick to inject a cautionary note. “These genomic studies can show us that having lower levels of these proteins is associated with lower risk. But that doesn’t necessarily mean that lowering levels of these proteins will lower risk, and it certainly doesn’t tell us anything about potential safety concerns.”
In an interview, AHA spokesperson Jennifer Robinson, MD, made a similar point: “We have had lots of fibrate trials in which we’ve lowered triglycerides, and they didn’t really work.”
Yet she, too, was clearly caught up in the thrill of the early evidence of a novel means of treating new targets in dyslipidemia.
“We’re on the cusp of the genetic revolution,” declared Dr. Robinson, professor of epidemiology and director of the preventive and intervention center at the University of Iowa, Iowa City. “For us science nerds, this is so exciting. It’s so cool. The brilliance of these compounds is they have a very focused target in a very focused organ. If you’re just in the liver, you’re limiting off-target effects, so the safety issue should be better than with what we have now.”
Dr. Rader commented that plenty of questions remain to be answered about siRNA therapy for hyperlipidemia. These include which target – APOC3 or ANG3 – is the more effective for treating severe hypertriglyceridemia and/or for preventing major cardiovascular events, how frequently these agents will need to be dosed, whether there’s a clinical downside to the substantial HDL cholesterol lowering seen with silencing of ANG3, and whether the APOC3 that’s produced in the intestine – and which isn’t touched by hepatocentric ARO-APOC3 – will cause problems.
Dr. Ballantyne reported serving as a consultant to Arrowhead Pharmaceutics, which is developing the RNA inhibitors for hypertriglyceridemia, as well as numerous other pharmaceutical companies. Dr. Watts has received research grants from Amgen and Sanofi-Regeneron.
PHILADELPHIA – A novel treatment strategy tackling hypertriglyceridemia via long-acting agents targeting two specific culprit genes caused a stir based on the highly encouraging early results of two small proof-of-concept studies presented at the American Heart Association scientific sessions.
ARO-APOC3 is a small interfering ribonucleic acid molecule (siRNA) targeting the apolipoprotein C-III gene (APOC3) specifically within hepatocytes, while ARO-ANG3 is an siRNA targeting hepatic angiotensinlike protein 3 (ANG3). ARO-APOC3 is being developed as a potential treatment for familial chylomicronemia syndrome, a rare disorder associated with triglyceride levels in excess of 800 mg/dL, as well as for patients with severe hypertriglyceridemia and associated pancreatitis – a far more common condition – and ultimately, perhaps, for patients with hypertriglyceridemia and heart disease. ARO-ANG3, which lowers very-low-density lipoprotein (VLDL) as well as LDL cholesterol while increasing HDL cholesterol levels, is under development as a treatment for high triglycerides, homozygous familial hypercholesterolemia, nonalcoholic fatty liver disease, and metabolic diseases.
Christie M. Ballantyne, MD, presented the results of the phase 1/2a study of ARO-APOC3, which included 40 healthy subjects who received a single subcutaneous injection of the RNA inhibitor at 10, 25, 50, or 100 mg and were followed for 16 weeks. At the highest dose, it reduced serum APOC3 levels by 94%, triglyceride levels by 64%, LDL cholesterol levels by up to 25%, and VLDL by a maximum of 68%, while boosting HDL cholesterol levels by up to 69%. These substantial changes in lipids remained stable through week 16.
The observed prolonged duration of effect provides a potential opportunity for dosing quarterly or perhaps even twice a year. This would be ideal for patients who have problems with adherence to daily therapy with statins and other oral agents, observed Dr. Ballantyne, professor of medicine and professor of molecular and human genetics at Baylor College of Medicine, Houston.
Gerald F. Watts, MBBS, DM, DSc, PhD, presented a separate phase 1/2a, 16-week study of a single dose of ARO-ANG3 at 35, 100, 200, or 300 mg in 40 dyslipidemic subjects who were not on background lipid-lowering therapy. The impact on lipids was similar to that achieved by silencing apolipoprotein C-III, except that the reduction in LDL cholesterol was larger and ARO-ANG3 reduced HDL cholesterol in dose-dependent fashion by up to 26%. As in the ARO-APOC3 study, the safety profile of the ANG3 RNA inhibitor raised no concerns, with no study dropouts and no serious adverse events, added Dr. Watts, professor of medicine at the University of Western Australia, Perth.
Discussant Daniel J. Rader, MD, noted that there is an unmet need for hypertriglyceridemia-lowering therapies, because elevated triglycerides can cause pancreatitis as well as coronary disease.
“These siRNA molecules are catalytic: They can go around and destroy multiple aspects of the target RNAs in a way that provides substantial longevity of effect, which is quite remarkable,” explained Dr. Rader, professor of molecular medicine and director of the preventive cardiology program at the University of Pennsylvania, Philadelphia.
Hypertriglyceridemia is often a challenge to treat successfully in clinical practice, so the siRNA studies drew considerable attention, not only for the impressive size and durability of the lipid changes, but also because of the way in which the target genes were identified, a process that began by genetic analysis of individuals with inherently low levels of APOC3 and ANG3.
“One of the really interesting parts of this story is the rapidity with which we went from target identification to therapeutics, now moving into phase 1 and 2 trials. It’s happening much more rapidly than we’ve ever seen before,” commented AHA scientific sessions program chair Donald Lloyd-Jones, MD, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.
Still, he was quick to inject a cautionary note. “These genomic studies can show us that having lower levels of these proteins is associated with lower risk. But that doesn’t necessarily mean that lowering levels of these proteins will lower risk, and it certainly doesn’t tell us anything about potential safety concerns.”
In an interview, AHA spokesperson Jennifer Robinson, MD, made a similar point: “We have had lots of fibrate trials in which we’ve lowered triglycerides, and they didn’t really work.”
Yet she, too, was clearly caught up in the thrill of the early evidence of a novel means of treating new targets in dyslipidemia.
“We’re on the cusp of the genetic revolution,” declared Dr. Robinson, professor of epidemiology and director of the preventive and intervention center at the University of Iowa, Iowa City. “For us science nerds, this is so exciting. It’s so cool. The brilliance of these compounds is they have a very focused target in a very focused organ. If you’re just in the liver, you’re limiting off-target effects, so the safety issue should be better than with what we have now.”
Dr. Rader commented that plenty of questions remain to be answered about siRNA therapy for hyperlipidemia. These include which target – APOC3 or ANG3 – is the more effective for treating severe hypertriglyceridemia and/or for preventing major cardiovascular events, how frequently these agents will need to be dosed, whether there’s a clinical downside to the substantial HDL cholesterol lowering seen with silencing of ANG3, and whether the APOC3 that’s produced in the intestine – and which isn’t touched by hepatocentric ARO-APOC3 – will cause problems.
