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Mitchel is a reporter for MDedge based in the Philadelphia area. He started with the company in 1992, when it was International Medical News Group (IMNG), and has since covered a range of medical specialties. Mitchel trained as a virologist at Roswell Park Memorial Institute in Buffalo, and then worked briefly as a researcher at Boston Children's Hospital before pivoting to journalism as a AAAS Mass Media Fellow in 1980. His first reporting job was with Science Digest magazine, and from the mid-1980s to early-1990s he was a reporter with Medical World News. @mitchelzoler
ESC’s new lipid guidelines keep LDL-cholesterol targets
ROME – LDL cholesterol treatment targets remain alive and well in non-U.S. lipid management guidelines.
New dyslipidemia management guidelines from the European Society of Cardiology, issued in late August, retain the same LDL cholesterol targets as the prior, 2011 guidelines, a sharp and purposeful departure from the “risk-based” U.S. guidelines introduced in 2013 that eliminated treating patients to specific LDL cholesterol targets.
The new ESC guidelines also incorporated the new class of lipid-lowering drugs, PCSK9 inhibitors (evolocumab [Repatha] and alirocumab [Praluent]), into the treatment algorithm, and carved out a role for ezetimibe (Zetia) following its proven success as an add-on agent to statins (Eur Heart J. 2016. doi: 10.1093/eurheartj/ehw272).
But it’s retention of LDL cholesterol targets as a cornerstone of dyslipidemia management in the new ESC report, written jointly with the European Atherosclerosis Society, that especially distinguishes the new guidelines.
“It seemed to us logical that if you have drugs [statins] that lower LDL cholesterol, then you target LDL cholesterol,” explained Ian M. Graham, MD, professor of cardiovascular medicine at Trinity College in Dublin and cochair of the guidelines panel. “If a patient’s risk is high, they still need to lower LDL cholesterol. It’s not really contradictory to the U.S. approach,” Dr. Graham said in an interview.
The ESC panel’s discussions about the LDL cholesterol targets were “difficult and long,” said Guy De Backer, MD, a member of the guidelines committee and professor of cardiology at the University of Ghent, Belgium, in a session devoted to the new guidelines during the annual congress of the ESC.
The ESC’s decision to retain the 2011 LDL cholesterol targets won praise from U.S. cardiologist Eugene Braunwald, MD. “I think that not measuring and following LDL cholesterol is silly. I don’t agree” with current U.S. guidelines, he said in a talk during the congress. “If you don’t follow LDL cholesterol then you don’t know a patient’s compliance.
Regularly measuring LDL cholesterol is important,” said Dr. Braunwald, professor of medicine at Harvard Medical School in Boston. But he questioned the LDL cholesterol targets set by the ESC panel, specifically the LDL cholesterol goal of less than 70 mg/dL for very-high-risk patients.
“I don’t think the ESC went low enough; the goal should be less than 50 mg/dL,” declared Dr. Braunwald, who added “anything above 50 mg/dL is toxic.”
The new guidelines also made the definition of “very-high-risk” patients “stricter and more precise,” said Alberico L. Catapano, MD, cochair of the panel and professor of pharmacology at the University of Milan.
The guideline’s detailed list defining very-high-risk patients includes those with either clinical or “unequivocal” imaging evidence for cardiovascular disease, as well as patients with diabetes and target-organ damage, severe chronic kidney disease, or a 10% or greater 10-year risk for fatal cardiovascular disease calculated by the European Score risk formula.
The potent lipid-lowering PCSK9 inhibitors came onto the U.S. and European markets in 2015, labeled in the United States specifically for patients with familial hypercholesterolemia.
In July 2016, an American College of Cardiology Task Force issued a model clinical-decision pathway for lowering LDL cholesterol levels that for the first time included the PCSK9 inhibitors, specified as a “may be considered” option for selected patients (J Am Coll Cardiol. 2016 Jul;68[1]:92-125). This consensus decision pathway was not a set of actual guidelines, which means the ESC revision is the first guideline to include the PCSK9 inhibitors. The panel took the same stance as the U.S. decision pathway and designated the PCSK9 inhibitors as a “may be considered” option.
Dr. Graham explained that this designation was driven by the current absence of evidence for clinical benefit from the large lipid-lowering effect of the PCSK9 antibodies, although trial results that address this are expected to appear very soon. Experts not on the guidelines panel agreed with this decision.
“We know that it’s crucial to await results from the clinical endpoint studies” before the guidelines committee makes a more forceful recommendation, commented Erik S.G. Stroes, MD, professor of vascular medicine at the Academic Medical Center in Amsterdam. He added, however, that many clinicians, himself included, have been pleased to offer PCSK9-inhibitor treatment to very-high-risk patients with no good alternatives for effectively lowering their LDL cholesterol to target levels, such as statin-intolerant patients or those with LDL cholesterol levels that remain high despite maximal therapy.
The current ESC guideline’s statement on when to use a PCSK9 inhibitor “is vague” said Dr. Braunwald. “Within the next year, we’ll have results from two huge trials that will show clinical outcomes. We know that PCSK9 inhibitors are extremely powerful at lowering LDL cholesterol, but I would like to see the loop closed” with proven effects on clinical outcomes. “I would bet 100 to 1 that they will be effective, but LDL cholesterol is just a surrogate marker, and you need to look in large populations before you make a guideline recommendation to use these drugs, so we’ll wait.”
Once the clinical value of treatment with PCSK9 inhibitors is settled, the next issue will be the cost of these drugs, something that will become a big consideration once they become more widely used, Dr. Braunwald added.
Dr. De Backer and Dr. Graham had no disclosures. Dr. Catapano has been a consultant to Aegerion, Amgen, AstraZeneca, Merck, Pfizer, and Sigma-Tau. Dr. Braunwald has been a consultant to Bayer, Daiichi Sankyo, the Medicines Company, Merck, Novartis, and Sanofi. Dr. Stroes has been a consultant to Amgen, Bristol-Myers Squibb, Merck, and Sanofi.
On Twitter @mitchelzoler
ROME – LDL cholesterol treatment targets remain alive and well in non-U.S. lipid management guidelines.
New dyslipidemia management guidelines from the European Society of Cardiology, issued in late August, retain the same LDL cholesterol targets as the prior, 2011 guidelines, a sharp and purposeful departure from the “risk-based” U.S. guidelines introduced in 2013 that eliminated treating patients to specific LDL cholesterol targets.
The new ESC guidelines also incorporated the new class of lipid-lowering drugs, PCSK9 inhibitors (evolocumab [Repatha] and alirocumab [Praluent]), into the treatment algorithm, and carved out a role for ezetimibe (Zetia) following its proven success as an add-on agent to statins (Eur Heart J. 2016. doi: 10.1093/eurheartj/ehw272).
But it’s retention of LDL cholesterol targets as a cornerstone of dyslipidemia management in the new ESC report, written jointly with the European Atherosclerosis Society, that especially distinguishes the new guidelines.
“It seemed to us logical that if you have drugs [statins] that lower LDL cholesterol, then you target LDL cholesterol,” explained Ian M. Graham, MD, professor of cardiovascular medicine at Trinity College in Dublin and cochair of the guidelines panel. “If a patient’s risk is high, they still need to lower LDL cholesterol. It’s not really contradictory to the U.S. approach,” Dr. Graham said in an interview.
The ESC panel’s discussions about the LDL cholesterol targets were “difficult and long,” said Guy De Backer, MD, a member of the guidelines committee and professor of cardiology at the University of Ghent, Belgium, in a session devoted to the new guidelines during the annual congress of the ESC.
The ESC’s decision to retain the 2011 LDL cholesterol targets won praise from U.S. cardiologist Eugene Braunwald, MD. “I think that not measuring and following LDL cholesterol is silly. I don’t agree” with current U.S. guidelines, he said in a talk during the congress. “If you don’t follow LDL cholesterol then you don’t know a patient’s compliance.
Regularly measuring LDL cholesterol is important,” said Dr. Braunwald, professor of medicine at Harvard Medical School in Boston. But he questioned the LDL cholesterol targets set by the ESC panel, specifically the LDL cholesterol goal of less than 70 mg/dL for very-high-risk patients.
“I don’t think the ESC went low enough; the goal should be less than 50 mg/dL,” declared Dr. Braunwald, who added “anything above 50 mg/dL is toxic.”
The new guidelines also made the definition of “very-high-risk” patients “stricter and more precise,” said Alberico L. Catapano, MD, cochair of the panel and professor of pharmacology at the University of Milan.
The guideline’s detailed list defining very-high-risk patients includes those with either clinical or “unequivocal” imaging evidence for cardiovascular disease, as well as patients with diabetes and target-organ damage, severe chronic kidney disease, or a 10% or greater 10-year risk for fatal cardiovascular disease calculated by the European Score risk formula.
The potent lipid-lowering PCSK9 inhibitors came onto the U.S. and European markets in 2015, labeled in the United States specifically for patients with familial hypercholesterolemia.
In July 2016, an American College of Cardiology Task Force issued a model clinical-decision pathway for lowering LDL cholesterol levels that for the first time included the PCSK9 inhibitors, specified as a “may be considered” option for selected patients (J Am Coll Cardiol. 2016 Jul;68[1]:92-125). This consensus decision pathway was not a set of actual guidelines, which means the ESC revision is the first guideline to include the PCSK9 inhibitors. The panel took the same stance as the U.S. decision pathway and designated the PCSK9 inhibitors as a “may be considered” option.
Dr. Graham explained that this designation was driven by the current absence of evidence for clinical benefit from the large lipid-lowering effect of the PCSK9 antibodies, although trial results that address this are expected to appear very soon. Experts not on the guidelines panel agreed with this decision.
“We know that it’s crucial to await results from the clinical endpoint studies” before the guidelines committee makes a more forceful recommendation, commented Erik S.G. Stroes, MD, professor of vascular medicine at the Academic Medical Center in Amsterdam. He added, however, that many clinicians, himself included, have been pleased to offer PCSK9-inhibitor treatment to very-high-risk patients with no good alternatives for effectively lowering their LDL cholesterol to target levels, such as statin-intolerant patients or those with LDL cholesterol levels that remain high despite maximal therapy.
The current ESC guideline’s statement on when to use a PCSK9 inhibitor “is vague” said Dr. Braunwald. “Within the next year, we’ll have results from two huge trials that will show clinical outcomes. We know that PCSK9 inhibitors are extremely powerful at lowering LDL cholesterol, but I would like to see the loop closed” with proven effects on clinical outcomes. “I would bet 100 to 1 that they will be effective, but LDL cholesterol is just a surrogate marker, and you need to look in large populations before you make a guideline recommendation to use these drugs, so we’ll wait.”
Once the clinical value of treatment with PCSK9 inhibitors is settled, the next issue will be the cost of these drugs, something that will become a big consideration once they become more widely used, Dr. Braunwald added.
Dr. De Backer and Dr. Graham had no disclosures. Dr. Catapano has been a consultant to Aegerion, Amgen, AstraZeneca, Merck, Pfizer, and Sigma-Tau. Dr. Braunwald has been a consultant to Bayer, Daiichi Sankyo, the Medicines Company, Merck, Novartis, and Sanofi. Dr. Stroes has been a consultant to Amgen, Bristol-Myers Squibb, Merck, and Sanofi.
On Twitter @mitchelzoler
ROME – LDL cholesterol treatment targets remain alive and well in non-U.S. lipid management guidelines.
New dyslipidemia management guidelines from the European Society of Cardiology, issued in late August, retain the same LDL cholesterol targets as the prior, 2011 guidelines, a sharp and purposeful departure from the “risk-based” U.S. guidelines introduced in 2013 that eliminated treating patients to specific LDL cholesterol targets.
The new ESC guidelines also incorporated the new class of lipid-lowering drugs, PCSK9 inhibitors (evolocumab [Repatha] and alirocumab [Praluent]), into the treatment algorithm, and carved out a role for ezetimibe (Zetia) following its proven success as an add-on agent to statins (Eur Heart J. 2016. doi: 10.1093/eurheartj/ehw272).
But it’s retention of LDL cholesterol targets as a cornerstone of dyslipidemia management in the new ESC report, written jointly with the European Atherosclerosis Society, that especially distinguishes the new guidelines.
“It seemed to us logical that if you have drugs [statins] that lower LDL cholesterol, then you target LDL cholesterol,” explained Ian M. Graham, MD, professor of cardiovascular medicine at Trinity College in Dublin and cochair of the guidelines panel. “If a patient’s risk is high, they still need to lower LDL cholesterol. It’s not really contradictory to the U.S. approach,” Dr. Graham said in an interview.
The ESC panel’s discussions about the LDL cholesterol targets were “difficult and long,” said Guy De Backer, MD, a member of the guidelines committee and professor of cardiology at the University of Ghent, Belgium, in a session devoted to the new guidelines during the annual congress of the ESC.
The ESC’s decision to retain the 2011 LDL cholesterol targets won praise from U.S. cardiologist Eugene Braunwald, MD. “I think that not measuring and following LDL cholesterol is silly. I don’t agree” with current U.S. guidelines, he said in a talk during the congress. “If you don’t follow LDL cholesterol then you don’t know a patient’s compliance.
Regularly measuring LDL cholesterol is important,” said Dr. Braunwald, professor of medicine at Harvard Medical School in Boston. But he questioned the LDL cholesterol targets set by the ESC panel, specifically the LDL cholesterol goal of less than 70 mg/dL for very-high-risk patients.
“I don’t think the ESC went low enough; the goal should be less than 50 mg/dL,” declared Dr. Braunwald, who added “anything above 50 mg/dL is toxic.”
The new guidelines also made the definition of “very-high-risk” patients “stricter and more precise,” said Alberico L. Catapano, MD, cochair of the panel and professor of pharmacology at the University of Milan.
The guideline’s detailed list defining very-high-risk patients includes those with either clinical or “unequivocal” imaging evidence for cardiovascular disease, as well as patients with diabetes and target-organ damage, severe chronic kidney disease, or a 10% or greater 10-year risk for fatal cardiovascular disease calculated by the European Score risk formula.
The potent lipid-lowering PCSK9 inhibitors came onto the U.S. and European markets in 2015, labeled in the United States specifically for patients with familial hypercholesterolemia.
In July 2016, an American College of Cardiology Task Force issued a model clinical-decision pathway for lowering LDL cholesterol levels that for the first time included the PCSK9 inhibitors, specified as a “may be considered” option for selected patients (J Am Coll Cardiol. 2016 Jul;68[1]:92-125). This consensus decision pathway was not a set of actual guidelines, which means the ESC revision is the first guideline to include the PCSK9 inhibitors. The panel took the same stance as the U.S. decision pathway and designated the PCSK9 inhibitors as a “may be considered” option.
Dr. Graham explained that this designation was driven by the current absence of evidence for clinical benefit from the large lipid-lowering effect of the PCSK9 antibodies, although trial results that address this are expected to appear very soon. Experts not on the guidelines panel agreed with this decision.
“We know that it’s crucial to await results from the clinical endpoint studies” before the guidelines committee makes a more forceful recommendation, commented Erik S.G. Stroes, MD, professor of vascular medicine at the Academic Medical Center in Amsterdam. He added, however, that many clinicians, himself included, have been pleased to offer PCSK9-inhibitor treatment to very-high-risk patients with no good alternatives for effectively lowering their LDL cholesterol to target levels, such as statin-intolerant patients or those with LDL cholesterol levels that remain high despite maximal therapy.
The current ESC guideline’s statement on when to use a PCSK9 inhibitor “is vague” said Dr. Braunwald. “Within the next year, we’ll have results from two huge trials that will show clinical outcomes. We know that PCSK9 inhibitors are extremely powerful at lowering LDL cholesterol, but I would like to see the loop closed” with proven effects on clinical outcomes. “I would bet 100 to 1 that they will be effective, but LDL cholesterol is just a surrogate marker, and you need to look in large populations before you make a guideline recommendation to use these drugs, so we’ll wait.”
Once the clinical value of treatment with PCSK9 inhibitors is settled, the next issue will be the cost of these drugs, something that will become a big consideration once they become more widely used, Dr. Braunwald added.
Dr. De Backer and Dr. Graham had no disclosures. Dr. Catapano has been a consultant to Aegerion, Amgen, AstraZeneca, Merck, Pfizer, and Sigma-Tau. Dr. Braunwald has been a consultant to Bayer, Daiichi Sankyo, the Medicines Company, Merck, Novartis, and Sanofi. Dr. Stroes has been a consultant to Amgen, Bristol-Myers Squibb, Merck, and Sanofi.
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM THE ESC CONGRESS 2016
More TOPCAT flaws back spironolactone’s HFpEF efficacy
ORLANDO – Spironolactone inched a little closer toward becoming the first and only agent with proven efficacy for treating patients with heart failure with preserved ejection fraction based on further evidence for the drug’s efficacy in a subgroup of patients enrolled in the TOPCAT trial.
In 2014, the initial TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) report showed that spironolactone treatment of patients with heart failure with preserved ejection fraction (HFpEF) for 3 years produced a small, 11% relative reduction in the primary risk endpoint, compared with placebo that was not statistically significant (N Engl J Med. 2014 Apr 10;370[15]:1383-92).
But a follow-up post hoc analysis a year later showed evidence that the roughly half of patients in TOPCAT enrolled at centers in Russia and the Republic of Georgia may not have had HFpEF and also may not have received the planned dosage of spironolactone (Circulation. 2015 Jan 6;131[1]:34-42). An analysis that focused only on the 1,767 HFpEF patients (51% of the total TOPCAT cohort) enrolled in the Americas (United States, Canada, Argentina, and Brazil) showed that, compared with placebo, treatment with spironolactone cut the combined rate of cardiovascular death, nonfatal cardiac arrest, and heart failure hospitalization by 4.5 percentage points, an 18% relative risk reduction that was statistically significant. In the Americas, spironolactone also cut cardiovascular death alone by a relative 26%, and reduced heart failure hospitalization by a relative 18%, both statistically significant.
Additional analysis reported at the annual scientific meeting of the Heart Failure Society of America further supported the idea that many TOPCAT patients enrolled in Russia did not receive a physiologically meaningful dosage of spironolactone. Among 66 Russian patients randomized to the spironolactone arm who reported taking their drug as prescribed and who participated in a random draw of blood specimens 1 year into the study, 20 (30%) failed to show detectable blood levels of canrenone, a characteristic spironolactone metabolite, reported Eileen O’Meara, MD, at the meeting. In contrast, 2 (3%) of 76 enrolled U.S. patients failed to show detectable blood levels of the canrenone metabolite, a 10-fold difference said Dr. O’Meara, a cardiologist at the Montreal Heart Institute.The tested U.S. patients also showed a clear dose-response relationship between their reported spironolactone dosage and their canrenone levels, something not seen in the Russian patients. These new findings, plus the evidence cited in the 2015 analysis, create a compelling case that “actual use of spironolactone in Russia was lower than reported” by the trial participants in Russia and probably in Georgia as well, Dr. O’Meara said. The implication is that spironolactone’s real impact on HFpEF patients is best represented in the 51% of TOPCAT patients from the Americas, she added.
“We believe these findings emphasize the reliability of the Americas data,” said Marc A. Pfeffer, MD, a coinvestigator for TOPCAT and lead author of the 2015 post hoc analysis. “Until someone comes up with a better treatment for patients with HFpEF, we should pay attention to this. People need to get this message. And spironolactone costs 7 cents a day,” said Dr. Pfeffer, professor of medicine at Harvard Medical School in Boston.Currently, no agent is considered proven effective for improving outcomes in HFpEF patients. The 2016 guidelinesfor heart failure treatment from the European Society of Cardiology said “no treatment has yet been shown, convincingly, to reduce morbidity or mortality in patients with HFpEF.”
