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SGLT2 inhibitor ertugliflozin shows no CV death or renal benefit
The sodium-glucose transporter 2 (SGLT-2) inhibitor ertugliflozin broke ranks with the other drugs in its class and failed to produce statistically significant drops in the both the combined incidence of cardiovascular (CV) death or heart failure hospitalization, and the rate of adverse renal outcomes, in the mandated CV outcomes trial run for ertugliflozin with more than 8,200 patients with type 2 diabetes and established CV disease.
Merck, one of the companies that markets the drug, announced the topline results in a quarterly financial report released on April 28, 2020.
According to the report, the results from the ertugliflozin cardiovascular outcomes trial “achieved its primary endpoint of noninferiority for major adverse CV events (MACE), compared to placebo in patients with type 2 diabetes mellitus and established atherosclerotic CV disease,” but “the key secondary endpoints of superiority” of ertugliflozin, compared with placebo, “for time to the composite of CV death or hospitalization for heart failure, CV death alone, and the composite of renal death, dialysis/transplant or doubling of serum creatinine from baseline were not met.”
However, the report added that, “while not a prespecified hypothesis for statistical testing, a reduction in hospitalization for heart failure was observed” with ertugliflozin treatment, and the report further said that the drug’s safety profile in the trial “was consistent with that reported in previous studies.” The statement closed by saying that detailed results from the trial are scheduled to be presented on June 16, 2020, at the virtual American Diabetes Association’s 80th Scientific Sessions.
These results came from the VERTIS CV (Evaluation of Ertugliflozin EffIcacy and Safety Cardiovascular Outcomes) trial, which researchers said in 2018 had administered at least one investigational dose to 8,238 randomized patients at centers in any of 34 countries during two enrollment periods in 2013-2015 and 2016-2017 (Am Heart J. 2018 Dec;206:11-23). The tested agent, ertugliflozin (Steglatro) received Food and Drug Administration marketing approval late in 2017 for the indication of improving glycemic control in patients with type 2 diabetes.
The FDA mandated cardiovascular outcomes trials for new glycemic control drugs in guidance the agency issued in 2008 (the FDA released in March 2020 a draft of updated guidance on this topic).
Other FDA-approved agents from the SGLT2 inhibitor class include canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), and all three showed evidence for a statistically significant effect on reducing the incidence of CV disease death and heart failure hospitalizations, as well as renal complications (Can J Diabetes. 2020 Feb;44[1]:61-7). The evidence showing that several SGLT2 drugs have important and consistent effects on endpoints like CV death, heart failure hospitalizations, and renal complications has helped propel this class of agents to the forefront of glycemic control treatments. More recently, one agent from this group, dapagliflozin, also significantly cut the rate of heart failure worsening or CV disease death in patients with heart failure with reduced ejection fraction but without diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008). Based on this evidence, the FDA is currently considering adding a new indication for dapagliflozin that would also label it for use in patients with heart failure with reduced ejection fraction but without diabetes.
The sodium-glucose transporter 2 (SGLT-2) inhibitor ertugliflozin broke ranks with the other drugs in its class and failed to produce statistically significant drops in the both the combined incidence of cardiovascular (CV) death or heart failure hospitalization, and the rate of adverse renal outcomes, in the mandated CV outcomes trial run for ertugliflozin with more than 8,200 patients with type 2 diabetes and established CV disease.
Merck, one of the companies that markets the drug, announced the topline results in a quarterly financial report released on April 28, 2020.
According to the report, the results from the ertugliflozin cardiovascular outcomes trial “achieved its primary endpoint of noninferiority for major adverse CV events (MACE), compared to placebo in patients with type 2 diabetes mellitus and established atherosclerotic CV disease,” but “the key secondary endpoints of superiority” of ertugliflozin, compared with placebo, “for time to the composite of CV death or hospitalization for heart failure, CV death alone, and the composite of renal death, dialysis/transplant or doubling of serum creatinine from baseline were not met.”
However, the report added that, “while not a prespecified hypothesis for statistical testing, a reduction in hospitalization for heart failure was observed” with ertugliflozin treatment, and the report further said that the drug’s safety profile in the trial “was consistent with that reported in previous studies.” The statement closed by saying that detailed results from the trial are scheduled to be presented on June 16, 2020, at the virtual American Diabetes Association’s 80th Scientific Sessions.
These results came from the VERTIS CV (Evaluation of Ertugliflozin EffIcacy and Safety Cardiovascular Outcomes) trial, which researchers said in 2018 had administered at least one investigational dose to 8,238 randomized patients at centers in any of 34 countries during two enrollment periods in 2013-2015 and 2016-2017 (Am Heart J. 2018 Dec;206:11-23). The tested agent, ertugliflozin (Steglatro) received Food and Drug Administration marketing approval late in 2017 for the indication of improving glycemic control in patients with type 2 diabetes.
The FDA mandated cardiovascular outcomes trials for new glycemic control drugs in guidance the agency issued in 2008 (the FDA released in March 2020 a draft of updated guidance on this topic).
Other FDA-approved agents from the SGLT2 inhibitor class include canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), and all three showed evidence for a statistically significant effect on reducing the incidence of CV disease death and heart failure hospitalizations, as well as renal complications (Can J Diabetes. 2020 Feb;44[1]:61-7). The evidence showing that several SGLT2 drugs have important and consistent effects on endpoints like CV death, heart failure hospitalizations, and renal complications has helped propel this class of agents to the forefront of glycemic control treatments. More recently, one agent from this group, dapagliflozin, also significantly cut the rate of heart failure worsening or CV disease death in patients with heart failure with reduced ejection fraction but without diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008). Based on this evidence, the FDA is currently considering adding a new indication for dapagliflozin that would also label it for use in patients with heart failure with reduced ejection fraction but without diabetes.
The sodium-glucose transporter 2 (SGLT-2) inhibitor ertugliflozin broke ranks with the other drugs in its class and failed to produce statistically significant drops in the both the combined incidence of cardiovascular (CV) death or heart failure hospitalization, and the rate of adverse renal outcomes, in the mandated CV outcomes trial run for ertugliflozin with more than 8,200 patients with type 2 diabetes and established CV disease.
Merck, one of the companies that markets the drug, announced the topline results in a quarterly financial report released on April 28, 2020.
According to the report, the results from the ertugliflozin cardiovascular outcomes trial “achieved its primary endpoint of noninferiority for major adverse CV events (MACE), compared to placebo in patients with type 2 diabetes mellitus and established atherosclerotic CV disease,” but “the key secondary endpoints of superiority” of ertugliflozin, compared with placebo, “for time to the composite of CV death or hospitalization for heart failure, CV death alone, and the composite of renal death, dialysis/transplant or doubling of serum creatinine from baseline were not met.”
However, the report added that, “while not a prespecified hypothesis for statistical testing, a reduction in hospitalization for heart failure was observed” with ertugliflozin treatment, and the report further said that the drug’s safety profile in the trial “was consistent with that reported in previous studies.” The statement closed by saying that detailed results from the trial are scheduled to be presented on June 16, 2020, at the virtual American Diabetes Association’s 80th Scientific Sessions.
These results came from the VERTIS CV (Evaluation of Ertugliflozin EffIcacy and Safety Cardiovascular Outcomes) trial, which researchers said in 2018 had administered at least one investigational dose to 8,238 randomized patients at centers in any of 34 countries during two enrollment periods in 2013-2015 and 2016-2017 (Am Heart J. 2018 Dec;206:11-23). The tested agent, ertugliflozin (Steglatro) received Food and Drug Administration marketing approval late in 2017 for the indication of improving glycemic control in patients with type 2 diabetes.
The FDA mandated cardiovascular outcomes trials for new glycemic control drugs in guidance the agency issued in 2008 (the FDA released in March 2020 a draft of updated guidance on this topic).
Other FDA-approved agents from the SGLT2 inhibitor class include canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), and all three showed evidence for a statistically significant effect on reducing the incidence of CV disease death and heart failure hospitalizations, as well as renal complications (Can J Diabetes. 2020 Feb;44[1]:61-7). The evidence showing that several SGLT2 drugs have important and consistent effects on endpoints like CV death, heart failure hospitalizations, and renal complications has helped propel this class of agents to the forefront of glycemic control treatments. More recently, one agent from this group, dapagliflozin, also significantly cut the rate of heart failure worsening or CV disease death in patients with heart failure with reduced ejection fraction but without diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008). Based on this evidence, the FDA is currently considering adding a new indication for dapagliflozin that would also label it for use in patients with heart failure with reduced ejection fraction but without diabetes.
Evidence on spironolactone safety, COVID-19 reassuring for acne patients
according to a report in the Journal of the American Academy of Dermatology.
The virus needs androgens to infect cells, and uses androgen-dependent transmembrane protease serine 2 to prime viral protein spikes to anchor onto ACE2 receptors. Without that step, the virus can’t enter cells. Androgens are the only known activator in humans, so androgen blockers like spironolactone probably short-circuit the process, said the report’s lead author Carlos Wambier, MD, PhD, of the department of dermatology at Brown University, Providence, R.I (J Am Acad Dermatol. 2020 Apr 10. doi: 10.1016/j.jaad.2020.04.032).
The lack of androgens could be a possible explanation as to why mortality is so rare among children with COVID-19, and why fatalities among men are higher than among women with COVID-19, he said in an interview.
There are a lot of androgen blocker candidates, but he said spironolactone – a mainstay of acne treatment – might well be the best for the pandemic because of its concomitant lung and heart benefits.
The message counters a post on Instagram in March from a New York City dermatologist in private practice, Ellen Marmur, MD, that raised a question about spironolactone. Concerned about the situation in New York, she reviewed the literature and found a 2005 study that reported that macrophages drawn from 10 heart failure patients had increased ACE2 activity and increased messenger RNA expression after the subjects had been on spironolactone 25 mg per day for a month.
In an interview, she said she has been sharing her concerns with patients on spironolactone and offering them an alternative, such as minocycline, until this issue is better elucidated. To date, she has had one young patient who declined to switch to another treatment, and about six patients who were comfortable switching to another treatment for 1-2 months. She said that she is “clearly cautious yet uncertain about the influence of chronic spironolactone for acne on COVID infection in acne patients,” and that eventually she would be interested in seeing retrospective data on outcomes of patients on spironolactone for hypertension versus acne during the pandemic.
Dr. Marmur’s post was spread on social media and was picked up by a few online news outlets.
In an interview, Adam Friedman, MD, professor and interim chair of dermatology at George Washington University, Washington, said he’s been addressing concerns about spironolactone in educational webinars because of it.
He tells his audience that “you can’t make any claims” for COVID-19 based on the 2005 study. It was a small clinical study in heart failure patients and only assessed ACE2 expression on macrophages, not respiratory, cardiac, or mesangial cells, which are the relevant locations for viral invasion and damage. In fact, there are studies showing that spironolactone reduced ACE2 in renal mesangial cells. Also of note, spironolactone has been used with no indication of virus risk since the 1950s, he pointed out. The American Academy of Dermatology has not said to stop spironolactone.
At least one study is underway to see if spironolactone is beneficial: 100 mg twice a day for 5 days is being pitted against placebo in Turkey among people hospitalized with acute respiratory distress. The study will evaluate the effect of spironolactone on oxygenation.
“There’s no evidence to show spironolactone can increase mortality levels,” Dr. Wambier said. He is using it more now in patients with acne – a sign of androgen hyperactivity – convinced that it will protect against COVID-19. He even started his sister on it to help with androgenic hair loss, and maybe the virus.
Observations in Spain – increased prevalence of androgenic alopecia among hospitalized patients – support the androgen link; 29 of 41 men (71%) hospitalized with bilateral pneumonia had male pattern baldness, which was severe in 16 (39%), according to a recent report (J Cosmet Dermatol. 2020 Apr 16. doi: 10.1111/jocd.13443). The expected prevalence in a similar age-matched population is 31%-53%.
“Based on the scientific rationale combined with this preliminary observation, we believe investigating the potential association between androgens and COVID‐19 disease severity warrants further merit,” concluded the authors, who included Dr. Wambier, and other dermatologists from the United States, as well as Spain, Australia, Croatia, and Switzerland. “If such an association is confirmed, antiandrogens could be evaluated as a potential treatment for COVID‐19 infection,” they wrote.
The numbers are holding up in a larger series from three Spanish hospitals, and also showing a greater prevalence of androgenic hair loss among hospitalized women, Dr. Wambier said in the interview.
Authors of the two studies include an employee of Applied Biology. No conflicts were declared in the Journal of Cosmetic Dermatology study; no disclosures were listed in the JAAD study. Dr. Friedman had no disclosures.
according to a report in the Journal of the American Academy of Dermatology.
The virus needs androgens to infect cells, and uses androgen-dependent transmembrane protease serine 2 to prime viral protein spikes to anchor onto ACE2 receptors. Without that step, the virus can’t enter cells. Androgens are the only known activator in humans, so androgen blockers like spironolactone probably short-circuit the process, said the report’s lead author Carlos Wambier, MD, PhD, of the department of dermatology at Brown University, Providence, R.I (J Am Acad Dermatol. 2020 Apr 10. doi: 10.1016/j.jaad.2020.04.032).
The lack of androgens could be a possible explanation as to why mortality is so rare among children with COVID-19, and why fatalities among men are higher than among women with COVID-19, he said in an interview.
There are a lot of androgen blocker candidates, but he said spironolactone – a mainstay of acne treatment – might well be the best for the pandemic because of its concomitant lung and heart benefits.
The message counters a post on Instagram in March from a New York City dermatologist in private practice, Ellen Marmur, MD, that raised a question about spironolactone. Concerned about the situation in New York, she reviewed the literature and found a 2005 study that reported that macrophages drawn from 10 heart failure patients had increased ACE2 activity and increased messenger RNA expression after the subjects had been on spironolactone 25 mg per day for a month.
In an interview, she said she has been sharing her concerns with patients on spironolactone and offering them an alternative, such as minocycline, until this issue is better elucidated. To date, she has had one young patient who declined to switch to another treatment, and about six patients who were comfortable switching to another treatment for 1-2 months. She said that she is “clearly cautious yet uncertain about the influence of chronic spironolactone for acne on COVID infection in acne patients,” and that eventually she would be interested in seeing retrospective data on outcomes of patients on spironolactone for hypertension versus acne during the pandemic.
Dr. Marmur’s post was spread on social media and was picked up by a few online news outlets.
In an interview, Adam Friedman, MD, professor and interim chair of dermatology at George Washington University, Washington, said he’s been addressing concerns about spironolactone in educational webinars because of it.
He tells his audience that “you can’t make any claims” for COVID-19 based on the 2005 study. It was a small clinical study in heart failure patients and only assessed ACE2 expression on macrophages, not respiratory, cardiac, or mesangial cells, which are the relevant locations for viral invasion and damage. In fact, there are studies showing that spironolactone reduced ACE2 in renal mesangial cells. Also of note, spironolactone has been used with no indication of virus risk since the 1950s, he pointed out. The American Academy of Dermatology has not said to stop spironolactone.
At least one study is underway to see if spironolactone is beneficial: 100 mg twice a day for 5 days is being pitted against placebo in Turkey among people hospitalized with acute respiratory distress. The study will evaluate the effect of spironolactone on oxygenation.
“There’s no evidence to show spironolactone can increase mortality levels,” Dr. Wambier said. He is using it more now in patients with acne – a sign of androgen hyperactivity – convinced that it will protect against COVID-19. He even started his sister on it to help with androgenic hair loss, and maybe the virus.
Observations in Spain – increased prevalence of androgenic alopecia among hospitalized patients – support the androgen link; 29 of 41 men (71%) hospitalized with bilateral pneumonia had male pattern baldness, which was severe in 16 (39%), according to a recent report (J Cosmet Dermatol. 2020 Apr 16. doi: 10.1111/jocd.13443). The expected prevalence in a similar age-matched population is 31%-53%.
“Based on the scientific rationale combined with this preliminary observation, we believe investigating the potential association between androgens and COVID‐19 disease severity warrants further merit,” concluded the authors, who included Dr. Wambier, and other dermatologists from the United States, as well as Spain, Australia, Croatia, and Switzerland. “If such an association is confirmed, antiandrogens could be evaluated as a potential treatment for COVID‐19 infection,” they wrote.
The numbers are holding up in a larger series from three Spanish hospitals, and also showing a greater prevalence of androgenic hair loss among hospitalized women, Dr. Wambier said in the interview.
Authors of the two studies include an employee of Applied Biology. No conflicts were declared in the Journal of Cosmetic Dermatology study; no disclosures were listed in the JAAD study. Dr. Friedman had no disclosures.
according to a report in the Journal of the American Academy of Dermatology.
The virus needs androgens to infect cells, and uses androgen-dependent transmembrane protease serine 2 to prime viral protein spikes to anchor onto ACE2 receptors. Without that step, the virus can’t enter cells. Androgens are the only known activator in humans, so androgen blockers like spironolactone probably short-circuit the process, said the report’s lead author Carlos Wambier, MD, PhD, of the department of dermatology at Brown University, Providence, R.I (J Am Acad Dermatol. 2020 Apr 10. doi: 10.1016/j.jaad.2020.04.032).
The lack of androgens could be a possible explanation as to why mortality is so rare among children with COVID-19, and why fatalities among men are higher than among women with COVID-19, he said in an interview.
There are a lot of androgen blocker candidates, but he said spironolactone – a mainstay of acne treatment – might well be the best for the pandemic because of its concomitant lung and heart benefits.
The message counters a post on Instagram in March from a New York City dermatologist in private practice, Ellen Marmur, MD, that raised a question about spironolactone. Concerned about the situation in New York, she reviewed the literature and found a 2005 study that reported that macrophages drawn from 10 heart failure patients had increased ACE2 activity and increased messenger RNA expression after the subjects had been on spironolactone 25 mg per day for a month.
In an interview, she said she has been sharing her concerns with patients on spironolactone and offering them an alternative, such as minocycline, until this issue is better elucidated. To date, she has had one young patient who declined to switch to another treatment, and about six patients who were comfortable switching to another treatment for 1-2 months. She said that she is “clearly cautious yet uncertain about the influence of chronic spironolactone for acne on COVID infection in acne patients,” and that eventually she would be interested in seeing retrospective data on outcomes of patients on spironolactone for hypertension versus acne during the pandemic.
Dr. Marmur’s post was spread on social media and was picked up by a few online news outlets.
In an interview, Adam Friedman, MD, professor and interim chair of dermatology at George Washington University, Washington, said he’s been addressing concerns about spironolactone in educational webinars because of it.
He tells his audience that “you can’t make any claims” for COVID-19 based on the 2005 study. It was a small clinical study in heart failure patients and only assessed ACE2 expression on macrophages, not respiratory, cardiac, or mesangial cells, which are the relevant locations for viral invasion and damage. In fact, there are studies showing that spironolactone reduced ACE2 in renal mesangial cells. Also of note, spironolactone has been used with no indication of virus risk since the 1950s, he pointed out. The American Academy of Dermatology has not said to stop spironolactone.