Dr. Ballantyne reported serving as a consultant to Arrowhead Pharmaceutics, which is developing the RNA inhibitors for hypertriglyceridemia, as well as numerous other pharmaceutical companies. Dr. Watts has received research grants from Amgen and Sanofi-Regeneron.
REPORTING FROM AHA 2019
The TWILIGHT of aspirin post-PCI for ACS?
PHILADELPHIA – Downshifting to ticagrelor monotherapy after just 3 months of dual antiplatelet therapy is a winning strategy in high-risk patients who’ve undergone PCI for non-ST-elevation acute coronary syndrome, Usman Baber, MD, reported at the American Heart Association scientific sessions.
He presented a prespecified subgroup analysis of the previously reported TWILIGHT study that was restricted to the 4,614 participants with non-ST-elevation ACS who underwent PCI, completed 3 months of dual antiplatelet therapy (DAPT) with ticagrelor and aspirin, and were then randomized double-blind to an additional 12 months on the same regimen or to ticagrelor plus placebo.
The key finding: After a year on ticagrelor monotherapy, the risk of clinically significant or major bleeding was reduced by 53%, compared with the DAPT group, and with no increased risk of ischemic major adverse cardiovascular events, said Dr. Baber, a cardiologist at the Icahn School of Medicine at Mount Sinai, New York.
This secondary analysis of the TWILIGHT study was carried out because none of the several prior studies of short-term DAPT followed by an aspirin-free strategy after PCI was double-blind. Nor did any include patients with non-ST-elevation ACS, he explained.
The TWILIGHT substudy included 2,494 participants with unstable angina and 2,120 with non-ST-elevation MI. Roughly two-thirds had four or more high-risk clinical or angiographic features, such as diabetes, chronic kidney disease, multivessel CAD, or left main lesions.
The primary study endpoint at month 15 – the rate of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding events – was 7.6% with ticagrelor plus aspirin, compared with 3.6% with ticagrelor plus placebo, for a highly significant 53% relative risk reduction in favor of ticagrelor monotherapy. The key secondary endpoint, a composite of all-cause mortality, MI, or stroke, occurred in roughly 4.4% of patients in each study arm.
Of note, ticagrelor monotherapy after 3 months of DAPT was associated with a similar 50%-60% reduction in the risk of BARC 2, 3, or 5 bleeding regardless of whether patients had 1-3, 4 or 5, or 6-9 prespecified high-risk clinical and angiographic features. Nor was the impact of ticagrelor monotherapy on ischemic events impacted by risk factor burden.
Discussant Michelle L. O’Donoghue, MD, observed that while the current practice of most cardiologists in patients undergoing stenting in the setting of ACS is 12 months of DAPT followed by discontinuation of the P2Y12 inhibitor and indefinite continuation of aspirin, mounting evidence suggests there’s a better approach.
Indeed, the new TWILIGHT findings in patients with non-ST-elevation ACS dovetail nicely with the results of three other recent studies of discontinuing aspirin after 1-3 months versus continuing DAPT with ticagrelor or another P2Y12 inhibitor plus aspirin. These studies, GLOBAL LEADERS (Lancet. 2018 Sep 15;392[10151]:940-9); SMART CHOICE (JAMA. 2019 Jun 25;321[24]:2428-37); and STOPDAPT-2 (JAMA. 2019 Jun 25;321[24]:2414-27) included patients undergoing PCI either for stable coronary disease or for ST-elevation MI, but not for non-ST-elevation ACS.
Dr. O’Donoghue, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School, Boston, conducted a meta-analysis including the TWILIGHT ACS trial and the other three studies. In a total population of 29,205 patients, a strategy of dropping aspirin while continuing a P2Y12 inhibitor after 1-3 months of DAPT was associated with a 40% relative risk reduction in major bleeding events when compared with continued DAPT, with no indication of an increased risk of major adverse cardiovascular events. When she looked specifically at the nearly 14,000 post-ACS patients in the studies, the same consistency with respect to outcomes held true: an overall 51% reduction in bleeding, and – if anything – a favorable trend involving an 11% reduction in the risk of major adverse cardiovascular events, although this difference didn’t reach statistical significance.
“I believe that discontinuation of aspirin markedly reduces bleeding when stopped 1-3 months post PCI for patients initially started on DAPT,” Dr. O’Donoghue declared. “The evidence to date does not indicate that stopping aspirin leads to any increase in the risk of major adverse cardiovascular events. And these findings now extend to patients with ACS, including those with high-risk clinical and angiographic features.”
The important remaining questions, she added, include the best-choice P2Y12 inhibitor for early monotherapy post-PCI, whether the medication should be continued indefinitely past the 12-month mark, and whether aspirin might be safely discontinued even earlier than at 1-3 months.
“If you are thinking about establishing a clopidogrel monotherapy, you need to keep in mind that there exists significant interpatient variability in terms of pharmacodynamic response,” she noted, adding that platelet function testing or genotyping to identify clopidogrel resistance is worth considering in such patients.
The primary results of the full TWILIGHT study, which included 7,119 randomized patients, have been published (N Engl J Med. 2019 Sep 26. doi: 10.1056/NEJMoa1908419).
The TWILIGHT study was sponsored by AstraZeneca. Dr. Baber reported receiving honoraria from that company as well as Boston Scientific.
Dr. O’Donoghue reported receiving institutional research support from a handful of pharmaceutical companies.
SOURCE: Baber U. AHA late breaker.
PHILADELPHIA – Downshifting to ticagrelor monotherapy after just 3 months of dual antiplatelet therapy is a winning strategy in high-risk patients who’ve undergone PCI for non-ST-elevation acute coronary syndrome, Usman Baber, MD, reported at the American Heart Association scientific sessions.
He presented a prespecified subgroup analysis of the previously reported TWILIGHT study that was restricted to the 4,614 participants with non-ST-elevation ACS who underwent PCI, completed 3 months of dual antiplatelet therapy (DAPT) with ticagrelor and aspirin, and were then randomized double-blind to an additional 12 months on the same regimen or to ticagrelor plus placebo.
The key finding: After a year on ticagrelor monotherapy, the risk of clinically significant or major bleeding was reduced by 53%, compared with the DAPT group, and with no increased risk of ischemic major adverse cardiovascular events, said Dr. Baber, a cardiologist at the Icahn School of Medicine at Mount Sinai, New York.