After the TOPCAT results and post hoc analysis came out in 2014 and 2015 and word spread of spironolactone’s apparent efficacy in the American half of the trial, use of spironolactone to treat HFpEF patient has increased, commented Margaret M. Redfield, MD, a heart failure physician and professor at the Mayo Clinic in Rochester, Minn. She said she often prescribes spironolactone patients to HFpEF patients who require potassium supplementation, generally because of their diuretic treatment. These are the “safest” HFpEF patients for spironolactone treatment, she said, because they face the lowest risk for hyperkalemia, the major adverse effect from spironolactone.
On Twitter @mitchelzoler
This is extraordinarily important information from an extraordinarily important study. I’m strongly persuaded that the data from the Americas in TOPCAT show that spironolactone worked. The new data presented on canrenone levels make me even more ready to exclude from consideration the TOPCAT data from Russia and Georgia.
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| Mitchel L. Zoler/Frontline Medical News Dr. Barry H. Greenberg |
The heart failure community is left to decide what conclusions to draw from TOPCAT. I think guideline committees will struggle over what to make of the TOPCAT evidence. Any recommendation in favor of spironolactone needs to be somewhat guarded, but if a group made recommendations in support of spironolactone it would add an impetus for using it.
There has been long-standing interest in treating patients with heart failure with preserved ejection fraction with spironolactone. Currently, about a quarter of these patients take spironolactone. I’m not sure this level of use will increase dramatically because of what we now know about TOPCAT.
Dr. Barry H. Greenberg is professor of medicine and director of the advanced heart failure treatment program at the University of California, San Diego. He had no relevant disclosures. He made these comments in an interview.
This is extraordinarily important information from an extraordinarily important study. I’m strongly persuaded that the data from the Americas in TOPCAT show that spironolactone worked. The new data presented on canrenone levels make me even more ready to exclude from consideration the TOPCAT data from Russia and Georgia.
|
|
| Mitchel L. Zoler/Frontline Medical News Dr. Barry H. Greenberg |
The heart failure community is left to decide what conclusions to draw from TOPCAT. I think guideline committees will struggle over what to make of the TOPCAT evidence. Any recommendation in favor of spironolactone needs to be somewhat guarded, but if a group made recommendations in support of spironolactone it would add an impetus for using it.
There has been long-standing interest in treating patients with heart failure with preserved ejection fraction with spironolactone. Currently, about a quarter of these patients take spironolactone. I’m not sure this level of use will increase dramatically because of what we now know about TOPCAT.
Dr. Barry H. Greenberg is professor of medicine and director of the advanced heart failure treatment program at the University of California, San Diego. He had no relevant disclosures. He made these comments in an interview.
This is extraordinarily important information from an extraordinarily important study. I’m strongly persuaded that the data from the Americas in TOPCAT show that spironolactone worked. The new data presented on canrenone levels make me even more ready to exclude from consideration the TOPCAT data from Russia and Georgia.
|
|
| Mitchel L. Zoler/Frontline Medical News Dr. Barry H. Greenberg |
The heart failure community is left to decide what conclusions to draw from TOPCAT. I think guideline committees will struggle over what to make of the TOPCAT evidence. Any recommendation in favor of spironolactone needs to be somewhat guarded, but if a group made recommendations in support of spironolactone it would add an impetus for using it.
There has been long-standing interest in treating patients with heart failure with preserved ejection fraction with spironolactone. Currently, about a quarter of these patients take spironolactone. I’m not sure this level of use will increase dramatically because of what we now know about TOPCAT.
Dr. Barry H. Greenberg is professor of medicine and director of the advanced heart failure treatment program at the University of California, San Diego. He had no relevant disclosures. He made these comments in an interview.
ORLANDO – Spironolactone inched a little closer toward becoming the first and only agent with proven efficacy for treating patients with heart failure with preserved ejection fraction based on further evidence for the drug’s efficacy in a subgroup of patients enrolled in the TOPCAT trial.
In 2014, the initial TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) report showed that spironolactone treatment of patients with heart failure with preserved ejection fraction (HFpEF) for 3 years produced a small, 11% relative reduction in the primary risk endpoint, compared with placebo that was not statistically significant (N Engl J Med. 2014 Apr 10;370[15]:1383-92).
But a follow-up post hoc analysis a year later showed evidence that the roughly half of patients in TOPCAT enrolled at centers in Russia and the Republic of Georgia may not have had HFpEF and also may not have received the planned dosage of spironolactone (Circulation. 2015 Jan 6;131[1]:34-42). An analysis that focused only on the 1,767 HFpEF patients (51% of the total TOPCAT cohort) enrolled in the Americas (United States, Canada, Argentina, and Brazil) showed that, compared with placebo, treatment with spironolactone cut the combined rate of cardiovascular death, nonfatal cardiac arrest, and heart failure hospitalization by 4.5 percentage points, an 18% relative risk reduction that was statistically significant. In the Americas, spironolactone also cut cardiovascular death alone by a relative 26%, and reduced heart failure hospitalization by a relative 18%, both statistically significant.
Additional analysis reported at the annual scientific meeting of the Heart Failure Society of America further supported the idea that many TOPCAT patients enrolled in Russia did not receive a physiologically meaningful dosage of spironolactone. Among 66 Russian patients randomized to the spironolactone arm who reported taking their drug as prescribed and who participated in a random draw of blood specimens 1 year into the study, 20 (30%) failed to show detectable blood levels of canrenone, a characteristic spironolactone metabolite, reported Eileen O’Meara, MD, at the meeting. In contrast, 2 (3%) of 76 enrolled U.S. patients failed to show detectable blood levels of the canrenone metabolite, a 10-fold difference said Dr. O’Meara, a cardiologist at the Montreal Heart Institute.The tested U.S. patients also showed a clear dose-response relationship between their reported spironolactone dosage and their canrenone levels, something not seen in the Russian patients. These new findings, plus the evidence cited in the 2015 analysis, create a compelling case that “actual use of spironolactone in Russia was lower than reported” by the trial participants in Russia and probably in Georgia as well, Dr. O’Meara said. The implication is that spironolactone’s real impact on HFpEF patients is best represented in the 51% of TOPCAT patients from the Americas, she added.
“We believe these findings emphasize the reliability of the Americas data,” said Marc A. Pfeffer, MD, a coinvestigator for TOPCAT and lead author of the 2015 post hoc analysis. “Until someone comes up with a better treatment for patients with HFpEF, we should pay attention to this. People need to get this message. And spironolactone costs 7 cents a day,” said Dr. Pfeffer, professor of medicine at Harvard Medical School in Boston.Currently, no agent is considered proven effective for improving outcomes in HFpEF patients. The 2016 guidelinesfor heart failure treatment from the European Society of Cardiology said “no treatment has yet been shown, convincingly, to reduce morbidity or mortality in patients with HFpEF.”
After the TOPCAT results and post hoc analysis came out in 2014 and 2015 and word spread of spironolactone’s apparent efficacy in the American half of the trial, use of spironolactone to treat HFpEF patient has increased, commented Margaret M. Redfield, MD, a heart failure physician and professor at the Mayo Clinic in Rochester, Minn. She said she often prescribes spironolactone patients to HFpEF patients who require potassium supplementation, generally because of their diuretic treatment. These are the “safest” HFpEF patients for spironolactone treatment, she said, because they face the lowest risk for hyperkalemia, the major adverse effect from spironolactone.
On Twitter @mitchelzoler
ORLANDO – Spironolactone inched a little closer toward becoming the first and only agent with proven efficacy for treating patients with heart failure with preserved ejection fraction based on further evidence for the drug’s efficacy in a subgroup of patients enrolled in the TOPCAT trial.
In 2014, the initial TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) report showed that spironolactone treatment of patients with heart failure with preserved ejection fraction (HFpEF) for 3 years produced a small, 11% relative reduction in the primary risk endpoint, compared with placebo that was not statistically significant (N Engl J Med. 2014 Apr 10;370[15]:1383-92).
But a follow-up post hoc analysis a year later showed evidence that the roughly half of patients in TOPCAT enrolled at centers in Russia and the Republic of Georgia may not have had HFpEF and also may not have received the planned dosage of spironolactone (Circulation. 2015 Jan 6;131[1]:34-42). An analysis that focused only on the 1,767 HFpEF patients (51% of the total TOPCAT cohort) enrolled in the Americas (United States, Canada, Argentina, and Brazil) showed that, compared with placebo, treatment with spironolactone cut the combined rate of cardiovascular death, nonfatal cardiac arrest, and heart failure hospitalization by 4.5 percentage points, an 18% relative risk reduction that was statistically significant. In the Americas, spironolactone also cut cardiovascular death alone by a relative 26%, and reduced heart failure hospitalization by a relative 18%, both statistically significant.
Additional analysis reported at the annual scientific meeting of the Heart Failure Society of America further supported the idea that many TOPCAT patients enrolled in Russia did not receive a physiologically meaningful dosage of spironolactone. Among 66 Russian patients randomized to the spironolactone arm who reported taking their drug as prescribed and who participated in a random draw of blood specimens 1 year into the study, 20 (30%) failed to show detectable blood levels of canrenone, a characteristic spironolactone metabolite, reported Eileen O’Meara, MD, at the meeting. In contrast, 2 (3%) of 76 enrolled U.S. patients failed to show detectable blood levels of the canrenone metabolite, a 10-fold difference said Dr. O’Meara, a cardiologist at the Montreal Heart Institute.The tested U.S. patients also showed a clear dose-response relationship between their reported spironolactone dosage and their canrenone levels, something not seen in the Russian patients. These new findings, plus the evidence cited in the 2015 analysis, create a compelling case that “actual use of spironolactone in Russia was lower than reported” by the trial participants in Russia and probably in Georgia as well, Dr. O’Meara said. The implication is that spironolactone’s real impact on HFpEF patients is best represented in the 51% of TOPCAT patients from the Americas, she added.
“We believe these findings emphasize the reliability of the Americas data,” said Marc A. Pfeffer, MD, a coinvestigator for TOPCAT and lead author of the 2015 post hoc analysis. “Until someone comes up with a better treatment for patients with HFpEF, we should pay attention to this. People need to get this message. And spironolactone costs 7 cents a day,” said Dr. Pfeffer, professor of medicine at Harvard Medical School in Boston.Currently, no agent is considered proven effective for improving outcomes in HFpEF patients. The 2016 guidelinesfor heart failure treatment from the European Society of Cardiology said “no treatment has yet been shown, convincingly, to reduce morbidity or mortality in patients with HFpEF.”
After the TOPCAT results and post hoc analysis came out in 2014 and 2015 and word spread of spironolactone’s apparent efficacy in the American half of the trial, use of spironolactone to treat HFpEF patient has increased, commented Margaret M. Redfield, MD, a heart failure physician and professor at the Mayo Clinic in Rochester, Minn. She said she often prescribes spironolactone patients to HFpEF patients who require potassium supplementation, generally because of their diuretic treatment. These are the “safest” HFpEF patients for spironolactone treatment, she said, because they face the lowest risk for hyperkalemia, the major adverse effect from spironolactone.
On Twitter @mitchelzoler
AT THE HFSA ANNUAL SCIENTIFIC MEETING
Key clinical point: A post hoc analysis of spironolactone use among TOPCAT participants further fueled the idea that spironolactone provides real benefit to patients with HFpEF.
Major finding: Among patients reportedly taking spironolactone, 30% of tested Russians and 3% of tested Americans did not have detectable canrenone levels.
Data source: TOPCAT, a multicenter, randomized trial with 3,445 HFpEF patients.
Disclosures: TOPCAT received no commercial funding. Dr. O’Meara, Dr. Pfeffer, and Dr. Redfield had no relevant disclosures.
Trials offer lessons despite negative primary endpoints
Conventional wisdom holds that for randomized, controlled trials, it’s all about the primary endpoint. If it’s negative or neutral, then none of the other results means much beyond “hypothesis generating.”
This strict-constructionist thinking has now been called into question. A recent article in the New England Journal of Medicine declared “an unreasonable yet widespread practice is the labeling of all randomized trials as either positive or negative on the basis of whether the P value for the primary outcome is less than .05. This view is overly simplistic.” (2016 Sept 1;375[9]:861-70).
The article, by the highly experienced and respected trialists Stuart J. Pocock, PhD, and Gregg W. Stone, MD, adds this: “If the primary outcome is negative, positive findings for secondary outcomes are usually considered to be hypothesis generating. Certainly, regulatory approval of a new drug is unlikely to follow. However, in some instances, secondary findings are compelling enough to affect guidelines and practice.”
This unconventional take from a pair of high-level trialists was especially timely given the buzz around the results from two studies reported at the European Society of Cardiology annual congress in late August, DANISH and NORSTENT.
The DANISH trial compared the impact of implantable cardioverter-defibrillators (ICDs) plus optimal care against optimal care without ICDs in 1,116 patients with nonischemic systolic heart failure. The primary outcome, all-cause death during more than 5 years of follow-up, was a relative 13% less with ICD use, a difference that was not statistically significant, and one secondary outcome, cardiovascular death, was cut by a relative 25% with ICD use, also not statistically significant.
But for the study’s second prespecified secondary endpoint of sudden cardiac death, treatment with ICDs cut the rate in half, compared with nonischemic heart failure patients who did not receive an ICD, a 4-percentage-point difference that was statistically significant.
And in a prespecified secondary analysis of the primary endpoint that broke down the study group by age, the two-thirds of patients younger than 68 years had a significant reduction in all-cause mortality with ICD use, a benefit not seen in patients aged 68 or older.
Discussion of the results at the meeting mainly focused on what meaning, if any, could be drawn from these strongly positive secondary outcomes in a trial neutral for its primary outcome.
“The ICDs did what they were supposed to, prevent sudden cardiac death,” said the lead investigator of the study, Lars Køber, MD. “As a principle I say don’t believe in a subgroup, but guidelines are often based on subgroup analyses.”
“The primary outcome was neutral, but the reduction in sudden cardiac death, the primary objective of an ICD, was significant, so an ICD should be taken into consideration,” commented Michel Komajda, MD, a discussant for the report.
After I wrote a news article about the DANISH report at ESC, I received an email from a reader who objected to spinning the results this way and insisted that no valid lessons can be drawn from the DANISH results because the study’s primary endpoint failed to show a statistical significance. This purist view misses the important, relevant lessons from the DANISH results. The DANISH trial was not designed to provide pivotal data for regulatory approval of ICDs in these patients. Rather, Dr. Køber and his associates designed DANISH to see whether ICD use in these patients could cut all-cause death over a fairly long follow-up. It was a very high bar and ICDs failed, but the deck was stacked against an ICD win. Enrolled patients averaged 64 years old at entry into the study, and they all had New York Heart Association class II or III heart failure. “The overall survival curves start to diverge, but then converge after 5 years because of the comorbidities and patients dying for other reasons,” Dr. Køber noted.
“The message is, in younger patients with less morbidity and more life expectancy, sudden cardiac death is a bigger problem, and they had a substantial drop in mortality” with ICD use, commented heart failure specialist Javed Butler, MD. “It’s very consistent with the way we think about providing ICD treatment to patients.”
In other words, the DANISH results showed that all patients with nonischemic systolic heart failure can’t expect to live substantially longer during extended follow-up if they get an ICD, because the cut in sudden cardiac death the devices provide eventually gets washed out by the many other risks for death these patients face. But younger, relatively healthier patients might very well see their reduced rate of sudden cardiac death translate into an overall mortality benefit even when they are followed for at least 5 years. That’s important information to help an individual patient decide whether to have an ICD placed, and an important message from the DANISH trial despite the neutral primary endpoint.
NORSTENT involved a similar scenario in a trial that addressed a totally different issue: Should patients with either stable or unstable coronary artery disease who are undergoing coronary stenting receive a drug-eluting stent (DES) or a bare metal stent (BMS)? The trial randomized 9,013 patients to receive either of the two stent types plus optimal medical therapy. The primary endpoint was the rate of all-cause death or nonfatal MI during 5 years of follow-up, and the results showed no statistically significant difference between the patients who received a DES and those who got a BMS (N Engl J Med. 2016 Aug 30. doi: 10.1056/NEJMoa1607991).
But for the secondary endpoint of repeat revascularizations performed during follow-up, the use of a DES cut the procedure rate by 3.3 percentage points, a 17% relative risk reduction that was statistically significant. The use of a DES also cut the stent thrombosis rate by 0.4 percentage points, a one-third relative drop in these events that was also statistically significant.
In short, despite the neutral primary endpoint for the trial, the results showed that drug-eluting stents did what they were designed to do relative to bare metal stents: cut the rate of target lesion restenosis and the need for repeat revascularization. Several interventional cardiologists who heard the results at the meeting said that the findings would not change their practice and that they would continue to use the DES as their default device for percutaneous coronary interventions. Although “the long-term benefit of contemporary DES over BMS was less than expected,” said Kaare H. Bønaa, MD, lead investigator for the NORSTENT trial, the secondary benefit of significantly reduced repeat revascularization and the very modest price difference that now exists between drug-eluting stents and bare metal stents means that many interventionalists will continue to use a DES for most patients.
The message from Dr. Pocock and Dr. Stone, underscored by the DANISH and NORSTENT results, is that large and well-run randomized trials can yield important evidence to inform practice that transcends a simple black or white statistical assessment of the primary endpoint.
On Twitter @mitchelzoler
Conventional wisdom holds that for randomized, controlled trials, it’s all about the primary endpoint. If it’s negative or neutral, then none of the other results means much beyond “hypothesis generating.”
This strict-constructionist thinking has now been called into question. A recent article in the New England Journal of Medicine declared “an unreasonable yet widespread practice is the labeling of all randomized trials as either positive or negative on the basis of whether the P value for the primary outcome is less than .05. This view is overly simplistic.” (2016 Sept 1;375[9]:861-70).
The article, by the highly experienced and respected trialists Stuart J. Pocock, PhD, and Gregg W. Stone, MD, adds this: “If the primary outcome is negative, positive findings for secondary outcomes are usually considered to be hypothesis generating. Certainly, regulatory approval of a new drug is unlikely to follow. However, in some instances, secondary findings are compelling enough to affect guidelines and practice.”
This unconventional take from a pair of high-level trialists was especially timely given the buzz around the results from two studies reported at the European Society of Cardiology annual congress in late August, DANISH and NORSTENT.
The DANISH trial compared the impact of implantable cardioverter-defibrillators (ICDs) plus optimal care against optimal care without ICDs in 1,116 patients with nonischemic systolic heart failure. The primary outcome, all-cause death during more than 5 years of follow-up, was a relative 13% less with ICD use, a difference that was not statistically significant, and one secondary outcome, cardiovascular death, was cut by a relative 25% with ICD use, also not statistically significant.
But for the study’s second prespecified secondary endpoint of sudden cardiac death, treatment with ICDs cut the rate in half, compared with nonischemic heart failure patients who did not receive an ICD, a 4-percentage-point difference that was statistically significant.
And in a prespecified secondary analysis of the primary endpoint that broke down the study group by age, the two-thirds of patients younger than 68 years had a significant reduction in all-cause mortality with ICD use, a benefit not seen in patients aged 68 or older.
Discussion of the results at the meeting mainly focused on what meaning, if any, could be drawn from these strongly positive secondary outcomes in a trial neutral for its primary outcome.
“The ICDs did what they were supposed to, prevent sudden cardiac death,” said the lead investigator of the study, Lars Køber, MD. “As a principle I say don’t believe in a subgroup, but guidelines are often based on subgroup analyses.”
“The primary outcome was neutral, but the reduction in sudden cardiac death, the primary objective of an ICD, was significant, so an ICD should be taken into consideration,” commented Michel Komajda, MD, a discussant for the report.