At least one study is underway to see if spironolactone is beneficial: 100 mg twice a day for 5 days is being pitted against placebo in Turkey among people hospitalized with acute respiratory distress. The study will evaluate the effect of spironolactone on oxygenation.
“There’s no evidence to show spironolactone can increase mortality levels,” Dr. Wambier said. He is using it more now in patients with acne – a sign of androgen hyperactivity – convinced that it will protect against COVID-19. He even started his sister on it to help with androgenic hair loss, and maybe the virus.
Observations in Spain – increased prevalence of androgenic alopecia among hospitalized patients – support the androgen link; 29 of 41 men (71%) hospitalized with bilateral pneumonia had male pattern baldness, which was severe in 16 (39%), according to a recent report (J Cosmet Dermatol. 2020 Apr 16. doi: 10.1111/jocd.13443). The expected prevalence in a similar age-matched population is 31%-53%.
“Based on the scientific rationale combined with this preliminary observation, we believe investigating the potential association between androgens and COVID‐19 disease severity warrants further merit,” concluded the authors, who included Dr. Wambier, and other dermatologists from the United States, as well as Spain, Australia, Croatia, and Switzerland. “If such an association is confirmed, antiandrogens could be evaluated as a potential treatment for COVID‐19 infection,” they wrote.
The numbers are holding up in a larger series from three Spanish hospitals, and also showing a greater prevalence of androgenic hair loss among hospitalized women, Dr. Wambier said in the interview.
Authors of the two studies include an employee of Applied Biology. No conflicts were declared in the Journal of Cosmetic Dermatology study; no disclosures were listed in the JAAD study. Dr. Friedman had no disclosures.
HFpEF: Gender difference in sacubitril/valsartan response remains mystery
The explanation for the impressive clinical benefits of sacubitril/valsartan in women with heart failure with preserved ejection fraction in the PARAGON-HF trial – but not in the men – remains elusive, Jonathan W. Cunningham, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“We’ve all been trying to unravel the explanation for the differential effects between men and women in the primary trial. I don’t know that this NT-proBNP substudy gives a clear answer because we did see similar reduction in NT-proBNP in the men and women,” said Dr. Cunningham of Brigham and Women’s Hospital, Boston.
“Unfortunately, I think we’re still looking for the underlying physiological explanation for that very interesting interaction,” he added.
The PARAGON-HF trial included 4,796 patients with heart failure with preserved ejection fraction (HFpEF) who were randomized double-blind to sacubitril/valsartan (Entresto) or valsartan on top of background guideline-directed medical therapy and followed for a median of 34 months (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The sacubitril/valsartan group’s 13% relative risk reduction in the primary composite endpoint of cardiovascular death and total heart failure hospitalizations fell tantalizingly short of statistical significance (P = 0.058).
In women, however, who comprised more than half of the study population, the benefit of sacubitril/valsartan was larger: a 27% relative risk reduction compared to valsartan alone. That’s a statistically significant difference in a prespecified subgroup analysis, but according to the rules of clinical trials and statistics it must be considered hypothesis-generating and nondefinitive, since the overall trial was negative. Men randomized to sacubitril/valsartan had a modest 3% increased risk of the primary endpoint compared to men on valsartan.
Because of the enormous unmet need for effective therapy for HFpEF, and the fact that HFpEF is more common in women than men, the search is on for an explanation that would account for the striking gender difference in outcome in PARAGON-HF. At ACC 2020, Dr. Cunningham presented a secondary analysis of the trial focusing on the relationships between baseline and on-treatment N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and clinical outcomes.
Among the key findings was that the higher the baseline NT-proBNP, the greater the likelihood of the primary endpoint. Also, sacubitril/valsartan reduced NT-proBNP to a similar extent in men and women: For example, by 20% compared to valsartan in men and by 18% in women when measured 16 weeks after randomization. And reduction in NT-proBNP was associated with reduced risk of cardiovascular death and heart failure hospitalizations; indeed, 60% of participants in PARAGON-HF experienced a decrease in NT-proBNP, and they had a 23% lower event rate compared to patients whose NT-proBNP increased during the course of the study.
Another intriguing finding in the parent PARAGON-HF trial was that HFpEF patients with an LVEF of 45%-57% had a 22% lower rate of the primary endpoint than those with an LVEF of 58% or more. But as with the gender difference in clinical outcomes in response to sacubitril/valsartan, the difference in outcomes based on ejection fraction was not mediated by the drug’s impact on NT-proBNP, since sacubitril/valsartan reduced NT-proBNP to a similar degree in HFpEF patients with an LVEF above or below 57%.
The difference in outcomes by ejection fraction wasn’t entirely surprising, because those low-normal–range ejection fractions where sacubitril/valsartan had a favorable impact approach those characteristic of heart failure with reduced ejection fraction (HFrEF), and guidelines give sacubitril/valsartan a class I recommendation in patients with HFrEF on the strength of the medication’s demonstrated reduction in morbidity and mortality in the PARADIGM-HF trial.
Discussant Lee R. Goldberg, MD, predicted this analysis will have an impact on the design of future clinical trials in HFpEF, which up until now have required certain minimum NT-proBNP levels for participation.
“Maybe this is why so many of our trials in HFpEF have been unsuccessful. It’s a very heterogeneous population and perhaps NT-proBNP cutoffs are leading to a lot of mischief or heterogeneity that causes us some difficulty,” said Dr. Goldberg, professor of medicine and chief of the section of advanced heart failure and cardiac transplantation at the University of Pennsylvania, Philadelphia.
Dr. Cunningham reported having no financial conflicts regarding his study. The PARAGON-HF trial was funded by Novartis.
Simultaneously with Dr. Cunningham’s presentation at ACC 2020, the study results were published online (JACC Heart Fail. 2020 Mar 26; doi: 10.1016/j.jchf.2020.03.002.
SOURCE: Cunningham JW. ACC 2020, Abstract 412-08.
The explanation for the impressive clinical benefits of sacubitril/valsartan in women with heart failure with preserved ejection fraction in the PARAGON-HF trial – but not in the men – remains elusive, Jonathan W. Cunningham, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“We’ve all been trying to unravel the explanation for the differential effects between men and women in the primary trial. I don’t know that this NT-proBNP substudy gives a clear answer because we did see similar reduction in NT-proBNP in the men and women,” said Dr. Cunningham of Brigham and Women’s Hospital, Boston.
“Unfortunately, I think we’re still looking for the underlying physiological explanation for that very interesting interaction,” he added.
The PARAGON-HF trial included 4,796 patients with heart failure with preserved ejection fraction (HFpEF) who were randomized double-blind to sacubitril/valsartan (Entresto) or valsartan on top of background guideline-directed medical therapy and followed for a median of 34 months (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The sacubitril/valsartan group’s 13% relative risk reduction in the primary composite endpoint of cardiovascular death and total heart failure hospitalizations fell tantalizingly short of statistical significance (P = 0.058).
In women, however, who comprised more than half of the study population, the benefit of sacubitril/valsartan was larger: a 27% relative risk reduction compared to valsartan alone. That’s a statistically significant difference in a prespecified subgroup analysis, but according to the rules of clinical trials and statistics it must be considered hypothesis-generating and nondefinitive, since the overall trial was negative. Men randomized to sacubitril/valsartan had a modest 3% increased risk of the primary endpoint compared to men on valsartan.
Because of the enormous unmet need for effective therapy for HFpEF, and the fact that HFpEF is more common in women than men, the search is on for an explanation that would account for the striking gender difference in outcome in PARAGON-HF. At ACC 2020, Dr. Cunningham presented a secondary analysis of the trial focusing on the relationships between baseline and on-treatment N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and clinical outcomes.
Among the key findings was that the higher the baseline NT-proBNP, the greater the likelihood of the primary endpoint. Also, sacubitril/valsartan reduced NT-proBNP to a similar extent in men and women: For example, by 20% compared to valsartan in men and by 18% in women when measured 16 weeks after randomization. And reduction in NT-proBNP was associated with reduced risk of cardiovascular death and heart failure hospitalizations; indeed, 60% of participants in PARAGON-HF experienced a decrease in NT-proBNP, and they had a 23% lower event rate compared to patients whose NT-proBNP increased during the course of the study.
Another intriguing finding in the parent PARAGON-HF trial was that HFpEF patients with an LVEF of 45%-57% had a 22% lower rate of the primary endpoint than those with an LVEF of 58% or more. But as with the gender difference in clinical outcomes in response to sacubitril/valsartan, the difference in outcomes based on ejection fraction was not mediated by the drug’s impact on NT-proBNP, since sacubitril/valsartan reduced NT-proBNP to a similar degree in HFpEF patients with an LVEF above or below 57%.
The difference in outcomes by ejection fraction wasn’t entirely surprising, because those low-normal–range ejection fractions where sacubitril/valsartan had a favorable impact approach those characteristic of heart failure with reduced ejection fraction (HFrEF), and guidelines give sacubitril/valsartan a class I recommendation in patients with HFrEF on the strength of the medication’s demonstrated reduction in morbidity and mortality in the PARADIGM-HF trial.
Discussant Lee R. Goldberg, MD, predicted this analysis will have an impact on the design of future clinical trials in HFpEF, which up until now have required certain minimum NT-proBNP levels for participation.
“Maybe this is why so many of our trials in HFpEF have been unsuccessful. It’s a very heterogeneous population and perhaps NT-proBNP cutoffs are leading to a lot of mischief or heterogeneity that causes us some difficulty,” said Dr. Goldberg, professor of medicine and chief of the section of advanced heart failure and cardiac transplantation at the University of Pennsylvania, Philadelphia.
Dr. Cunningham reported having no financial conflicts regarding his study. The PARAGON-HF trial was funded by Novartis.
Simultaneously with Dr. Cunningham’s presentation at ACC 2020, the study results were published online (JACC Heart Fail. 2020 Mar 26; doi: 10.1016/j.jchf.2020.03.002.
SOURCE: Cunningham JW. ACC 2020, Abstract 412-08.
The explanation for the impressive clinical benefits of sacubitril/valsartan in women with heart failure with preserved ejection fraction in the PARAGON-HF trial – but not in the men – remains elusive, Jonathan W. Cunningham, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“We’ve all been trying to unravel the explanation for the differential effects between men and women in the primary trial. I don’t know that this NT-proBNP substudy gives a clear answer because we did see similar reduction in NT-proBNP in the men and women,” said Dr. Cunningham of Brigham and Women’s Hospital, Boston.
“Unfortunately, I think we’re still looking for the underlying physiological explanation for that very interesting interaction,” he added.
The PARAGON-HF trial included 4,796 patients with heart failure with preserved ejection fraction (HFpEF) who were randomized double-blind to sacubitril/valsartan (Entresto) or valsartan on top of background guideline-directed medical therapy and followed for a median of 34 months (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The sacubitril/valsartan group’s 13% relative risk reduction in the primary composite endpoint of cardiovascular death and total heart failure hospitalizations fell tantalizingly short of statistical significance (P = 0.058).
In women, however, who comprised more than half of the study population, the benefit of sacubitril/valsartan was larger: a 27% relative risk reduction compared to valsartan alone. That’s a statistically significant difference in a prespecified subgroup analysis, but according to the rules of clinical trials and statistics it must be considered hypothesis-generating and nondefinitive, since the overall trial was negative. Men randomized to sacubitril/valsartan had a modest 3% increased risk of the primary endpoint compared to men on valsartan.
Because of the enormous unmet need for effective therapy for HFpEF, and the fact that HFpEF is more common in women than men, the search is on for an explanation that would account for the striking gender difference in outcome in PARAGON-HF. At ACC 2020, Dr. Cunningham presented a secondary analysis of the trial focusing on the relationships between baseline and on-treatment N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and clinical outcomes.
Among the key findings was that the higher the baseline NT-proBNP, the greater the likelihood of the primary endpoint. Also, sacubitril/valsartan reduced NT-proBNP to a similar extent in men and women: For example, by 20% compared to valsartan in men and by 18% in women when measured 16 weeks after randomization. And reduction in NT-proBNP was associated with reduced risk of cardiovascular death and heart failure hospitalizations; indeed, 60% of participants in PARAGON-HF experienced a decrease in NT-proBNP, and they had a 23% lower event rate compared to patients whose NT-proBNP increased during the course of the study.
Another intriguing finding in the parent PARAGON-HF trial was that HFpEF patients with an LVEF of 45%-57% had a 22% lower rate of the primary endpoint than those with an LVEF of 58% or more. But as with the gender difference in clinical outcomes in response to sacubitril/valsartan, the difference in outcomes based on ejection fraction was not mediated by the drug’s impact on NT-proBNP, since sacubitril/valsartan reduced NT-proBNP to a similar degree in HFpEF patients with an LVEF above or below 57%.
The difference in outcomes by ejection fraction wasn’t entirely surprising, because those low-normal–range ejection fractions where sacubitril/valsartan had a favorable impact approach those characteristic of heart failure with reduced ejection fraction (HFrEF), and guidelines give sacubitril/valsartan a class I recommendation in patients with HFrEF on the strength of the medication’s demonstrated reduction in morbidity and mortality in the PARADIGM-HF trial.
Discussant Lee R. Goldberg, MD, predicted this analysis will have an impact on the design of future clinical trials in HFpEF, which up until now have required certain minimum NT-proBNP levels for participation.
“Maybe this is why so many of our trials in HFpEF have been unsuccessful. It’s a very heterogeneous population and perhaps NT-proBNP cutoffs are leading to a lot of mischief or heterogeneity that causes us some difficulty,” said Dr. Goldberg, professor of medicine and chief of the section of advanced heart failure and cardiac transplantation at the University of Pennsylvania, Philadelphia.
Dr. Cunningham reported having no financial conflicts regarding his study. The PARAGON-HF trial was funded by Novartis.
Simultaneously with Dr. Cunningham’s presentation at ACC 2020, the study results were published online (JACC Heart Fail. 2020 Mar 26; doi: 10.1016/j.jchf.2020.03.002.
SOURCE: Cunningham JW. ACC 2020, Abstract 412-08.
FROM ACC 2020
AHA updates management when CAD and T2DM coincide
Patients with stable coronary artery disease and type 2 diabetes mellitus could benefit from a “plethora of newly available risk-reduction strategies,” but their “adoption into clinical practice has been slow” and inconsistent, prompting an expert panel organized by the American Heart Association to collate the range of treatment recommendations now applicable to this patient population in a scientific statement released on April 13.
“There are a number of things to consider when treating patients with stable coronary artery disease [CAD] and type 2 diabetes mellitus [T2DM], with new medications and trials and data emerging. It’s difficult to keep up with all of the complexities,” which was why the Association’s Councils on Lifestyle and Cardiometabolic Health and on Clinical Cardiology put together a writing group to summarize and prioritize the range of lifestyle, medical, and interventional options that now require consideration and potential use on patients managed in routine practice, explained Suzanne V. Arnold, MD, chair of the writing group, in an interview.
The new scientific statement (Circulation. 2020 Apr 13; doi: 10.1161/CIR.0000000000000766), aimed primarily at cardiologists but also intended to inform primary care physicians, endocrinologists, and all other clinicians who deal with these patients, pulls together “everything someone needs to think about if they care for patients with CAD and T2DM,” said Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston and vice chair of the statement-writing panel in an interview. “There is a lot to know,” he added.
The statement covers antithrombotic therapies; blood pressure control, with a discussion of both the appropriate pressure goal and the best drug types used to reach it; lipid management; glycemic control; lifestyle modification; weight management, including the role of bariatric surgery; and approaches to managing stable angina, both medically and with revascularization.
“The goal was to give clinicians a good sense of what new treatments they should consider” for these patients, said Dr. Bhatt, who is also director of interventional cardiovascular programs at Brigham and Women’s Hospital, also in Boston. Because of the tight associations between T2DM and cardiovascular disease in general including CAD, “cardiologists are increasingly involved in managing patients with T2DM,” he noted. The statement gives a comprehensive overview and critical assessment of the management of these patients as of the end of 2019 as a consensus from a panel of 11 experts .
The statement also stressed that “substantial portions of patients with T2DM and CAD, including those after an acute coronary syndrome, do not receive therapies with proven cardiovascular benefit, such as high-intensity statins, dual-antiplatelet therapy, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and glucose-lowering agents with proven cardiovascular benefits.
“These gaps in care highlight a critical opportunity for cardiovascular specialists to assume a more active role in the collaborative care of patients with T2DM and CAD,” the statement said. This includes “encouraging cardiologists to become more active in the selection of glucose-lowering medications” for these patients because it could “really move the needle,” said Dr. Arnold, a cardiologist with Saint Luke’s Health System in Kansas City, Mo. She was referring specifically to broader reliance on both the SGTL2 (sodium-glucose cotransporter 2) inhibitors and the GLP-1 (glucagonlike peptide-1) receptor agonists as top choices for controlling hyperglycemia. Based on recent evidence drugs in these two classes “could be considered first line for patients with T2DM and CAD, and would likely be preferred over metformin,” Dr. Arnold said in an interview. Although the statement identified the SGLT2 inhibitors as “the first drug class [for glycemic control] to show clear benefits on cardiovascular outcomes,” it does not explicitly label the class first-line and it also skirts that designation for the GLP-1 receptor agonist class, while noting that metformin “remains the drug most frequently recommended as first-line therapy in treatment guidelines.”
“I wouldn’t disagree with someone who said that SGLT2 inhibitors and GLP-1 receptor agonists are first line,” but prescribing patterns also depend on familiarity, cost, and access, noted Dr. Bhatt, which can all be issues with agents from these classes compared with metformin, a widely available generic with decades of use. “Metformin is safe and cheap, so we did not want to discount it,” said Dr. Arnold. Dr. Bhatt recently coauthored an editorial that gave an enthusiastic endorsement to using SGLT2 inhibitors in patients with diabetes (Cell Metab. 2019 Nov 5;30[5]:47-9).
Another notable feature of the statement is the potential it assigns to bariatric surgery as a management tool with documented safety and efficacy for improving cardiovascular risk factors. However, the statement also notes that randomized trials “have thus far been inadequately powered to assess cardiovascular events and mortality, although observational studies have consistently shown cardiovascular risk reduction with such procedures.” The statement continues that despite potential cardiovascular benefits “bariatric surgery remains underused among eligible patients,” and said that surgery performed as Roux-en-Y bypass or sleeve gastrectomy “may be another effective tool for cardiovascular risk reduction in the subset of patients with obesity,” particularly patients with a body mass index of at least 35 kg/m2.
“While the percentage of patients who are optimal for bariatric surgery is not known, the most recent NHANES [National Health and Nutrition Examination Study] study showed that less than 0.5% of eligible patients underwent bariatric surgery,” Dr. Arnold noted. Bariatric surgery is “certainly not a recommendation for everyone, or even a majority of patients, but bariatric surgery should be on our radar,” for patients with CAD and T2DM, she said.