This secondary analysis of the TWILIGHT study was carried out because none of the several prior studies of short-term DAPT followed by an aspirin-free strategy after PCI was double-blind. Nor did any include patients with non-ST-elevation ACS, he explained.
The TWILIGHT substudy included 2,494 participants with unstable angina and 2,120 with non-ST-elevation MI. Roughly two-thirds had four or more high-risk clinical or angiographic features, such as diabetes, chronic kidney disease, multivessel CAD, or left main lesions.
The primary study endpoint at month 15 – the rate of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding events – was 7.6% with ticagrelor plus aspirin, compared with 3.6% with ticagrelor plus placebo, for a highly significant 53% relative risk reduction in favor of ticagrelor monotherapy. The key secondary endpoint, a composite of all-cause mortality, MI, or stroke, occurred in roughly 4.4% of patients in each study arm.
Of note, ticagrelor monotherapy after 3 months of DAPT was associated with a similar 50%-60% reduction in the risk of BARC 2, 3, or 5 bleeding regardless of whether patients had 1-3, 4 or 5, or 6-9 prespecified high-risk clinical and angiographic features. Nor was the impact of ticagrelor monotherapy on ischemic events impacted by risk factor burden.
Discussant Michelle L. O’Donoghue, MD, observed that while the current practice of most cardiologists in patients undergoing stenting in the setting of ACS is 12 months of DAPT followed by discontinuation of the P2Y12 inhibitor and indefinite continuation of aspirin, mounting evidence suggests there’s a better approach.
Indeed, the new TWILIGHT findings in patients with non-ST-elevation ACS dovetail nicely with the results of three other recent studies of discontinuing aspirin after 1-3 months versus continuing DAPT with ticagrelor or another P2Y12 inhibitor plus aspirin. These studies, GLOBAL LEADERS (Lancet. 2018 Sep 15;392[10151]:940-9); SMART CHOICE (JAMA. 2019 Jun 25;321[24]:2428-37); and STOPDAPT-2 (JAMA. 2019 Jun 25;321[24]:2414-27) included patients undergoing PCI either for stable coronary disease or for ST-elevation MI, but not for non-ST-elevation ACS.
Dr. O’Donoghue, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School, Boston, conducted a meta-analysis including the TWILIGHT ACS trial and the other three studies. In a total population of 29,205 patients, a strategy of dropping aspirin while continuing a P2Y12 inhibitor after 1-3 months of DAPT was associated with a 40% relative risk reduction in major bleeding events when compared with continued DAPT, with no indication of an increased risk of major adverse cardiovascular events. When she looked specifically at the nearly 14,000 post-ACS patients in the studies, the same consistency with respect to outcomes held true: an overall 51% reduction in bleeding, and – if anything – a favorable trend involving an 11% reduction in the risk of major adverse cardiovascular events, although this difference didn’t reach statistical significance.
“I believe that discontinuation of aspirin markedly reduces bleeding when stopped 1-3 months post PCI for patients initially started on DAPT,” Dr. O’Donoghue declared. “The evidence to date does not indicate that stopping aspirin leads to any increase in the risk of major adverse cardiovascular events. And these findings now extend to patients with ACS, including those with high-risk clinical and angiographic features.”
The important remaining questions, she added, include the best-choice P2Y12 inhibitor for early monotherapy post-PCI, whether the medication should be continued indefinitely past the 12-month mark, and whether aspirin might be safely discontinued even earlier than at 1-3 months.
“If you are thinking about establishing a clopidogrel monotherapy, you need to keep in mind that there exists significant interpatient variability in terms of pharmacodynamic response,” she noted, adding that platelet function testing or genotyping to identify clopidogrel resistance is worth considering in such patients.
The primary results of the full TWILIGHT study, which included 7,119 randomized patients, have been published (N Engl J Med. 2019 Sep 26. doi: 10.1056/NEJMoa1908419).
The TWILIGHT study was sponsored by AstraZeneca. Dr. Baber reported receiving honoraria from that company as well as Boston Scientific.
Dr. O’Donoghue reported receiving institutional research support from a handful of pharmaceutical companies.
SOURCE: Baber U. AHA late breaker.
PHILADELPHIA – Downshifting to ticagrelor monotherapy after just 3 months of dual antiplatelet therapy is a winning strategy in high-risk patients who’ve undergone PCI for non-ST-elevation acute coronary syndrome, Usman Baber, MD, reported at the American Heart Association scientific sessions.
He presented a prespecified subgroup analysis of the previously reported TWILIGHT study that was restricted to the 4,614 participants with non-ST-elevation ACS who underwent PCI, completed 3 months of dual antiplatelet therapy (DAPT) with ticagrelor and aspirin, and were then randomized double-blind to an additional 12 months on the same regimen or to ticagrelor plus placebo.
The key finding: After a year on ticagrelor monotherapy, the risk of clinically significant or major bleeding was reduced by 53%, compared with the DAPT group, and with no increased risk of ischemic major adverse cardiovascular events, said Dr. Baber, a cardiologist at the Icahn School of Medicine at Mount Sinai, New York.
This secondary analysis of the TWILIGHT study was carried out because none of the several prior studies of short-term DAPT followed by an aspirin-free strategy after PCI was double-blind. Nor did any include patients with non-ST-elevation ACS, he explained.
The TWILIGHT substudy included 2,494 participants with unstable angina and 2,120 with non-ST-elevation MI. Roughly two-thirds had four or more high-risk clinical or angiographic features, such as diabetes, chronic kidney disease, multivessel CAD, or left main lesions.
The primary study endpoint at month 15 – the rate of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding events – was 7.6% with ticagrelor plus aspirin, compared with 3.6% with ticagrelor plus placebo, for a highly significant 53% relative risk reduction in favor of ticagrelor monotherapy. The key secondary endpoint, a composite of all-cause mortality, MI, or stroke, occurred in roughly 4.4% of patients in each study arm.
Of note, ticagrelor monotherapy after 3 months of DAPT was associated with a similar 50%-60% reduction in the risk of BARC 2, 3, or 5 bleeding regardless of whether patients had 1-3, 4 or 5, or 6-9 prespecified high-risk clinical and angiographic features. Nor was the impact of ticagrelor monotherapy on ischemic events impacted by risk factor burden.
Discussant Michelle L. O’Donoghue, MD, observed that while the current practice of most cardiologists in patients undergoing stenting in the setting of ACS is 12 months of DAPT followed by discontinuation of the P2Y12 inhibitor and indefinite continuation of aspirin, mounting evidence suggests there’s a better approach.