After I wrote a news article about the DANISH report at ESC, I received an email from a reader who objected to spinning the results this way and insisted that no valid lessons can be drawn from the DANISH results because the study’s primary endpoint failed to show a statistical significance. This purist view misses the important, relevant lessons from the DANISH results. The DANISH trial was not designed to provide pivotal data for regulatory approval of ICDs in these patients. Rather, Dr. Køber and his associates designed DANISH to see whether ICD use in these patients could cut all-cause death over a fairly long follow-up. It was a very high bar and ICDs failed, but the deck was stacked against an ICD win. Enrolled patients averaged 64 years old at entry into the study, and they all had New York Heart Association class II or III heart failure. “The overall survival curves start to diverge, but then converge after 5 years because of the comorbidities and patients dying for other reasons,” Dr. Køber noted.
“The message is, in younger patients with less morbidity and more life expectancy, sudden cardiac death is a bigger problem, and they had a substantial drop in mortality” with ICD use, commented heart failure specialist Javed Butler, MD. “It’s very consistent with the way we think about providing ICD treatment to patients.”
In other words, the DANISH results showed that all patients with nonischemic systolic heart failure can’t expect to live substantially longer during extended follow-up if they get an ICD, because the cut in sudden cardiac death the devices provide eventually gets washed out by the many other risks for death these patients face. But younger, relatively healthier patients might very well see their reduced rate of sudden cardiac death translate into an overall mortality benefit even when they are followed for at least 5 years. That’s important information to help an individual patient decide whether to have an ICD placed, and an important message from the DANISH trial despite the neutral primary endpoint.
NORSTENT involved a similar scenario in a trial that addressed a totally different issue: Should patients with either stable or unstable coronary artery disease who are undergoing coronary stenting receive a drug-eluting stent (DES) or a bare metal stent (BMS)? The trial randomized 9,013 patients to receive either of the two stent types plus optimal medical therapy. The primary endpoint was the rate of all-cause death or nonfatal MI during 5 years of follow-up, and the results showed no statistically significant difference between the patients who received a DES and those who got a BMS (N Engl J Med. 2016 Aug 30. doi: 10.1056/NEJMoa1607991).
But for the secondary endpoint of repeat revascularizations performed during follow-up, the use of a DES cut the procedure rate by 3.3 percentage points, a 17% relative risk reduction that was statistically significant. The use of a DES also cut the stent thrombosis rate by 0.4 percentage points, a one-third relative drop in these events that was also statistically significant.
In short, despite the neutral primary endpoint for the trial, the results showed that drug-eluting stents did what they were designed to do relative to bare metal stents: cut the rate of target lesion restenosis and the need for repeat revascularization. Several interventional cardiologists who heard the results at the meeting said that the findings would not change their practice and that they would continue to use the DES as their default device for percutaneous coronary interventions. Although “the long-term benefit of contemporary DES over BMS was less than expected,” said Kaare H. Bønaa, MD, lead investigator for the NORSTENT trial, the secondary benefit of significantly reduced repeat revascularization and the very modest price difference that now exists between drug-eluting stents and bare metal stents means that many interventionalists will continue to use a DES for most patients.
The message from Dr. Pocock and Dr. Stone, underscored by the DANISH and NORSTENT results, is that large and well-run randomized trials can yield important evidence to inform practice that transcends a simple black or white statistical assessment of the primary endpoint.
On Twitter @mitchelzoler
Conventional wisdom holds that for randomized, controlled trials, it’s all about the primary endpoint. If it’s negative or neutral, then none of the other results means much beyond “hypothesis generating.”
This strict-constructionist thinking has now been called into question. A recent article in the New England Journal of Medicine declared “an unreasonable yet widespread practice is the labeling of all randomized trials as either positive or negative on the basis of whether the P value for the primary outcome is less than .05. This view is overly simplistic.” (2016 Sept 1;375[9]:861-70).
The article, by the highly experienced and respected trialists Stuart J. Pocock, PhD, and Gregg W. Stone, MD, adds this: “If the primary outcome is negative, positive findings for secondary outcomes are usually considered to be hypothesis generating. Certainly, regulatory approval of a new drug is unlikely to follow. However, in some instances, secondary findings are compelling enough to affect guidelines and practice.”
This unconventional take from a pair of high-level trialists was especially timely given the buzz around the results from two studies reported at the European Society of Cardiology annual congress in late August, DANISH and NORSTENT.
The DANISH trial compared the impact of implantable cardioverter-defibrillators (ICDs) plus optimal care against optimal care without ICDs in 1,116 patients with nonischemic systolic heart failure. The primary outcome, all-cause death during more than 5 years of follow-up, was a relative 13% less with ICD use, a difference that was not statistically significant, and one secondary outcome, cardiovascular death, was cut by a relative 25% with ICD use, also not statistically significant.
But for the study’s second prespecified secondary endpoint of sudden cardiac death, treatment with ICDs cut the rate in half, compared with nonischemic heart failure patients who did not receive an ICD, a 4-percentage-point difference that was statistically significant.
And in a prespecified secondary analysis of the primary endpoint that broke down the study group by age, the two-thirds of patients younger than 68 years had a significant reduction in all-cause mortality with ICD use, a benefit not seen in patients aged 68 or older.
Discussion of the results at the meeting mainly focused on what meaning, if any, could be drawn from these strongly positive secondary outcomes in a trial neutral for its primary outcome.
“The ICDs did what they were supposed to, prevent sudden cardiac death,” said the lead investigator of the study, Lars Køber, MD. “As a principle I say don’t believe in a subgroup, but guidelines are often based on subgroup analyses.”
“The primary outcome was neutral, but the reduction in sudden cardiac death, the primary objective of an ICD, was significant, so an ICD should be taken into consideration,” commented Michel Komajda, MD, a discussant for the report.
After I wrote a news article about the DANISH report at ESC, I received an email from a reader who objected to spinning the results this way and insisted that no valid lessons can be drawn from the DANISH results because the study’s primary endpoint failed to show a statistical significance. This purist view misses the important, relevant lessons from the DANISH results. The DANISH trial was not designed to provide pivotal data for regulatory approval of ICDs in these patients. Rather, Dr. Køber and his associates designed DANISH to see whether ICD use in these patients could cut all-cause death over a fairly long follow-up. It was a very high bar and ICDs failed, but the deck was stacked against an ICD win. Enrolled patients averaged 64 years old at entry into the study, and they all had New York Heart Association class II or III heart failure. “The overall survival curves start to diverge, but then converge after 5 years because of the comorbidities and patients dying for other reasons,” Dr. Køber noted.
“The message is, in younger patients with less morbidity and more life expectancy, sudden cardiac death is a bigger problem, and they had a substantial drop in mortality” with ICD use, commented heart failure specialist Javed Butler, MD. “It’s very consistent with the way we think about providing ICD treatment to patients.”
In other words, the DANISH results showed that all patients with nonischemic systolic heart failure can’t expect to live substantially longer during extended follow-up if they get an ICD, because the cut in sudden cardiac death the devices provide eventually gets washed out by the many other risks for death these patients face. But younger, relatively healthier patients might very well see their reduced rate of sudden cardiac death translate into an overall mortality benefit even when they are followed for at least 5 years. That’s important information to help an individual patient decide whether to have an ICD placed, and an important message from the DANISH trial despite the neutral primary endpoint.
NORSTENT involved a similar scenario in a trial that addressed a totally different issue: Should patients with either stable or unstable coronary artery disease who are undergoing coronary stenting receive a drug-eluting stent (DES) or a bare metal stent (BMS)? The trial randomized 9,013 patients to receive either of the two stent types plus optimal medical therapy. The primary endpoint was the rate of all-cause death or nonfatal MI during 5 years of follow-up, and the results showed no statistically significant difference between the patients who received a DES and those who got a BMS (N Engl J Med. 2016 Aug 30. doi: 10.1056/NEJMoa1607991).
But for the secondary endpoint of repeat revascularizations performed during follow-up, the use of a DES cut the procedure rate by 3.3 percentage points, a 17% relative risk reduction that was statistically significant. The use of a DES also cut the stent thrombosis rate by 0.4 percentage points, a one-third relative drop in these events that was also statistically significant.
In short, despite the neutral primary endpoint for the trial, the results showed that drug-eluting stents did what they were designed to do relative to bare metal stents: cut the rate of target lesion restenosis and the need for repeat revascularization. Several interventional cardiologists who heard the results at the meeting said that the findings would not change their practice and that they would continue to use the DES as their default device for percutaneous coronary interventions. Although “the long-term benefit of contemporary DES over BMS was less than expected,” said Kaare H. Bønaa, MD, lead investigator for the NORSTENT trial, the secondary benefit of significantly reduced repeat revascularization and the very modest price difference that now exists between drug-eluting stents and bare metal stents means that many interventionalists will continue to use a DES for most patients.
The message from Dr. Pocock and Dr. Stone, underscored by the DANISH and NORSTENT results, is that large and well-run randomized trials can yield important evidence to inform practice that transcends a simple black or white statistical assessment of the primary endpoint.
On Twitter @mitchelzoler
VIDEO: Coronary DES outperform BMS mostly on restenosis
ROME – The difference between contemporary drug-eluting coronary stents and bare-metal stents is not very great, a large Norwegian coronary stent trial showed.
Today’s drug-eluting stents (DES), often called second-generation DES, largely do only what they were designed to do, compared with bare-metal stents (BMS): reduce the rate of stent restenosis and the need for target-lesion revascularization.
“The long-term benefit of contemporary DES over BMS was less that expected,” Kaare H. Bønaa, MD, reported at the annual congress of the European Society of Cardiology.
Results from the Norwegian Coronary Stent Trial (NORSTENT), run with 9,013 patients, showed that patients who received one or more drug-eluting stents had, during nearly 5 years of follow-up, a 5% absolute drop in target-lesion revascularizations (a 53% relative risk reduction), and a 3.3% reduction in all revascularizations (a 24% relative risk reduction), compared with patients who received bare-metal stents, said Dr. Bønaa.
The results also showed that patients who received DES had a 0.4% reduced rate of stent thrombosis (a 36% relative risk reduction), compared with patients treated with BMS during nearly 5 years of follow-up. All three differences were statistically significant.
But the NORSTENT findings also documented that the patients who received either DES or BMS had virtually identical rates of all-cause deaths and nonfatal myocardial infarctions. And, on average, the two different types of coronary stents produced identical improvements in patients’ quality of life, reported Dr. Bønaa, a professor and researcher in the Clinic for Heart Disease at St. Olav’s University Hospital in Trondheim, Norway.
The study’s primary endpoint was the combined rate of death or nonfatal MI, and so the nonsignificant difference in that outcome between the two study arms meant that, formally, the NORSTENT trial produced a neutral result. Concurrently with his report, the results appeared in an article online (New Engl J Med. 2016 Aug 30. doi: 10.1056/NEJMoa1607991).
“The difference between the two stent types is not as great as we thought. Patients who get DES do not live longer or better” than those who receive BMS, Dr. Bønaa said. “We suggest that both contemporary DES and BMS can be recommended for contemporary revascularization. The results open up use of BMS for certain patients,” such as those scheduled for surgery or patients who cannot tolerate or afford the drugs used for dual antiplatelet therapy following coronary stent placement.
But the designated discussant for the study, Stefan James, MD, insisted that recent-generation DES “should remain recommended over BMS,” particularly the specific DES that underwent testing in randomized trials that used hard clinical endpoints. The 2014 revascularization guidelines of the European Society of Cardiology recommend new-generation DES over BMS, he noted.
In addition, “BMS should not be specifically recommended for patients at high risk of stent thrombosis or for patients who do not tolerate dual-antiplatelet therapy,” said Dr. James, professor of cardiology at Uppsala University in Sweden.
NORSTENT ran at eight centers in Norway during 2008-2011, and enrolled patients either had acute coronary syndrome (71% of those in the study) or stable coronary disease. Patients averaged 63 years old. The trial excluded patients with prior stents or bifurcated coronary lesions. Enrolled patients received, on average, 1.7 stents. The specific stent in each class that patients received was left to the discretion of each operator, and 95% of patients in the DES arm received a second-generation device. All patients in both arms of the study received dual-antiplatelet therapy for 9 months.
The finding that DES cut the rate of revascularization procedures by 3.3%, compared with patients treated with BMS, means that, on average, clinicians would need to treat 30 patients with DES to avoid the need for one additional repeat revascularization procedure that would occur if BMS were used instead.
That number needed to treat of 30 to avoid one repeat revascularization may seem high, but the money saved that way would still counterbalance the incremental cost of a DES over a BMS, which today in Europe would be about 50-100 euros, noted one cardiologist.
If you multiply 30 procedures by 100 extra euros per stent and by an average of 1.7 stents per patient, you may spend 5,100 euros, less than the cost of a repeat revascularization procedure, commented Carlo Di Mario, MD, a professor of cardiology and an interventional cardiologist at Royal Brompton & Harefield Hospitals in London.
In a video interview, Steen D. Kristensen, MD, of Aarhus University, Denmark, discussed the NORSTENT findings and their implications.
NORSTENT received no commercial support. Dr. Bønaa and Dr. Di Mario had no disclosures. Dr. James has been a consultant to Boston Scientific and has received research support from Boston Scientific and Abbott Vascular.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @mitchelzoler
NORSTENT was a very well-performed trial. It produced a neutral result for its primary endpoint, but for the secondary endpoint of repeat revascularization, there were significantly more events using bare-metal stents. This is a major finding, and NORSTENT’s design make the results very generalizable.
It may be slightly surprising that the newer drug-eluting stents did not perform better for the primary endpoint of reducing deaths and MIs during 5 years of follow-up, but seeing a difference in the revascularization rate is not surprising; that is what we would expect. We use DES to reduce the problem of restenosis. Results from several earlier studies that had compared DES with BMS had suggested other benefits from DES, and that is also what the European Society of Cardiology guidelines say.
I will not go home now and start using BMS in my own practice. I will continue to use DES, because they have an advantage. I use BMS in patients who cannot tolerate long-term treatment with dual antiplatelet therapy. The results are encouraging for centers where there is a large price difference between DES and BMS, but that is not the case where I practice in Denmark.
Steen D. Kristensen, MD, is a professor of interventional cardiologist at Aarhus University, Denmark. He made these comments in an interview. He had no relevant disclosures.
NORSTENT was a very well-performed trial. It produced a neutral result for its primary endpoint, but for the secondary endpoint of repeat revascularization, there were significantly more events using bare-metal stents. This is a major finding, and NORSTENT’s design make the results very generalizable.
It may be slightly surprising that the newer drug-eluting stents did not perform better for the primary endpoint of reducing deaths and MIs during 5 years of follow-up, but seeing a difference in the revascularization rate is not surprising; that is what we would expect. We use DES to reduce the problem of restenosis. Results from several earlier studies that had compared DES with BMS had suggested other benefits from DES, and that is also what the European Society of Cardiology guidelines say.
I will not go home now and start using BMS in my own practice. I will continue to use DES, because they have an advantage. I use BMS in patients who cannot tolerate long-term treatment with dual antiplatelet therapy. The results are encouraging for centers where there is a large price difference between DES and BMS, but that is not the case where I practice in Denmark.
Steen D. Kristensen, MD, is a professor of interventional cardiologist at Aarhus University, Denmark. He made these comments in an interview. He had no relevant disclosures.
NORSTENT was a very well-performed trial. It produced a neutral result for its primary endpoint, but for the secondary endpoint of repeat revascularization, there were significantly more events using bare-metal stents. This is a major finding, and NORSTENT’s design make the results very generalizable.
It may be slightly surprising that the newer drug-eluting stents did not perform better for the primary endpoint of reducing deaths and MIs during 5 years of follow-up, but seeing a difference in the revascularization rate is not surprising; that is what we would expect. We use DES to reduce the problem of restenosis. Results from several earlier studies that had compared DES with BMS had suggested other benefits from DES, and that is also what the European Society of Cardiology guidelines say.
I will not go home now and start using BMS in my own practice. I will continue to use DES, because they have an advantage. I use BMS in patients who cannot tolerate long-term treatment with dual antiplatelet therapy. The results are encouraging for centers where there is a large price difference between DES and BMS, but that is not the case where I practice in Denmark.
Steen D. Kristensen, MD, is a professor of interventional cardiologist at Aarhus University, Denmark. He made these comments in an interview. He had no relevant disclosures.
ROME – The difference between contemporary drug-eluting coronary stents and bare-metal stents is not very great, a large Norwegian coronary stent trial showed.
Today’s drug-eluting stents (DES), often called second-generation DES, largely do only what they were designed to do, compared with bare-metal stents (BMS): reduce the rate of stent restenosis and the need for target-lesion revascularization.
“The long-term benefit of contemporary DES over BMS was less that expected,” Kaare H. Bønaa, MD, reported at the annual congress of the European Society of Cardiology.
Results from the Norwegian Coronary Stent Trial (NORSTENT), run with 9,013 patients, showed that patients who received one or more drug-eluting stents had, during nearly 5 years of follow-up, a 5% absolute drop in target-lesion revascularizations (a 53% relative risk reduction), and a 3.3% reduction in all revascularizations (a 24% relative risk reduction), compared with patients who received bare-metal stents, said Dr. Bønaa.
The results also showed that patients who received DES had a 0.4% reduced rate of stent thrombosis (a 36% relative risk reduction), compared with patients treated with BMS during nearly 5 years of follow-up. All three differences were statistically significant.
But the NORSTENT findings also documented that the patients who received either DES or BMS had virtually identical rates of all-cause deaths and nonfatal myocardial infarctions. And, on average, the two different types of coronary stents produced identical improvements in patients’ quality of life, reported Dr. Bønaa, a professor and researcher in the Clinic for Heart Disease at St. Olav’s University Hospital in Trondheim, Norway.
The study’s primary endpoint was the combined rate of death or nonfatal MI, and so the nonsignificant difference in that outcome between the two study arms meant that, formally, the NORSTENT trial produced a neutral result. Concurrently with his report, the results appeared in an article online (New Engl J Med. 2016 Aug 30. doi: 10.1056/NEJMoa1607991).
“The difference between the two stent types is not as great as we thought. Patients who get DES do not live longer or better” than those who receive BMS, Dr. Bønaa said. “We suggest that both contemporary DES and BMS can be recommended for contemporary revascularization. The results open up use of BMS for certain patients,” such as those scheduled for surgery or patients who cannot tolerate or afford the drugs used for dual antiplatelet therapy following coronary stent placement.
But the designated discussant for the study, Stefan James, MD, insisted that recent-generation DES “should remain recommended over BMS,” particularly the specific DES that underwent testing in randomized trials that used hard clinical endpoints. The 2014 revascularization guidelines of the European Society of Cardiology recommend new-generation DES over BMS, he noted.
In addition, “BMS should not be specifically recommended for patients at high risk of stent thrombosis or for patients who do not tolerate dual-antiplatelet therapy,” said Dr. James, professor of cardiology at Uppsala University in Sweden.
NORSTENT ran at eight centers in Norway during 2008-2011, and enrolled patients either had acute coronary syndrome (71% of those in the study) or stable coronary disease. Patients averaged 63 years old. The trial excluded patients with prior stents or bifurcated coronary lesions. Enrolled patients received, on average, 1.7 stents. The specific stent in each class that patients received was left to the discretion of each operator, and 95% of patients in the DES arm received a second-generation device. All patients in both arms of the study received dual-antiplatelet therapy for 9 months.
The finding that DES cut the rate of revascularization procedures by 3.3%, compared with patients treated with BMS, means that, on average, clinicians would need to treat 30 patients with DES to avoid the need for one additional repeat revascularization procedure that would occur if BMS were used instead.
That number needed to treat of 30 to avoid one repeat revascularization may seem high, but the money saved that way would still counterbalance the incremental cost of a DES over a BMS, which today in Europe would be about 50-100 euros, noted one cardiologist.
If you multiply 30 procedures by 100 extra euros per stent and by an average of 1.7 stents per patient, you may spend 5,100 euros, less than the cost of a repeat revascularization procedure, commented Carlo Di Mario, MD, a professor of cardiology and an interventional cardiologist at Royal Brompton & Harefield Hospitals in London.