Right now, “few cardiologists think about bariatric surgery,” as a treatment option, but study results have shown that “in carefully selected patients treated by skilled surgeons at high-volume centers, patients will do better with bariatric surgery than with best medical therapy for improvements in multiple risk factors, including glycemic control,” Dr. Bhatt said in the interview. “It’s not first-line treatment, but it’s an option to consider,” he added, while also noting that bariatric surgery is most beneficial to patients relatively early in the course of T2DM, when its been in place for just a few years rather than a couple of decades.
The statement also notably included a “first-line” call out for icosapent ethyl (Vascepa), a novel agent approved in December 2019 for routine use in U.S. patients, including those with CAD and T2DM as long as their blood triglyceride level was at least 150 mg/dL. Dr. Bhatt, who led the REDUCE-IT study that was pivotal for proving the safety and efficacy of icosapent ethyl (N Engl J Med. 2019 Jan 3;380[1]:11-22), estimated that anywhere from 15% to as many as half the patients with CAD and T2DM might have a triglyceride level that would allow them to receive icosapent ethyl. One population-based study in Canada of nearly 200,000 people with atherosclerotic cardiovascular disease found a 25% prevalence of the triglyceride level needed to qualify to receive icosapent ethyl under current labeling, he noted (Eur Heart J. 2020 Jan 1;41[1]:86-94). However, the FDA label does not specify that triglycerides be measured when fasting, and a nonfasting level of about 150 mg/dL will likely appear for patients with fasting levels that fall as low as about 100 mg/dL, Dr. Bhatt said. He hoped that future studies will assess the efficacy of icosapent ethyl in patients with even lower triglyceride levels.
Other sections of the statement also recommend that clinicians: Target long-term dual-antiplatelet therapy to CAD and T2DM patients with additional high-risk markers such as prior MI, younger age, and tobacco use; prescribe a low-dose oral anticoagulant along with an antiplatelet drug such as aspirin for secondary-prevention patients; promote a blood pressure target of less than 140/90 mm Hg for all CAD and T2DM patients and apply a goal of less than 130/80 mm Hg in higher-risk patients such as blacks, Asians, and those with cerebrovascular disease; and reassure patients that “despite a modest increase in blood sugars, the risk-benefit ratio is clearly in favor of administering statins to people with T2DM and CAD.”
Dr. Arnold had no disclosures. Dr. Bhatt has been an adviser to Cardax, Cereno Scientific, Medscape Cardiology, PhaseBio; PLx Pharma, and Regado Biosciences, and he has received research funding from numerous companies including Amarin, the company that markets icosapent ethyl.
Patients with stable coronary artery disease and type 2 diabetes mellitus could benefit from a “plethora of newly available risk-reduction strategies,” but their “adoption into clinical practice has been slow” and inconsistent, prompting an expert panel organized by the American Heart Association to collate the range of treatment recommendations now applicable to this patient population in a scientific statement released on April 13.
“There are a number of things to consider when treating patients with stable coronary artery disease [CAD] and type 2 diabetes mellitus [T2DM], with new medications and trials and data emerging. It’s difficult to keep up with all of the complexities,” which was why the Association’s Councils on Lifestyle and Cardiometabolic Health and on Clinical Cardiology put together a writing group to summarize and prioritize the range of lifestyle, medical, and interventional options that now require consideration and potential use on patients managed in routine practice, explained Suzanne V. Arnold, MD, chair of the writing group, in an interview.
The new scientific statement (Circulation. 2020 Apr 13; doi: 10.1161/CIR.0000000000000766), aimed primarily at cardiologists but also intended to inform primary care physicians, endocrinologists, and all other clinicians who deal with these patients, pulls together “everything someone needs to think about if they care for patients with CAD and T2DM,” said Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston and vice chair of the statement-writing panel in an interview. “There is a lot to know,” he added.
The statement covers antithrombotic therapies; blood pressure control, with a discussion of both the appropriate pressure goal and the best drug types used to reach it; lipid management; glycemic control; lifestyle modification; weight management, including the role of bariatric surgery; and approaches to managing stable angina, both medically and with revascularization.
“The goal was to give clinicians a good sense of what new treatments they should consider” for these patients, said Dr. Bhatt, who is also director of interventional cardiovascular programs at Brigham and Women’s Hospital, also in Boston. Because of the tight associations between T2DM and cardiovascular disease in general including CAD, “cardiologists are increasingly involved in managing patients with T2DM,” he noted. The statement gives a comprehensive overview and critical assessment of the management of these patients as of the end of 2019 as a consensus from a panel of 11 experts .
The statement also stressed that “substantial portions of patients with T2DM and CAD, including those after an acute coronary syndrome, do not receive therapies with proven cardiovascular benefit, such as high-intensity statins, dual-antiplatelet therapy, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and glucose-lowering agents with proven cardiovascular benefits.
“These gaps in care highlight a critical opportunity for cardiovascular specialists to assume a more active role in the collaborative care of patients with T2DM and CAD,” the statement said. This includes “encouraging cardiologists to become more active in the selection of glucose-lowering medications” for these patients because it could “really move the needle,” said Dr. Arnold, a cardiologist with Saint Luke’s Health System in Kansas City, Mo. She was referring specifically to broader reliance on both the SGTL2 (sodium-glucose cotransporter 2) inhibitors and the GLP-1 (glucagonlike peptide-1) receptor agonists as top choices for controlling hyperglycemia. Based on recent evidence drugs in these two classes “could be considered first line for patients with T2DM and CAD, and would likely be preferred over metformin,” Dr. Arnold said in an interview. Although the statement identified the SGLT2 inhibitors as “the first drug class [for glycemic control] to show clear benefits on cardiovascular outcomes,” it does not explicitly label the class first-line and it also skirts that designation for the GLP-1 receptor agonist class, while noting that metformin “remains the drug most frequently recommended as first-line therapy in treatment guidelines.”
“I wouldn’t disagree with someone who said that SGLT2 inhibitors and GLP-1 receptor agonists are first line,” but prescribing patterns also depend on familiarity, cost, and access, noted Dr. Bhatt, which can all be issues with agents from these classes compared with metformin, a widely available generic with decades of use. “Metformin is safe and cheap, so we did not want to discount it,” said Dr. Arnold. Dr. Bhatt recently coauthored an editorial that gave an enthusiastic endorsement to using SGLT2 inhibitors in patients with diabetes (Cell Metab. 2019 Nov 5;30[5]:47-9).
Another notable feature of the statement is the potential it assigns to bariatric surgery as a management tool with documented safety and efficacy for improving cardiovascular risk factors. However, the statement also notes that randomized trials “have thus far been inadequately powered to assess cardiovascular events and mortality, although observational studies have consistently shown cardiovascular risk reduction with such procedures.” The statement continues that despite potential cardiovascular benefits “bariatric surgery remains underused among eligible patients,” and said that surgery performed as Roux-en-Y bypass or sleeve gastrectomy “may be another effective tool for cardiovascular risk reduction in the subset of patients with obesity,” particularly patients with a body mass index of at least 35 kg/m2.
“While the percentage of patients who are optimal for bariatric surgery is not known, the most recent NHANES [National Health and Nutrition Examination Study] study showed that less than 0.5% of eligible patients underwent bariatric surgery,” Dr. Arnold noted. Bariatric surgery is “certainly not a recommendation for everyone, or even a majority of patients, but bariatric surgery should be on our radar,” for patients with CAD and T2DM, she said.
Right now, “few cardiologists think about bariatric surgery,” as a treatment option, but study results have shown that “in carefully selected patients treated by skilled surgeons at high-volume centers, patients will do better with bariatric surgery than with best medical therapy for improvements in multiple risk factors, including glycemic control,” Dr. Bhatt said in the interview. “It’s not first-line treatment, but it’s an option to consider,” he added, while also noting that bariatric surgery is most beneficial to patients relatively early in the course of T2DM, when its been in place for just a few years rather than a couple of decades.
The statement also notably included a “first-line” call out for icosapent ethyl (Vascepa), a novel agent approved in December 2019 for routine use in U.S. patients, including those with CAD and T2DM as long as their blood triglyceride level was at least 150 mg/dL. Dr. Bhatt, who led the REDUCE-IT study that was pivotal for proving the safety and efficacy of icosapent ethyl (N Engl J Med. 2019 Jan 3;380[1]:11-22), estimated that anywhere from 15% to as many as half the patients with CAD and T2DM might have a triglyceride level that would allow them to receive icosapent ethyl. One population-based study in Canada of nearly 200,000 people with atherosclerotic cardiovascular disease found a 25% prevalence of the triglyceride level needed to qualify to receive icosapent ethyl under current labeling, he noted (Eur Heart J. 2020 Jan 1;41[1]:86-94). However, the FDA label does not specify that triglycerides be measured when fasting, and a nonfasting level of about 150 mg/dL will likely appear for patients with fasting levels that fall as low as about 100 mg/dL, Dr. Bhatt said. He hoped that future studies will assess the efficacy of icosapent ethyl in patients with even lower triglyceride levels.
Other sections of the statement also recommend that clinicians: Target long-term dual-antiplatelet therapy to CAD and T2DM patients with additional high-risk markers such as prior MI, younger age, and tobacco use; prescribe a low-dose oral anticoagulant along with an antiplatelet drug such as aspirin for secondary-prevention patients; promote a blood pressure target of less than 140/90 mm Hg for all CAD and T2DM patients and apply a goal of less than 130/80 mm Hg in higher-risk patients such as blacks, Asians, and those with cerebrovascular disease; and reassure patients that “despite a modest increase in blood sugars, the risk-benefit ratio is clearly in favor of administering statins to people with T2DM and CAD.”
Dr. Arnold had no disclosures. Dr. Bhatt has been an adviser to Cardax, Cereno Scientific, Medscape Cardiology, PhaseBio; PLx Pharma, and Regado Biosciences, and he has received research funding from numerous companies including Amarin, the company that markets icosapent ethyl.
Patients with stable coronary artery disease and type 2 diabetes mellitus could benefit from a “plethora of newly available risk-reduction strategies,” but their “adoption into clinical practice has been slow” and inconsistent, prompting an expert panel organized by the American Heart Association to collate the range of treatment recommendations now applicable to this patient population in a scientific statement released on April 13.
“There are a number of things to consider when treating patients with stable coronary artery disease [CAD] and type 2 diabetes mellitus [T2DM], with new medications and trials and data emerging. It’s difficult to keep up with all of the complexities,” which was why the Association’s Councils on Lifestyle and Cardiometabolic Health and on Clinical Cardiology put together a writing group to summarize and prioritize the range of lifestyle, medical, and interventional options that now require consideration and potential use on patients managed in routine practice, explained Suzanne V. Arnold, MD, chair of the writing group, in an interview.
The new scientific statement (Circulation. 2020 Apr 13; doi: 10.1161/CIR.0000000000000766), aimed primarily at cardiologists but also intended to inform primary care physicians, endocrinologists, and all other clinicians who deal with these patients, pulls together “everything someone needs to think about if they care for patients with CAD and T2DM,” said Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston and vice chair of the statement-writing panel in an interview. “There is a lot to know,” he added.
The statement covers antithrombotic therapies; blood pressure control, with a discussion of both the appropriate pressure goal and the best drug types used to reach it; lipid management; glycemic control; lifestyle modification; weight management, including the role of bariatric surgery; and approaches to managing stable angina, both medically and with revascularization.
“The goal was to give clinicians a good sense of what new treatments they should consider” for these patients, said Dr. Bhatt, who is also director of interventional cardiovascular programs at Brigham and Women’s Hospital, also in Boston. Because of the tight associations between T2DM and cardiovascular disease in general including CAD, “cardiologists are increasingly involved in managing patients with T2DM,” he noted. The statement gives a comprehensive overview and critical assessment of the management of these patients as of the end of 2019 as a consensus from a panel of 11 experts .
The statement also stressed that “substantial portions of patients with T2DM and CAD, including those after an acute coronary syndrome, do not receive therapies with proven cardiovascular benefit, such as high-intensity statins, dual-antiplatelet therapy, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and glucose-lowering agents with proven cardiovascular benefits.
“These gaps in care highlight a critical opportunity for cardiovascular specialists to assume a more active role in the collaborative care of patients with T2DM and CAD,” the statement said. This includes “encouraging cardiologists to become more active in the selection of glucose-lowering medications” for these patients because it could “really move the needle,” said Dr. Arnold, a cardiologist with Saint Luke’s Health System in Kansas City, Mo. She was referring specifically to broader reliance on both the SGTL2 (sodium-glucose cotransporter 2) inhibitors and the GLP-1 (glucagonlike peptide-1) receptor agonists as top choices for controlling hyperglycemia. Based on recent evidence drugs in these two classes “could be considered first line for patients with T2DM and CAD, and would likely be preferred over metformin,” Dr. Arnold said in an interview. Although the statement identified the SGLT2 inhibitors as “the first drug class [for glycemic control] to show clear benefits on cardiovascular outcomes,” it does not explicitly label the class first-line and it also skirts that designation for the GLP-1 receptor agonist class, while noting that metformin “remains the drug most frequently recommended as first-line therapy in treatment guidelines.”
“I wouldn’t disagree with someone who said that SGLT2 inhibitors and GLP-1 receptor agonists are first line,” but prescribing patterns also depend on familiarity, cost, and access, noted Dr. Bhatt, which can all be issues with agents from these classes compared with metformin, a widely available generic with decades of use. “Metformin is safe and cheap, so we did not want to discount it,” said Dr. Arnold. Dr. Bhatt recently coauthored an editorial that gave an enthusiastic endorsement to using SGLT2 inhibitors in patients with diabetes (Cell Metab. 2019 Nov 5;30[5]:47-9).
Another notable feature of the statement is the potential it assigns to bariatric surgery as a management tool with documented safety and efficacy for improving cardiovascular risk factors. However, the statement also notes that randomized trials “have thus far been inadequately powered to assess cardiovascular events and mortality, although observational studies have consistently shown cardiovascular risk reduction with such procedures.” The statement continues that despite potential cardiovascular benefits “bariatric surgery remains underused among eligible patients,” and said that surgery performed as Roux-en-Y bypass or sleeve gastrectomy “may be another effective tool for cardiovascular risk reduction in the subset of patients with obesity,” particularly patients with a body mass index of at least 35 kg/m2.
“While the percentage of patients who are optimal for bariatric surgery is not known, the most recent NHANES [National Health and Nutrition Examination Study] study showed that less than 0.5% of eligible patients underwent bariatric surgery,” Dr. Arnold noted. Bariatric surgery is “certainly not a recommendation for everyone, or even a majority of patients, but bariatric surgery should be on our radar,” for patients with CAD and T2DM, she said.
Right now, “few cardiologists think about bariatric surgery,” as a treatment option, but study results have shown that “in carefully selected patients treated by skilled surgeons at high-volume centers, patients will do better with bariatric surgery than with best medical therapy for improvements in multiple risk factors, including glycemic control,” Dr. Bhatt said in the interview. “It’s not first-line treatment, but it’s an option to consider,” he added, while also noting that bariatric surgery is most beneficial to patients relatively early in the course of T2DM, when its been in place for just a few years rather than a couple of decades.
The statement also notably included a “first-line” call out for icosapent ethyl (Vascepa), a novel agent approved in December 2019 for routine use in U.S. patients, including those with CAD and T2DM as long as their blood triglyceride level was at least 150 mg/dL. Dr. Bhatt, who led the REDUCE-IT study that was pivotal for proving the safety and efficacy of icosapent ethyl (N Engl J Med. 2019 Jan 3;380[1]:11-22), estimated that anywhere from 15% to as many as half the patients with CAD and T2DM might have a triglyceride level that would allow them to receive icosapent ethyl. One population-based study in Canada of nearly 200,000 people with atherosclerotic cardiovascular disease found a 25% prevalence of the triglyceride level needed to qualify to receive icosapent ethyl under current labeling, he noted (Eur Heart J. 2020 Jan 1;41[1]:86-94). However, the FDA label does not specify that triglycerides be measured when fasting, and a nonfasting level of about 150 mg/dL will likely appear for patients with fasting levels that fall as low as about 100 mg/dL, Dr. Bhatt said. He hoped that future studies will assess the efficacy of icosapent ethyl in patients with even lower triglyceride levels.
Other sections of the statement also recommend that clinicians: Target long-term dual-antiplatelet therapy to CAD and T2DM patients with additional high-risk markers such as prior MI, younger age, and tobacco use; prescribe a low-dose oral anticoagulant along with an antiplatelet drug such as aspirin for secondary-prevention patients; promote a blood pressure target of less than 140/90 mm Hg for all CAD and T2DM patients and apply a goal of less than 130/80 mm Hg in higher-risk patients such as blacks, Asians, and those with cerebrovascular disease; and reassure patients that “despite a modest increase in blood sugars, the risk-benefit ratio is clearly in favor of administering statins to people with T2DM and CAD.”
Dr. Arnold had no disclosures. Dr. Bhatt has been an adviser to Cardax, Cereno Scientific, Medscape Cardiology, PhaseBio; PLx Pharma, and Regado Biosciences, and he has received research funding from numerous companies including Amarin, the company that markets icosapent ethyl.
FROM CIRCULATION
COVID-19 linked to multiple cardiovascular presentations
It’s becoming clear that COVID-19 infection can involve the cardiovascular system in many different ways, and this has “evolving” potential implications for treatment, say a team of cardiologists on the frontlines of the COVID-19 battle in New York City.
In an article published online April 3 in Circulation, Justin Fried, MD, Division of Cardiology, Columbia University, New York City, and colleagues present four case studies of COVID-19 patients with various cardiovascular presentations.
Case 1 is a 64-year-old woman whose predominant symptoms on admission were cardiac in nature, including chest pain and ST elevation, but without fever, cough, or other symptoms suggestive of COVID-19.
“In patients presenting with what appears to be a typical cardiac syndrome, COVID-19 infection should be in the differential during the current pandemic, even in the absence of fever or cough,” the clinicians advise.
Case 2 is a 38-year-old man with cardiogenic shock and acute respiratory distress with profound hypoxia who was rescued with veno-arterial-venous extracorporeal membrane oxygenation (VV ECMO).
The initial presentation of this patient was more characteristic of severe COVID-19 disease, and cardiac involvement only became apparent after the initiation of ECMO, Fried and colleagues report.
Based on this case, they advise a “low threshold” to assess for cardiogenic shock in patients with acute systolic heart failure related to COVID-19. If inotropic support fails in these patients, intra-aortic balloon pump should be considered first for mechanical circulatory support because it requires the least maintenance from medical support staff.
In addition, in their experience, when a patient on VV ECMO develops superimposed cardiogenic shock, adding an arterial conduit at a relatively low blood flow rate may provide the necessary circulatory support without inducing left ventricular distension, they note.