Indeed, the new TWILIGHT findings in patients with non-ST-elevation ACS dovetail nicely with the results of three other recent studies of discontinuing aspirin after 1-3 months versus continuing DAPT with ticagrelor or another P2Y12 inhibitor plus aspirin. These studies, GLOBAL LEADERS (Lancet. 2018 Sep 15;392[10151]:940-9); SMART CHOICE (JAMA. 2019 Jun 25;321[24]:2428-37); and STOPDAPT-2 (JAMA. 2019 Jun 25;321[24]:2414-27) included patients undergoing PCI either for stable coronary disease or for ST-elevation MI, but not for non-ST-elevation ACS.
Dr. O’Donoghue, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School, Boston, conducted a meta-analysis including the TWILIGHT ACS trial and the other three studies. In a total population of 29,205 patients, a strategy of dropping aspirin while continuing a P2Y12 inhibitor after 1-3 months of DAPT was associated with a 40% relative risk reduction in major bleeding events when compared with continued DAPT, with no indication of an increased risk of major adverse cardiovascular events. When she looked specifically at the nearly 14,000 post-ACS patients in the studies, the same consistency with respect to outcomes held true: an overall 51% reduction in bleeding, and – if anything – a favorable trend involving an 11% reduction in the risk of major adverse cardiovascular events, although this difference didn’t reach statistical significance.
“I believe that discontinuation of aspirin markedly reduces bleeding when stopped 1-3 months post PCI for patients initially started on DAPT,” Dr. O’Donoghue declared. “The evidence to date does not indicate that stopping aspirin leads to any increase in the risk of major adverse cardiovascular events. And these findings now extend to patients with ACS, including those with high-risk clinical and angiographic features.”
The important remaining questions, she added, include the best-choice P2Y12 inhibitor for early monotherapy post-PCI, whether the medication should be continued indefinitely past the 12-month mark, and whether aspirin might be safely discontinued even earlier than at 1-3 months.
“If you are thinking about establishing a clopidogrel monotherapy, you need to keep in mind that there exists significant interpatient variability in terms of pharmacodynamic response,” she noted, adding that platelet function testing or genotyping to identify clopidogrel resistance is worth considering in such patients.
The primary results of the full TWILIGHT study, which included 7,119 randomized patients, have been published (N Engl J Med. 2019 Sep 26. doi: 10.1056/NEJMoa1908419).
The TWILIGHT study was sponsored by AstraZeneca. Dr. Baber reported receiving honoraria from that company as well as Boston Scientific.
Dr. O’Donoghue reported receiving institutional research support from a handful of pharmaceutical companies.
SOURCE: Baber U. AHA late breaker.
REPORTING FROM AHA 2019
GALILEO, GALILEO 4D: Mixed results in post-TAVR anticoagulation
PHILADELPHIA – The results of the first randomized prospective trial of an anticoagulation strategy versus standard dual antiplatelet (DAPT) therapy for patients undergoing transcatheter aortic valve replacement (TAVR) show that routine anticoagulation is not suitable for all comers in a high-risk population.
In the main GALILEO trial of elderly patients after TAVR, those who received an investigational anticoagulation strategy with the direct factor Xa inhibitor rivaroxaban (Xarelto; Bayer/Janssen) had worse survival and more thromboembolic and bleeding events than patients who received standard DAPT.
However, in the GALILEO 4D substudy of patients who underwent four-dimensional computed tomography (4DCT) randomized to the two therapies, those in the rivaroxaban arm were less likely to show subclinical leaflet motion abnormalities and leaflet thickening.
Preliminary results from GALILEO were disclosed in an October 3, 2018, “Dear Healthcare Professional” letter from Bayer, and the trial was stopped after a median of 17 months due to safety concerns.
The full data analysis from GALILEO as well as the results from GALILEO 4D were presented at the American Heart Association scientific sessions to coincide with their publication on Nov. 16, 2019, in the New England Journal of Medicine.
The takeaway message is that, despite the positive imaging finding in GALILEO 4D, “there is no reason to give 10 mg rivaroxaban-based treatment routinely after TAVR in patients who don’t need anticoagulation anyhow,” lead author in the main GALILEO trial, George D. Dangas, MD, PhD, Mount Sinai Hospital, New York, said in an interview.
However, because rivaroxaban had an effect in reducing the clots on leaflets, he said, further investigation is required to determine the optimal therapeutic strategy after TAVR.
Similarly, the assigned discussant for GALILEO, Elaine Hylek, MD, of Boston University said in an interview that “we just don’t know right now what the overall added benefit of an oral anticoagulant would be in this high-risk patient population after having a TAVR.”
Ole De Backer, MD, PhD, of Rigshospitalet University Hospital, Copenhagen, lead author of the GALILEO 4D substudy, concluded that, although the rivaroxaban-based strategy was associated with fewer valve abnormalities in this analysis, those positive outcomes need to be taken in context with worse clinical outcomes in the main GALILEO trial.
GALILEO
Guidelines recommend DAPT after TAVR, but this advice is based on expert consensus or small studies, the GALILEO study authors noted. Several years ago, there were random case reports and then case series of patients who had undergone TAVR or surgical aortic valve replacement (SAVR) and developed clots around the valve, Dr. Dangas explained.
These developments coincided with the first available high-quality CT angiography images that captured valve abnormalities that had not been seen before.
In parallel, there were rare reports of stroke and transient ischemic attack (TIA) that may have been associated with TAVR or SAVR. This triggered a series of studies to investigate an anticoagulation strategy after TAVR.
From December 2015 to May 2018, GALILEO enrolled 1,644 patients at 136 sites in 16 countries who had undergone successful TAVR, and had no indication for an anticoagulant (e.g., no atrial fibrillation).
The patients had a mean age of 80.6 years (plus or minus 6.6 years) and 49.5% were female. The median time from TAVR to randomization was 2 days (range, 0-8 days).
Half were randomized to receive an antithrombotic strategy, rivaroxaban 10 mg once daily plus aspirin 75-100 mg once daily for the first 90 days followed by rivaroxaban alone. The other half received an antiplatelet-based strategy, aspirin 75-100 mg once daily plus clopidogrel 75 mg once daily for the first 90 days followed by aspirin alone.
In the intention-to-treat analysis, death or first thromboembolic event, the primary efficacy outcome, occurred in 105 patients in the rivaroxaban group and 78 patients in the antiplatelet group (hazard ratio, 1.35; 95% CI, 1.01-1.81; P = .04).