In a video interview, Steen D. Kristensen, MD, of Aarhus University, Denmark, discussed the NORSTENT findings and their implications.
NORSTENT received no commercial support. Dr. Bønaa and Dr. Di Mario had no disclosures. Dr. James has been a consultant to Boston Scientific and has received research support from Boston Scientific and Abbott Vascular.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @mitchelzoler
ROME – The difference between contemporary drug-eluting coronary stents and bare-metal stents is not very great, a large Norwegian coronary stent trial showed.
Today’s drug-eluting stents (DES), often called second-generation DES, largely do only what they were designed to do, compared with bare-metal stents (BMS): reduce the rate of stent restenosis and the need for target-lesion revascularization.
“The long-term benefit of contemporary DES over BMS was less that expected,” Kaare H. Bønaa, MD, reported at the annual congress of the European Society of Cardiology.
Results from the Norwegian Coronary Stent Trial (NORSTENT), run with 9,013 patients, showed that patients who received one or more drug-eluting stents had, during nearly 5 years of follow-up, a 5% absolute drop in target-lesion revascularizations (a 53% relative risk reduction), and a 3.3% reduction in all revascularizations (a 24% relative risk reduction), compared with patients who received bare-metal stents, said Dr. Bønaa.
The results also showed that patients who received DES had a 0.4% reduced rate of stent thrombosis (a 36% relative risk reduction), compared with patients treated with BMS during nearly 5 years of follow-up. All three differences were statistically significant.
But the NORSTENT findings also documented that the patients who received either DES or BMS had virtually identical rates of all-cause deaths and nonfatal myocardial infarctions. And, on average, the two different types of coronary stents produced identical improvements in patients’ quality of life, reported Dr. Bønaa, a professor and researcher in the Clinic for Heart Disease at St. Olav’s University Hospital in Trondheim, Norway.
The study’s primary endpoint was the combined rate of death or nonfatal MI, and so the nonsignificant difference in that outcome between the two study arms meant that, formally, the NORSTENT trial produced a neutral result. Concurrently with his report, the results appeared in an article online (New Engl J Med. 2016 Aug 30. doi: 10.1056/NEJMoa1607991).
“The difference between the two stent types is not as great as we thought. Patients who get DES do not live longer or better” than those who receive BMS, Dr. Bønaa said. “We suggest that both contemporary DES and BMS can be recommended for contemporary revascularization. The results open up use of BMS for certain patients,” such as those scheduled for surgery or patients who cannot tolerate or afford the drugs used for dual antiplatelet therapy following coronary stent placement.
But the designated discussant for the study, Stefan James, MD, insisted that recent-generation DES “should remain recommended over BMS,” particularly the specific DES that underwent testing in randomized trials that used hard clinical endpoints. The 2014 revascularization guidelines of the European Society of Cardiology recommend new-generation DES over BMS, he noted.
In addition, “BMS should not be specifically recommended for patients at high risk of stent thrombosis or for patients who do not tolerate dual-antiplatelet therapy,” said Dr. James, professor of cardiology at Uppsala University in Sweden.
NORSTENT ran at eight centers in Norway during 2008-2011, and enrolled patients either had acute coronary syndrome (71% of those in the study) or stable coronary disease. Patients averaged 63 years old. The trial excluded patients with prior stents or bifurcated coronary lesions. Enrolled patients received, on average, 1.7 stents. The specific stent in each class that patients received was left to the discretion of each operator, and 95% of patients in the DES arm received a second-generation device. All patients in both arms of the study received dual-antiplatelet therapy for 9 months.
The finding that DES cut the rate of revascularization procedures by 3.3%, compared with patients treated with BMS, means that, on average, clinicians would need to treat 30 patients with DES to avoid the need for one additional repeat revascularization procedure that would occur if BMS were used instead.
That number needed to treat of 30 to avoid one repeat revascularization may seem high, but the money saved that way would still counterbalance the incremental cost of a DES over a BMS, which today in Europe would be about 50-100 euros, noted one cardiologist.
If you multiply 30 procedures by 100 extra euros per stent and by an average of 1.7 stents per patient, you may spend 5,100 euros, less than the cost of a repeat revascularization procedure, commented Carlo Di Mario, MD, a professor of cardiology and an interventional cardiologist at Royal Brompton & Harefield Hospitals in London.
In a video interview, Steen D. Kristensen, MD, of Aarhus University, Denmark, discussed the NORSTENT findings and their implications.
NORSTENT received no commercial support. Dr. Bønaa and Dr. Di Mario had no disclosures. Dr. James has been a consultant to Boston Scientific and has received research support from Boston Scientific and Abbott Vascular.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @mitchelzoler
AT THE ESC CONGRESS 2016
Key clinical point: The benefit from coronary revascularization with drug-eluting stents, compared with bare-metal stents, was mostly in a reduced need for repeat revascularization, with no difference in mortality or MIs during 5 years of follow-up.
Major finding: Thirty patients need to be treated with drug-eluting stents to prevent one repeat revascularization, compared with bare-metal stents.
Data source: NORSTENT, a randomized, multicenter trial with 9,013 patients.
Disclosures: NORSTENT received no commercial support. Dr. Bønaa and Dr. Di Mario had no disclosures. Dr. James has been a consultant to Boston Scientific and has received research support from Boston Scientific and Abbott Vascular.
VIDEO: Functional noninvasive imaging cuts unnecessary angiography
ROME – Functional, noninvasive cardiac imaging using cardiovascular MR or myocardial perfusion scintigraphy was significantly better than was a current and well regarded guideline-based approach to identifying patients with chest pain and suspected coronary artery disease who could safely avoid angiography, thereby cutting the rate of unnecessary angiography by about 75%.
Following the guideline formula adopted by the British National Institute for Health and Care Excellence (NICE) resulted in a 29% rate of unnecessary angiography compared with rates of 7.5% using cardiovascular MR (CMR) and 7.1% using myocardial perfusion scintigraphy (MPS) in a multicenter randomized trial with 1,202 patients, John P. Greenwood, MBChB, said at the annual congress of the European Society of Cardiology.
This universal use of a functional, noninvasive imaging strategy to guide angiography resulted in no significant penalty of missed coronary disease or subsequent coronary events. The rate of positive angiography findings was 12% among the 240 patients managed according to the NICE guidelines, 10% among 481 patients screened by CMR, and 9% among the 481 patients screened using MPS, reported Dr. Greenwood, professor of cardiology at the University of Leeds (England). The rate of major adverse coronary events after 12 months of follow-up were 3% following the NICE protocol and 4% when screening by CMR or with MPS.
Concurrently with Dr. Greenwood’s report, the findings from the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2 (CE-MARC2) study appeared in an article online (JAMA. 2016 Aug 29. doi: 10.1001/jama.2016.12680).
“We showed that a functional test with CMR or MPS can reduce the rate of unnecessary coronary angiography. Cutting unnecessary angiography is really important to patients, and it may also cost effective,” he said, but cautioned that a formal cost analysis of the options tested in this study is still being run.
The NICE guidelines manage patients with chest pain that could be angina by their pretest probability of having coronary artery disease (CAD), and at the time the study was designed the NICE guidelines, issued in 2010, provided the most up-to-date expert guidance on how to triage these patients. The study enrolled patients with a pretest probability for CAD of 10%-90%; collectively their average probability was 50%. The patients participated in the study at one of six U.K. centers during November 2012 to March 2015. The average age was 56 years.
MPS is “probably the noninvasive imaging approach most commonly used worldwide to detect coronary ischemia,” Dr. Greenwood said. But he led an earlier study that showed that CMR, using a gadolinium-based tracing agent, works even better than MPS (in this study single photon emission CT) to predict a patient’s risk for major cardiac events. He said this superiority is probably because of the greater spatial resolution with CMR.
“The higher spatial resolution of CMR, about 5- to 10-fold greater that MPS, is less likely to produce false negative results,” he said in an interview. “We showed that CMR has higher diagnostic accuracy, is a better prognosticator, and is more cost effective” than MPS. Dr. Greenwood attributed the similar performance of CMR and MPS in CE-MARC2 to the study’s design, which led to fewer patients undergoing each of the two imaging methods and made CE-MARC2 underpowered to discern a difference in specificity. In his earlier study, which included 752 patients who underwent examination with both CMR and MPS, the negative predictive value of CMR was 91% compared with 79% with MPS.
CMR uses conventional MR machines, is now widely available, and is being widely used today as a first-line test in the United Kingdom and Europe, he added.
Dr. Greenwood believes that in his new study functional imaging outperformed the NICE guidelines because the pretest models used in the guidelines “tend to overestimate risk,” the factor that produces angiography overuse.
His report included two additional analyses that assessed the impact of CMR and MPS in the subgroup of patients with a high pretest probability for CAD, 61%-90%, and in the subgroup with a low pretest probability, 10%-29%. Among the patients with a high likelihood for CAD the two functional imaging methods cut the rate of unnecessary angiography by 95%, a statistically significant difference. Among those with a low likelihood functional imaging cut the rate 56%, a difference that did not reach statistical significance.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The results from CE-MARC2 very nicely showed that imaging-guided angiography is as safe as compulsory angiography in the highest-risk subgroup of the enrolled patients, those with a pretest probability of 61%-90% for having coronary artery disease. Findings from the economic analysis of this study that remains pending will be crucial for eventually recommending one strategy over the other in this setting.
|
| Mitchel L. Zoler/Frontline Medical News Dr. Udo Sechtem |
The 12-month rate of the hardest clinical endpoints measured in this study, cardiovascular deaths and MIs, was very low in this study: 1.3% in the patients managed with NICE guidance, 1% in those who first underwent cardiovascular MR, and 0.8% in the patients who first underwent myocardial perfusion scintigraphy. Despite this low risk, the patients in each of the three arms of the study underwent roughly 500 test procedures.
We should therefore consider a totally different approach. Instead of immediately performing a noninvasive test or the tests called for by the NICE guidelines, what about no testing at all. Instead, patients would first undergo optimal preventive and symptomatic medical treatments. If patients failed this strategy they then could be considered for revascularization. I propose a study that would compare imaging-guided conditional angiography, as tested in CE-MARC2, with symptom-guided conditional angiography. Functional, noninvasive testing for all needs to be compared against optimal management and symptom driven interventions.
Udo Sechtem, Dr Med, is head of cardiology at the Robert-Bosch-Hospital in Stuttgart, Germany. He made these comments as the designated discussant for the study. He had no disclosures.
The results from CE-MARC2 very nicely showed that imaging-guided angiography is as safe as compulsory angiography in the highest-risk subgroup of the enrolled patients, those with a pretest probability of 61%-90% for having coronary artery disease. Findings from the economic analysis of this study that remains pending will be crucial for eventually recommending one strategy over the other in this setting.
|
|
| Mitchel L. Zoler/Frontline Medical News Dr. Udo Sechtem |
The 12-month rate of the hardest clinical endpoints measured in this study, cardiovascular deaths and MIs, was very low in this study: 1.3% in the patients managed with NICE guidance, 1% in those who first underwent cardiovascular MR, and 0.8% in the patients who first underwent myocardial perfusion scintigraphy. Despite this low risk, the patients in each of the three arms of the study underwent roughly 500 test procedures.
We should therefore consider a totally different approach. Instead of immediately performing a noninvasive test or the tests called for by the NICE guidelines, what about no testing at all. Instead, patients would first undergo optimal preventive and symptomatic medical treatments. If patients failed this strategy they then could be considered for revascularization. I propose a study that would compare imaging-guided conditional angiography, as tested in CE-MARC2, with symptom-guided conditional angiography. Functional, noninvasive testing for all needs to be compared against optimal management and symptom driven interventions.
Udo Sechtem, Dr Med, is head of cardiology at the Robert-Bosch-Hospital in Stuttgart, Germany. He made these comments as the designated discussant for the study. He had no disclosures.
The results from CE-MARC2 very nicely showed that imaging-guided angiography is as safe as compulsory angiography in the highest-risk subgroup of the enrolled patients, those with a pretest probability of 61%-90% for having coronary artery disease. Findings from the economic analysis of this study that remains pending will be crucial for eventually recommending one strategy over the other in this setting.
|
|
| Mitchel L. Zoler/Frontline Medical News Dr. Udo Sechtem |
The 12-month rate of the hardest clinical endpoints measured in this study, cardiovascular deaths and MIs, was very low in this study: 1.3% in the patients managed with NICE guidance, 1% in those who first underwent cardiovascular MR, and 0.8% in the patients who first underwent myocardial perfusion scintigraphy. Despite this low risk, the patients in each of the three arms of the study underwent roughly 500 test procedures.
We should therefore consider a totally different approach. Instead of immediately performing a noninvasive test or the tests called for by the NICE guidelines, what about no testing at all. Instead, patients would first undergo optimal preventive and symptomatic medical treatments. If patients failed this strategy they then could be considered for revascularization. I propose a study that would compare imaging-guided conditional angiography, as tested in CE-MARC2, with symptom-guided conditional angiography. Functional, noninvasive testing for all needs to be compared against optimal management and symptom driven interventions.
Udo Sechtem, Dr Med, is head of cardiology at the Robert-Bosch-Hospital in Stuttgart, Germany. He made these comments as the designated discussant for the study. He had no disclosures.
ROME – Functional, noninvasive cardiac imaging using cardiovascular MR or myocardial perfusion scintigraphy was significantly better than was a current and well regarded guideline-based approach to identifying patients with chest pain and suspected coronary artery disease who could safely avoid angiography, thereby cutting the rate of unnecessary angiography by about 75%.
Following the guideline formula adopted by the British National Institute for Health and Care Excellence (NICE) resulted in a 29% rate of unnecessary angiography compared with rates of 7.5% using cardiovascular MR (CMR) and 7.1% using myocardial perfusion scintigraphy (MPS) in a multicenter randomized trial with 1,202 patients, John P. Greenwood, MBChB, said at the annual congress of the European Society of Cardiology.
This universal use of a functional, noninvasive imaging strategy to guide angiography resulted in no significant penalty of missed coronary disease or subsequent coronary events. The rate of positive angiography findings was 12% among the 240 patients managed according to the NICE guidelines, 10% among 481 patients screened by CMR, and 9% among the 481 patients screened using MPS, reported Dr. Greenwood, professor of cardiology at the University of Leeds (England). The rate of major adverse coronary events after 12 months of follow-up were 3% following the NICE protocol and 4% when screening by CMR or with MPS.
Concurrently with Dr. Greenwood’s report, the findings from the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2 (CE-MARC2) study appeared in an article online (JAMA. 2016 Aug 29. doi: 10.1001/jama.2016.12680).
“We showed that a functional test with CMR or MPS can reduce the rate of unnecessary coronary angiography. Cutting unnecessary angiography is really important to patients, and it may also cost effective,” he said, but cautioned that a formal cost analysis of the options tested in this study is still being run.
The NICE guidelines manage patients with chest pain that could be angina by their pretest probability of having coronary artery disease (CAD), and at the time the study was designed the NICE guidelines, issued in 2010, provided the most up-to-date expert guidance on how to triage these patients. The study enrolled patients with a pretest probability for CAD of 10%-90%; collectively their average probability was 50%. The patients participated in the study at one of six U.K. centers during November 2012 to March 2015. The average age was 56 years.
MPS is “probably the noninvasive imaging approach most commonly used worldwide to detect coronary ischemia,” Dr. Greenwood said. But he led an earlier study that showed that CMR, using a gadolinium-based tracing agent, works even better than MPS (in this study single photon emission CT) to predict a patient’s risk for major cardiac events. He said this superiority is probably because of the greater spatial resolution with CMR.
“The higher spatial resolution of CMR, about 5- to 10-fold greater that MPS, is less likely to produce false negative results,” he said in an interview. “We showed that CMR has higher diagnostic accuracy, is a better prognosticator, and is more cost effective” than MPS. Dr. Greenwood attributed the similar performance of CMR and MPS in CE-MARC2 to the study’s design, which led to fewer patients undergoing each of the two imaging methods and made CE-MARC2 underpowered to discern a difference in specificity. In his earlier study, which included 752 patients who underwent examination with both CMR and MPS, the negative predictive value of CMR was 91% compared with 79% with MPS.
CMR uses conventional MR machines, is now widely available, and is being widely used today as a first-line test in the United Kingdom and Europe, he added.
Dr. Greenwood believes that in his new study functional imaging outperformed the NICE guidelines because the pretest models used in the guidelines “tend to overestimate risk,” the factor that produces angiography overuse.
His report included two additional analyses that assessed the impact of CMR and MPS in the subgroup of patients with a high pretest probability for CAD, 61%-90%, and in the subgroup with a low pretest probability, 10%-29%. Among the patients with a high likelihood for CAD the two functional imaging methods cut the rate of unnecessary angiography by 95%, a statistically significant difference. Among those with a low likelihood functional imaging cut the rate 56%, a difference that did not reach statistical significance.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ROME – Functional, noninvasive cardiac imaging using cardiovascular MR or myocardial perfusion scintigraphy was significantly better than was a current and well regarded guideline-based approach to identifying patients with chest pain and suspected coronary artery disease who could safely avoid angiography, thereby cutting the rate of unnecessary angiography by about 75%.
Following the guideline formula adopted by the British National Institute for Health and Care Excellence (NICE) resulted in a 29% rate of unnecessary angiography compared with rates of 7.5% using cardiovascular MR (CMR) and 7.1% using myocardial perfusion scintigraphy (MPS) in a multicenter randomized trial with 1,202 patients, John P. Greenwood, MBChB, said at the annual congress of the European Society of Cardiology.
This universal use of a functional, noninvasive imaging strategy to guide angiography resulted in no significant penalty of missed coronary disease or subsequent coronary events. The rate of positive angiography findings was 12% among the 240 patients managed according to the NICE guidelines, 10% among 481 patients screened by CMR, and 9% among the 481 patients screened using MPS, reported Dr. Greenwood, professor of cardiology at the University of Leeds (England). The rate of major adverse coronary events after 12 months of follow-up were 3% following the NICE protocol and 4% when screening by CMR or with MPS.
Concurrently with Dr. Greenwood’s report, the findings from the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2 (CE-MARC2) study appeared in an article online (JAMA. 2016 Aug 29. doi: 10.1001/jama.2016.12680).
“We showed that a functional test with CMR or MPS can reduce the rate of unnecessary coronary angiography. Cutting unnecessary angiography is really important to patients, and it may also cost effective,” he said, but cautioned that a formal cost analysis of the options tested in this study is still being run.
The NICE guidelines manage patients with chest pain that could be angina by their pretest probability of having coronary artery disease (CAD), and at the time the study was designed the NICE guidelines, issued in 2010, provided the most up-to-date expert guidance on how to triage these patients. The study enrolled patients with a pretest probability for CAD of 10%-90%; collectively their average probability was 50%. The patients participated in the study at one of six U.K. centers during November 2012 to March 2015. The average age was 56 years.
MPS is “probably the noninvasive imaging approach most commonly used worldwide to detect coronary ischemia,” Dr. Greenwood said. But he led an earlier study that showed that CMR, using a gadolinium-based tracing agent, works even better than MPS (in this study single photon emission CT) to predict a patient’s risk for major cardiac events. He said this superiority is probably because of the greater spatial resolution with CMR.
“The higher spatial resolution of CMR, about 5- to 10-fold greater that MPS, is less likely to produce false negative results,” he said in an interview. “We showed that CMR has higher diagnostic accuracy, is a better prognosticator, and is more cost effective” than MPS. Dr. Greenwood attributed the similar performance of CMR and MPS in CE-MARC2 to the study’s design, which led to fewer patients undergoing each of the two imaging methods and made CE-MARC2 underpowered to discern a difference in specificity. In his earlier study, which included 752 patients who underwent examination with both CMR and MPS, the negative predictive value of CMR was 91% compared with 79% with MPS.