“Our experience confirms that rescue of patients even with profound cardiogenic or mixed shock may be possible with temporary hemodynamic support at centers with availability of such devices,” Fried and colleagues report.
Case 3 is a 64-year-old woman with underlying cardiac disease who developed profound decompensation with COVID-19 infection.
This case demonstrates that the infection can cause decompensation of underlying heart failure and may lead to mixed shock, the clinicians say.
“Invasive hemodynamic monitoring, if feasible, may be helpful to manage the cardiac component of shock in such cases. Medications that prolong the QT interval are being considered for COVID-19 patients and may require closer monitoring in patients with underlying structural heart disease,” they note.
Case 4 is a 51-year-old man who underwent a heart transplant in 2007 and a kidney transplant in 2010. He had COVID-19 symptoms akin to those seen in nonimmunosuppressed patients with COVID-19.
The COVID-19 pandemic presents a “unique challenge” for solid organ transplant recipients, with only “limited” data on how to adjust immunosuppression during COVID-19 infection, Fried and colleagues say.
The pandemic also creates a challenge for the management of heart failure patients on the heart transplant wait list; the risks of delaying a transplant need to be balanced against the risks of donor infection and uncertainty regarding the impact of post-transplant immunosuppression protocols, they note.
As reported by Medscape Medical News, the American Heart Association has developed a COVID-19 patient registry to collect data on cardiovascular conditions and outcomes related to COVID-19 infection.
To participate in the registry, contact qualityresearch@heart.org.
This article first appeared on Medscape.com.
It’s becoming clear that COVID-19 infection can involve the cardiovascular system in many different ways, and this has “evolving” potential implications for treatment, say a team of cardiologists on the frontlines of the COVID-19 battle in New York City.
In an article published online April 3 in Circulation, Justin Fried, MD, Division of Cardiology, Columbia University, New York City, and colleagues present four case studies of COVID-19 patients with various cardiovascular presentations.
Case 1 is a 64-year-old woman whose predominant symptoms on admission were cardiac in nature, including chest pain and ST elevation, but without fever, cough, or other symptoms suggestive of COVID-19.
“In patients presenting with what appears to be a typical cardiac syndrome, COVID-19 infection should be in the differential during the current pandemic, even in the absence of fever or cough,” the clinicians advise.
Case 2 is a 38-year-old man with cardiogenic shock and acute respiratory distress with profound hypoxia who was rescued with veno-arterial-venous extracorporeal membrane oxygenation (VV ECMO).
The initial presentation of this patient was more characteristic of severe COVID-19 disease, and cardiac involvement only became apparent after the initiation of ECMO, Fried and colleagues report.
Based on this case, they advise a “low threshold” to assess for cardiogenic shock in patients with acute systolic heart failure related to COVID-19. If inotropic support fails in these patients, intra-aortic balloon pump should be considered first for mechanical circulatory support because it requires the least maintenance from medical support staff.
In addition, in their experience, when a patient on VV ECMO develops superimposed cardiogenic shock, adding an arterial conduit at a relatively low blood flow rate may provide the necessary circulatory support without inducing left ventricular distension, they note.
“Our experience confirms that rescue of patients even with profound cardiogenic or mixed shock may be possible with temporary hemodynamic support at centers with availability of such devices,” Fried and colleagues report.
Case 3 is a 64-year-old woman with underlying cardiac disease who developed profound decompensation with COVID-19 infection.
This case demonstrates that the infection can cause decompensation of underlying heart failure and may lead to mixed shock, the clinicians say.
“Invasive hemodynamic monitoring, if feasible, may be helpful to manage the cardiac component of shock in such cases. Medications that prolong the QT interval are being considered for COVID-19 patients and may require closer monitoring in patients with underlying structural heart disease,” they note.
Case 4 is a 51-year-old man who underwent a heart transplant in 2007 and a kidney transplant in 2010. He had COVID-19 symptoms akin to those seen in nonimmunosuppressed patients with COVID-19.
The COVID-19 pandemic presents a “unique challenge” for solid organ transplant recipients, with only “limited” data on how to adjust immunosuppression during COVID-19 infection, Fried and colleagues say.
The pandemic also creates a challenge for the management of heart failure patients on the heart transplant wait list; the risks of delaying a transplant need to be balanced against the risks of donor infection and uncertainty regarding the impact of post-transplant immunosuppression protocols, they note.
As reported by Medscape Medical News, the American Heart Association has developed a COVID-19 patient registry to collect data on cardiovascular conditions and outcomes related to COVID-19 infection.
To participate in the registry, contact qualityresearch@heart.org.
This article first appeared on Medscape.com.
It’s becoming clear that COVID-19 infection can involve the cardiovascular system in many different ways, and this has “evolving” potential implications for treatment, say a team of cardiologists on the frontlines of the COVID-19 battle in New York City.
In an article published online April 3 in Circulation, Justin Fried, MD, Division of Cardiology, Columbia University, New York City, and colleagues present four case studies of COVID-19 patients with various cardiovascular presentations.
Case 1 is a 64-year-old woman whose predominant symptoms on admission were cardiac in nature, including chest pain and ST elevation, but without fever, cough, or other symptoms suggestive of COVID-19.
“In patients presenting with what appears to be a typical cardiac syndrome, COVID-19 infection should be in the differential during the current pandemic, even in the absence of fever or cough,” the clinicians advise.
Case 2 is a 38-year-old man with cardiogenic shock and acute respiratory distress with profound hypoxia who was rescued with veno-arterial-venous extracorporeal membrane oxygenation (VV ECMO).
The initial presentation of this patient was more characteristic of severe COVID-19 disease, and cardiac involvement only became apparent after the initiation of ECMO, Fried and colleagues report.
Based on this case, they advise a “low threshold” to assess for cardiogenic shock in patients with acute systolic heart failure related to COVID-19. If inotropic support fails in these patients, intra-aortic balloon pump should be considered first for mechanical circulatory support because it requires the least maintenance from medical support staff.
In addition, in their experience, when a patient on VV ECMO develops superimposed cardiogenic shock, adding an arterial conduit at a relatively low blood flow rate may provide the necessary circulatory support without inducing left ventricular distension, they note.
“Our experience confirms that rescue of patients even with profound cardiogenic or mixed shock may be possible with temporary hemodynamic support at centers with availability of such devices,” Fried and colleagues report.
Case 3 is a 64-year-old woman with underlying cardiac disease who developed profound decompensation with COVID-19 infection.
This case demonstrates that the infection can cause decompensation of underlying heart failure and may lead to mixed shock, the clinicians say.
“Invasive hemodynamic monitoring, if feasible, may be helpful to manage the cardiac component of shock in such cases. Medications that prolong the QT interval are being considered for COVID-19 patients and may require closer monitoring in patients with underlying structural heart disease,” they note.
Case 4 is a 51-year-old man who underwent a heart transplant in 2007 and a kidney transplant in 2010. He had COVID-19 symptoms akin to those seen in nonimmunosuppressed patients with COVID-19.
The COVID-19 pandemic presents a “unique challenge” for solid organ transplant recipients, with only “limited” data on how to adjust immunosuppression during COVID-19 infection, Fried and colleagues say.
The pandemic also creates a challenge for the management of heart failure patients on the heart transplant wait list; the risks of delaying a transplant need to be balanced against the risks of donor infection and uncertainty regarding the impact of post-transplant immunosuppression protocols, they note.
As reported by Medscape Medical News, the American Heart Association has developed a COVID-19 patient registry to collect data on cardiovascular conditions and outcomes related to COVID-19 infection.
To participate in the registry, contact qualityresearch@heart.org.
This article first appeared on Medscape.com.
Dapagliflozin trial in CKD halted because of high efficacy
AstraZeneca has announced that the phase 3 DAPA-CKD trial for dapagliflozin (Farxiga) in patients with chronic kidney disease has been halted early because of overwhelming efficacy of the drug, at the recommendation of an independent data monitoring committee.
DAPA-CKD is an international, multicenter, randomized, double-blinded trial in 4,245 patients with stage 2-4 chronic kidney disease. Patients received either 10 mg of the dapagliflozin once-daily or a placebo. The primary composite endpoint is worsening of renal function, defined as a composite of an estimated glomerular filtration rate decline of at least 50%, onset of end-stage kidney disease, and death from cardiovascular or renal cause.
The decision to stop the trial came after a routine assessment of efficacy and safety that showed dapagliflozin’s benefits significantly earlier than expected. AstraZeneca will initiate closure of the study, and results will be published and submitted for presentation at a forthcoming medical meeting.
Dapagliflozin is a sodium-glucose transporter 2 inhibitor currently indicated for the treatment type 2 diabetes patients with inadequately controlled type 2 diabetes and for reduction of the risk of hospitalization for heart failure. In August 2019, the drug was granted Fast Track status by the Food and Drug Administration for the treatment of chronic kidney disease. In January 2020, the agency also granted Fast Track status for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients, regardless of diabetes status, with heart failure with reduced ejection fraction.
“Chronic kidney disease patients have limited treatment options, particularly those without type-2 diabetes. We are very pleased the data monitoring committee concluded that patients experienced overwhelming benefit. Farxiga has the potential to change the management of chronic kidney disease for patients around the world,” Mene Pangalos, executive vice president of BioPharmaceuticals R&D, said in the press release.
AstraZeneca has announced that the phase 3 DAPA-CKD trial for dapagliflozin (Farxiga) in patients with chronic kidney disease has been halted early because of overwhelming efficacy of the drug, at the recommendation of an independent data monitoring committee.
DAPA-CKD is an international, multicenter, randomized, double-blinded trial in 4,245 patients with stage 2-4 chronic kidney disease. Patients received either 10 mg of the dapagliflozin once-daily or a placebo. The primary composite endpoint is worsening of renal function, defined as a composite of an estimated glomerular filtration rate decline of at least 50%, onset of end-stage kidney disease, and death from cardiovascular or renal cause.
The decision to stop the trial came after a routine assessment of efficacy and safety that showed dapagliflozin’s benefits significantly earlier than expected. AstraZeneca will initiate closure of the study, and results will be published and submitted for presentation at a forthcoming medical meeting.
Dapagliflozin is a sodium-glucose transporter 2 inhibitor currently indicated for the treatment type 2 diabetes patients with inadequately controlled type 2 diabetes and for reduction of the risk of hospitalization for heart failure. In August 2019, the drug was granted Fast Track status by the Food and Drug Administration for the treatment of chronic kidney disease. In January 2020, the agency also granted Fast Track status for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients, regardless of diabetes status, with heart failure with reduced ejection fraction.
“Chronic kidney disease patients have limited treatment options, particularly those without type-2 diabetes. We are very pleased the data monitoring committee concluded that patients experienced overwhelming benefit. Farxiga has the potential to change the management of chronic kidney disease for patients around the world,” Mene Pangalos, executive vice president of BioPharmaceuticals R&D, said in the press release.
AstraZeneca has announced that the phase 3 DAPA-CKD trial for dapagliflozin (Farxiga) in patients with chronic kidney disease has been halted early because of overwhelming efficacy of the drug, at the recommendation of an independent data monitoring committee.
DAPA-CKD is an international, multicenter, randomized, double-blinded trial in 4,245 patients with stage 2-4 chronic kidney disease. Patients received either 10 mg of the dapagliflozin once-daily or a placebo. The primary composite endpoint is worsening of renal function, defined as a composite of an estimated glomerular filtration rate decline of at least 50%, onset of end-stage kidney disease, and death from cardiovascular or renal cause.
The decision to stop the trial came after a routine assessment of efficacy and safety that showed dapagliflozin’s benefits significantly earlier than expected. AstraZeneca will initiate closure of the study, and results will be published and submitted for presentation at a forthcoming medical meeting.
Dapagliflozin is a sodium-glucose transporter 2 inhibitor currently indicated for the treatment type 2 diabetes patients with inadequately controlled type 2 diabetes and for reduction of the risk of hospitalization for heart failure. In August 2019, the drug was granted Fast Track status by the Food and Drug Administration for the treatment of chronic kidney disease. In January 2020, the agency also granted Fast Track status for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients, regardless of diabetes status, with heart failure with reduced ejection fraction.
“Chronic kidney disease patients have limited treatment options, particularly those without type-2 diabetes. We are very pleased the data monitoring committee concluded that patients experienced overwhelming benefit. Farxiga has the potential to change the management of chronic kidney disease for patients around the world,” Mene Pangalos, executive vice president of BioPharmaceuticals R&D, said in the press release.
VICTORIA: Vericiguat seen as novel success in tough-to-treat, high-risk heart failure
Not too many years ago, clinicians who treat patients with heart failure, especially those at high risk for decompensation, lamented what seemed a dearth of new drug therapy options.
Now, with the toolbox brimming with new guideline-supported alternatives, .
Importantly, it entered an especially high-risk population with heart failure and reduced ejection fraction (HFrEF); everyone in the trial had experienced a prior, usually quite recent, heart failure exacerbation.
In such patients, the addition of vericiguat (Merck/Bayer) to standard drug and device therapies was followed by a moderately but significantly reduced relative risk for the trial’s primary clinical endpoint over about 11 months.
Recipients benefited with a 10% drop in adjusted risk (P = .019) for cardiovascular (CV) death or first heart failure hospitalization compared to a placebo control group.
But researchers leading the 5050-patient Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA), as well as unaffiliated experts who have studied the trial, say that in this case, risk reduction in absolute numbers is a more telling outcome.
“Remember who we’re talking about here in terms of the patients who have this degree of morbidity and mortality,” VICTORIA study chair Paul W. Armstrong, MD, University of Alberta, Edmonton, Canada, told theheart.org | Medscape Cardiology, pointing to the “incredible placebo-group event rate and relatively modest follow-up of 10.8 months.”
The control group’s primary-endpoint event rate was 37.8 per 100 patient-years, 4.2 points higher than the rate for patients who received vericiguat. “And from there you get a number needed to treat of 24 to prevent one event, which is low,” Armstrong said.
“Think about the hundreds of thousands of people with this disease and what that means at the public health level.” About one in four patients with heart failure experience such exacerbations each year, he said.
Armstrong is lead author on the 42-country trial’s publication today in the New England Journal of Medicine, timed to coincide with his online presentation for the American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). The annual session was conducted virtually this year following the traditional live meeting’s cancelation due to the COVID-19 pandemic.
The VICTORIA presentation and publication flesh out the cursory top-line primary results that Merck unveiled in November 2019, which had not included the magnitude of the vericiguat relative benefit for the primary endpoint.
The trial represents “another win” for the treatment of heart failure, Clyde W. Yancy, MD, Northwestern University, Chicago, Illinois, said as an invited discussant following Armstrong’s presentation.
“Hospitalization for heart failure generates a major inflection point in the natural history of this condition, with a marked change in the risk for re-hospitalization and death. Up until now, no prior therapies have attenuated this risk, except for more intensive processes and care improvement strategies,” he said.
“Now we have a therapy that may be the first one to change that natural history after a person with heart failure has had a worsening event.”
Interestingly, the primary-endpoint reduction was driven by a significant drop in heart failure hospitalizations, even within a fairly short follow-up time.
“What was fascinating is that the requisite number of events were accrued in less than 12 months — meaning that inexplicably, this is one of the few times we’ve had a trial where the event rate realized was higher than the event rate predicted,” Yancy observed for theheart.org | Medscape Cardiology.
Although the effect size was similar to what was observed for dapagliflozin (Farxiga, AstraZeneca) in DAPA-HF and sacubitril/valsartan (Entresto, Novartis) in PARADIGM-HF, he said, VICTORIA’s population was much sicker and had an “astonishingly high” event rate even while receiving aggressive background heart failure therapy.
It included “triple therapy with renin-angiotensin system inhibitors, β-blockers, and mineralocorticoid receptor antagonists in 60% of patients, and at least double therapy in 90% of patients.” Also, Yancy said, 30% of the population had implantable devices, such as defibrillators and biventricular pacemakers.
Such patients with advanced, late-stage disease are common as the latest therapies for heart failure prolong their survival, notes Lynne W. Stevenson, MD, Vanderbilt University, Nashville, Tennessee, also as an invited discussant after Armstrong’s presentation.
“It’s a unique population with longer disease duration, more severe disease, and narrow options,” one in which personalized approaches are needed. Yet VICTORIA-like patients “have been actively excluded from all the trials that have shown benefit,” she said.
“VICTORIA finally addresses this population of decompensated patients,” she said, and seems to show that vericiguat may help some of them.
At the University of Glasgow, United Kingdom, John J.V. McMurray, MBChB, MD, agreed that the relative risk reduction was “small but significant,” but also that the control group’s event rate was “very high, reflecting the inclusion and exclusion criteria.”
As a result, McMurray told theheart.org | Medscape Cardiology, there was “quite a large absolute risk reduction and small number needed to treat. Also on the positive side: no significant excess of the adverse effects we might have been concerned about,” for example, hypotension.
Vericiguat, if ultimately approved in heart failure, “isn’t going to be first-line or widely used, but it is an additional asset,” he said. “Anything that helps in heart failure is valuable. There are always patients who can’t tolerate treatments, and always people who need more done.”
It’s appealing that the drug works by a long but unfruitfully explored mechanism that has little to do directly with the renin-angiotensin-aldosterone system.
Vericiguat is a soluble guanylate cyclase stimulator that boosts cyclic guanosine monophosphate activity along several pathways, potentiating the salutary pulmonary artery–vasodilating effects of nitric oxide. It improved natriuretic peptide levels in the preceding phase 2 SOCRATES-REDUCED study.
“This is not a me-too drug. It’s a new avenue for heart failure patients,” Armstrong said in an interview. It’s taken once daily, “was relatively easy to titrate up to the target dose, pretty well tolerated, and very safe. And remarkably, you don’t need to measure renal function.”
However, because the drug’s mechanism resides in the same neighborhood of biochemical pathways affected by chronic nitrates and by phosphodiesterase type 5 inhibitors, such as sildenafil and tadalafil, patients taking those drugs were excluded from VICTORIA. Acute nitrates were allowed, however.
“Hospitalization for heart failure generates a major inflection point in the natural history of this condition, with a marked change in the risk for re-hospitalization and death. Up until now, no prior therapies have attenuated this risk, except for more intensive processes and care improvement strategies,” he said.
“Now we have a therapy that may be the first one to change that natural history after a person with heart failure has had a worsening event.”
Interestingly, the primary-endpoint reduction was driven by a significant drop in heart failure hospitalizations, even within a fairly short follow-up time.
“What was fascinating is that the requisite number of events were accrued in less than 12 months — meaning that inexplicably, this is one of the few times we’ve had a trial where the event rate realized was higher than the event rate predicted,” Yancy observed for theheart.org | Medscape Cardiology.
Although the effect size was similar to what was observed for dapagliflozin (Farxiga, AstraZeneca) in DAPA-HF and sacubitril/valsartan (Entresto, Novartis) in PARADIGM-HF, he said, VICTORIA’s population was much sicker and had an “astonishingly high” event rate even while receiving aggressive background heart failure therapy.