Major, disabling, or life-threatening bleeding, the primary safety outcome, occurred in 46 and 31 patients, respectively (HR, 1.50; P = .08).
A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (HR, 1.69; 95% CI, 1.13-2.53).
The individuals who were enrolled in this study were 80 and older, Dr. Hylek pointed out. “The age in and of itself is an uncontested risk factor for everything, whether it be bleeding, embolic event, or obviously mortality.”
Although the dose was half that used to prevent stroke in patients with atrial fibrillation, perhaps a “twice-daily lower dose” might be the way to go, moving forward, she said.
Patients who did not have atrial fibrillation may have developed atrial fibrillation in the interim, and “you would have to change the dose of the rivaroxaban.”
Also, patients who may have been taking aspirin for 5 or 10 years and “survived” aspirin, who were then newly exposed to an anticoagulant, would be more likely to experience bleeding.
“I certainly wouldn’t close the door on novel anticoagulants,” she concluded. “There are still other drug trials that are out there with this TAVR population. We’ll wait for that,” and see if the results corroborate these findings.
The high-risk patients may turn out to be a potential niche group for drugs being developed to inhibit factor XIa, she speculated.
GALILEO 4D
However, despite the negative results of the overall GALILEO study, results from the substudy that used 4DCT to evaluate function of the bioprosthetic aortic valves suggested rivaroxaban may have potentially beneficial effects on valve function.
The results showed that patients on the rivaroxaban and aspirin regimen had lower rates of subclinical reduced leaflet motion and leaflet thickening than patients on the antiplatelet strategy, said Dr. De Backer, reporting on behalf of the GALILEO-4D investigators.
The substudy evaluated 205 patients who had 4DCT 90 days after TAVR. The primary substudy endpoint was at least one prosthetic valve leaflet with a grade 3 or higher motion reduction, which 2 of 97 patients in the rivaroxaban group had (2.1%) versus 11 of 101 in the antiplatelet group (10.9%, P = .01).
“This indicated an 80% greater reduction of the primary endpoint in the rivaroxaban arm,” Dr. De Backer said. The chief secondary endpoint, the proportion of patients with at least one thickened leaflet, was met by 12.4% of the rivaroxaban group and 32.4% of the antiplatelet arm, “a 60% significant reduction by rivaroxaban,” Dr. De Backer said.
However, when the 10 patients in each group who didn’t adhere to the study drug regimen were excluded, he said, “then we see no single patient had reduced leaflet motion of grade 3 or more in the rivaroxaban arm.”
Another takeaway from the substudy is the ineffectiveness of transthoracic echocardiography as opposed to 4DCT in TAVR patients. Echocardiography (ECG) failed to show any significant differences in the mean valve gradient between the treatment groups, Dr. De Backer said.
Eleven patients who didn’t have leaflet thickening (7.3%) and 7 patients who did (15.9%) showed an increase of 5 mm Hg or more in the mean valve gradient on echo. ECG also showed a similar increase in the mean valve gradient in 14 patients who had no to moderate reduced leaflet motion (grade 3 or lower, 7.7%) and in four patients (30.8) who had grade 3 or higher reduced leaflet motion.
“This basically confirms results from observational studies that transthoracic echocardiography is often not good enough to detect these phenomena,” Dr. De Backer said.
The percentages of substudy patients who had major clinical events – major bleeding, thromboembolic events, or death at 90 days – were each less than 3%, he said. “There were too few clinical events to permit any assessment of the impact of leaflet thickening or reduced leaflet motion on clinical outcomes,” he said.
That lack of clarity with regard to clinical events is one of the questions the study leaves unanswered, said discussant Victoria Delgado, MD, PhD, of Leiden University Medical Center in the Netherlands.
“With stroke or TIA, there are too few events to draw any conclusions,” she said of the substudy. “We don’t know when we need to use CT, when we need to evaluate these patients, or maybe when we should go for more advanced imaging techniques where we can see the biology of those changes in the leaflets.” Hopefully, she said, future studies provide those insights.
“CT can be more sensitive than ECG to see these subclinical changes,” she said, “but the open questions that we have are to see if there is a correlation between thrombosis rate on imaging versus the stroke rate.”
The substudy’s conclusion on ECG, however, has been borne out by previous retrospective studies, Dr. Delgado added.
Robert A. Harrington, MD, of Stanford Medicine, tried to put the seemingly conflicting findings of the main GALILEO study and the 4D substudy into context.
“There you have the disconnect between the mechanism and the clinical observation and those are sometimes difficult to reconcile because the assumption is that the mechanism leads to the clinical outcome.”
While the main study shows that routine anticoagulation after TAVR is not indicated, the findings raise questions about the risk of clots forming on bioprosthetic valves. “Yes, maybe there are clots forming on these valves, but maybe that’s not causing the bad clinical outcomes,” Dr. Harrington said.
The findings also raise questions about the use of newer anticoagulants to prevent stroke post TAVR, he said. “It appears that warfarin is better than the newer anticoagulants for reasons that aren’t entirely clear.”
Dr. Dangas, lead author of the main GALILEO trial, said the substudy results could help design future trials of even-lower doses of anticoagulation in a more selective group of TAVR patients.
“In order to decrease the clots, first of all you don’t need the full dose of anticoagulation; even a low dose may do the trick,” he said. Further investigations can evaluate the clinical significance of having a blood clot in the valve as an indication for anticoagulation versus antiplatelet therapy.
“Even though this obviously doesn’t mean you’re going to have a stroke in a year or two,” Dr. Dangas said, “could it perhaps mean that the valve is not going to have such a good durability later on?”
Perhaps future studies of anticoagulation in TAVR should concentrate on patients who actually have clotting in the valve, he said.
The trial was supported by Bayer and Janssen. Dr. Dangas reported receiving grants from Bayer during the conduct of the study, personal fees from Bayer and Janssen, grants and personal fees from Daiichi-Sankyo, and “other” funding from Medtronic outside the submitted work. Dr. De Backer reported receiving grants from Bayer during the conduct of the study and personal fees from Abbott and Boston Scientific outside the submitted work.
SOURCE: Dangas GD and De Backer O. AHA 19, Late-Breaking Science 3 session.
This article also appears on Medscape.com.
PHILADELPHIA – The results of the first randomized prospective trial of an anticoagulation strategy versus standard dual antiplatelet (DAPT) therapy for patients undergoing transcatheter aortic valve replacement (TAVR) show that routine anticoagulation is not suitable for all comers in a high-risk population.