CMR uses conventional MR machines, is now widely available, and is being widely used today as a first-line test in the United Kingdom and Europe, he added.
Dr. Greenwood believes that in his new study functional imaging outperformed the NICE guidelines because the pretest models used in the guidelines “tend to overestimate risk,” the factor that produces angiography overuse.
His report included two additional analyses that assessed the impact of CMR and MPS in the subgroup of patients with a high pretest probability for CAD, 61%-90%, and in the subgroup with a low pretest probability, 10%-29%. Among the patients with a high likelihood for CAD the two functional imaging methods cut the rate of unnecessary angiography by 95%, a statistically significant difference. Among those with a low likelihood functional imaging cut the rate 56%, a difference that did not reach statistical significance.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE ESC CONGRESS 2016
Key clinical point: Screening patients with suspected angina via cardiovascular MR or myocardial perfusion imaging substantially reduced the rate of unnecessary angiography compared with the screening algorithm currently endorsed by British national guidelines.
Major finding: The unnecessary angiography rate was 29% with the guideline algorithm, 7.5% with cardiovascular MR, and 7.1% with myocardial perfusion scintigraphy.
Data source: CE MARC2, a multicenter, randomized trial with 1,202 patients.
Disclosures: Dr. Greenwood had no disclosures.
Navigating the obstacle course of diagnosing, managing pediatric hypertension
The clinical context of high blood pressure shifts abruptly when a person comes of age.
In adults 18 years old and up it’s fairly simple. Blood pressure above 140/90 mm Hg is generally a clear problem, less than 130/85 is probably okay for now, and in between is something to monitor. When pressure stays above 140/90 mm Hg despite lifestyle interventions it’s time to start treatment with any of several antihypertensive drug options that mostly have well-documented safety and efficacy track records in adults and widely agreed-on benefits that outweigh risks.
For pediatric practice, children and adolescents 3-17 years old, dealing with high blood pressure is much more an obstacle course of complex diagnostic criteria, challenges in pressure measurement, and seemingly inconsistent recommendations. Pediatric hypertension also often brings clinicians up against the child and adolescent obesity epidemic, which has made pediatric hypertension more common than ever.
Against this backdrop, a panel assembled by the American Academy of Pediatrics is revising the 2004 The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents, the reigning standard for pediatric blood pressure assessment and hypertension management and now more than a decade old. With new guidance from the AAP expected in the second half of 2017, best-practice approaches to pediatric hypertension are in flux and need updating just when the disorder is more prevalent than it’s ever been.
Diagnosing pediatric hypertension falls short
This shifting landscape and increasing burden of pediatric hypertension comes at a time when primary-care pediatricians and family practice physicians are failing to perform fully comprehensive blood pressure monitoring of their pediatric patients. Current practice recommendations from the National Heart Lung and Blood Institute (in the form of the 2004 Fourth Report), and from American Heart Association (most recently reiterated in a scientific statement in August 2016) call measuring blood pressure levels at every patient encounter starting at 3 years old, the approach also endorsed by the American Academy of Pediatrics.
But that’s often not done. “Results from plenty of studies show that we are not doing a great job” identifying children and adolescents with hypertension, said Tammy M. Brady, MD, a pediatric nephrologist at Johns Hopkins Medical Center in Baltimore.
One piece of evidence she cited was a study of more than 93,000 U.S. ambulatory pediatric visits during 2000-2009 in data collected by the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey, and sampling that represented an average 142 million ambulatory visits each year by 3-18 year olds. The data showed blood pressure screening occurred during 35% of ambulatory visits, 67% of preventive visits, and during 84% of preventive visits for a child or adolescent who was overweight or obese (Pediatrics. 2012 October;130[4]:604-10).
While the numbers showed good practice with a reasonably high level of routine blood pressure measurement in overweight and obese patients, they also suggest that perhaps a third of all U.S. children and adolescents don’t have their blood pressure checked at least once a year. Statistical analyses from this study showed that blood pressure measurement was about twice as likely in children diagnosed as overweight or obese than normal-weight patients, and that blood pressure measurement was 2.6-fold more common in adolescents 13-18 years old compared with children 3-7 years old.
In a second, recent study of 29,000 2-17 years old seen at Children’s Hospital of Chicago, 3% had at least three elevated blood pressure measurements in their hospital record, but in this subset of patients at high risk of having hypertension 21% were actually identified in their medical record as having high blood pressure.
Dr. Brady pointed out that while many of the children and adolescents in this study with three or more high blood pressure readings may not actually have hypertension, defined as a sustained elevation of blood pressure, they are all at risk for development of hypertension and should be targeted for prevention.
“We do a bad job identifying when blood pressure is high,” Dr. Brady said in an interview. She cited a study she recently ran that examined the impact that EMR alerts could have on this diagnostic challenge. She reviewed records for 1,305 patient encounters done before or after institution of a EMR alert that warmed clinicians when a patient’s blood pressure measurement fell above the normal range. The results showed that for these patients, 3-21 years old, the rate of recognition of a high pressure measurement increased from 13% before the alert system started to 42% with the alert system in place (Clin Ped. 2015 June;54[7]:667-75). “That meant more than half the patients with high blood pressure measurements were still going unrecognized”, even with an EMR alert, Dr. Brady said.
“The U.S. clinical community falls way short” of adequately following blood pressure levels in children and adolescents, agreed Julia Steinberger, MD, professor and director of pediatric cardiology at the University of Minnesota in Minneapolis. She chalks this up to several factors: time-pressured clinicians who may let blood pressure slide when other aspects of a visit require more attention and the index of suspicion for elevated blood pressure is low, insufficient education to the primary-care community on how to proceed once an elevated blood pressure reading is made, the difficulty of measuring blood pressure in young or uncooperative patients, and lack of size-appropriate equipment.
Once a single high pressure is recorded, ideal follow-up means measuring and finding elevated blood pressures again on at least two subsequent visits, followed by even more confirmation with home monitoring or 24-hour ambulatory blood pressure monitoring (ABPM), now considered the gold standard for both diagnosing and following pediatric patients with hypertension, especially if they receive antihypertensive medications. In 2014, a scientific statement from the American Heart Association said routine APBM was indicated to confirm the diagnosis of hypertension in a patient with high casual blood pressure measurements. Not many primary-care physicians have ready access to or experience using and interpreting ABPM.
Other reasons for low diagnostic rates include therapeutic inertia, and the sheer complexity and time of identifying what is a high blood pressure reading, at least until automated calculation of high levels by EMRs became possible. “With a paper analysis you need to look at two different charts” and factor in the patient’s sex, age, and height to determine if a pressure reading is high or not for a particular patient. “Diagnosis has been a problem, especially in busy practice,” noted Dr. Brady. “I think we are addressing that with the EMR and pop-up alerts.”
Streamlining the diagnostic process
“We have a complex way to diagnose hypertension in kids,” admitted Bonita Falkner, MD, who chaired the Fourth Report panel that produced the complicated diagnostic process still used today. “It’s complex and tedious to calculate. There have been a number of reports of missed hypertension because of the complexity of the tables,” said Dr. Falkner, professor and director of hypertension and obesity research at Thomas Jefferson University in Philadelphia. “Because it’s so burdensome to diagnose the detection rate of hypertension is not as accurate as it should be. Hopefully this will be improved with the new guidelines. We plan to make them simpler, easier to use and more streamlined,” she said in an interview.
“One of the challenges is how to make high blood pressure identification simpler and more straightforward. Without question there are children and adolescents with persistently high blood pressures who fall through the cracks,” said Stephen R. Daniels, MD, professor and chairman of pediatrics at the University of Colorado in Aurora. “Recognizing hypertension in adults is much simpler, with a single set of values. The AAP is in the process of developing new guidelines and one goal is to make blood pressure measurement and recognition of hypertension as simple as possible. There is a tension between simplicity and precision. Finding the right balance will be the trick.”
Dr. Falkner highlighted two other new aspects the revised pediatric hypertension recommendations will address. The panel appears to be on track to recalculate the reference blood pressure tables to eliminate the contribution of overweight and obese children and adolescents. Because high blood pressure is defined statistically--pressures at or above the 95th percentile for a child’s sex, age and height--inclusion of overweight and obese children and adolescents in the databases that produced the original tables skewed the 95th percentile thresholds higher than they would be for those who are at normal-weights. “It will make the reference numbers somewhat lower, but not dramatically lower,” Dr. Falkner said.
When the 2004 Fourth Report was written and the calculation tables created “it was early in the obesity epidemic and we were not as tuned into it as a problem” for hypertension,” said Dr. Daniels, also a member of the Fourth Report panel.
Another new aspect will likely be highlighting the role of overweight in addition to obesity as a hypertension risk factor. “In 2004, obesity was a concern but overweight was considered just a risk factor for obesity. Now if a child is overweight we know they are also at increased risk for having high blood pressure,” said Dr. Falkner. “We’ve been trying to get an update of the Fourth Report going for some time; a lot has happened since 2004.”
The Preventive Services Task Force effect
One notable recent development in the field of pediatric hypertension was the 2013 statement by the U.S. Preventive Services Task Force that reinforced a similar conclusion the group had reached a decade before, in 2003. In 2013, the USPSTF said that following a review of the evidence “the USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for primary hypertension in asymptomatic children and adolescents to prevent subsequent cardiovascular disease in childhood or adulthood. (I statement)” (Pediatrics. 2013 Nov;132[5]:907-14).
The USPSTF’s 2013 reassertion of this position triggered several strong reactions from pediatric hypertension specialists, who critiqued the Task Force’s analysis as being overly restrictive. Among those weighing with comments that highlighted the flaws in the Task Force’s reasoning were Dr. Falkner, Dr. Brady, and Dr. Steinberger. Earlier in 2013, before the Task Force statement, Dr. Daniels wrote a commentary with similar arguments in favor of routine blood pressure measurements in response to a published assessment of pediatric blood pressure screening that largely presaged what the USPSTF said.
In brief, the USPSTF analysis “was flawed by an overly-narrow selection of evidence,” Dr. Steinberger said recently. “Short-term and observational studies were not considered. We think that in the absence of perfect data the practitioner must use common sense when superior evidence does not exist. The question of whether hypertension in adults can be prevented or modified by early intervention will never be answered unless we continue to measure blood pressure in children.”
“One of the problems with the USPSTF statement was the questions they addressed: Is blood pressure in children and adolescents clearly associated with hard cardiovascular disease outcomes in adults? That is a very tough question to answer. It would need studies that are 30, 40 years in duration, and is almost unanswerable,” said Dr. Daniels in an interview. “I think the USPSTF paid less attention to the fact that clearly a certain percentage of children and adolescents with hypertension already have developed left ventricular hypertrophy, increased carotid intimal-medial thickness and vascular stiffness. This shows that higher blood pressure in the short term is having several adverse effects on the cardiovascular system. If you insist on seeing a connection between pediatric blood pressure and adult outcomes there will always be insufficient evidence.”
Although, as Dr. Steinberger pointed out, the International Childhood Cardiovascular Cohort Consortium has been putting together long-term follow-up data from seven observational cohorts established in several different world regions. Collectively these seven cohorts include more than 340,000 people who have now been followed for about 40 years. This analysis may soon yield more definitive insight into the long-term consequences of childhood hypertension, Dr. Steinberger said.
Another relevant issue is that prevention of adult cardiovascular disease “is not why children are screened for hypertension, or at least not the primary reason,” Dr. Falkner said. “They are screened to find high blood pressure with an underlying cause, like coarctation of the aorta, which is only picked up by first noting a high blood pressure. Several other cardiovascular and renal disorders that can exist in childhood can also cause high blood pressure and measuring blood pressure is the only way to find them. It would be a tragedy to miss coarctation of the aorta by not measuring blood pressure.”
The family practice position
Despite rejection of the USPSTF analysis by many pediatric hypertension specialists, the USPSTF position has been officially embraced by the family practice community. The American Academy of Family Practice has adopted the USPSTF position as its own, although family practice physicians are also quick to point out that the USPSTF conclusion does not say that pediatric blood pressures should not be measured.
“An I level from the USPSTF doesn’t mean that screening is harmful or shouldn’t be done, just that more research is needed to fully evaluate if blood pressure screening in childhood has long-term health impacts,” said Margaret A. Riley, MD, a family practice physician at the University of Michigan in Ann Arbor with an interest in pediatric hypertension.
“I think the I rating has had little impact on practice. Measuring blood pressure is a routine and standard part of office practice. If the USPSTF had given blood pressure screening a D rating, causing more harm than good, that would be different. In my practice I screen blood pressure at every visit or at least once a year,” Dr. Riley said in an interview.
That’s the same approach taken by Wanda D. Filer, MD, a family practice physician in York, Pa. and president of the American Academy of Family Physicians. “This does not mean you don’t screen blood pressure, and it doesn’t mean you should screen. It says that data are not there either way. In my office we check everyone age 3 and up, and I think a lot of family practice physicians do that routinely.
“Most of us screen blood pressure, but the AAFP approach is to always look at the evidence. The AAFP stand is not opposite to other organizations [that have endorsed routine blood pressure measurements]. They take a stronger position in favor of screening than we do, but we don’t say do not screen. Other societies have relied on less direct evidence or expert opinion. Our approach is to see proof of benefit,” Dr. Filer said in an interview.
“I imagine most family practice physicians measure blood pressure in children aged 3 or older,” she added. “I work in a Federally-qualified health center, and we have a very diverse population. We routinely measure blood pressures because the patients are so diverse. Other family practice practices may come to a different decision. You need to look at your practice and your work flow and decide whether it is an appropriate use of time.
“I do it because I’m convinced there is a possibility of benefit from screening,” Dr. Filer said. “I am also convinced that the evidence is not there [to prove benefits]. But I won’t wait for the evidence to do this in my practice. For the mix of patients I see it is important to screen blood pressures, but I am comfortable if a family practice physician with a different patient population says that high blood pressure yields are not there; they never see them.”
Overweight and obesity raise a red flag
If there is one subgroup of the pediatric population that most everyone agrees needs close attention to blood pressure it’s the overweight or obese child or teenager. “Primary hypertension in children and adolescents is largely associated with obesity,” said Dr. Falkner. Study findings also suggest that obese children and teens with hypertension are much more likely to have or develop left ventricular hypertrophy than normal-weight patients with elevated blood pressures.
The consequences are two fold: First, it suggests that even if the entire pediatric population fails to get their blood pressures checked regularly diligent attention to blood pressure is a must for overweight and obese children and adolescents, many experts agree. “A child who is overweight as well as obese requires attention to their blood pressure. That is emerging as a guideline,” Dr. Falkner said.
Second, a growing number of U.S. clinical programs are geared to addressing hypertension in the overweight or obese pediatric patient using an aggressive and multidisciplinary treatment approach.
For example, a clinic devoted to the overweight or obese child or teen with hypertension, the ReNEW (Reversing the Negative Cardiovascular Effects of Weight) program, opened at Johns Hopkins Medical Center in February 2015.
“We were seeing a lot of obesity-related hypertension without an underlying secondary cause. And in a study we ran the only thing that could predict left ventricular hypertrophy in children with hypertension was body mass index,” said Dr. Brady, medical director for ReNEW. “This motivated me to try to find a better way to treat obesity and hypertension; the only real treatment for hypertension in obese patients is to treat the obesity.”
During its first year, the ReNEW program enrolled 35 patients 5-22 years old. “We assess them for any secondary cause of hypertension,” Dr. Brady said. “We do an echocardiography examination and assess left ventricular hypertrophy and the need for blood pressure reducing medications. We do interventions for weight loss, diet, exercise, a musculoskeletal assessment, psychiatric assessment and other comorbidity interventions such as for sleep apnea. We start blood pressure reducing drugs when appropriate.”
The average body mass index among the first 35 patients was 38 kg/m2, with an average 31 kg/m2 in kids 5-10 years old and 43 kg/m2 in those 18-21 years old. Fifty percent had obstructive sleep apnea, 33% had anxiety or depression, and about 25%-33% had diabetes. “These kids are at a really great risk for a cardiac event in early adulthood. They are probably one of the most vulnerable populations we see,” she said.
A major lesson she’s learned from the ReNEW experience so far is the spectrum of comorbidities that can affect these patients and the importance of behavioral change for the entire family to produce favorable changes in the patient. “Depression and anxiety are big factors that can affect a family’s success with weight loss. Many kids also have underlying orthopedic issues. There remains a lot of confusion about diet. We try to offer families a one-stop shop, a multidisciplinary clinic that can thoroughly address the patient’s full range of cardiovascular-disease risk factors.
“I’ve been how shocked by how complex these patients are. When there is a significant overweight or obesity problem the only way to succeed is to involve the whole family. And don’t forget about the role of mental health. That is a significant part of overweight and obesity,” Many of the psychiatric disorders that overweight and obese children and teenagers show results from learned family behaviors, Dr. Brady said.
Another U.S. clinic specifically targeted at obese children and adolescents also sees many patients with hypertension at the University of Minnesota, a program begun in about 2010 that now has treated more than 1,000 patients including “hundreds” with comorbid hypertension, as well as similar numbers with comorbid hyperlipidemia and comorbid diabetes , said Dr. Steinberger.
“There are very few of these programs in the U.S.; it is not widely available. The cardiovascular health promotion effort should include this approach because for the primary care physician there is insufficient time or expertise to do these evaluations and treatments. You need a group of clinicians with the needed expertise,” she said. “Our multidisciplinary approach to treating comorbidities like hypertension, dyslipidemia and elevated glucose uses specialists for each of these areas as well as dieticians, social workers, and other specialists.
“In general, when the primary care physician does not have the resources to further evaluate and treat overweight or obesity they should be able to refer the patient to a program like this. It is never too soon to refer and treat. To treat overweight you need to involve the whole family. Most children do not ‘grow out’ of overweight or obesity. The overweight or obese child will generally grow up to be the overweight or obese adult,” Dr. Steinberger said.
Targeting the greatest hypertension risk
The growing trend to focus multidisciplinary resources on hypertension in the overweight or obese pediatric patient may exemplify part of a new era of targeted attention for pediatric blood pressure screening.
“We have a hard time measuring blood pressure in kids, we know the importance of obesity [in causing hypertension] and we also know that first-line management for most hypertensive patients is non-drug, lifestyle interventions. Therefore, is it possible that a greater good can be achieved by addressing lifestyle and all the health issues that would reduce the risk for hypertension, such as making sure all children engage in more movement and exercise and get off devices rather than medicalizing the problem” with frequent blood pressure measurement, wondered Howard Trachtman, MD, a pediatric nephrologist at New York University.
“Routinely screening blood pressure in every child and adolescent is very burdensome and carries the potential cost of inconvenience and mislabeling errors. Could clinicians focus on the children and adolescents who really are at risk of high blood pressure? Can we use the EMR and alerts to make sure that repeated measures of blood pressure are done only when needed, after we identify who is at greatest risk?
“We need to become more precise in defining who is it in the age range of 8-17 years old who needs to be regularly screened for high blood pressure so we can focus our resources on these people and better avoid mislabeling and causing anxiety” for the many children and adolescents who have a very low risk for having hypertension, said Dr. Trachtman. He said that he is currently collaborating on a study that is examining whether data contained in a patient’s EMR can help in improving blood pressure assessment.
“We need to keep an open mind about who might have hypertension, but there are good data that it tracks with waist circumference, hypertriglyceridemia, and insulin resistance. The more of these you have the greater your risk. This is the kind of productive research I’m talking about, to determine whether you can be more thoughtful in identifying who is at risk of high blood pressure and who needs more systematic screening. Targeting blood pressure screening to overweight or obese kids is a step toward trying to be more methodical. The USPSTF statement should be a spur to pediatric nephrologists to make our case for blood pressure screening more cogently and to collect better data so that when we speak about this it is not based on speculation or extrapolation but on data,” Dr. Trachtman said.