It included “triple therapy with renin-angiotensin system inhibitors, β-blockers, and mineralocorticoid receptor antagonists in 60% of patients, and at least double therapy in 90% of patients.” Also, Yancy said, 30% of the population had implantable devices, such as defibrillators and biventricular pacemakers.
Such patients with advanced, late-stage disease are common as the latest therapies for heart failure prolong their survival, notes Lynne W. Stevenson, MD, Vanderbilt University, Nashville, Tennessee, also as an invited discussant after Armstrong’s presentation.
“It’s a unique population with longer disease duration, more severe disease, and narrow options,” one in which personalized approaches are needed. Yet VICTORIA-like patients “have been actively excluded from all the trials that have shown benefit,” she said.
“VICTORIA finally addresses this population of decompensated patients,” she said, and seems to show that vericiguat may help some of them.
At the University of Glasgow, United Kingdom, John J.V. McMurray, MBChB, MD, agreed that the relative risk reduction was “small but significant,” but also that the control group’s event rate was “very high, reflecting the inclusion and exclusion criteria.”
As a result, McMurray told theheart.org | Medscape Cardiology, there was “quite a large absolute risk reduction and small number needed to treat. Also on the positive side: no significant excess of the adverse effects we might have been concerned about,” for example, hypotension.
Vericiguat, if ultimately approved in heart failure, “isn’t going to be first-line or widely used, but it is an additional asset,” he said. “Anything that helps in heart failure is valuable. There are always patients who can’t tolerate treatments, and always people who need more done.”
It’s appealing that the drug works by a long but unfruitfully explored mechanism that has little to do directly with the renin-angiotensin-aldosterone system.
Vericiguat is a soluble guanylate cyclase stimulator that boosts cyclic guanosine monophosphate activity along several pathways, potentiating the salutary pulmonary artery–vasodilating effects of nitric oxide. It improved natriuretic peptide levels in the preceding phase 2 SOCRATES-REDUCED study.
“This is not a me-too drug. It’s a new avenue for heart failure patients,” Armstrong said in an interview. It’s taken once daily, “was relatively easy to titrate up to the target dose, pretty well tolerated, and very safe. And remarkably, you don’t need to measure renal function.”
However, because the drug’s mechanism resides in the same neighborhood of biochemical pathways affected by chronic nitrates and by phosphodiesterase type 5 inhibitors, such as sildenafil and tadalafil, patients taking those drugs were excluded from VICTORIA. Acute nitrates were allowed, however.
Symptomatic hypotension occurred in less than 10% and syncope in 4% or less of both groups; neither difference between the two groups was significant. Anemia developed more often in patients receiving vericiguat (7.6%) than in the control group (5.7%).
“We think that on balance, vericiguat is a useful alternative option for patients. But certainly the only thing we can say at this point is it works in the high-risk population that we studied,” Armstrong said. “Whether it works in lower-risk populations and how it compares is speculation, of course.”
The drug’s cost, whatever it might be if approved, is another factor affecting how it would be used, noted several observers.
“We don’t know what the cost-effectiveness will be. It should be reasonable because the benefit was on hospitalization. That’s a costly outcome,” Yancy said.
McMurray was also hopeful. “If the treatment is well tolerated and reasonably priced, it may still be a valuable asset for at least a subset of patients.”
VICTORIA was supported by Merck Sharp & Dohme Corp and Bayer AG. Armstrong discloses receiving research grants from Merck, Bayer AG, Sanofi-Aventis, Boehringer Ingelheim, and CSL Ltd and consulting fees from Merck, Bayer AG, AstraZeneca, and Novartis. Y ancy has previously disclosed no relevant financial relationships. Stevenson has previously disclosed receiving research grants from Novartis, consulting or serving on an advisory board for Abbott and travel expenses or meals from Novartis and St Jude Medical. McMurray has previously disclosed nonfinancial support or other support from AstraZeneca, Bayer, Cardiorentis, Amgen, Oxford University/Bayer, Theracos, AbbVie, DalCor, Pfizer, Merck, Novartis, GlaxoSmithKline, Bristol-Myers Squibb, and Vifor-Fresenius.
American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Presented March 28, 2020. Session 402-08.
N Engl J Med. Published online March 28, 2020. Full text; Circulation. Published online March 28, 2020. Full text.
This article first appeared on Medscape.com.
Not too many years ago, clinicians who treat patients with heart failure, especially those at high risk for decompensation, lamented what seemed a dearth of new drug therapy options.
Now, with the toolbox brimming with new guideline-supported alternatives, .
Importantly, it entered an especially high-risk population with heart failure and reduced ejection fraction (HFrEF); everyone in the trial had experienced a prior, usually quite recent, heart failure exacerbation.
In such patients, the addition of vericiguat (Merck/Bayer) to standard drug and device therapies was followed by a moderately but significantly reduced relative risk for the trial’s primary clinical endpoint over about 11 months.
Recipients benefited with a 10% drop in adjusted risk (P = .019) for cardiovascular (CV) death or first heart failure hospitalization compared to a placebo control group.
But researchers leading the 5050-patient Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA), as well as unaffiliated experts who have studied the trial, say that in this case, risk reduction in absolute numbers is a more telling outcome.
“Remember who we’re talking about here in terms of the patients who have this degree of morbidity and mortality,” VICTORIA study chair Paul W. Armstrong, MD, University of Alberta, Edmonton, Canada, told theheart.org | Medscape Cardiology, pointing to the “incredible placebo-group event rate and relatively modest follow-up of 10.8 months.”
The control group’s primary-endpoint event rate was 37.8 per 100 patient-years, 4.2 points higher than the rate for patients who received vericiguat. “And from there you get a number needed to treat of 24 to prevent one event, which is low,” Armstrong said.
“Think about the hundreds of thousands of people with this disease and what that means at the public health level.” About one in four patients with heart failure experience such exacerbations each year, he said.
Armstrong is lead author on the 42-country trial’s publication today in the New England Journal of Medicine, timed to coincide with his online presentation for the American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). The annual session was conducted virtually this year following the traditional live meeting’s cancelation due to the COVID-19 pandemic.
The VICTORIA presentation and publication flesh out the cursory top-line primary results that Merck unveiled in November 2019, which had not included the magnitude of the vericiguat relative benefit for the primary endpoint.
The trial represents “another win” for the treatment of heart failure, Clyde W. Yancy, MD, Northwestern University, Chicago, Illinois, said as an invited discussant following Armstrong’s presentation.
“Hospitalization for heart failure generates a major inflection point in the natural history of this condition, with a marked change in the risk for re-hospitalization and death. Up until now, no prior therapies have attenuated this risk, except for more intensive processes and care improvement strategies,” he said.
“Now we have a therapy that may be the first one to change that natural history after a person with heart failure has had a worsening event.”
Interestingly, the primary-endpoint reduction was driven by a significant drop in heart failure hospitalizations, even within a fairly short follow-up time.
“What was fascinating is that the requisite number of events were accrued in less than 12 months — meaning that inexplicably, this is one of the few times we’ve had a trial where the event rate realized was higher than the event rate predicted,” Yancy observed for theheart.org | Medscape Cardiology.
Although the effect size was similar to what was observed for dapagliflozin (Farxiga, AstraZeneca) in DAPA-HF and sacubitril/valsartan (Entresto, Novartis) in PARADIGM-HF, he said, VICTORIA’s population was much sicker and had an “astonishingly high” event rate even while receiving aggressive background heart failure therapy.
It included “triple therapy with renin-angiotensin system inhibitors, β-blockers, and mineralocorticoid receptor antagonists in 60% of patients, and at least double therapy in 90% of patients.” Also, Yancy said, 30% of the population had implantable devices, such as defibrillators and biventricular pacemakers.
Such patients with advanced, late-stage disease are common as the latest therapies for heart failure prolong their survival, notes Lynne W. Stevenson, MD, Vanderbilt University, Nashville, Tennessee, also as an invited discussant after Armstrong’s presentation.
“It’s a unique population with longer disease duration, more severe disease, and narrow options,” one in which personalized approaches are needed. Yet VICTORIA-like patients “have been actively excluded from all the trials that have shown benefit,” she said.
“VICTORIA finally addresses this population of decompensated patients,” she said, and seems to show that vericiguat may help some of them.
At the University of Glasgow, United Kingdom, John J.V. McMurray, MBChB, MD, agreed that the relative risk reduction was “small but significant,” but also that the control group’s event rate was “very high, reflecting the inclusion and exclusion criteria.”
As a result, McMurray told theheart.org | Medscape Cardiology, there was “quite a large absolute risk reduction and small number needed to treat. Also on the positive side: no significant excess of the adverse effects we might have been concerned about,” for example, hypotension.
Vericiguat, if ultimately approved in heart failure, “isn’t going to be first-line or widely used, but it is an additional asset,” he said. “Anything that helps in heart failure is valuable. There are always patients who can’t tolerate treatments, and always people who need more done.”
It’s appealing that the drug works by a long but unfruitfully explored mechanism that has little to do directly with the renin-angiotensin-aldosterone system.
Vericiguat is a soluble guanylate cyclase stimulator that boosts cyclic guanosine monophosphate activity along several pathways, potentiating the salutary pulmonary artery–vasodilating effects of nitric oxide. It improved natriuretic peptide levels in the preceding phase 2 SOCRATES-REDUCED study.
“This is not a me-too drug. It’s a new avenue for heart failure patients,” Armstrong said in an interview. It’s taken once daily, “was relatively easy to titrate up to the target dose, pretty well tolerated, and very safe. And remarkably, you don’t need to measure renal function.”
However, because the drug’s mechanism resides in the same neighborhood of biochemical pathways affected by chronic nitrates and by phosphodiesterase type 5 inhibitors, such as sildenafil and tadalafil, patients taking those drugs were excluded from VICTORIA. Acute nitrates were allowed, however.
“Hospitalization for heart failure generates a major inflection point in the natural history of this condition, with a marked change in the risk for re-hospitalization and death. Up until now, no prior therapies have attenuated this risk, except for more intensive processes and care improvement strategies,” he said.
“Now we have a therapy that may be the first one to change that natural history after a person with heart failure has had a worsening event.”
Interestingly, the primary-endpoint reduction was driven by a significant drop in heart failure hospitalizations, even within a fairly short follow-up time.
“What was fascinating is that the requisite number of events were accrued in less than 12 months — meaning that inexplicably, this is one of the few times we’ve had a trial where the event rate realized was higher than the event rate predicted,” Yancy observed for theheart.org | Medscape Cardiology.
Although the effect size was similar to what was observed for dapagliflozin (Farxiga, AstraZeneca) in DAPA-HF and sacubitril/valsartan (Entresto, Novartis) in PARADIGM-HF, he said, VICTORIA’s population was much sicker and had an “astonishingly high” event rate even while receiving aggressive background heart failure therapy.
It included “triple therapy with renin-angiotensin system inhibitors, β-blockers, and mineralocorticoid receptor antagonists in 60% of patients, and at least double therapy in 90% of patients.” Also, Yancy said, 30% of the population had implantable devices, such as defibrillators and biventricular pacemakers.
Such patients with advanced, late-stage disease are common as the latest therapies for heart failure prolong their survival, notes Lynne W. Stevenson, MD, Vanderbilt University, Nashville, Tennessee, also as an invited discussant after Armstrong’s presentation.
“It’s a unique population with longer disease duration, more severe disease, and narrow options,” one in which personalized approaches are needed. Yet VICTORIA-like patients “have been actively excluded from all the trials that have shown benefit,” she said.
“VICTORIA finally addresses this population of decompensated patients,” she said, and seems to show that vericiguat may help some of them.
At the University of Glasgow, United Kingdom, John J.V. McMurray, MBChB, MD, agreed that the relative risk reduction was “small but significant,” but also that the control group’s event rate was “very high, reflecting the inclusion and exclusion criteria.”
As a result, McMurray told theheart.org | Medscape Cardiology, there was “quite a large absolute risk reduction and small number needed to treat. Also on the positive side: no significant excess of the adverse effects we might have been concerned about,” for example, hypotension.
Vericiguat, if ultimately approved in heart failure, “isn’t going to be first-line or widely used, but it is an additional asset,” he said. “Anything that helps in heart failure is valuable. There are always patients who can’t tolerate treatments, and always people who need more done.”
It’s appealing that the drug works by a long but unfruitfully explored mechanism that has little to do directly with the renin-angiotensin-aldosterone system.
Vericiguat is a soluble guanylate cyclase stimulator that boosts cyclic guanosine monophosphate activity along several pathways, potentiating the salutary pulmonary artery–vasodilating effects of nitric oxide. It improved natriuretic peptide levels in the preceding phase 2 SOCRATES-REDUCED study.
“This is not a me-too drug. It’s a new avenue for heart failure patients,” Armstrong said in an interview. It’s taken once daily, “was relatively easy to titrate up to the target dose, pretty well tolerated, and very safe. And remarkably, you don’t need to measure renal function.”
However, because the drug’s mechanism resides in the same neighborhood of biochemical pathways affected by chronic nitrates and by phosphodiesterase type 5 inhibitors, such as sildenafil and tadalafil, patients taking those drugs were excluded from VICTORIA. Acute nitrates were allowed, however.
Symptomatic hypotension occurred in less than 10% and syncope in 4% or less of both groups; neither difference between the two groups was significant. Anemia developed more often in patients receiving vericiguat (7.6%) than in the control group (5.7%).
“We think that on balance, vericiguat is a useful alternative option for patients. But certainly the only thing we can say at this point is it works in the high-risk population that we studied,” Armstrong said. “Whether it works in lower-risk populations and how it compares is speculation, of course.”
The drug’s cost, whatever it might be if approved, is another factor affecting how it would be used, noted several observers.
“We don’t know what the cost-effectiveness will be. It should be reasonable because the benefit was on hospitalization. That’s a costly outcome,” Yancy said.
McMurray was also hopeful. “If the treatment is well tolerated and reasonably priced, it may still be a valuable asset for at least a subset of patients.”
VICTORIA was supported by Merck Sharp & Dohme Corp and Bayer AG. Armstrong discloses receiving research grants from Merck, Bayer AG, Sanofi-Aventis, Boehringer Ingelheim, and CSL Ltd and consulting fees from Merck, Bayer AG, AstraZeneca, and Novartis. Y ancy has previously disclosed no relevant financial relationships. Stevenson has previously disclosed receiving research grants from Novartis, consulting or serving on an advisory board for Abbott and travel expenses or meals from Novartis and St Jude Medical. McMurray has previously disclosed nonfinancial support or other support from AstraZeneca, Bayer, Cardiorentis, Amgen, Oxford University/Bayer, Theracos, AbbVie, DalCor, Pfizer, Merck, Novartis, GlaxoSmithKline, Bristol-Myers Squibb, and Vifor-Fresenius.
American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Presented March 28, 2020. Session 402-08.
N Engl J Med. Published online March 28, 2020. Full text; Circulation. Published online March 28, 2020. Full text.
This article first appeared on Medscape.com.
Not too many years ago, clinicians who treat patients with heart failure, especially those at high risk for decompensation, lamented what seemed a dearth of new drug therapy options.
Now, with the toolbox brimming with new guideline-supported alternatives, .
Importantly, it entered an especially high-risk population with heart failure and reduced ejection fraction (HFrEF); everyone in the trial had experienced a prior, usually quite recent, heart failure exacerbation.
In such patients, the addition of vericiguat (Merck/Bayer) to standard drug and device therapies was followed by a moderately but significantly reduced relative risk for the trial’s primary clinical endpoint over about 11 months.
Recipients benefited with a 10% drop in adjusted risk (P = .019) for cardiovascular (CV) death or first heart failure hospitalization compared to a placebo control group.
But researchers leading the 5050-patient Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA), as well as unaffiliated experts who have studied the trial, say that in this case, risk reduction in absolute numbers is a more telling outcome.
“Remember who we’re talking about here in terms of the patients who have this degree of morbidity and mortality,” VICTORIA study chair Paul W. Armstrong, MD, University of Alberta, Edmonton, Canada, told theheart.org | Medscape Cardiology, pointing to the “incredible placebo-group event rate and relatively modest follow-up of 10.8 months.”
The control group’s primary-endpoint event rate was 37.8 per 100 patient-years, 4.2 points higher than the rate for patients who received vericiguat. “And from there you get a number needed to treat of 24 to prevent one event, which is low,” Armstrong said.
“Think about the hundreds of thousands of people with this disease and what that means at the public health level.” About one in four patients with heart failure experience such exacerbations each year, he said.
Armstrong is lead author on the 42-country trial’s publication today in the New England Journal of Medicine, timed to coincide with his online presentation for the American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). The annual session was conducted virtually this year following the traditional live meeting’s cancelation due to the COVID-19 pandemic.
The VICTORIA presentation and publication flesh out the cursory top-line primary results that Merck unveiled in November 2019, which had not included the magnitude of the vericiguat relative benefit for the primary endpoint.
The trial represents “another win” for the treatment of heart failure, Clyde W. Yancy, MD, Northwestern University, Chicago, Illinois, said as an invited discussant following Armstrong’s presentation.
“Hospitalization for heart failure generates a major inflection point in the natural history of this condition, with a marked change in the risk for re-hospitalization and death. Up until now, no prior therapies have attenuated this risk, except for more intensive processes and care improvement strategies,” he said.
“Now we have a therapy that may be the first one to change that natural history after a person with heart failure has had a worsening event.”
Interestingly, the primary-endpoint reduction was driven by a significant drop in heart failure hospitalizations, even within a fairly short follow-up time.
“What was fascinating is that the requisite number of events were accrued in less than 12 months — meaning that inexplicably, this is one of the few times we’ve had a trial where the event rate realized was higher than the event rate predicted,” Yancy observed for theheart.org | Medscape Cardiology.
Although the effect size was similar to what was observed for dapagliflozin (Farxiga, AstraZeneca) in DAPA-HF and sacubitril/valsartan (Entresto, Novartis) in PARADIGM-HF, he said, VICTORIA’s population was much sicker and had an “astonishingly high” event rate even while receiving aggressive background heart failure therapy.
It included “triple therapy with renin-angiotensin system inhibitors, β-blockers, and mineralocorticoid receptor antagonists in 60% of patients, and at least double therapy in 90% of patients.” Also, Yancy said, 30% of the population had implantable devices, such as defibrillators and biventricular pacemakers.
Such patients with advanced, late-stage disease are common as the latest therapies for heart failure prolong their survival, notes Lynne W. Stevenson, MD, Vanderbilt University, Nashville, Tennessee, also as an invited discussant after Armstrong’s presentation.
“It’s a unique population with longer disease duration, more severe disease, and narrow options,” one in which personalized approaches are needed. Yet VICTORIA-like patients “have been actively excluded from all the trials that have shown benefit,” she said.