In the main GALILEO trial of elderly patients after TAVR, those who received an investigational anticoagulation strategy with the direct factor Xa inhibitor rivaroxaban (Xarelto; Bayer/Janssen) had worse survival and more thromboembolic and bleeding events than patients who received standard DAPT.
However, in the GALILEO 4D substudy of patients who underwent four-dimensional computed tomography (4DCT) randomized to the two therapies, those in the rivaroxaban arm were less likely to show subclinical leaflet motion abnormalities and leaflet thickening.
Preliminary results from GALILEO were disclosed in an October 3, 2018, “Dear Healthcare Professional” letter from Bayer, and the trial was stopped after a median of 17 months due to safety concerns.
The full data analysis from GALILEO as well as the results from GALILEO 4D were presented at the American Heart Association scientific sessions to coincide with their publication on Nov. 16, 2019, in the New England Journal of Medicine.
The takeaway message is that, despite the positive imaging finding in GALILEO 4D, “there is no reason to give 10 mg rivaroxaban-based treatment routinely after TAVR in patients who don’t need anticoagulation anyhow,” lead author in the main GALILEO trial, George D. Dangas, MD, PhD, Mount Sinai Hospital, New York, said in an interview.
However, because rivaroxaban had an effect in reducing the clots on leaflets, he said, further investigation is required to determine the optimal therapeutic strategy after TAVR.
Similarly, the assigned discussant for GALILEO, Elaine Hylek, MD, of Boston University said in an interview that “we just don’t know right now what the overall added benefit of an oral anticoagulant would be in this high-risk patient population after having a TAVR.”
Ole De Backer, MD, PhD, of Rigshospitalet University Hospital, Copenhagen, lead author of the GALILEO 4D substudy, concluded that, although the rivaroxaban-based strategy was associated with fewer valve abnormalities in this analysis, those positive outcomes need to be taken in context with worse clinical outcomes in the main GALILEO trial.
GALILEO
Guidelines recommend DAPT after TAVR, but this advice is based on expert consensus or small studies, the GALILEO study authors noted. Several years ago, there were random case reports and then case series of patients who had undergone TAVR or surgical aortic valve replacement (SAVR) and developed clots around the valve, Dr. Dangas explained.
These developments coincided with the first available high-quality CT angiography images that captured valve abnormalities that had not been seen before.
In parallel, there were rare reports of stroke and transient ischemic attack (TIA) that may have been associated with TAVR or SAVR. This triggered a series of studies to investigate an anticoagulation strategy after TAVR.
From December 2015 to May 2018, GALILEO enrolled 1,644 patients at 136 sites in 16 countries who had undergone successful TAVR, and had no indication for an anticoagulant (e.g., no atrial fibrillation).
The patients had a mean age of 80.6 years (plus or minus 6.6 years) and 49.5% were female. The median time from TAVR to randomization was 2 days (range, 0-8 days).
Half were randomized to receive an antithrombotic strategy, rivaroxaban 10 mg once daily plus aspirin 75-100 mg once daily for the first 90 days followed by rivaroxaban alone. The other half received an antiplatelet-based strategy, aspirin 75-100 mg once daily plus clopidogrel 75 mg once daily for the first 90 days followed by aspirin alone.
In the intention-to-treat analysis, death or first thromboembolic event, the primary efficacy outcome, occurred in 105 patients in the rivaroxaban group and 78 patients in the antiplatelet group (hazard ratio, 1.35; 95% CI, 1.01-1.81; P = .04).
Major, disabling, or life-threatening bleeding, the primary safety outcome, occurred in 46 and 31 patients, respectively (HR, 1.50; P = .08).
A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (HR, 1.69; 95% CI, 1.13-2.53).
The individuals who were enrolled in this study were 80 and older, Dr. Hylek pointed out. “The age in and of itself is an uncontested risk factor for everything, whether it be bleeding, embolic event, or obviously mortality.”
Although the dose was half that used to prevent stroke in patients with atrial fibrillation, perhaps a “twice-daily lower dose” might be the way to go, moving forward, she said.
Patients who did not have atrial fibrillation may have developed atrial fibrillation in the interim, and “you would have to change the dose of the rivaroxaban.”
Also, patients who may have been taking aspirin for 5 or 10 years and “survived” aspirin, who were then newly exposed to an anticoagulant, would be more likely to experience bleeding.
“I certainly wouldn’t close the door on novel anticoagulants,” she concluded. “There are still other drug trials that are out there with this TAVR population. We’ll wait for that,” and see if the results corroborate these findings.
The high-risk patients may turn out to be a potential niche group for drugs being developed to inhibit factor XIa, she speculated.
GALILEO 4D
However, despite the negative results of the overall GALILEO study, results from the substudy that used 4DCT to evaluate function of the bioprosthetic aortic valves suggested rivaroxaban may have potentially beneficial effects on valve function.
The results showed that patients on the rivaroxaban and aspirin regimen had lower rates of subclinical reduced leaflet motion and leaflet thickening than patients on the antiplatelet strategy, said Dr. De Backer, reporting on behalf of the GALILEO-4D investigators.
The substudy evaluated 205 patients who had 4DCT 90 days after TAVR. The primary substudy endpoint was at least one prosthetic valve leaflet with a grade 3 or higher motion reduction, which 2 of 97 patients in the rivaroxaban group had (2.1%) versus 11 of 101 in the antiplatelet group (10.9%, P = .01).
“This indicated an 80% greater reduction of the primary endpoint in the rivaroxaban arm,” Dr. De Backer said. The chief secondary endpoint, the proportion of patients with at least one thickened leaflet, was met by 12.4% of the rivaroxaban group and 32.4% of the antiplatelet arm, “a 60% significant reduction by rivaroxaban,” Dr. De Backer said.
However, when the 10 patients in each group who didn’t adhere to the study drug regimen were excluded, he said, “then we see no single patient had reduced leaflet motion of grade 3 or more in the rivaroxaban arm.”
Another takeaway from the substudy is the ineffectiveness of transthoracic echocardiography as opposed to 4DCT in TAVR patients. Echocardiography (ECG) failed to show any significant differences in the mean valve gradient between the treatment groups, Dr. De Backer said.
Eleven patients who didn’t have leaflet thickening (7.3%) and 7 patients who did (15.9%) showed an increase of 5 mm Hg or more in the mean valve gradient on echo. ECG also showed a similar increase in the mean valve gradient in 14 patients who had no to moderate reduced leaflet motion (grade 3 or lower, 7.7%) and in four patients (30.8) who had grade 3 or higher reduced leaflet motion.