“There are no arguments against optimizing health and reducing risk factors in all children, but that is not an acceptable rationale for not measuring blood pressure and attending to elevated levels in children,” responded Dr. Falkner. Dr Trachtman’s proposal to reduce health risks in all children “is a public health issue whereas the issue of detecting and managing hypertension in childhood is a clinical issue” faced by physicians as they see individual patients, she said.
Many pediatric hypertension specialists may not warm to a screening proposition that retreats from the notion that every child and teen 3 years old and up should have their blood pressure checked at least annually. But many of those specialists also realize that what’s now done has a lot of problems and that a more user-friendly approach is needed. As an expert panel works to produce a revision to the Fourth Report next year (which will not be the Fifth Report as the update is now outside the NHLBI purview), changes in how pediatric hypertension will be approached in the future seem likely.
Dr. Brady, Dr. Steinberger, Dr. Falkner, Dr. Daniels, Dr. Riley, Dr. Filer, and Dr. Trachtman had no disclosures.
On Twitter @mitchelzoler
The clinical context of high blood pressure shifts abruptly when a person comes of age.
In adults 18 years old and up it’s fairly simple. Blood pressure above 140/90 mm Hg is generally a clear problem, less than 130/85 is probably okay for now, and in between is something to monitor. When pressure stays above 140/90 mm Hg despite lifestyle interventions it’s time to start treatment with any of several antihypertensive drug options that mostly have well-documented safety and efficacy track records in adults and widely agreed-on benefits that outweigh risks.
For pediatric practice, children and adolescents 3-17 years old, dealing with high blood pressure is much more an obstacle course of complex diagnostic criteria, challenges in pressure measurement, and seemingly inconsistent recommendations. Pediatric hypertension also often brings clinicians up against the child and adolescent obesity epidemic, which has made pediatric hypertension more common than ever.
Against this backdrop, a panel assembled by the American Academy of Pediatrics is revising the 2004 The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents, the reigning standard for pediatric blood pressure assessment and hypertension management and now more than a decade old. With new guidance from the AAP expected in the second half of 2017, best-practice approaches to pediatric hypertension are in flux and need updating just when the disorder is more prevalent than it’s ever been.
Diagnosing pediatric hypertension falls short
This shifting landscape and increasing burden of pediatric hypertension comes at a time when primary-care pediatricians and family practice physicians are failing to perform fully comprehensive blood pressure monitoring of their pediatric patients. Current practice recommendations from the National Heart Lung and Blood Institute (in the form of the 2004 Fourth Report), and from American Heart Association (most recently reiterated in a scientific statement in August 2016) call measuring blood pressure levels at every patient encounter starting at 3 years old, the approach also endorsed by the American Academy of Pediatrics.
But that’s often not done. “Results from plenty of studies show that we are not doing a great job” identifying children and adolescents with hypertension, said Tammy M. Brady, MD, a pediatric nephrologist at Johns Hopkins Medical Center in Baltimore.
One piece of evidence she cited was a study of more than 93,000 U.S. ambulatory pediatric visits during 2000-2009 in data collected by the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey, and sampling that represented an average 142 million ambulatory visits each year by 3-18 year olds. The data showed blood pressure screening occurred during 35% of ambulatory visits, 67% of preventive visits, and during 84% of preventive visits for a child or adolescent who was overweight or obese (Pediatrics. 2012 October;130[4]:604-10).
While the numbers showed good practice with a reasonably high level of routine blood pressure measurement in overweight and obese patients, they also suggest that perhaps a third of all U.S. children and adolescents don’t have their blood pressure checked at least once a year. Statistical analyses from this study showed that blood pressure measurement was about twice as likely in children diagnosed as overweight or obese than normal-weight patients, and that blood pressure measurement was 2.6-fold more common in adolescents 13-18 years old compared with children 3-7 years old.
In a second, recent study of 29,000 2-17 years old seen at Children’s Hospital of Chicago, 3% had at least three elevated blood pressure measurements in their hospital record, but in this subset of patients at high risk of having hypertension 21% were actually identified in their medical record as having high blood pressure.
Dr. Brady pointed out that while many of the children and adolescents in this study with three or more high blood pressure readings may not actually have hypertension, defined as a sustained elevation of blood pressure, they are all at risk for development of hypertension and should be targeted for prevention.
“We do a bad job identifying when blood pressure is high,” Dr. Brady said in an interview. She cited a study she recently ran that examined the impact that EMR alerts could have on this diagnostic challenge. She reviewed records for 1,305 patient encounters done before or after institution of a EMR alert that warmed clinicians when a patient’s blood pressure measurement fell above the normal range. The results showed that for these patients, 3-21 years old, the rate of recognition of a high pressure measurement increased from 13% before the alert system started to 42% with the alert system in place (Clin Ped. 2015 June;54[7]:667-75). “That meant more than half the patients with high blood pressure measurements were still going unrecognized”, even with an EMR alert, Dr. Brady said.
“The U.S. clinical community falls way short” of adequately following blood pressure levels in children and adolescents, agreed Julia Steinberger, MD, professor and director of pediatric cardiology at the University of Minnesota in Minneapolis. She chalks this up to several factors: time-pressured clinicians who may let blood pressure slide when other aspects of a visit require more attention and the index of suspicion for elevated blood pressure is low, insufficient education to the primary-care community on how to proceed once an elevated blood pressure reading is made, the difficulty of measuring blood pressure in young or uncooperative patients, and lack of size-appropriate equipment.
Once a single high pressure is recorded, ideal follow-up means measuring and finding elevated blood pressures again on at least two subsequent visits, followed by even more confirmation with home monitoring or 24-hour ambulatory blood pressure monitoring (ABPM), now considered the gold standard for both diagnosing and following pediatric patients with hypertension, especially if they receive antihypertensive medications. In 2014, a scientific statement from the American Heart Association said routine APBM was indicated to confirm the diagnosis of hypertension in a patient with high casual blood pressure measurements. Not many primary-care physicians have ready access to or experience using and interpreting ABPM.
Other reasons for low diagnostic rates include therapeutic inertia, and the sheer complexity and time of identifying what is a high blood pressure reading, at least until automated calculation of high levels by EMRs became possible. “With a paper analysis you need to look at two different charts” and factor in the patient’s sex, age, and height to determine if a pressure reading is high or not for a particular patient. “Diagnosis has been a problem, especially in busy practice,” noted Dr. Brady. “I think we are addressing that with the EMR and pop-up alerts.”
Streamlining the diagnostic process
“We have a complex way to diagnose hypertension in kids,” admitted Bonita Falkner, MD, who chaired the Fourth Report panel that produced the complicated diagnostic process still used today. “It’s complex and tedious to calculate. There have been a number of reports of missed hypertension because of the complexity of the tables,” said Dr. Falkner, professor and director of hypertension and obesity research at Thomas Jefferson University in Philadelphia. “Because it’s so burdensome to diagnose the detection rate of hypertension is not as accurate as it should be. Hopefully this will be improved with the new guidelines. We plan to make them simpler, easier to use and more streamlined,” she said in an interview.
“One of the challenges is how to make high blood pressure identification simpler and more straightforward. Without question there are children and adolescents with persistently high blood pressures who fall through the cracks,” said Stephen R. Daniels, MD, professor and chairman of pediatrics at the University of Colorado in Aurora. “Recognizing hypertension in adults is much simpler, with a single set of values. The AAP is in the process of developing new guidelines and one goal is to make blood pressure measurement and recognition of hypertension as simple as possible. There is a tension between simplicity and precision. Finding the right balance will be the trick.”
Dr. Falkner highlighted two other new aspects the revised pediatric hypertension recommendations will address. The panel appears to be on track to recalculate the reference blood pressure tables to eliminate the contribution of overweight and obese children and adolescents. Because high blood pressure is defined statistically--pressures at or above the 95th percentile for a child’s sex, age and height--inclusion of overweight and obese children and adolescents in the databases that produced the original tables skewed the 95th percentile thresholds higher than they would be for those who are at normal-weights. “It will make the reference numbers somewhat lower, but not dramatically lower,” Dr. Falkner said.
When the 2004 Fourth Report was written and the calculation tables created “it was early in the obesity epidemic and we were not as tuned into it as a problem” for hypertension,” said Dr. Daniels, also a member of the Fourth Report panel.
Another new aspect will likely be highlighting the role of overweight in addition to obesity as a hypertension risk factor. “In 2004, obesity was a concern but overweight was considered just a risk factor for obesity. Now if a child is overweight we know they are also at increased risk for having high blood pressure,” said Dr. Falkner. “We’ve been trying to get an update of the Fourth Report going for some time; a lot has happened since 2004.”
The Preventive Services Task Force effect
One notable recent development in the field of pediatric hypertension was the 2013 statement by the U.S. Preventive Services Task Force that reinforced a similar conclusion the group had reached a decade before, in 2003. In 2013, the USPSTF said that following a review of the evidence “the USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for primary hypertension in asymptomatic children and adolescents to prevent subsequent cardiovascular disease in childhood or adulthood. (I statement)” (Pediatrics. 2013 Nov;132[5]:907-14).
The USPSTF’s 2013 reassertion of this position triggered several strong reactions from pediatric hypertension specialists, who critiqued the Task Force’s analysis as being overly restrictive. Among those weighing with comments that highlighted the flaws in the Task Force’s reasoning were Dr. Falkner, Dr. Brady, and Dr. Steinberger. Earlier in 2013, before the Task Force statement, Dr. Daniels wrote a commentary with similar arguments in favor of routine blood pressure measurements in response to a published assessment of pediatric blood pressure screening that largely presaged what the USPSTF said.
In brief, the USPSTF analysis “was flawed by an overly-narrow selection of evidence,” Dr. Steinberger said recently. “Short-term and observational studies were not considered. We think that in the absence of perfect data the practitioner must use common sense when superior evidence does not exist. The question of whether hypertension in adults can be prevented or modified by early intervention will never be answered unless we continue to measure blood pressure in children.”
“One of the problems with the USPSTF statement was the questions they addressed: Is blood pressure in children and adolescents clearly associated with hard cardiovascular disease outcomes in adults? That is a very tough question to answer. It would need studies that are 30, 40 years in duration, and is almost unanswerable,” said Dr. Daniels in an interview. “I think the USPSTF paid less attention to the fact that clearly a certain percentage of children and adolescents with hypertension already have developed left ventricular hypertrophy, increased carotid intimal-medial thickness and vascular stiffness. This shows that higher blood pressure in the short term is having several adverse effects on the cardiovascular system. If you insist on seeing a connection between pediatric blood pressure and adult outcomes there will always be insufficient evidence.”
Although, as Dr. Steinberger pointed out, the International Childhood Cardiovascular Cohort Consortium has been putting together long-term follow-up data from seven observational cohorts established in several different world regions. Collectively these seven cohorts include more than 340,000 people who have now been followed for about 40 years. This analysis may soon yield more definitive insight into the long-term consequences of childhood hypertension, Dr. Steinberger said.
Another relevant issue is that prevention of adult cardiovascular disease “is not why children are screened for hypertension, or at least not the primary reason,” Dr. Falkner said. “They are screened to find high blood pressure with an underlying cause, like coarctation of the aorta, which is only picked up by first noting a high blood pressure. Several other cardiovascular and renal disorders that can exist in childhood can also cause high blood pressure and measuring blood pressure is the only way to find them. It would be a tragedy to miss coarctation of the aorta by not measuring blood pressure.”
The family practice position
Despite rejection of the USPSTF analysis by many pediatric hypertension specialists, the USPSTF position has been officially embraced by the family practice community. The American Academy of Family Practice has adopted the USPSTF position as its own, although family practice physicians are also quick to point out that the USPSTF conclusion does not say that pediatric blood pressures should not be measured.
“An I level from the USPSTF doesn’t mean that screening is harmful or shouldn’t be done, just that more research is needed to fully evaluate if blood pressure screening in childhood has long-term health impacts,” said Margaret A. Riley, MD, a family practice physician at the University of Michigan in Ann Arbor with an interest in pediatric hypertension.
“I think the I rating has had little impact on practice. Measuring blood pressure is a routine and standard part of office practice. If the USPSTF had given blood pressure screening a D rating, causing more harm than good, that would be different. In my practice I screen blood pressure at every visit or at least once a year,” Dr. Riley said in an interview.
That’s the same approach taken by Wanda D. Filer, MD, a family practice physician in York, Pa. and president of the American Academy of Family Physicians. “This does not mean you don’t screen blood pressure, and it doesn’t mean you should screen. It says that data are not there either way. In my office we check everyone age 3 and up, and I think a lot of family practice physicians do that routinely.
“Most of us screen blood pressure, but the AAFP approach is to always look at the evidence. The AAFP stand is not opposite to other organizations [that have endorsed routine blood pressure measurements]. They take a stronger position in favor of screening than we do, but we don’t say do not screen. Other societies have relied on less direct evidence or expert opinion. Our approach is to see proof of benefit,” Dr. Filer said in an interview.
“I imagine most family practice physicians measure blood pressure in children aged 3 or older,” she added. “I work in a Federally-qualified health center, and we have a very diverse population. We routinely measure blood pressures because the patients are so diverse. Other family practice practices may come to a different decision. You need to look at your practice and your work flow and decide whether it is an appropriate use of time.
“I do it because I’m convinced there is a possibility of benefit from screening,” Dr. Filer said. “I am also convinced that the evidence is not there [to prove benefits]. But I won’t wait for the evidence to do this in my practice. For the mix of patients I see it is important to screen blood pressures, but I am comfortable if a family practice physician with a different patient population says that high blood pressure yields are not there; they never see them.”
Overweight and obesity raise a red flag
If there is one subgroup of the pediatric population that most everyone agrees needs close attention to blood pressure it’s the overweight or obese child or teenager. “Primary hypertension in children and adolescents is largely associated with obesity,” said Dr. Falkner. Study findings also suggest that obese children and teens with hypertension are much more likely to have or develop left ventricular hypertrophy than normal-weight patients with elevated blood pressures.
The consequences are two fold: First, it suggests that even if the entire pediatric population fails to get their blood pressures checked regularly diligent attention to blood pressure is a must for overweight and obese children and adolescents, many experts agree. “A child who is overweight as well as obese requires attention to their blood pressure. That is emerging as a guideline,” Dr. Falkner said.
Second, a growing number of U.S. clinical programs are geared to addressing hypertension in the overweight or obese pediatric patient using an aggressive and multidisciplinary treatment approach.
For example, a clinic devoted to the overweight or obese child or teen with hypertension, the ReNEW (Reversing the Negative Cardiovascular Effects of Weight) program, opened at Johns Hopkins Medical Center in February 2015.
“We were seeing a lot of obesity-related hypertension without an underlying secondary cause. And in a study we ran the only thing that could predict left ventricular hypertrophy in children with hypertension was body mass index,” said Dr. Brady, medical director for ReNEW. “This motivated me to try to find a better way to treat obesity and hypertension; the only real treatment for hypertension in obese patients is to treat the obesity.”
During its first year, the ReNEW program enrolled 35 patients 5-22 years old. “We assess them for any secondary cause of hypertension,” Dr. Brady said. “We do an echocardiography examination and assess left ventricular hypertrophy and the need for blood pressure reducing medications. We do interventions for weight loss, diet, exercise, a musculoskeletal assessment, psychiatric assessment and other comorbidity interventions such as for sleep apnea. We start blood pressure reducing drugs when appropriate.”
The average body mass index among the first 35 patients was 38 kg/m2, with an average 31 kg/m2 in kids 5-10 years old and 43 kg/m2 in those 18-21 years old. Fifty percent had obstructive sleep apnea, 33% had anxiety or depression, and about 25%-33% had diabetes. “These kids are at a really great risk for a cardiac event in early adulthood. They are probably one of the most vulnerable populations we see,” she said.
A major lesson she’s learned from the ReNEW experience so far is the spectrum of comorbidities that can affect these patients and the importance of behavioral change for the entire family to produce favorable changes in the patient. “Depression and anxiety are big factors that can affect a family’s success with weight loss. Many kids also have underlying orthopedic issues. There remains a lot of confusion about diet. We try to offer families a one-stop shop, a multidisciplinary clinic that can thoroughly address the patient’s full range of cardiovascular-disease risk factors.
“I’ve been how shocked by how complex these patients are. When there is a significant overweight or obesity problem the only way to succeed is to involve the whole family. And don’t forget about the role of mental health. That is a significant part of overweight and obesity,” Many of the psychiatric disorders that overweight and obese children and teenagers show results from learned family behaviors, Dr. Brady said.
Another U.S. clinic specifically targeted at obese children and adolescents also sees many patients with hypertension at the University of Minnesota, a program begun in about 2010 that now has treated more than 1,000 patients including “hundreds” with comorbid hypertension, as well as similar numbers with comorbid hyperlipidemia and comorbid diabetes , said Dr. Steinberger.
“There are very few of these programs in the U.S.; it is not widely available. The cardiovascular health promotion effort should include this approach because for the primary care physician there is insufficient time or expertise to do these evaluations and treatments. You need a group of clinicians with the needed expertise,” she said. “Our multidisciplinary approach to treating comorbidities like hypertension, dyslipidemia and elevated glucose uses specialists for each of these areas as well as dieticians, social workers, and other specialists.
“In general, when the primary care physician does not have the resources to further evaluate and treat overweight or obesity they should be able to refer the patient to a program like this. It is never too soon to refer and treat. To treat overweight you need to involve the whole family. Most children do not ‘grow out’ of overweight or obesity. The overweight or obese child will generally grow up to be the overweight or obese adult,” Dr. Steinberger said.
Targeting the greatest hypertension risk
The growing trend to focus multidisciplinary resources on hypertension in the overweight or obese pediatric patient may exemplify part of a new era of targeted attention for pediatric blood pressure screening.
“We have a hard time measuring blood pressure in kids, we know the importance of obesity [in causing hypertension] and we also know that first-line management for most hypertensive patients is non-drug, lifestyle interventions. Therefore, is it possible that a greater good can be achieved by addressing lifestyle and all the health issues that would reduce the risk for hypertension, such as making sure all children engage in more movement and exercise and get off devices rather than medicalizing the problem” with frequent blood pressure measurement, wondered Howard Trachtman, MD, a pediatric nephrologist at New York University.
“Routinely screening blood pressure in every child and adolescent is very burdensome and carries the potential cost of inconvenience and mislabeling errors. Could clinicians focus on the children and adolescents who really are at risk of high blood pressure? Can we use the EMR and alerts to make sure that repeated measures of blood pressure are done only when needed, after we identify who is at greatest risk?
“We need to become more precise in defining who is it in the age range of 8-17 years old who needs to be regularly screened for high blood pressure so we can focus our resources on these people and better avoid mislabeling and causing anxiety” for the many children and adolescents who have a very low risk for having hypertension, said Dr. Trachtman. He said that he is currently collaborating on a study that is examining whether data contained in a patient’s EMR can help in improving blood pressure assessment.
“We need to keep an open mind about who might have hypertension, but there are good data that it tracks with waist circumference, hypertriglyceridemia, and insulin resistance. The more of these you have the greater your risk. This is the kind of productive research I’m talking about, to determine whether you can be more thoughtful in identifying who is at risk of high blood pressure and who needs more systematic screening. Targeting blood pressure screening to overweight or obese kids is a step toward trying to be more methodical. The USPSTF statement should be a spur to pediatric nephrologists to make our case for blood pressure screening more cogently and to collect better data so that when we speak about this it is not based on speculation or extrapolation but on data,” Dr. Trachtman said.
“There are no arguments against optimizing health and reducing risk factors in all children, but that is not an acceptable rationale for not measuring blood pressure and attending to elevated levels in children,” responded Dr. Falkner. Dr Trachtman’s proposal to reduce health risks in all children “is a public health issue whereas the issue of detecting and managing hypertension in childhood is a clinical issue” faced by physicians as they see individual patients, she said.