“VICTORIA finally addresses this population of decompensated patients,” she said, and seems to show that vericiguat may help some of them.
At the University of Glasgow, United Kingdom, John J.V. McMurray, MBChB, MD, agreed that the relative risk reduction was “small but significant,” but also that the control group’s event rate was “very high, reflecting the inclusion and exclusion criteria.”
As a result, McMurray told theheart.org | Medscape Cardiology, there was “quite a large absolute risk reduction and small number needed to treat. Also on the positive side: no significant excess of the adverse effects we might have been concerned about,” for example, hypotension.
Vericiguat, if ultimately approved in heart failure, “isn’t going to be first-line or widely used, but it is an additional asset,” he said. “Anything that helps in heart failure is valuable. There are always patients who can’t tolerate treatments, and always people who need more done.”
It’s appealing that the drug works by a long but unfruitfully explored mechanism that has little to do directly with the renin-angiotensin-aldosterone system.
Vericiguat is a soluble guanylate cyclase stimulator that boosts cyclic guanosine monophosphate activity along several pathways, potentiating the salutary pulmonary artery–vasodilating effects of nitric oxide. It improved natriuretic peptide levels in the preceding phase 2 SOCRATES-REDUCED study.
“This is not a me-too drug. It’s a new avenue for heart failure patients,” Armstrong said in an interview. It’s taken once daily, “was relatively easy to titrate up to the target dose, pretty well tolerated, and very safe. And remarkably, you don’t need to measure renal function.”
However, because the drug’s mechanism resides in the same neighborhood of biochemical pathways affected by chronic nitrates and by phosphodiesterase type 5 inhibitors, such as sildenafil and tadalafil, patients taking those drugs were excluded from VICTORIA. Acute nitrates were allowed, however.
“Hospitalization for heart failure generates a major inflection point in the natural history of this condition, with a marked change in the risk for re-hospitalization and death. Up until now, no prior therapies have attenuated this risk, except for more intensive processes and care improvement strategies,” he said.
“Now we have a therapy that may be the first one to change that natural history after a person with heart failure has had a worsening event.”
Interestingly, the primary-endpoint reduction was driven by a significant drop in heart failure hospitalizations, even within a fairly short follow-up time.
“What was fascinating is that the requisite number of events were accrued in less than 12 months — meaning that inexplicably, this is one of the few times we’ve had a trial where the event rate realized was higher than the event rate predicted,” Yancy observed for theheart.org | Medscape Cardiology.
Although the effect size was similar to what was observed for dapagliflozin (Farxiga, AstraZeneca) in DAPA-HF and sacubitril/valsartan (Entresto, Novartis) in PARADIGM-HF, he said, VICTORIA’s population was much sicker and had an “astonishingly high” event rate even while receiving aggressive background heart failure therapy.
It included “triple therapy with renin-angiotensin system inhibitors, β-blockers, and mineralocorticoid receptor antagonists in 60% of patients, and at least double therapy in 90% of patients.” Also, Yancy said, 30% of the population had implantable devices, such as defibrillators and biventricular pacemakers.
Such patients with advanced, late-stage disease are common as the latest therapies for heart failure prolong their survival, notes Lynne W. Stevenson, MD, Vanderbilt University, Nashville, Tennessee, also as an invited discussant after Armstrong’s presentation.
“It’s a unique population with longer disease duration, more severe disease, and narrow options,” one in which personalized approaches are needed. Yet VICTORIA-like patients “have been actively excluded from all the trials that have shown benefit,” she said.
“VICTORIA finally addresses this population of decompensated patients,” she said, and seems to show that vericiguat may help some of them.
At the University of Glasgow, United Kingdom, John J.V. McMurray, MBChB, MD, agreed that the relative risk reduction was “small but significant,” but also that the control group’s event rate was “very high, reflecting the inclusion and exclusion criteria.”
As a result, McMurray told theheart.org | Medscape Cardiology, there was “quite a large absolute risk reduction and small number needed to treat. Also on the positive side: no significant excess of the adverse effects we might have been concerned about,” for example, hypotension.
Vericiguat, if ultimately approved in heart failure, “isn’t going to be first-line or widely used, but it is an additional asset,” he said. “Anything that helps in heart failure is valuable. There are always patients who can’t tolerate treatments, and always people who need more done.”
It’s appealing that the drug works by a long but unfruitfully explored mechanism that has little to do directly with the renin-angiotensin-aldosterone system.
Vericiguat is a soluble guanylate cyclase stimulator that boosts cyclic guanosine monophosphate activity along several pathways, potentiating the salutary pulmonary artery–vasodilating effects of nitric oxide. It improved natriuretic peptide levels in the preceding phase 2 SOCRATES-REDUCED study.
“This is not a me-too drug. It’s a new avenue for heart failure patients,” Armstrong said in an interview. It’s taken once daily, “was relatively easy to titrate up to the target dose, pretty well tolerated, and very safe. And remarkably, you don’t need to measure renal function.”
However, because the drug’s mechanism resides in the same neighborhood of biochemical pathways affected by chronic nitrates and by phosphodiesterase type 5 inhibitors, such as sildenafil and tadalafil, patients taking those drugs were excluded from VICTORIA. Acute nitrates were allowed, however.
Symptomatic hypotension occurred in less than 10% and syncope in 4% or less of both groups; neither difference between the two groups was significant. Anemia developed more often in patients receiving vericiguat (7.6%) than in the control group (5.7%).
“We think that on balance, vericiguat is a useful alternative option for patients. But certainly the only thing we can say at this point is it works in the high-risk population that we studied,” Armstrong said. “Whether it works in lower-risk populations and how it compares is speculation, of course.”
The drug’s cost, whatever it might be if approved, is another factor affecting how it would be used, noted several observers.
“We don’t know what the cost-effectiveness will be. It should be reasonable because the benefit was on hospitalization. That’s a costly outcome,” Yancy said.
McMurray was also hopeful. “If the treatment is well tolerated and reasonably priced, it may still be a valuable asset for at least a subset of patients.”
VICTORIA was supported by Merck Sharp & Dohme Corp and Bayer AG. Armstrong discloses receiving research grants from Merck, Bayer AG, Sanofi-Aventis, Boehringer Ingelheim, and CSL Ltd and consulting fees from Merck, Bayer AG, AstraZeneca, and Novartis. Y ancy has previously disclosed no relevant financial relationships. Stevenson has previously disclosed receiving research grants from Novartis, consulting or serving on an advisory board for Abbott and travel expenses or meals from Novartis and St Jude Medical. McMurray has previously disclosed nonfinancial support or other support from AstraZeneca, Bayer, Cardiorentis, Amgen, Oxford University/Bayer, Theracos, AbbVie, DalCor, Pfizer, Merck, Novartis, GlaxoSmithKline, Bristol-Myers Squibb, and Vifor-Fresenius.
American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Presented March 28, 2020. Session 402-08.
N Engl J Med. Published online March 28, 2020. Full text; Circulation. Published online March 28, 2020. Full text.
This article first appeared on Medscape.com.
Wuhan data link COVID-19 with myocardial damage
The first data on myocardial injury linked with COVID-19 disease during the start of the pandemic in Wuhan, China serves as a “wake up call” for clinicians and the general public on what the United States and other Western countries can expect as the SARS-CoV-2 virus spreads and case numbers mount: a potentially “daunting” toll of deaths as an infection with a tendency to be most severe in patients with underlying cardiovascular disease hits populations that include large numbers of such patients.
“A consistent picture emerges” from two reports on a total of 603 COVID-19 patients treated at two academic hospitals in Wuhan, which described “remarkably similar characteristics of patients who develop myocardial injury” associated with their infection. “Patients who develop myocardial injury with COVID-19 have clinical evidence of higher acuity, with a higher incidence of acute respiratory distress syndrome and more frequent need for assisted ventilation than those without myocardial injury, and the patients who are more prone to have myocardial injury are “older patients with preexisting cardiovascular complications and diabetes,” Robert O. Bonow, MD, and coauthors wrote in an editorial published online (JAMA Cardiol. 2020 Mar 27. doi: 10.1001/jamacardio.2020.1105).
These new findings have special relevance to the United States and other Western countries because of their substantial numbers of elderly patients with cardiovascular diseases, said Dr. Bonow, professor of medicine at Northwestern University, Chicago, and coauthors.
One of the two reports cited in the editorial reviewed 416 patients hospitalized at Renmin Hospital in Wuhan during the period of Jan. 20 to Feb. 10, 2020, with confirmed COVID-19 disease, and found that 20% of the cohort had evidence of cardiac injury, defined as blood levels of the high-sensitivity troponin I cardiac biomarker above the 99th-percentile upper reference limit, regardless of new abnormalities in electrocardiography and echocardiography.
The analysis also showed that patients with myocardial injury had a significantly higher in-hospital mortality rate, 51%, compared with a 5% mortality rate among patients without myocardial injury, and among patients with myocardial injury those with elevated high-sensitivity troponin I had an even higher mortality rate (JAMA Cardiol. 2020 Mar 25. doi: 10.1001/jamacardio.2020.0950).
A second review of 187 confirmed COVID-19 cases at Seventh Hospital in Wuhan during the period of Jan. 23 to Feb. 23, 2020, showed similar findings, with a 28% prevalence of myocardial injury at admission based on an elevated level of plasma troponin T (TnT), and 35% had cardiovascular disease (CVD) including hypertension, coronary heart disease, and cardiomyopathy. Elevated TnT levels and CVD at entry each linked with substantially increased mortality. The incidence of death among patients with elevated TnT and no underlying CVD was 38% compared with 8% among patients without elevated TnT or underlying CVD. Among patients admitted with underlying CVD those who also had an elevated TnT had a 69% death rate during hospitalization compared with a 13% rate in those without TnT elevation (JAMA Cardiol. 2020 Mar 27. doi: 10.1001/jamacardio.2020.1017).
Dr. Bonow and coauthors noted that patients with chronic coronary artery disease have a heightened risk for developing acute coronary syndrome during acute infection, potentially resulting from a severe increase in myocardial demand during infection, or severe systemic inflammatory stress that could result in atherosclerotic plaque instability and rupture as well as vascular and myocardial inflammation.
In addition, patients with heart failure are prone to hemodynamic instability during severe infection. “Thus it is anticipated that patients with underlying cardiovascular diseases, which are more prevalent in older adults, would be susceptible to higher risks of adverse outcomes and death during the severe and aggressive inflammatory responses to COVID-19 than individuals who are younger and healthier,” they wrote.
They also cited the potential for acute or fulminant myocarditis as well as new-onset heart failure caused by the SARS-CoV-2 virus that causes COVID-19 disease based on experience with the related Middle East respiratory syndrome coronavirus. Another concerning observation is that the SARS-CoV-2 virus binds to the angiotensin-converting enzyme 2 protein on cell surfaces as its main entry receptor, “raising the possibility of direct viral infection of vascular endothelium and myocardium,” a process that itself could produce myocardial injury and myocarditis.
These new findings from COVID-19 patients in Wuhan represent early data from what has become a global pandemic, and raise questions about generalizability, but for the time being a key message from these early cases is that prevention of SARS-CoV-2 infection is paramount. “Until we know more, the populations described in these primary data reports should be most observant of strict hand hygiene, social distancing, and, where available, COVID-19 testing,” the authors said.
Dr. Bonow and coauthors had no disclosures.
The first data on myocardial injury linked with COVID-19 disease during the start of the pandemic in Wuhan, China serves as a “wake up call” for clinicians and the general public on what the United States and other Western countries can expect as the SARS-CoV-2 virus spreads and case numbers mount: a potentially “daunting” toll of deaths as an infection with a tendency to be most severe in patients with underlying cardiovascular disease hits populations that include large numbers of such patients.
“A consistent picture emerges” from two reports on a total of 603 COVID-19 patients treated at two academic hospitals in Wuhan, which described “remarkably similar characteristics of patients who develop myocardial injury” associated with their infection. “Patients who develop myocardial injury with COVID-19 have clinical evidence of higher acuity, with a higher incidence of acute respiratory distress syndrome and more frequent need for assisted ventilation than those without myocardial injury, and the patients who are more prone to have myocardial injury are “older patients with preexisting cardiovascular complications and diabetes,” Robert O. Bonow, MD, and coauthors wrote in an editorial published online (JAMA Cardiol. 2020 Mar 27. doi: 10.1001/jamacardio.2020.1105).
These new findings have special relevance to the United States and other Western countries because of their substantial numbers of elderly patients with cardiovascular diseases, said Dr. Bonow, professor of medicine at Northwestern University, Chicago, and coauthors.
One of the two reports cited in the editorial reviewed 416 patients hospitalized at Renmin Hospital in Wuhan during the period of Jan. 20 to Feb. 10, 2020, with confirmed COVID-19 disease, and found that 20% of the cohort had evidence of cardiac injury, defined as blood levels of the high-sensitivity troponin I cardiac biomarker above the 99th-percentile upper reference limit, regardless of new abnormalities in electrocardiography and echocardiography.
The analysis also showed that patients with myocardial injury had a significantly higher in-hospital mortality rate, 51%, compared with a 5% mortality rate among patients without myocardial injury, and among patients with myocardial injury those with elevated high-sensitivity troponin I had an even higher mortality rate (JAMA Cardiol. 2020 Mar 25. doi: 10.1001/jamacardio.2020.0950).
A second review of 187 confirmed COVID-19 cases at Seventh Hospital in Wuhan during the period of Jan. 23 to Feb. 23, 2020, showed similar findings, with a 28% prevalence of myocardial injury at admission based on an elevated level of plasma troponin T (TnT), and 35% had cardiovascular disease (CVD) including hypertension, coronary heart disease, and cardiomyopathy. Elevated TnT levels and CVD at entry each linked with substantially increased mortality. The incidence of death among patients with elevated TnT and no underlying CVD was 38% compared with 8% among patients without elevated TnT or underlying CVD. Among patients admitted with underlying CVD those who also had an elevated TnT had a 69% death rate during hospitalization compared with a 13% rate in those without TnT elevation (JAMA Cardiol. 2020 Mar 27. doi: 10.1001/jamacardio.2020.1017).
Dr. Bonow and coauthors noted that patients with chronic coronary artery disease have a heightened risk for developing acute coronary syndrome during acute infection, potentially resulting from a severe increase in myocardial demand during infection, or severe systemic inflammatory stress that could result in atherosclerotic plaque instability and rupture as well as vascular and myocardial inflammation.
In addition, patients with heart failure are prone to hemodynamic instability during severe infection. “Thus it is anticipated that patients with underlying cardiovascular diseases, which are more prevalent in older adults, would be susceptible to higher risks of adverse outcomes and death during the severe and aggressive inflammatory responses to COVID-19 than individuals who are younger and healthier,” they wrote.
They also cited the potential for acute or fulminant myocarditis as well as new-onset heart failure caused by the SARS-CoV-2 virus that causes COVID-19 disease based on experience with the related Middle East respiratory syndrome coronavirus. Another concerning observation is that the SARS-CoV-2 virus binds to the angiotensin-converting enzyme 2 protein on cell surfaces as its main entry receptor, “raising the possibility of direct viral infection of vascular endothelium and myocardium,” a process that itself could produce myocardial injury and myocarditis.
These new findings from COVID-19 patients in Wuhan represent early data from what has become a global pandemic, and raise questions about generalizability, but for the time being a key message from these early cases is that prevention of SARS-CoV-2 infection is paramount. “Until we know more, the populations described in these primary data reports should be most observant of strict hand hygiene, social distancing, and, where available, COVID-19 testing,” the authors said.
Dr. Bonow and coauthors had no disclosures.
The first data on myocardial injury linked with COVID-19 disease during the start of the pandemic in Wuhan, China serves as a “wake up call” for clinicians and the general public on what the United States and other Western countries can expect as the SARS-CoV-2 virus spreads and case numbers mount: a potentially “daunting” toll of deaths as an infection with a tendency to be most severe in patients with underlying cardiovascular disease hits populations that include large numbers of such patients.
“A consistent picture emerges” from two reports on a total of 603 COVID-19 patients treated at two academic hospitals in Wuhan, which described “remarkably similar characteristics of patients who develop myocardial injury” associated with their infection. “Patients who develop myocardial injury with COVID-19 have clinical evidence of higher acuity, with a higher incidence of acute respiratory distress syndrome and more frequent need for assisted ventilation than those without myocardial injury, and the patients who are more prone to have myocardial injury are “older patients with preexisting cardiovascular complications and diabetes,” Robert O. Bonow, MD, and coauthors wrote in an editorial published online (JAMA Cardiol. 2020 Mar 27. doi: 10.1001/jamacardio.2020.1105).
These new findings have special relevance to the United States and other Western countries because of their substantial numbers of elderly patients with cardiovascular diseases, said Dr. Bonow, professor of medicine at Northwestern University, Chicago, and coauthors.
One of the two reports cited in the editorial reviewed 416 patients hospitalized at Renmin Hospital in Wuhan during the period of Jan. 20 to Feb. 10, 2020, with confirmed COVID-19 disease, and found that 20% of the cohort had evidence of cardiac injury, defined as blood levels of the high-sensitivity troponin I cardiac biomarker above the 99th-percentile upper reference limit, regardless of new abnormalities in electrocardiography and echocardiography.
The analysis also showed that patients with myocardial injury had a significantly higher in-hospital mortality rate, 51%, compared with a 5% mortality rate among patients without myocardial injury, and among patients with myocardial injury those with elevated high-sensitivity troponin I had an even higher mortality rate (JAMA Cardiol. 2020 Mar 25. doi: 10.1001/jamacardio.2020.0950).
A second review of 187 confirmed COVID-19 cases at Seventh Hospital in Wuhan during the period of Jan. 23 to Feb. 23, 2020, showed similar findings, with a 28% prevalence of myocardial injury at admission based on an elevated level of plasma troponin T (TnT), and 35% had cardiovascular disease (CVD) including hypertension, coronary heart disease, and cardiomyopathy. Elevated TnT levels and CVD at entry each linked with substantially increased mortality. The incidence of death among patients with elevated TnT and no underlying CVD was 38% compared with 8% among patients without elevated TnT or underlying CVD. Among patients admitted with underlying CVD those who also had an elevated TnT had a 69% death rate during hospitalization compared with a 13% rate in those without TnT elevation (JAMA Cardiol. 2020 Mar 27. doi: 10.1001/jamacardio.2020.1017).
Dr. Bonow and coauthors noted that patients with chronic coronary artery disease have a heightened risk for developing acute coronary syndrome during acute infection, potentially resulting from a severe increase in myocardial demand during infection, or severe systemic inflammatory stress that could result in atherosclerotic plaque instability and rupture as well as vascular and myocardial inflammation.
In addition, patients with heart failure are prone to hemodynamic instability during severe infection. “Thus it is anticipated that patients with underlying cardiovascular diseases, which are more prevalent in older adults, would be susceptible to higher risks of adverse outcomes and death during the severe and aggressive inflammatory responses to COVID-19 than individuals who are younger and healthier,” they wrote.