“This basically confirms results from observational studies that transthoracic echocardiography is often not good enough to detect these phenomena,” Dr. De Backer said.
The percentages of substudy patients who had major clinical events – major bleeding, thromboembolic events, or death at 90 days – were each less than 3%, he said. “There were too few clinical events to permit any assessment of the impact of leaflet thickening or reduced leaflet motion on clinical outcomes,” he said.
That lack of clarity with regard to clinical events is one of the questions the study leaves unanswered, said discussant Victoria Delgado, MD, PhD, of Leiden University Medical Center in the Netherlands.
“With stroke or TIA, there are too few events to draw any conclusions,” she said of the substudy. “We don’t know when we need to use CT, when we need to evaluate these patients, or maybe when we should go for more advanced imaging techniques where we can see the biology of those changes in the leaflets.” Hopefully, she said, future studies provide those insights.
“CT can be more sensitive than ECG to see these subclinical changes,” she said, “but the open questions that we have are to see if there is a correlation between thrombosis rate on imaging versus the stroke rate.”
The substudy’s conclusion on ECG, however, has been borne out by previous retrospective studies, Dr. Delgado added.
Robert A. Harrington, MD, of Stanford Medicine, tried to put the seemingly conflicting findings of the main GALILEO study and the 4D substudy into context.
“There you have the disconnect between the mechanism and the clinical observation and those are sometimes difficult to reconcile because the assumption is that the mechanism leads to the clinical outcome.”
While the main study shows that routine anticoagulation after TAVR is not indicated, the findings raise questions about the risk of clots forming on bioprosthetic valves. “Yes, maybe there are clots forming on these valves, but maybe that’s not causing the bad clinical outcomes,” Dr. Harrington said.
The findings also raise questions about the use of newer anticoagulants to prevent stroke post TAVR, he said. “It appears that warfarin is better than the newer anticoagulants for reasons that aren’t entirely clear.”
Dr. Dangas, lead author of the main GALILEO trial, said the substudy results could help design future trials of even-lower doses of anticoagulation in a more selective group of TAVR patients.
“In order to decrease the clots, first of all you don’t need the full dose of anticoagulation; even a low dose may do the trick,” he said. Further investigations can evaluate the clinical significance of having a blood clot in the valve as an indication for anticoagulation versus antiplatelet therapy.
“Even though this obviously doesn’t mean you’re going to have a stroke in a year or two,” Dr. Dangas said, “could it perhaps mean that the valve is not going to have such a good durability later on?”
Perhaps future studies of anticoagulation in TAVR should concentrate on patients who actually have clotting in the valve, he said.
The trial was supported by Bayer and Janssen. Dr. Dangas reported receiving grants from Bayer during the conduct of the study, personal fees from Bayer and Janssen, grants and personal fees from Daiichi-Sankyo, and “other” funding from Medtronic outside the submitted work. Dr. De Backer reported receiving grants from Bayer during the conduct of the study and personal fees from Abbott and Boston Scientific outside the submitted work.
SOURCE: Dangas GD and De Backer O. AHA 19, Late-Breaking Science 3 session.
This article also appears on Medscape.com.
PHILADELPHIA – The results of the first randomized prospective trial of an anticoagulation strategy versus standard dual antiplatelet (DAPT) therapy for patients undergoing transcatheter aortic valve replacement (TAVR) show that routine anticoagulation is not suitable for all comers in a high-risk population.
In the main GALILEO trial of elderly patients after TAVR, those who received an investigational anticoagulation strategy with the direct factor Xa inhibitor rivaroxaban (Xarelto; Bayer/Janssen) had worse survival and more thromboembolic and bleeding events than patients who received standard DAPT.
However, in the GALILEO 4D substudy of patients who underwent four-dimensional computed tomography (4DCT) randomized to the two therapies, those in the rivaroxaban arm were less likely to show subclinical leaflet motion abnormalities and leaflet thickening.
Preliminary results from GALILEO were disclosed in an October 3, 2018, “Dear Healthcare Professional” letter from Bayer, and the trial was stopped after a median of 17 months due to safety concerns.
The full data analysis from GALILEO as well as the results from GALILEO 4D were presented at the American Heart Association scientific sessions to coincide with their publication on Nov. 16, 2019, in the New England Journal of Medicine.
The takeaway message is that, despite the positive imaging finding in GALILEO 4D, “there is no reason to give 10 mg rivaroxaban-based treatment routinely after TAVR in patients who don’t need anticoagulation anyhow,” lead author in the main GALILEO trial, George D. Dangas, MD, PhD, Mount Sinai Hospital, New York, said in an interview.
However, because rivaroxaban had an effect in reducing the clots on leaflets, he said, further investigation is required to determine the optimal therapeutic strategy after TAVR.
Similarly, the assigned discussant for GALILEO, Elaine Hylek, MD, of Boston University said in an interview that “we just don’t know right now what the overall added benefit of an oral anticoagulant would be in this high-risk patient population after having a TAVR.”
Ole De Backer, MD, PhD, of Rigshospitalet University Hospital, Copenhagen, lead author of the GALILEO 4D substudy, concluded that, although the rivaroxaban-based strategy was associated with fewer valve abnormalities in this analysis, those positive outcomes need to be taken in context with worse clinical outcomes in the main GALILEO trial.
GALILEO
Guidelines recommend DAPT after TAVR, but this advice is based on expert consensus or small studies, the GALILEO study authors noted. Several years ago, there were random case reports and then case series of patients who had undergone TAVR or surgical aortic valve replacement (SAVR) and developed clots around the valve, Dr. Dangas explained.
These developments coincided with the first available high-quality CT angiography images that captured valve abnormalities that had not been seen before.
In parallel, there were rare reports of stroke and transient ischemic attack (TIA) that may have been associated with TAVR or SAVR. This triggered a series of studies to investigate an anticoagulation strategy after TAVR.
From December 2015 to May 2018, GALILEO enrolled 1,644 patients at 136 sites in 16 countries who had undergone successful TAVR, and had no indication for an anticoagulant (e.g., no atrial fibrillation).
The patients had a mean age of 80.6 years (plus or minus 6.6 years) and 49.5% were female. The median time from TAVR to randomization was 2 days (range, 0-8 days).
Half were randomized to receive an antithrombotic strategy, rivaroxaban 10 mg once daily plus aspirin 75-100 mg once daily for the first 90 days followed by rivaroxaban alone. The other half received an antiplatelet-based strategy, aspirin 75-100 mg once daily plus clopidogrel 75 mg once daily for the first 90 days followed by aspirin alone.