Many pediatric hypertension specialists may not warm to a screening proposition that retreats from the notion that every child and teen 3 years old and up should have their blood pressure checked at least annually. But many of those specialists also realize that what’s now done has a lot of problems and that a more user-friendly approach is needed. As an expert panel works to produce a revision to the Fourth Report next year (which will not be the Fifth Report as the update is now outside the NHLBI purview), changes in how pediatric hypertension will be approached in the future seem likely.
Dr. Brady, Dr. Steinberger, Dr. Falkner, Dr. Daniels, Dr. Riley, Dr. Filer, and Dr. Trachtman had no disclosures.
On Twitter @mitchelzoler
The clinical context of high blood pressure shifts abruptly when a person comes of age.
In adults 18 years old and up it’s fairly simple. Blood pressure above 140/90 mm Hg is generally a clear problem, less than 130/85 is probably okay for now, and in between is something to monitor. When pressure stays above 140/90 mm Hg despite lifestyle interventions it’s time to start treatment with any of several antihypertensive drug options that mostly have well-documented safety and efficacy track records in adults and widely agreed-on benefits that outweigh risks.
For pediatric practice, children and adolescents 3-17 years old, dealing with high blood pressure is much more an obstacle course of complex diagnostic criteria, challenges in pressure measurement, and seemingly inconsistent recommendations. Pediatric hypertension also often brings clinicians up against the child and adolescent obesity epidemic, which has made pediatric hypertension more common than ever.
Against this backdrop, a panel assembled by the American Academy of Pediatrics is revising the 2004 The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents, the reigning standard for pediatric blood pressure assessment and hypertension management and now more than a decade old. With new guidance from the AAP expected in the second half of 2017, best-practice approaches to pediatric hypertension are in flux and need updating just when the disorder is more prevalent than it’s ever been.
Diagnosing pediatric hypertension falls short
This shifting landscape and increasing burden of pediatric hypertension comes at a time when primary-care pediatricians and family practice physicians are failing to perform fully comprehensive blood pressure monitoring of their pediatric patients. Current practice recommendations from the National Heart Lung and Blood Institute (in the form of the 2004 Fourth Report), and from American Heart Association (most recently reiterated in a scientific statement in August 2016) call measuring blood pressure levels at every patient encounter starting at 3 years old, the approach also endorsed by the American Academy of Pediatrics.
But that’s often not done. “Results from plenty of studies show that we are not doing a great job” identifying children and adolescents with hypertension, said Tammy M. Brady, MD, a pediatric nephrologist at Johns Hopkins Medical Center in Baltimore.
One piece of evidence she cited was a study of more than 93,000 U.S. ambulatory pediatric visits during 2000-2009 in data collected by the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey, and sampling that represented an average 142 million ambulatory visits each year by 3-18 year olds. The data showed blood pressure screening occurred during 35% of ambulatory visits, 67% of preventive visits, and during 84% of preventive visits for a child or adolescent who was overweight or obese (Pediatrics. 2012 October;130[4]:604-10).
While the numbers showed good practice with a reasonably high level of routine blood pressure measurement in overweight and obese patients, they also suggest that perhaps a third of all U.S. children and adolescents don’t have their blood pressure checked at least once a year. Statistical analyses from this study showed that blood pressure measurement was about twice as likely in children diagnosed as overweight or obese than normal-weight patients, and that blood pressure measurement was 2.6-fold more common in adolescents 13-18 years old compared with children 3-7 years old.
In a second, recent study of 29,000 2-17 years old seen at Children’s Hospital of Chicago, 3% had at least three elevated blood pressure measurements in their hospital record, but in this subset of patients at high risk of having hypertension 21% were actually identified in their medical record as having high blood pressure.
Dr. Brady pointed out that while many of the children and adolescents in this study with three or more high blood pressure readings may not actually have hypertension, defined as a sustained elevation of blood pressure, they are all at risk for development of hypertension and should be targeted for prevention.
“We do a bad job identifying when blood pressure is high,” Dr. Brady said in an interview. She cited a study she recently ran that examined the impact that EMR alerts could have on this diagnostic challenge. She reviewed records for 1,305 patient encounters done before or after institution of a EMR alert that warmed clinicians when a patient’s blood pressure measurement fell above the normal range. The results showed that for these patients, 3-21 years old, the rate of recognition of a high pressure measurement increased from 13% before the alert system started to 42% with the alert system in place (Clin Ped. 2015 June;54[7]:667-75). “That meant more than half the patients with high blood pressure measurements were still going unrecognized”, even with an EMR alert, Dr. Brady said.
“The U.S. clinical community falls way short” of adequately following blood pressure levels in children and adolescents, agreed Julia Steinberger, MD, professor and director of pediatric cardiology at the University of Minnesota in Minneapolis. She chalks this up to several factors: time-pressured clinicians who may let blood pressure slide when other aspects of a visit require more attention and the index of suspicion for elevated blood pressure is low, insufficient education to the primary-care community on how to proceed once an elevated blood pressure reading is made, the difficulty of measuring blood pressure in young or uncooperative patients, and lack of size-appropriate equipment.
Once a single high pressure is recorded, ideal follow-up means measuring and finding elevated blood pressures again on at least two subsequent visits, followed by even more confirmation with home monitoring or 24-hour ambulatory blood pressure monitoring (ABPM), now considered the gold standard for both diagnosing and following pediatric patients with hypertension, especially if they receive antihypertensive medications. In 2014, a scientific statement from the American Heart Association said routine APBM was indicated to confirm the diagnosis of hypertension in a patient with high casual blood pressure measurements. Not many primary-care physicians have ready access to or experience using and interpreting ABPM.
Other reasons for low diagnostic rates include therapeutic inertia, and the sheer complexity and time of identifying what is a high blood pressure reading, at least until automated calculation of high levels by EMRs became possible. “With a paper analysis you need to look at two different charts” and factor in the patient’s sex, age, and height to determine if a pressure reading is high or not for a particular patient. “Diagnosis has been a problem, especially in busy practice,” noted Dr. Brady. “I think we are addressing that with the EMR and pop-up alerts.”
Streamlining the diagnostic process
“We have a complex way to diagnose hypertension in kids,” admitted Bonita Falkner, MD, who chaired the Fourth Report panel that produced the complicated diagnostic process still used today. “It’s complex and tedious to calculate. There have been a number of reports of missed hypertension because of the complexity of the tables,” said Dr. Falkner, professor and director of hypertension and obesity research at Thomas Jefferson University in Philadelphia. “Because it’s so burdensome to diagnose the detection rate of hypertension is not as accurate as it should be. Hopefully this will be improved with the new guidelines. We plan to make them simpler, easier to use and more streamlined,” she said in an interview.
“One of the challenges is how to make high blood pressure identification simpler and more straightforward. Without question there are children and adolescents with persistently high blood pressures who fall through the cracks,” said Stephen R. Daniels, MD, professor and chairman of pediatrics at the University of Colorado in Aurora. “Recognizing hypertension in adults is much simpler, with a single set of values. The AAP is in the process of developing new guidelines and one goal is to make blood pressure measurement and recognition of hypertension as simple as possible. There is a tension between simplicity and precision. Finding the right balance will be the trick.”
Dr. Falkner highlighted two other new aspects the revised pediatric hypertension recommendations will address. The panel appears to be on track to recalculate the reference blood pressure tables to eliminate the contribution of overweight and obese children and adolescents. Because high blood pressure is defined statistically--pressures at or above the 95th percentile for a child’s sex, age and height--inclusion of overweight and obese children and adolescents in the databases that produced the original tables skewed the 95th percentile thresholds higher than they would be for those who are at normal-weights. “It will make the reference numbers somewhat lower, but not dramatically lower,” Dr. Falkner said.
When the 2004 Fourth Report was written and the calculation tables created “it was early in the obesity epidemic and we were not as tuned into it as a problem” for hypertension,” said Dr. Daniels, also a member of the Fourth Report panel.
Another new aspect will likely be highlighting the role of overweight in addition to obesity as a hypertension risk factor. “In 2004, obesity was a concern but overweight was considered just a risk factor for obesity. Now if a child is overweight we know they are also at increased risk for having high blood pressure,” said Dr. Falkner. “We’ve been trying to get an update of the Fourth Report going for some time; a lot has happened since 2004.”
The Preventive Services Task Force effect
One notable recent development in the field of pediatric hypertension was the 2013 statement by the U.S. Preventive Services Task Force that reinforced a similar conclusion the group had reached a decade before, in 2003. In 2013, the USPSTF said that following a review of the evidence “the USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for primary hypertension in asymptomatic children and adolescents to prevent subsequent cardiovascular disease in childhood or adulthood. (I statement)” (Pediatrics. 2013 Nov;132[5]:907-14).
The USPSTF’s 2013 reassertion of this position triggered several strong reactions from pediatric hypertension specialists, who critiqued the Task Force’s analysis as being overly restrictive. Among those weighing with comments that highlighted the flaws in the Task Force’s reasoning were Dr. Falkner, Dr. Brady, and Dr. Steinberger. Earlier in 2013, before the Task Force statement, Dr. Daniels wrote a commentary with similar arguments in favor of routine blood pressure measurements in response to a published assessment of pediatric blood pressure screening that largely presaged what the USPSTF said.
In brief, the USPSTF analysis “was flawed by an overly-narrow selection of evidence,” Dr. Steinberger said recently. “Short-term and observational studies were not considered. We think that in the absence of perfect data the practitioner must use common sense when superior evidence does not exist. The question of whether hypertension in adults can be prevented or modified by early intervention will never be answered unless we continue to measure blood pressure in children.”
“One of the problems with the USPSTF statement was the questions they addressed: Is blood pressure in children and adolescents clearly associated with hard cardiovascular disease outcomes in adults? That is a very tough question to answer. It would need studies that are 30, 40 years in duration, and is almost unanswerable,” said Dr. Daniels in an interview. “I think the USPSTF paid less attention to the fact that clearly a certain percentage of children and adolescents with hypertension already have developed left ventricular hypertrophy, increased carotid intimal-medial thickness and vascular stiffness. This shows that higher blood pressure in the short term is having several adverse effects on the cardiovascular system. If you insist on seeing a connection between pediatric blood pressure and adult outcomes there will always be insufficient evidence.”
Although, as Dr. Steinberger pointed out, the International Childhood Cardiovascular Cohort Consortium has been putting together long-term follow-up data from seven observational cohorts established in several different world regions. Collectively these seven cohorts include more than 340,000 people who have now been followed for about 40 years. This analysis may soon yield more definitive insight into the long-term consequences of childhood hypertension, Dr. Steinberger said.
Another relevant issue is that prevention of adult cardiovascular disease “is not why children are screened for hypertension, or at least not the primary reason,” Dr. Falkner said. “They are screened to find high blood pressure with an underlying cause, like coarctation of the aorta, which is only picked up by first noting a high blood pressure. Several other cardiovascular and renal disorders that can exist in childhood can also cause high blood pressure and measuring blood pressure is the only way to find them. It would be a tragedy to miss coarctation of the aorta by not measuring blood pressure.”
The family practice position
Despite rejection of the USPSTF analysis by many pediatric hypertension specialists, the USPSTF position has been officially embraced by the family practice community. The American Academy of Family Practice has adopted the USPSTF position as its own, although family practice physicians are also quick to point out that the USPSTF conclusion does not say that pediatric blood pressures should not be measured.
“An I level from the USPSTF doesn’t mean that screening is harmful or shouldn’t be done, just that more research is needed to fully evaluate if blood pressure screening in childhood has long-term health impacts,” said Margaret A. Riley, MD, a family practice physician at the University of Michigan in Ann Arbor with an interest in pediatric hypertension.
“I think the I rating has had little impact on practice. Measuring blood pressure is a routine and standard part of office practice. If the USPSTF had given blood pressure screening a D rating, causing more harm than good, that would be different. In my practice I screen blood pressure at every visit or at least once a year,” Dr. Riley said in an interview.
That’s the same approach taken by Wanda D. Filer, MD, a family practice physician in York, Pa. and president of the American Academy of Family Physicians. “This does not mean you don’t screen blood pressure, and it doesn’t mean you should screen. It says that data are not there either way. In my office we check everyone age 3 and up, and I think a lot of family practice physicians do that routinely.
“Most of us screen blood pressure, but the AAFP approach is to always look at the evidence. The AAFP stand is not opposite to other organizations [that have endorsed routine blood pressure measurements]. They take a stronger position in favor of screening than we do, but we don’t say do not screen. Other societies have relied on less direct evidence or expert opinion. Our approach is to see proof of benefit,” Dr. Filer said in an interview.
“I imagine most family practice physicians measure blood pressure in children aged 3 or older,” she added. “I work in a Federally-qualified health center, and we have a very diverse population. We routinely measure blood pressures because the patients are so diverse. Other family practice practices may come to a different decision. You need to look at your practice and your work flow and decide whether it is an appropriate use of time.
“I do it because I’m convinced there is a possibility of benefit from screening,” Dr. Filer said. “I am also convinced that the evidence is not there [to prove benefits]. But I won’t wait for the evidence to do this in my practice. For the mix of patients I see it is important to screen blood pressures, but I am comfortable if a family practice physician with a different patient population says that high blood pressure yields are not there; they never see them.”
Overweight and obesity raise a red flag
If there is one subgroup of the pediatric population that most everyone agrees needs close attention to blood pressure it’s the overweight or obese child or teenager. “Primary hypertension in children and adolescents is largely associated with obesity,” said Dr. Falkner. Study findings also suggest that obese children and teens with hypertension are much more likely to have or develop left ventricular hypertrophy than normal-weight patients with elevated blood pressures.
The consequences are two fold: First, it suggests that even if the entire pediatric population fails to get their blood pressures checked regularly diligent attention to blood pressure is a must for overweight and obese children and adolescents, many experts agree. “A child who is overweight as well as obese requires attention to their blood pressure. That is emerging as a guideline,” Dr. Falkner said.
Second, a growing number of U.S. clinical programs are geared to addressing hypertension in the overweight or obese pediatric patient using an aggressive and multidisciplinary treatment approach.
For example, a clinic devoted to the overweight or obese child or teen with hypertension, the ReNEW (Reversing the Negative Cardiovascular Effects of Weight) program, opened at Johns Hopkins Medical Center in February 2015.
“We were seeing a lot of obesity-related hypertension without an underlying secondary cause. And in a study we ran the only thing that could predict left ventricular hypertrophy in children with hypertension was body mass index,” said Dr. Brady, medical director for ReNEW. “This motivated me to try to find a better way to treat obesity and hypertension; the only real treatment for hypertension in obese patients is to treat the obesity.”
During its first year, the ReNEW program enrolled 35 patients 5-22 years old. “We assess them for any secondary cause of hypertension,” Dr. Brady said. “We do an echocardiography examination and assess left ventricular hypertrophy and the need for blood pressure reducing medications. We do interventions for weight loss, diet, exercise, a musculoskeletal assessment, psychiatric assessment and other comorbidity interventions such as for sleep apnea. We start blood pressure reducing drugs when appropriate.”
The average body mass index among the first 35 patients was 38 kg/m2, with an average 31 kg/m2 in kids 5-10 years old and 43 kg/m2 in those 18-21 years old. Fifty percent had obstructive sleep apnea, 33% had anxiety or depression, and about 25%-33% had diabetes. “These kids are at a really great risk for a cardiac event in early adulthood. They are probably one of the most vulnerable populations we see,” she said.
A major lesson she’s learned from the ReNEW experience so far is the spectrum of comorbidities that can affect these patients and the importance of behavioral change for the entire family to produce favorable changes in the patient. “Depression and anxiety are big factors that can affect a family’s success with weight loss. Many kids also have underlying orthopedic issues. There remains a lot of confusion about diet. We try to offer families a one-stop shop, a multidisciplinary clinic that can thoroughly address the patient’s full range of cardiovascular-disease risk factors.
“I’ve been how shocked by how complex these patients are. When there is a significant overweight or obesity problem the only way to succeed is to involve the whole family. And don’t forget about the role of mental health. That is a significant part of overweight and obesity,” Many of the psychiatric disorders that overweight and obese children and teenagers show results from learned family behaviors, Dr. Brady said.
Another U.S. clinic specifically targeted at obese children and adolescents also sees many patients with hypertension at the University of Minnesota, a program begun in about 2010 that now has treated more than 1,000 patients including “hundreds” with comorbid hypertension, as well as similar numbers with comorbid hyperlipidemia and comorbid diabetes , said Dr. Steinberger.
“There are very few of these programs in the U.S.; it is not widely available. The cardiovascular health promotion effort should include this approach because for the primary care physician there is insufficient time or expertise to do these evaluations and treatments. You need a group of clinicians with the needed expertise,” she said. “Our multidisciplinary approach to treating comorbidities like hypertension, dyslipidemia and elevated glucose uses specialists for each of these areas as well as dieticians, social workers, and other specialists.
“In general, when the primary care physician does not have the resources to further evaluate and treat overweight or obesity they should be able to refer the patient to a program like this. It is never too soon to refer and treat. To treat overweight you need to involve the whole family. Most children do not ‘grow out’ of overweight or obesity. The overweight or obese child will generally grow up to be the overweight or obese adult,” Dr. Steinberger said.
Targeting the greatest hypertension risk
The growing trend to focus multidisciplinary resources on hypertension in the overweight or obese pediatric patient may exemplify part of a new era of targeted attention for pediatric blood pressure screening.
“We have a hard time measuring blood pressure in kids, we know the importance of obesity [in causing hypertension] and we also know that first-line management for most hypertensive patients is non-drug, lifestyle interventions. Therefore, is it possible that a greater good can be achieved by addressing lifestyle and all the health issues that would reduce the risk for hypertension, such as making sure all children engage in more movement and exercise and get off devices rather than medicalizing the problem” with frequent blood pressure measurement, wondered Howard Trachtman, MD, a pediatric nephrologist at New York University.
“Routinely screening blood pressure in every child and adolescent is very burdensome and carries the potential cost of inconvenience and mislabeling errors. Could clinicians focus on the children and adolescents who really are at risk of high blood pressure? Can we use the EMR and alerts to make sure that repeated measures of blood pressure are done only when needed, after we identify who is at greatest risk?
“We need to become more precise in defining who is it in the age range of 8-17 years old who needs to be regularly screened for high blood pressure so we can focus our resources on these people and better avoid mislabeling and causing anxiety” for the many children and adolescents who have a very low risk for having hypertension, said Dr. Trachtman. He said that he is currently collaborating on a study that is examining whether data contained in a patient’s EMR can help in improving blood pressure assessment.
“We need to keep an open mind about who might have hypertension, but there are good data that it tracks with waist circumference, hypertriglyceridemia, and insulin resistance. The more of these you have the greater your risk. This is the kind of productive research I’m talking about, to determine whether you can be more thoughtful in identifying who is at risk of high blood pressure and who needs more systematic screening. Targeting blood pressure screening to overweight or obese kids is a step toward trying to be more methodical. The USPSTF statement should be a spur to pediatric nephrologists to make our case for blood pressure screening more cogently and to collect better data so that when we speak about this it is not based on speculation or extrapolation but on data,” Dr. Trachtman said.
“There are no arguments against optimizing health and reducing risk factors in all children, but that is not an acceptable rationale for not measuring blood pressure and attending to elevated levels in children,” responded Dr. Falkner. Dr Trachtman’s proposal to reduce health risks in all children “is a public health issue whereas the issue of detecting and managing hypertension in childhood is a clinical issue” faced by physicians as they see individual patients, she said.
Many pediatric hypertension specialists may not warm to a screening proposition that retreats from the notion that every child and teen 3 years old and up should have their blood pressure checked at least annually. But many of those specialists also realize that what’s now done has a lot of problems and that a more user-friendly approach is needed. As an expert panel works to produce a revision to the Fourth Report next year (which will not be the Fifth Report as the update is now outside the NHLBI purview), changes in how pediatric hypertension will be approached in the future seem likely.