They also cited the potential for acute or fulminant myocarditis as well as new-onset heart failure caused by the SARS-CoV-2 virus that causes COVID-19 disease based on experience with the related Middle East respiratory syndrome coronavirus. Another concerning observation is that the SARS-CoV-2 virus binds to the angiotensin-converting enzyme 2 protein on cell surfaces as its main entry receptor, “raising the possibility of direct viral infection of vascular endothelium and myocardium,” a process that itself could produce myocardial injury and myocarditis.
These new findings from COVID-19 patients in Wuhan represent early data from what has become a global pandemic, and raise questions about generalizability, but for the time being a key message from these early cases is that prevention of SARS-CoV-2 infection is paramount. “Until we know more, the populations described in these primary data reports should be most observant of strict hand hygiene, social distancing, and, where available, COVID-19 testing,” the authors said.
Dr. Bonow and coauthors had no disclosures.
FROM JAMA CARDIOLOGY
Low fitness level linked to higher risk of heart failure in diabetes
PHOENIX – Lower baseline fitness and greater decline in fitness over time are independently associated with a higher risk of heart failure in patients with diabetes, results from a large analysis showed.
“Diabetes is an important risk factor for the development of heart failure, and the diagnosis of diabetes in newly diagnosed cases of heart failure has been increasing,” Ambarish Pandey, MD, said at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting. “Type 2 diabetes is associated with increased burden of traditional risk factors such as hypertension, kidney dysfunction, and dyslipidemia – each of which in turn increase the risk of both atherothrombotic disease as well as heart failure.”
Recent data from the Swedish National Diabetes Register have shown that optimal management of these risk factors in patients with type 2 diabetes can actually mitigate the risk of atherosclerotic events such as acute MI, but the risk of heart failure does not significantly lower with optimal management of these traditional cardiovascular risk factors (N Engl J Med. 2018;379:633-44). “These findings highlight that novel approaches that go beyond just managing traditional cardiovascular risk factors are needed for prevention of heart failure in patients with type 2 diabetes,” said Dr. Pandey, of the division of cardiology at the University of Texas Southwestern Medical Center, Dallas. “Our group has demonstrated that physical inactivity and low levels of fitness are associated with a higher risk of heart failure. We have also shown that the protective effect of physical activity against heart failure risk is stronger against heart failure with preserved ejection fraction, which is a subtype of heart failure that is increasing in prevalence and has no effective therapies.”
Dr. Pandey and his colleagues set out to test the research hypothesis that fitness decline and increases in body mass index over time are significantly associated with a higher risk of heart failure. To do this, they drew from the LookAHEAD Trial, a multicenter analysis of 5,145 overweight or obese patients with type 2 diabetes who were randomized to an intensive lifestyle intervention or to usual care. The intervention consisted of a caloric intake goal of 1,200 to 1,800 kcal per day and engaging in at least 175 minutes per week of physical activity. Participants were stratified into one of three fitness group levels: low, moderate, and high, from 5 metabolic equivalents (METs) in the lowest fitness tertile to 9 METs in the highest fitness tertile. The primary outcome of the trial was adverse cardiovascular events. The intervention was implemented for almost 10 years, and patients were followed for up to 12 years from baseline.
The heart failure outcomes were not systematically adjudicated in the primary LookAHEAD trial, so Dr. Pandey and colleagues conducted an ancillary study of all incident hospitalizations in the study and followed them for 2 additional years. Overall, the researchers identified 257 incident heart failure events. The cumulative incidence of heart failure for the usual care versus the intensive lifestyle intervention arm was not statistically different (an event rate of 4.53 vs. 4.32 per 1,000 person-years, respectively; hazard ratio, 0.96). “This demonstrated that the intensive lifestyle intervention in the LookAHEAD trial did not significantly modify the risk of heart failure,” Dr. Pandey said.
However, an adjusted analysis revealed that the risk of heart failure was 39% lower in the moderately fit group and 62% lower in the high fit group, compared with the low-fitness group. Among heart failure subtypes, the risk of heart failure with preserved ejection fraction (HFpEF) was 40% lower in the moderately fit group and 77% lower in the high-fitness group. On the other hand, baseline level of fitness level was not associated with risk of heart failure reduced ejection fraction (HFrEF) after the researchers adjusted for cardiovascular risk factors.
Next, Dr. Pandey and his colleagues used Cox modeling to examine the association of baseline and longitudinal changes in fitness and BMI with risk of heart failure. For change in fitness and BMI analysis, they used the 4-year follow-up data in 3,092 participants who underwent repeat fitness testing and had available data on BMI. They excluded patients who developed heart failure within the first 4 years of the study.
The mean age of the ancillary study population was about 60 years, and there was a lower proportion of women in the high fitness tertile (41%). The researchers observed a graded, inverse association between higher fitness levels and lower risk of heart failure such that increasing fitness from baseline was associated with a substantial decrease in the risk of heart failure. Specifically, a 10% decline in fitness over the 4 years of follow-up was associated with a 11% increase in the overall risk of heart failure (HR, 1.11). “This was largely consistent with the two heart failure subtypes,” he said. Similarly, a 10% increase in BMI over the 4 years of follow-up was associated with a 25% increase in the overall risk of heart failure (HR 1.25). On the other hand, a 10% decrease BMI was associated with a 20% decrease in the risk of heart failure (HR .80). This was also largely consistent for both heart failure subtypes. According to co-lead investigator Kershaw Patel, MD, “these findings suggest that therapies targeting large and sustained improvements in fitness and weight loss may modify the risk of heart failure among patients with diabetes.”
“Lower fitness at baseline was more strongly associated with the risk of HFpEF vs. HFrEF, and greater weight loss over follow-up is associated with a lower risk of heart failure independent of changes in other risk factors,” Dr. Pandey concluded at the meeting, which was sponsored by the American Heart Association.
In an interview, session moderator Joshua J. Joseph, MD, said that it remains unclear what type of setting is ideal for carrying out cardiorespiratory fitness in this patient population. “What is the supervision needed for that to occur?” asked Dr. Joseph, of The Ohio State University, Columbus. “Can patients do this on their own, or do they need guidance? What is the best approach? That’s the question we all have to answer individually in our own communities.”
Dr. Pandey reported having no disclosures.
SOURCE: Pandey A. Epi/Lifestyle 2020, Abstract 16.
PHOENIX – Lower baseline fitness and greater decline in fitness over time are independently associated with a higher risk of heart failure in patients with diabetes, results from a large analysis showed.
“Diabetes is an important risk factor for the development of heart failure, and the diagnosis of diabetes in newly diagnosed cases of heart failure has been increasing,” Ambarish Pandey, MD, said at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting. “Type 2 diabetes is associated with increased burden of traditional risk factors such as hypertension, kidney dysfunction, and dyslipidemia – each of which in turn increase the risk of both atherothrombotic disease as well as heart failure.”
Recent data from the Swedish National Diabetes Register have shown that optimal management of these risk factors in patients with type 2 diabetes can actually mitigate the risk of atherosclerotic events such as acute MI, but the risk of heart failure does not significantly lower with optimal management of these traditional cardiovascular risk factors (N Engl J Med. 2018;379:633-44). “These findings highlight that novel approaches that go beyond just managing traditional cardiovascular risk factors are needed for prevention of heart failure in patients with type 2 diabetes,” said Dr. Pandey, of the division of cardiology at the University of Texas Southwestern Medical Center, Dallas. “Our group has demonstrated that physical inactivity and low levels of fitness are associated with a higher risk of heart failure. We have also shown that the protective effect of physical activity against heart failure risk is stronger against heart failure with preserved ejection fraction, which is a subtype of heart failure that is increasing in prevalence and has no effective therapies.”
Dr. Pandey and his colleagues set out to test the research hypothesis that fitness decline and increases in body mass index over time are significantly associated with a higher risk of heart failure. To do this, they drew from the LookAHEAD Trial, a multicenter analysis of 5,145 overweight or obese patients with type 2 diabetes who were randomized to an intensive lifestyle intervention or to usual care. The intervention consisted of a caloric intake goal of 1,200 to 1,800 kcal per day and engaging in at least 175 minutes per week of physical activity. Participants were stratified into one of three fitness group levels: low, moderate, and high, from 5 metabolic equivalents (METs) in the lowest fitness tertile to 9 METs in the highest fitness tertile. The primary outcome of the trial was adverse cardiovascular events. The intervention was implemented for almost 10 years, and patients were followed for up to 12 years from baseline.
The heart failure outcomes were not systematically adjudicated in the primary LookAHEAD trial, so Dr. Pandey and colleagues conducted an ancillary study of all incident hospitalizations in the study and followed them for 2 additional years. Overall, the researchers identified 257 incident heart failure events. The cumulative incidence of heart failure for the usual care versus the intensive lifestyle intervention arm was not statistically different (an event rate of 4.53 vs. 4.32 per 1,000 person-years, respectively; hazard ratio, 0.96). “This demonstrated that the intensive lifestyle intervention in the LookAHEAD trial did not significantly modify the risk of heart failure,” Dr. Pandey said.
However, an adjusted analysis revealed that the risk of heart failure was 39% lower in the moderately fit group and 62% lower in the high fit group, compared with the low-fitness group. Among heart failure subtypes, the risk of heart failure with preserved ejection fraction (HFpEF) was 40% lower in the moderately fit group and 77% lower in the high-fitness group. On the other hand, baseline level of fitness level was not associated with risk of heart failure reduced ejection fraction (HFrEF) after the researchers adjusted for cardiovascular risk factors.
Next, Dr. Pandey and his colleagues used Cox modeling to examine the association of baseline and longitudinal changes in fitness and BMI with risk of heart failure. For change in fitness and BMI analysis, they used the 4-year follow-up data in 3,092 participants who underwent repeat fitness testing and had available data on BMI. They excluded patients who developed heart failure within the first 4 years of the study.
The mean age of the ancillary study population was about 60 years, and there was a lower proportion of women in the high fitness tertile (41%). The researchers observed a graded, inverse association between higher fitness levels and lower risk of heart failure such that increasing fitness from baseline was associated with a substantial decrease in the risk of heart failure. Specifically, a 10% decline in fitness over the 4 years of follow-up was associated with a 11% increase in the overall risk of heart failure (HR, 1.11). “This was largely consistent with the two heart failure subtypes,” he said. Similarly, a 10% increase in BMI over the 4 years of follow-up was associated with a 25% increase in the overall risk of heart failure (HR 1.25). On the other hand, a 10% decrease BMI was associated with a 20% decrease in the risk of heart failure (HR .80). This was also largely consistent for both heart failure subtypes. According to co-lead investigator Kershaw Patel, MD, “these findings suggest that therapies targeting large and sustained improvements in fitness and weight loss may modify the risk of heart failure among patients with diabetes.”
“Lower fitness at baseline was more strongly associated with the risk of HFpEF vs. HFrEF, and greater weight loss over follow-up is associated with a lower risk of heart failure independent of changes in other risk factors,” Dr. Pandey concluded at the meeting, which was sponsored by the American Heart Association.
In an interview, session moderator Joshua J. Joseph, MD, said that it remains unclear what type of setting is ideal for carrying out cardiorespiratory fitness in this patient population. “What is the supervision needed for that to occur?” asked Dr. Joseph, of The Ohio State University, Columbus. “Can patients do this on their own, or do they need guidance? What is the best approach? That’s the question we all have to answer individually in our own communities.”
Dr. Pandey reported having no disclosures.
SOURCE: Pandey A. Epi/Lifestyle 2020, Abstract 16.
PHOENIX – Lower baseline fitness and greater decline in fitness over time are independently associated with a higher risk of heart failure in patients with diabetes, results from a large analysis showed.
“Diabetes is an important risk factor for the development of heart failure, and the diagnosis of diabetes in newly diagnosed cases of heart failure has been increasing,” Ambarish Pandey, MD, said at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting. “Type 2 diabetes is associated with increased burden of traditional risk factors such as hypertension, kidney dysfunction, and dyslipidemia – each of which in turn increase the risk of both atherothrombotic disease as well as heart failure.”
Recent data from the Swedish National Diabetes Register have shown that optimal management of these risk factors in patients with type 2 diabetes can actually mitigate the risk of atherosclerotic events such as acute MI, but the risk of heart failure does not significantly lower with optimal management of these traditional cardiovascular risk factors (N Engl J Med. 2018;379:633-44). “These findings highlight that novel approaches that go beyond just managing traditional cardiovascular risk factors are needed for prevention of heart failure in patients with type 2 diabetes,” said Dr. Pandey, of the division of cardiology at the University of Texas Southwestern Medical Center, Dallas. “Our group has demonstrated that physical inactivity and low levels of fitness are associated with a higher risk of heart failure. We have also shown that the protective effect of physical activity against heart failure risk is stronger against heart failure with preserved ejection fraction, which is a subtype of heart failure that is increasing in prevalence and has no effective therapies.”
Dr. Pandey and his colleagues set out to test the research hypothesis that fitness decline and increases in body mass index over time are significantly associated with a higher risk of heart failure. To do this, they drew from the LookAHEAD Trial, a multicenter analysis of 5,145 overweight or obese patients with type 2 diabetes who were randomized to an intensive lifestyle intervention or to usual care. The intervention consisted of a caloric intake goal of 1,200 to 1,800 kcal per day and engaging in at least 175 minutes per week of physical activity. Participants were stratified into one of three fitness group levels: low, moderate, and high, from 5 metabolic equivalents (METs) in the lowest fitness tertile to 9 METs in the highest fitness tertile. The primary outcome of the trial was adverse cardiovascular events. The intervention was implemented for almost 10 years, and patients were followed for up to 12 years from baseline.
The heart failure outcomes were not systematically adjudicated in the primary LookAHEAD trial, so Dr. Pandey and colleagues conducted an ancillary study of all incident hospitalizations in the study and followed them for 2 additional years. Overall, the researchers identified 257 incident heart failure events. The cumulative incidence of heart failure for the usual care versus the intensive lifestyle intervention arm was not statistically different (an event rate of 4.53 vs. 4.32 per 1,000 person-years, respectively; hazard ratio, 0.96). “This demonstrated that the intensive lifestyle intervention in the LookAHEAD trial did not significantly modify the risk of heart failure,” Dr. Pandey said.
However, an adjusted analysis revealed that the risk of heart failure was 39% lower in the moderately fit group and 62% lower in the high fit group, compared with the low-fitness group. Among heart failure subtypes, the risk of heart failure with preserved ejection fraction (HFpEF) was 40% lower in the moderately fit group and 77% lower in the high-fitness group. On the other hand, baseline level of fitness level was not associated with risk of heart failure reduced ejection fraction (HFrEF) after the researchers adjusted for cardiovascular risk factors.
Next, Dr. Pandey and his colleagues used Cox modeling to examine the association of baseline and longitudinal changes in fitness and BMI with risk of heart failure. For change in fitness and BMI analysis, they used the 4-year follow-up data in 3,092 participants who underwent repeat fitness testing and had available data on BMI. They excluded patients who developed heart failure within the first 4 years of the study.
The mean age of the ancillary study population was about 60 years, and there was a lower proportion of women in the high fitness tertile (41%). The researchers observed a graded, inverse association between higher fitness levels and lower risk of heart failure such that increasing fitness from baseline was associated with a substantial decrease in the risk of heart failure. Specifically, a 10% decline in fitness over the 4 years of follow-up was associated with a 11% increase in the overall risk of heart failure (HR, 1.11). “This was largely consistent with the two heart failure subtypes,” he said. Similarly, a 10% increase in BMI over the 4 years of follow-up was associated with a 25% increase in the overall risk of heart failure (HR 1.25). On the other hand, a 10% decrease BMI was associated with a 20% decrease in the risk of heart failure (HR .80). This was also largely consistent for both heart failure subtypes. According to co-lead investigator Kershaw Patel, MD, “these findings suggest that therapies targeting large and sustained improvements in fitness and weight loss may modify the risk of heart failure among patients with diabetes.”
“Lower fitness at baseline was more strongly associated with the risk of HFpEF vs. HFrEF, and greater weight loss over follow-up is associated with a lower risk of heart failure independent of changes in other risk factors,” Dr. Pandey concluded at the meeting, which was sponsored by the American Heart Association.
In an interview, session moderator Joshua J. Joseph, MD, said that it remains unclear what type of setting is ideal for carrying out cardiorespiratory fitness in this patient population. “What is the supervision needed for that to occur?” asked Dr. Joseph, of The Ohio State University, Columbus. “Can patients do this on their own, or do they need guidance? What is the best approach? That’s the question we all have to answer individually in our own communities.”
Dr. Pandey reported having no disclosures.
SOURCE: Pandey A. Epi/Lifestyle 2020, Abstract 16.
REPORTING FROM EPI/LIFESTYLE 2020
PARAGON-HF: Optimal systolic pressure in HFpEF is 120-129 mm Hg
A target systolic blood pressure (SBP) of 120-129 mm Hg in patients with heart failure with preserved ejection fraction proved to be the sweet spot with the lowest rates of major adverse cardiovascular and renal events in a new analysis from the landmark PARAGON-HF trial.
This finding from the largest-ever randomized, controlled study in heart failure with preserved ejection fraction (HFpEF) strengthens support for current U.S. joint hypertension guidelines, which call for a target SBP less than 130 mm Hg in patients with HFpEF (J Am Coll Cardiol. 2017 Aug 8;70[6]:776-803), a recommendation based upon weak evidence until now. That’s because the SPRINT trial, the major impetus for adoption of intensive blood pressure control in the current guidelines, excluded patients with symptomatic HF, Scott D. Solomon, MD, and coinvestigators noted in their new analysis. The study was published in the Journal of the American College of Cardiology and had been planned for presentation during the joint scientific sessions of the American College of Cardiology and the World Heart Federation. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
The new analysis from PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) also ruled out the SBP-lowering effect of sacubitril/valsartan (Entresto) as the explanation for the combination drug’s demonstrated beneficial impact on outcomes in the subgroup with an SBP of 120-129 mm Hg. That wasn’t actually a surprise. Indeed, the new study had two hypotheses: one, that the relationship between SBP and cardiovascular and renal outcomes in HFpEF would follow a J-shaped curve, and two, that sacubitril/valsartan’s blood pressure–lowering effect would not account for the drug’s outcome benefits in the subset of HFpEF patients with an SBP in the sweet spot of 120-129 mm Hg. Both hypotheses were borne out, noted Dr. Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital, both in Boston.
“These data strongly support that additional mechanisms other than blood pressure–lowering account for the benefit. But this is not surprising. The same can be said for most of the therapies that work in heart failure,” he said in an interview.
Take, for example, spironolactone. In TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist), another major trial in which Dr. Solomon played a leadership role, the beneficial effect of spironolactone on clinical outcomes also proved unrelated to the drug’s blood pressure–lowering effect.