In the intention-to-treat analysis, death or first thromboembolic event, the primary efficacy outcome, occurred in 105 patients in the rivaroxaban group and 78 patients in the antiplatelet group (hazard ratio, 1.35; 95% CI, 1.01-1.81; P = .04).
Major, disabling, or life-threatening bleeding, the primary safety outcome, occurred in 46 and 31 patients, respectively (HR, 1.50; P = .08).
A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (HR, 1.69; 95% CI, 1.13-2.53).
The individuals who were enrolled in this study were 80 and older, Dr. Hylek pointed out. “The age in and of itself is an uncontested risk factor for everything, whether it be bleeding, embolic event, or obviously mortality.”
Although the dose was half that used to prevent stroke in patients with atrial fibrillation, perhaps a “twice-daily lower dose” might be the way to go, moving forward, she said.
Patients who did not have atrial fibrillation may have developed atrial fibrillation in the interim, and “you would have to change the dose of the rivaroxaban.”
Also, patients who may have been taking aspirin for 5 or 10 years and “survived” aspirin, who were then newly exposed to an anticoagulant, would be more likely to experience bleeding.
“I certainly wouldn’t close the door on novel anticoagulants,” she concluded. “There are still other drug trials that are out there with this TAVR population. We’ll wait for that,” and see if the results corroborate these findings.
The high-risk patients may turn out to be a potential niche group for drugs being developed to inhibit factor XIa, she speculated.
GALILEO 4D
However, despite the negative results of the overall GALILEO study, results from the substudy that used 4DCT to evaluate function of the bioprosthetic aortic valves suggested rivaroxaban may have potentially beneficial effects on valve function.
The results showed that patients on the rivaroxaban and aspirin regimen had lower rates of subclinical reduced leaflet motion and leaflet thickening than patients on the antiplatelet strategy, said Dr. De Backer, reporting on behalf of the GALILEO-4D investigators.
The substudy evaluated 205 patients who had 4DCT 90 days after TAVR. The primary substudy endpoint was at least one prosthetic valve leaflet with a grade 3 or higher motion reduction, which 2 of 97 patients in the rivaroxaban group had (2.1%) versus 11 of 101 in the antiplatelet group (10.9%, P = .01).
“This indicated an 80% greater reduction of the primary endpoint in the rivaroxaban arm,” Dr. De Backer said. The chief secondary endpoint, the proportion of patients with at least one thickened leaflet, was met by 12.4% of the rivaroxaban group and 32.4% of the antiplatelet arm, “a 60% significant reduction by rivaroxaban,” Dr. De Backer said.
However, when the 10 patients in each group who didn’t adhere to the study drug regimen were excluded, he said, “then we see no single patient had reduced leaflet motion of grade 3 or more in the rivaroxaban arm.”
Another takeaway from the substudy is the ineffectiveness of transthoracic echocardiography as opposed to 4DCT in TAVR patients. Echocardiography (ECG) failed to show any significant differences in the mean valve gradient between the treatment groups, Dr. De Backer said.
Eleven patients who didn’t have leaflet thickening (7.3%) and 7 patients who did (15.9%) showed an increase of 5 mm Hg or more in the mean valve gradient on echo. ECG also showed a similar increase in the mean valve gradient in 14 patients who had no to moderate reduced leaflet motion (grade 3 or lower, 7.7%) and in four patients (30.8) who had grade 3 or higher reduced leaflet motion.
“This basically confirms results from observational studies that transthoracic echocardiography is often not good enough to detect these phenomena,” Dr. De Backer said.
The percentages of substudy patients who had major clinical events – major bleeding, thromboembolic events, or death at 90 days – were each less than 3%, he said. “There were too few clinical events to permit any assessment of the impact of leaflet thickening or reduced leaflet motion on clinical outcomes,” he said.
That lack of clarity with regard to clinical events is one of the questions the study leaves unanswered, said discussant Victoria Delgado, MD, PhD, of Leiden University Medical Center in the Netherlands.
“With stroke or TIA, there are too few events to draw any conclusions,” she said of the substudy. “We don’t know when we need to use CT, when we need to evaluate these patients, or maybe when we should go for more advanced imaging techniques where we can see the biology of those changes in the leaflets.” Hopefully, she said, future studies provide those insights.
“CT can be more sensitive than ECG to see these subclinical changes,” she said, “but the open questions that we have are to see if there is a correlation between thrombosis rate on imaging versus the stroke rate.”
The substudy’s conclusion on ECG, however, has been borne out by previous retrospective studies, Dr. Delgado added.
Robert A. Harrington, MD, of Stanford Medicine, tried to put the seemingly conflicting findings of the main GALILEO study and the 4D substudy into context.
“There you have the disconnect between the mechanism and the clinical observation and those are sometimes difficult to reconcile because the assumption is that the mechanism leads to the clinical outcome.”
While the main study shows that routine anticoagulation after TAVR is not indicated, the findings raise questions about the risk of clots forming on bioprosthetic valves. “Yes, maybe there are clots forming on these valves, but maybe that’s not causing the bad clinical outcomes,” Dr. Harrington said.
The findings also raise questions about the use of newer anticoagulants to prevent stroke post TAVR, he said. “It appears that warfarin is better than the newer anticoagulants for reasons that aren’t entirely clear.”
Dr. Dangas, lead author of the main GALILEO trial, said the substudy results could help design future trials of even-lower doses of anticoagulation in a more selective group of TAVR patients.
“In order to decrease the clots, first of all you don’t need the full dose of anticoagulation; even a low dose may do the trick,” he said. Further investigations can evaluate the clinical significance of having a blood clot in the valve as an indication for anticoagulation versus antiplatelet therapy.
“Even though this obviously doesn’t mean you’re going to have a stroke in a year or two,” Dr. Dangas said, “could it perhaps mean that the valve is not going to have such a good durability later on?”
Perhaps future studies of anticoagulation in TAVR should concentrate on patients who actually have clotting in the valve, he said.
The trial was supported by Bayer and Janssen. Dr. Dangas reported receiving grants from Bayer during the conduct of the study, personal fees from Bayer and Janssen, grants and personal fees from Daiichi-Sankyo, and “other” funding from Medtronic outside the submitted work. Dr. De Backer reported receiving grants from Bayer during the conduct of the study and personal fees from Abbott and Boston Scientific outside the submitted work.
SOURCE: Dangas GD and De Backer O. AHA 19, Late-Breaking Science 3 session.
This article also appears on Medscape.com.
REPORTING FROM AHA 2019