Other known effects of sacubitril/valsartan, a novel angiotensin receptor–neprilysin inhibitor, or ARNI, might in theory account for the observed clinical benefits in ARNI-treated patients with an on-treatment SBP of 120-129 mm Hg in PARAGON-HF. These include improved left atrial remodeling, an increase in natriuretic peptides, and improved myocardial relaxation. However, the current lack of understanding of the basic mechanistic processes underlying the varied clinical expressions of HFpEF is a major factor contributing to the lack of any proven-effective therapy for this extremely common and costly disorder, according to Dr. Solomon and coinvestigators.
In contrast to HFpEF, for which to date there is no proven treatment, heart failure with reduced ejection fraction sacubitril/valsartan has a class I recommendation on the strength of its performance in significantly reducing cardiovascular deaths and heart failure hospitalizations in the PARADIGM-HF trial (N Engl J Med. 2014 Sep 11;371:993-1004).
PARAGON-HF included 4,822 patients with symptomatic HFpEF who were randomized to sacubitril/valsartan at 97/103 mg b.i.d. or valsartan at 160 mg b.i.d. As previously reported (N Engl J Med. 2019 Oct 24;381[17]:1609-20), at an average follow-up of 35 months, the primary outcome – a composite of total hospitalizations for heart failure and cardiovascular death – occurred at a rate of 12.8 events per 100 patient-years in the sacubitril/valsartan group and 14.6 per 100 patient-years in the valsartan arm, for a 13% relative risk reduction that narrowly missed statistical significance (P = .059).
However, sacubitril/valsartan showed significant benefit on some prespecified secondary endpoints, including worsening renal function, change in New York Heart Association class, and quality of life. Women, who notably accounted for 52% of study participants, appeared to benefit from sacubitril/valsartan more than men as evidenced by their 27% relative risk reduction in the primary endpoint. Also, in the roughly half of PARAGON-HF participants with a baseline left ventricular ejection fraction of 45%-57%, treatment with sacubitril/valsartan resulted in a statistically significant 22% relative risk reduction in the primary endpoint, compared with valsartan alone.
SBP and cardiovascular outcomes in HFpEF
In the new analysis, Dr. Solomon and coworkers examined outcomes based on baseline and mean achieved SBP quartiles regardless of treatment arm. In an unadjusted analysis, the primary composite endpoint occurred at a rate of 15.2 events/100 patient-years in HFpEF patients with an achieved SBP below 120 mm Hg, 11.4/100 patient-years at 120-129 mm Hg, 12.2/100 patient-years at 130-139 mm Hg, and 15.6/100 patient-years at 140 mm Hg or more. Further, in a multivariate regression analysis extensively adjusted for atrial fibrillation, sex, race, and numerous other potential confounders, the group with an achieved SBP of 120-129 mm Hg continued to fare best. The adjusted risks for the primary endpoint were 11% and 21% higher in patients in the first and third quartiles of achieved SBP, compared with those at 120-129 mm Hg, although neither trend reached statistical significance. But patients in the top quartile, with an achieved SBP of 140 mm Hg or more, had a highly significant 56% increase in risk, compared with patients in the second-lowest SBP quartile.
Change in blood pressure from baseline to week 48 had no impact on quality of life or high-sensitivity troponin T. However, each 10–mm Hg lowering of SBP was associated with a modest 2.1% reduction in log-transformed N-terminal of the prohormone brain natriuretic peptide.
Sacubitril/valsartan reduced SBP by an average of 5.2 mm Hg more than valsartan alone at 4 weeks regardless of baseline SBP. And the combo drug had a significantly greater SBP-lowering effect in women than men, by a margin of 6.3 mm Hg versus 4.0 mm Hg. But a Cox regression analysis showed that in women, as in the study population as a whole, sacubitril/valsartan’s SBP-lowering effects didn’t account for the drug’s impact on outcomes.
In an editorial accompanying publication of the new PARAGON-HF blood pressure analysis (J Am Coll Cardiol. 2020 Mar 16. doi: 10.1016/j.jacc.2020.02.024), Hector O. Ventura, MD, and colleagues at the Ochsner Clinic in New Orleans observed that the study results “lend some credence to the prognostic relationship of blood pressure in HFpEF, but whether they should serve as a therapeutic target or are merely a prognostic surrogate determined by other pathogenic factors, such as vascular ventricular uncoupling or aortic stiffness on one hand when blood pressure is greater than 140 mm Hg, or a reduced cardiac performance indicated by reduced blood pressure to less than 120 mm Hg, remains uncertain.”
“What is certain, however, is that the relationship and contributions of hypertension in manifest HFpEF are complex, multifactorial and likely go well beyond a simplistic framework of hemodynamic influences,” they added.
Dr. Solomon has received research grants from and serves as a consultant to Novartis, which funded PARAGON-HF, and has similar financial relationships with more than a dozen other pharmaceutical companies. Dr. Ventura reported having no relevant financial interests.
SOURCE: Solomon SD et al. J Am Coll Cardiol. 2020 Mar 16. doi: 10.1016/j.jacc.2020.02.009.
A target systolic blood pressure (SBP) of 120-129 mm Hg in patients with heart failure with preserved ejection fraction proved to be the sweet spot with the lowest rates of major adverse cardiovascular and renal events in a new analysis from the landmark PARAGON-HF trial.
This finding from the largest-ever randomized, controlled study in heart failure with preserved ejection fraction (HFpEF) strengthens support for current U.S. joint hypertension guidelines, which call for a target SBP less than 130 mm Hg in patients with HFpEF (J Am Coll Cardiol. 2017 Aug 8;70[6]:776-803), a recommendation based upon weak evidence until now. That’s because the SPRINT trial, the major impetus for adoption of intensive blood pressure control in the current guidelines, excluded patients with symptomatic HF, Scott D. Solomon, MD, and coinvestigators noted in their new analysis. The study was published in the Journal of the American College of Cardiology and had been planned for presentation during the joint scientific sessions of the American College of Cardiology and the World Heart Federation. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
The new analysis from PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) also ruled out the SBP-lowering effect of sacubitril/valsartan (Entresto) as the explanation for the combination drug’s demonstrated beneficial impact on outcomes in the subgroup with an SBP of 120-129 mm Hg. That wasn’t actually a surprise. Indeed, the new study had two hypotheses: one, that the relationship between SBP and cardiovascular and renal outcomes in HFpEF would follow a J-shaped curve, and two, that sacubitril/valsartan’s blood pressure–lowering effect would not account for the drug’s outcome benefits in the subset of HFpEF patients with an SBP in the sweet spot of 120-129 mm Hg. Both hypotheses were borne out, noted Dr. Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital, both in Boston.
“These data strongly support that additional mechanisms other than blood pressure–lowering account for the benefit. But this is not surprising. The same can be said for most of the therapies that work in heart failure,” he said in an interview.
Take, for example, spironolactone. In TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist), another major trial in which Dr. Solomon played a leadership role, the beneficial effect of spironolactone on clinical outcomes also proved unrelated to the drug’s blood pressure–lowering effect.
Other known effects of sacubitril/valsartan, a novel angiotensin receptor–neprilysin inhibitor, or ARNI, might in theory account for the observed clinical benefits in ARNI-treated patients with an on-treatment SBP of 120-129 mm Hg in PARAGON-HF. These include improved left atrial remodeling, an increase in natriuretic peptides, and improved myocardial relaxation. However, the current lack of understanding of the basic mechanistic processes underlying the varied clinical expressions of HFpEF is a major factor contributing to the lack of any proven-effective therapy for this extremely common and costly disorder, according to Dr. Solomon and coinvestigators.
In contrast to HFpEF, for which to date there is no proven treatment, heart failure with reduced ejection fraction sacubitril/valsartan has a class I recommendation on the strength of its performance in significantly reducing cardiovascular deaths and heart failure hospitalizations in the PARADIGM-HF trial (N Engl J Med. 2014 Sep 11;371:993-1004).
PARAGON-HF included 4,822 patients with symptomatic HFpEF who were randomized to sacubitril/valsartan at 97/103 mg b.i.d. or valsartan at 160 mg b.i.d. As previously reported (N Engl J Med. 2019 Oct 24;381[17]:1609-20), at an average follow-up of 35 months, the primary outcome – a composite of total hospitalizations for heart failure and cardiovascular death – occurred at a rate of 12.8 events per 100 patient-years in the sacubitril/valsartan group and 14.6 per 100 patient-years in the valsartan arm, for a 13% relative risk reduction that narrowly missed statistical significance (P = .059).
However, sacubitril/valsartan showed significant benefit on some prespecified secondary endpoints, including worsening renal function, change in New York Heart Association class, and quality of life. Women, who notably accounted for 52% of study participants, appeared to benefit from sacubitril/valsartan more than men as evidenced by their 27% relative risk reduction in the primary endpoint. Also, in the roughly half of PARAGON-HF participants with a baseline left ventricular ejection fraction of 45%-57%, treatment with sacubitril/valsartan resulted in a statistically significant 22% relative risk reduction in the primary endpoint, compared with valsartan alone.
SBP and cardiovascular outcomes in HFpEF
In the new analysis, Dr. Solomon and coworkers examined outcomes based on baseline and mean achieved SBP quartiles regardless of treatment arm. In an unadjusted analysis, the primary composite endpoint occurred at a rate of 15.2 events/100 patient-years in HFpEF patients with an achieved SBP below 120 mm Hg, 11.4/100 patient-years at 120-129 mm Hg, 12.2/100 patient-years at 130-139 mm Hg, and 15.6/100 patient-years at 140 mm Hg or more. Further, in a multivariate regression analysis extensively adjusted for atrial fibrillation, sex, race, and numerous other potential confounders, the group with an achieved SBP of 120-129 mm Hg continued to fare best. The adjusted risks for the primary endpoint were 11% and 21% higher in patients in the first and third quartiles of achieved SBP, compared with those at 120-129 mm Hg, although neither trend reached statistical significance. But patients in the top quartile, with an achieved SBP of 140 mm Hg or more, had a highly significant 56% increase in risk, compared with patients in the second-lowest SBP quartile.
Change in blood pressure from baseline to week 48 had no impact on quality of life or high-sensitivity troponin T. However, each 10–mm Hg lowering of SBP was associated with a modest 2.1% reduction in log-transformed N-terminal of the prohormone brain natriuretic peptide.
Sacubitril/valsartan reduced SBP by an average of 5.2 mm Hg more than valsartan alone at 4 weeks regardless of baseline SBP. And the combo drug had a significantly greater SBP-lowering effect in women than men, by a margin of 6.3 mm Hg versus 4.0 mm Hg. But a Cox regression analysis showed that in women, as in the study population as a whole, sacubitril/valsartan’s SBP-lowering effects didn’t account for the drug’s impact on outcomes.
In an editorial accompanying publication of the new PARAGON-HF blood pressure analysis (J Am Coll Cardiol. 2020 Mar 16. doi: 10.1016/j.jacc.2020.02.024), Hector O. Ventura, MD, and colleagues at the Ochsner Clinic in New Orleans observed that the study results “lend some credence to the prognostic relationship of blood pressure in HFpEF, but whether they should serve as a therapeutic target or are merely a prognostic surrogate determined by other pathogenic factors, such as vascular ventricular uncoupling or aortic stiffness on one hand when blood pressure is greater than 140 mm Hg, or a reduced cardiac performance indicated by reduced blood pressure to less than 120 mm Hg, remains uncertain.”
“What is certain, however, is that the relationship and contributions of hypertension in manifest HFpEF are complex, multifactorial and likely go well beyond a simplistic framework of hemodynamic influences,” they added.
Dr. Solomon has received research grants from and serves as a consultant to Novartis, which funded PARAGON-HF, and has similar financial relationships with more than a dozen other pharmaceutical companies. Dr. Ventura reported having no relevant financial interests.
SOURCE: Solomon SD et al. J Am Coll Cardiol. 2020 Mar 16. doi: 10.1016/j.jacc.2020.02.009.
A target systolic blood pressure (SBP) of 120-129 mm Hg in patients with heart failure with preserved ejection fraction proved to be the sweet spot with the lowest rates of major adverse cardiovascular and renal events in a new analysis from the landmark PARAGON-HF trial.
This finding from the largest-ever randomized, controlled study in heart failure with preserved ejection fraction (HFpEF) strengthens support for current U.S. joint hypertension guidelines, which call for a target SBP less than 130 mm Hg in patients with HFpEF (J Am Coll Cardiol. 2017 Aug 8;70[6]:776-803), a recommendation based upon weak evidence until now. That’s because the SPRINT trial, the major impetus for adoption of intensive blood pressure control in the current guidelines, excluded patients with symptomatic HF, Scott D. Solomon, MD, and coinvestigators noted in their new analysis. The study was published in the Journal of the American College of Cardiology and had been planned for presentation during the joint scientific sessions of the American College of Cardiology and the World Heart Federation. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
The new analysis from PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) also ruled out the SBP-lowering effect of sacubitril/valsartan (Entresto) as the explanation for the combination drug’s demonstrated beneficial impact on outcomes in the subgroup with an SBP of 120-129 mm Hg. That wasn’t actually a surprise. Indeed, the new study had two hypotheses: one, that the relationship between SBP and cardiovascular and renal outcomes in HFpEF would follow a J-shaped curve, and two, that sacubitril/valsartan’s blood pressure–lowering effect would not account for the drug’s outcome benefits in the subset of HFpEF patients with an SBP in the sweet spot of 120-129 mm Hg. Both hypotheses were borne out, noted Dr. Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital, both in Boston.
“These data strongly support that additional mechanisms other than blood pressure–lowering account for the benefit. But this is not surprising. The same can be said for most of the therapies that work in heart failure,” he said in an interview.
Take, for example, spironolactone. In TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist), another major trial in which Dr. Solomon played a leadership role, the beneficial effect of spironolactone on clinical outcomes also proved unrelated to the drug’s blood pressure–lowering effect.
Other known effects of sacubitril/valsartan, a novel angiotensin receptor–neprilysin inhibitor, or ARNI, might in theory account for the observed clinical benefits in ARNI-treated patients with an on-treatment SBP of 120-129 mm Hg in PARAGON-HF. These include improved left atrial remodeling, an increase in natriuretic peptides, and improved myocardial relaxation. However, the current lack of understanding of the basic mechanistic processes underlying the varied clinical expressions of HFpEF is a major factor contributing to the lack of any proven-effective therapy for this extremely common and costly disorder, according to Dr. Solomon and coinvestigators.
In contrast to HFpEF, for which to date there is no proven treatment, heart failure with reduced ejection fraction sacubitril/valsartan has a class I recommendation on the strength of its performance in significantly reducing cardiovascular deaths and heart failure hospitalizations in the PARADIGM-HF trial (N Engl J Med. 2014 Sep 11;371:993-1004).
PARAGON-HF included 4,822 patients with symptomatic HFpEF who were randomized to sacubitril/valsartan at 97/103 mg b.i.d. or valsartan at 160 mg b.i.d. As previously reported (N Engl J Med. 2019 Oct 24;381[17]:1609-20), at an average follow-up of 35 months, the primary outcome – a composite of total hospitalizations for heart failure and cardiovascular death – occurred at a rate of 12.8 events per 100 patient-years in the sacubitril/valsartan group and 14.6 per 100 patient-years in the valsartan arm, for a 13% relative risk reduction that narrowly missed statistical significance (P = .059).
However, sacubitril/valsartan showed significant benefit on some prespecified secondary endpoints, including worsening renal function, change in New York Heart Association class, and quality of life. Women, who notably accounted for 52% of study participants, appeared to benefit from sacubitril/valsartan more than men as evidenced by their 27% relative risk reduction in the primary endpoint. Also, in the roughly half of PARAGON-HF participants with a baseline left ventricular ejection fraction of 45%-57%, treatment with sacubitril/valsartan resulted in a statistically significant 22% relative risk reduction in the primary endpoint, compared with valsartan alone.
SBP and cardiovascular outcomes in HFpEF
In the new analysis, Dr. Solomon and coworkers examined outcomes based on baseline and mean achieved SBP quartiles regardless of treatment arm. In an unadjusted analysis, the primary composite endpoint occurred at a rate of 15.2 events/100 patient-years in HFpEF patients with an achieved SBP below 120 mm Hg, 11.4/100 patient-years at 120-129 mm Hg, 12.2/100 patient-years at 130-139 mm Hg, and 15.6/100 patient-years at 140 mm Hg or more. Further, in a multivariate regression analysis extensively adjusted for atrial fibrillation, sex, race, and numerous other potential confounders, the group with an achieved SBP of 120-129 mm Hg continued to fare best. The adjusted risks for the primary endpoint were 11% and 21% higher in patients in the first and third quartiles of achieved SBP, compared with those at 120-129 mm Hg, although neither trend reached statistical significance. But patients in the top quartile, with an achieved SBP of 140 mm Hg or more, had a highly significant 56% increase in risk, compared with patients in the second-lowest SBP quartile.
Change in blood pressure from baseline to week 48 had no impact on quality of life or high-sensitivity troponin T. However, each 10–mm Hg lowering of SBP was associated with a modest 2.1% reduction in log-transformed N-terminal of the prohormone brain natriuretic peptide.
Sacubitril/valsartan reduced SBP by an average of 5.2 mm Hg more than valsartan alone at 4 weeks regardless of baseline SBP. And the combo drug had a significantly greater SBP-lowering effect in women than men, by a margin of 6.3 mm Hg versus 4.0 mm Hg. But a Cox regression analysis showed that in women, as in the study population as a whole, sacubitril/valsartan’s SBP-lowering effects didn’t account for the drug’s impact on outcomes.
In an editorial accompanying publication of the new PARAGON-HF blood pressure analysis (J Am Coll Cardiol. 2020 Mar 16. doi: 10.1016/j.jacc.2020.02.024), Hector O. Ventura, MD, and colleagues at the Ochsner Clinic in New Orleans observed that the study results “lend some credence to the prognostic relationship of blood pressure in HFpEF, but whether they should serve as a therapeutic target or are merely a prognostic surrogate determined by other pathogenic factors, such as vascular ventricular uncoupling or aortic stiffness on one hand when blood pressure is greater than 140 mm Hg, or a reduced cardiac performance indicated by reduced blood pressure to less than 120 mm Hg, remains uncertain.”
“What is certain, however, is that the relationship and contributions of hypertension in manifest HFpEF are complex, multifactorial and likely go well beyond a simplistic framework of hemodynamic influences,” they added.
Dr. Solomon has received research grants from and serves as a consultant to Novartis, which funded PARAGON-HF, and has similar financial relationships with more than a dozen other pharmaceutical companies. Dr. Ventura reported having no relevant financial interests.
SOURCE: Solomon SD et al. J Am Coll Cardiol. 2020 Mar 16. doi: 10.1016/j.jacc.2020.02.009.
FROM ACC 2020