Dr. Brady, Dr. Steinberger, Dr. Falkner, Dr. Daniels, Dr. Riley, Dr. Filer, and Dr. Trachtman had no disclosures.
On Twitter @mitchelzoler
VIDEO: ICDs cut mortality in younger, healthier heart failure patients
ROME – Implantable cardioverter-defibrillators failed to significantly cut total mortality in patients with nonischemic systolic heart failure in the first large, randomized trial designed specifically to test the treatment in this setting. But the devices did show significant efficacy for doing what thy are specifically designed to do: prevent sudden cardiac death.
Results from the Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) also highlighted the importance of targeting implantable cardioverter-defibrillator (ICD) treatment to the patients with nonischemic systolic heart failure who are most likely to benefit from it, younger patients who can be expected to live substantially longer than 1 year after they receive the device.
As a consequence, although the DANISH outcome was neutral for the study’s primary endpoint of decreased all-cause mortality several experts who commented on the findings as well as its lead investigator saw the overall results as providing important new evidence that ICDs are beneficial as long as they get placed in relative young nonischemic heart failure patients who don’t have comorbidities that threaten a quick demise.
The DANISH results “tell us ICDs can benefit patients if we can be a little better in selecting the right patients,” said Lars Køber, MD, while presenting the results at the annual congress of the European Society of Cardiology.
He noted that “for us [in Denmark] the results actually mean we’ll implant more ICDs. We had not been using ICDs [in patients with nonischemic systolic heart failure] because we were not convinced we should use them on everyone,” said Dr. Køber, a professor of cardiology at the University of Copenhagen.
“The primary outcome was neutral, but the reduction in sudden cardiac death, the primary objective of an ICD, was significant, so placing an ICD should be taken into consideration,” commented Michel Komajda, MD, professor of cardiology at Pierre and Marie Curie University in Paris.
“This is the first trial to look at ICDs in the setting of modern therapy. Most of the ICD trials are very old now,” commented Mariell L. Jessup, MD, a heart failure specialist and professor of medicine at the University of Pennsylvania in Philadelphia. “In DANISH the ICDs significantly reduced the incidence of sudden cardiac death; that is what ICDs do.”
DANISH randomized 1,116 patients with nonischemic systolic heart failure at any of five Danish hospitals to either receive or not receive an ICD on top of optimal medical therapy and, when judged appropriate, placement of a cardiac resynchronization therapy (CRT) device. The patients averaged about 64 years of age, they all had New York Heart Association class II or III heart failure, and their maximum left ventricular ejection fraction was 35%. The researchers followed patients for a median of about 68 months (5.7 years).
The study’s primary endpoint, death from any cause, occurred in 22% of the ICD recipients and in 23% of control patients, a nonsignificant difference. The two prespecified secondary endpoints were cardiovascular death, which was a relative 23% lower in the ICD patients and also not statistically significant, but the rate of sudden cardiac death during follow-up was 4% in the ICD patients and 8% in the controls, a statistically significant 50% relative risk reduction. Concurrent with Dr. Køber’s report of these results at the meeting they also appeared online (N Engl J Med. 2016 Aug 28;doi: 10.1056/NEJMoa1608029).
The study design also included a set of prespecified subset analyses, and one of these showed a statistically significant interaction: When the analysis stratified patients into tertiles by age, those younger than 59 years old had a statistically significant 49% cut in all-cause mortality with ICD use, and patients 59-67 years old had a nonsignificant 25% reduction in all cause mortality when on ICD treatment. A second analysis that included all these patients less than 68 years old showed that ICD use linked with a statistically significant 36% relative cut in all-cause death, compared with the patients who did not receive an ICD. Older patients, those at least age 68 years, had a relative 20% increased rate of all-cause mortality with ICD use but not a statistically significant difference.
The results also showed a downside to ICD use. Among the 42% of patients who did not receive a CRT device, the rate of serious infection was 2.6% in the ICD recipients and 0.8% in the control. Serious infection rates with and without ICD placement were similar in the subgroup of patients who received a CRT device.
The results underscored the ability of ICDs to provide a substantial benefit to well-selected patients based on factors such as age. “Clearly we need more accurate selection of nonischemic systolic heart failure patients before implanting ICDs,” said Christophe Leclerqc, MD, designated discussant for the study and professor of cardiology at Central University Hospital of Rennes, France.
“It’s all about patient selection,” agreed Dr. Jessup, who added that currently many nonischemic heart failure patients worldwide who could benefit from an ICD and have a life expectancy beyond 1 year do not receive a device.
On Twitter @mitchelzoler
The message from this study is that in younger, nonischemic heart failure patients at risk for sudden cardiac death but with relatively less morbidity and more life expectancy, the placement of an implantable cardioverter-defibrillator produced a substantial reduction in all-cause mortality.
Although the all-cause mortality benefit was not statistically significant in the entire study population, the study results were very consistent with what we know about sudden cardiac death and why we give ICD therapy to heart failure patients. In DANISH the ICDs did what they are supposed to do, which is prevent sudden cardiac death.
The guidelines say that ICD treatment is appropriate when a patient’s life expectancy is “substantially” more than 1 year. They don’t specify an age cutoff because some 80-year-olds can have a good life expectancy while some younger patients may have comorbidities that make them unlikely to live more than 6 months. ICDs should be targeted to patients at high enough risk from sudden cardiac death to potentially get benefit from the device but not so high-risk that an ICD would be unlikely to make a difference in survival.
Many heart failure patients who could potentially get a benefit from an ICD still do not receive them. ICDs remain an underused treatment for heart failure patients in U.S. practice including patients with nonischemic systolic heart failure.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Javed Butler, MD, is a professor of medicine and chief of cardiology at Stony Brook (N.Y.) University. He made these comments in an interview. He has been a consultant to several drug and therapeutics companies but had no relevant disclosures.
The message from this study is that in younger, nonischemic heart failure patients at risk for sudden cardiac death but with relatively less morbidity and more life expectancy, the placement of an implantable cardioverter-defibrillator produced a substantial reduction in all-cause mortality.
Although the all-cause mortality benefit was not statistically significant in the entire study population, the study results were very consistent with what we know about sudden cardiac death and why we give ICD therapy to heart failure patients. In DANISH the ICDs did what they are supposed to do, which is prevent sudden cardiac death.
The guidelines say that ICD treatment is appropriate when a patient’s life expectancy is “substantially” more than 1 year. They don’t specify an age cutoff because some 80-year-olds can have a good life expectancy while some younger patients may have comorbidities that make them unlikely to live more than 6 months. ICDs should be targeted to patients at high enough risk from sudden cardiac death to potentially get benefit from the device but not so high-risk that an ICD would be unlikely to make a difference in survival.
Many heart failure patients who could potentially get a benefit from an ICD still do not receive them. ICDs remain an underused treatment for heart failure patients in U.S. practice including patients with nonischemic systolic heart failure.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Javed Butler, MD, is a professor of medicine and chief of cardiology at Stony Brook (N.Y.) University. He made these comments in an interview. He has been a consultant to several drug and therapeutics companies but had no relevant disclosures.
The message from this study is that in younger, nonischemic heart failure patients at risk for sudden cardiac death but with relatively less morbidity and more life expectancy, the placement of an implantable cardioverter-defibrillator produced a substantial reduction in all-cause mortality.
Although the all-cause mortality benefit was not statistically significant in the entire study population, the study results were very consistent with what we know about sudden cardiac death and why we give ICD therapy to heart failure patients. In DANISH the ICDs did what they are supposed to do, which is prevent sudden cardiac death.
The guidelines say that ICD treatment is appropriate when a patient’s life expectancy is “substantially” more than 1 year. They don’t specify an age cutoff because some 80-year-olds can have a good life expectancy while some younger patients may have comorbidities that make them unlikely to live more than 6 months. ICDs should be targeted to patients at high enough risk from sudden cardiac death to potentially get benefit from the device but not so high-risk that an ICD would be unlikely to make a difference in survival.
Many heart failure patients who could potentially get a benefit from an ICD still do not receive them. ICDs remain an underused treatment for heart failure patients in U.S. practice including patients with nonischemic systolic heart failure.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Javed Butler, MD, is a professor of medicine and chief of cardiology at Stony Brook (N.Y.) University. He made these comments in an interview. He has been a consultant to several drug and therapeutics companies but had no relevant disclosures.
ROME – Implantable cardioverter-defibrillators failed to significantly cut total mortality in patients with nonischemic systolic heart failure in the first large, randomized trial designed specifically to test the treatment in this setting. But the devices did show significant efficacy for doing what thy are specifically designed to do: prevent sudden cardiac death.
Results from the Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) also highlighted the importance of targeting implantable cardioverter-defibrillator (ICD) treatment to the patients with nonischemic systolic heart failure who are most likely to benefit from it, younger patients who can be expected to live substantially longer than 1 year after they receive the device.
As a consequence, although the DANISH outcome was neutral for the study’s primary endpoint of decreased all-cause mortality several experts who commented on the findings as well as its lead investigator saw the overall results as providing important new evidence that ICDs are beneficial as long as they get placed in relative young nonischemic heart failure patients who don’t have comorbidities that threaten a quick demise.
The DANISH results “tell us ICDs can benefit patients if we can be a little better in selecting the right patients,” said Lars Køber, MD, while presenting the results at the annual congress of the European Society of Cardiology.
He noted that “for us [in Denmark] the results actually mean we’ll implant more ICDs. We had not been using ICDs [in patients with nonischemic systolic heart failure] because we were not convinced we should use them on everyone,” said Dr. Køber, a professor of cardiology at the University of Copenhagen.
“The primary outcome was neutral, but the reduction in sudden cardiac death, the primary objective of an ICD, was significant, so placing an ICD should be taken into consideration,” commented Michel Komajda, MD, professor of cardiology at Pierre and Marie Curie University in Paris.
“This is the first trial to look at ICDs in the setting of modern therapy. Most of the ICD trials are very old now,” commented Mariell L. Jessup, MD, a heart failure specialist and professor of medicine at the University of Pennsylvania in Philadelphia. “In DANISH the ICDs significantly reduced the incidence of sudden cardiac death; that is what ICDs do.”
DANISH randomized 1,116 patients with nonischemic systolic heart failure at any of five Danish hospitals to either receive or not receive an ICD on top of optimal medical therapy and, when judged appropriate, placement of a cardiac resynchronization therapy (CRT) device. The patients averaged about 64 years of age, they all had New York Heart Association class II or III heart failure, and their maximum left ventricular ejection fraction was 35%. The researchers followed patients for a median of about 68 months (5.7 years).
The study’s primary endpoint, death from any cause, occurred in 22% of the ICD recipients and in 23% of control patients, a nonsignificant difference. The two prespecified secondary endpoints were cardiovascular death, which was a relative 23% lower in the ICD patients and also not statistically significant, but the rate of sudden cardiac death during follow-up was 4% in the ICD patients and 8% in the controls, a statistically significant 50% relative risk reduction. Concurrent with Dr. Køber’s report of these results at the meeting they also appeared online (N Engl J Med. 2016 Aug 28;doi: 10.1056/NEJMoa1608029).
The study design also included a set of prespecified subset analyses, and one of these showed a statistically significant interaction: When the analysis stratified patients into tertiles by age, those younger than 59 years old had a statistically significant 49% cut in all-cause mortality with ICD use, and patients 59-67 years old had a nonsignificant 25% reduction in all cause mortality when on ICD treatment. A second analysis that included all these patients less than 68 years old showed that ICD use linked with a statistically significant 36% relative cut in all-cause death, compared with the patients who did not receive an ICD. Older patients, those at least age 68 years, had a relative 20% increased rate of all-cause mortality with ICD use but not a statistically significant difference.
The results also showed a downside to ICD use. Among the 42% of patients who did not receive a CRT device, the rate of serious infection was 2.6% in the ICD recipients and 0.8% in the control. Serious infection rates with and without ICD placement were similar in the subgroup of patients who received a CRT device.
The results underscored the ability of ICDs to provide a substantial benefit to well-selected patients based on factors such as age. “Clearly we need more accurate selection of nonischemic systolic heart failure patients before implanting ICDs,” said Christophe Leclerqc, MD, designated discussant for the study and professor of cardiology at Central University Hospital of Rennes, France.
“It’s all about patient selection,” agreed Dr. Jessup, who added that currently many nonischemic heart failure patients worldwide who could benefit from an ICD and have a life expectancy beyond 1 year do not receive a device.
On Twitter @mitchelzoler
ROME – Implantable cardioverter-defibrillators failed to significantly cut total mortality in patients with nonischemic systolic heart failure in the first large, randomized trial designed specifically to test the treatment in this setting. But the devices did show significant efficacy for doing what thy are specifically designed to do: prevent sudden cardiac death.
Results from the Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) also highlighted the importance of targeting implantable cardioverter-defibrillator (ICD) treatment to the patients with nonischemic systolic heart failure who are most likely to benefit from it, younger patients who can be expected to live substantially longer than 1 year after they receive the device.
As a consequence, although the DANISH outcome was neutral for the study’s primary endpoint of decreased all-cause mortality several experts who commented on the findings as well as its lead investigator saw the overall results as providing important new evidence that ICDs are beneficial as long as they get placed in relative young nonischemic heart failure patients who don’t have comorbidities that threaten a quick demise.
The DANISH results “tell us ICDs can benefit patients if we can be a little better in selecting the right patients,” said Lars Køber, MD, while presenting the results at the annual congress of the European Society of Cardiology.
He noted that “for us [in Denmark] the results actually mean we’ll implant more ICDs. We had not been using ICDs [in patients with nonischemic systolic heart failure] because we were not convinced we should use them on everyone,” said Dr. Køber, a professor of cardiology at the University of Copenhagen.
“The primary outcome was neutral, but the reduction in sudden cardiac death, the primary objective of an ICD, was significant, so placing an ICD should be taken into consideration,” commented Michel Komajda, MD, professor of cardiology at Pierre and Marie Curie University in Paris.
“This is the first trial to look at ICDs in the setting of modern therapy. Most of the ICD trials are very old now,” commented Mariell L. Jessup, MD, a heart failure specialist and professor of medicine at the University of Pennsylvania in Philadelphia. “In DANISH the ICDs significantly reduced the incidence of sudden cardiac death; that is what ICDs do.”
DANISH randomized 1,116 patients with nonischemic systolic heart failure at any of five Danish hospitals to either receive or not receive an ICD on top of optimal medical therapy and, when judged appropriate, placement of a cardiac resynchronization therapy (CRT) device. The patients averaged about 64 years of age, they all had New York Heart Association class II or III heart failure, and their maximum left ventricular ejection fraction was 35%. The researchers followed patients for a median of about 68 months (5.7 years).
The study’s primary endpoint, death from any cause, occurred in 22% of the ICD recipients and in 23% of control patients, a nonsignificant difference. The two prespecified secondary endpoints were cardiovascular death, which was a relative 23% lower in the ICD patients and also not statistically significant, but the rate of sudden cardiac death during follow-up was 4% in the ICD patients and 8% in the controls, a statistically significant 50% relative risk reduction. Concurrent with Dr. Køber’s report of these results at the meeting they also appeared online (N Engl J Med. 2016 Aug 28;doi: 10.1056/NEJMoa1608029).
The study design also included a set of prespecified subset analyses, and one of these showed a statistically significant interaction: When the analysis stratified patients into tertiles by age, those younger than 59 years old had a statistically significant 49% cut in all-cause mortality with ICD use, and patients 59-67 years old had a nonsignificant 25% reduction in all cause mortality when on ICD treatment. A second analysis that included all these patients less than 68 years old showed that ICD use linked with a statistically significant 36% relative cut in all-cause death, compared with the patients who did not receive an ICD. Older patients, those at least age 68 years, had a relative 20% increased rate of all-cause mortality with ICD use but not a statistically significant difference.
The results also showed a downside to ICD use. Among the 42% of patients who did not receive a CRT device, the rate of serious infection was 2.6% in the ICD recipients and 0.8% in the control. Serious infection rates with and without ICD placement were similar in the subgroup of patients who received a CRT device.
The results underscored the ability of ICDs to provide a substantial benefit to well-selected patients based on factors such as age. “Clearly we need more accurate selection of nonischemic systolic heart failure patients before implanting ICDs,” said Christophe Leclerqc, MD, designated discussant for the study and professor of cardiology at Central University Hospital of Rennes, France.
“It’s all about patient selection,” agreed Dr. Jessup, who added that currently many nonischemic heart failure patients worldwide who could benefit from an ICD and have a life expectancy beyond 1 year do not receive a device.
On Twitter @mitchelzoler
AT THE ESC CONGRESS 2016
Key clinical point: Implantable cardioverter-defibrillators significantly cut the rate of sudden cardiac death in patients with nonishemic systolic heart failure, and reduced all-cause mortality in patients younger than 68 years.
Major finding: Sudden cardiac death was halved in patients who received an ICD compared with control patients.
Data source: DANISH, a multicenter, randomized trial in 1,116 patients with nonischemic systolic heart failure.
Disclosures: DANISH received partial funding from Medtronic and St. Jude, companies that market ICDs. Dr. Køber, Dr. Komajda, and Dr. Jessup had no relevant disclosures. Dr. Leclercq has been a consultant to or spoken on behalf of Biotronik, Boston Scientific, Medtronic, St. Jude, Livanova and several drug companies.
VIDEO: NOACs cut intracranial bleeds in real-world atrial fib patients
ROME – The new oral anticoagulants performed as advertised in a real-world, Danish registry of more than 40,000 patients with atrial fibrillation.
During the first year on anticoagulant treatment, patients who received a new oral anticoagulant (NOAC) had an ischemic stroke rate similar to that of patients who received the traditional oral anticoagulant, warfarin, but a significantly reduced rate of intracranial hemorrhage, Laila Stærk, MD, reported at the annual congress of the European Society of Cardiology.
These results “reinforce what we have seen in the clinical trials, but with the strength of looking in the entire Danish population,” said Dan Atar, MD, a cardiologist and professor of medicine at the University of Oslo.
“It is enlightening and very reassuring to have these real-world, unselected, registry data. They provide reassurance about safety and efficacy” when prescribing a NOAC, Dr. Atar said in an interview.
The study reported by Dr. Stærk and her associates included 43,299 Danish patients who were recently diagnosed with nonvalvular atrial fibrillation and started on treatment with an oral anticoagulant during the period August 2011 (when the first NOAC, dabigatran, became available for routine use in Denmark) through December 2015. During this period, 42% of these patients received warfarin, 29% received dabigatran (Pradaxa), 16% received apixaban (Eliquis) and 13% received rivaroxaban (Xarelto).
In a propensity-score type of analysis that controlled for baseline differences in clinical and demographic parameters, the results showed that the rate of ischemic stroke during the first year on treatment ranged from 2.0% to 2.5% in the four subgroups based on the anticoagulant received with no statistically-significant differences among the four subgroups. In other words, all three NOACs had efficacy profiles similar to those of warfarin, said Dr. Stærk, a cardiology researcher at Herlev and Gentofte University Hospitals in Hellerup, Denmark.
But on the safety side, all three NOACs were linked with lower rates of intracranial hemorrhages during the 1-year follow-up compared with the patients who received warfarin. In the cases of dabigatran and apixaban, the reduced intracranial hemorrhage rates were statistically significant, with a 0.6% rate among the patients on warfarin and rates that were reduced by a relative 34% for patients who received dabigatran and by a relative 20% among those on apixaban. Rivaroxaban linked with a 13% relative risk reduction in intracranial hemorrhage that was not statistically significant.
Dr. Atar said he would not make comparisons among the three NOACs based on these data, but rather interpreted the finding as showing that collectively the three NOACs assessed had comparable efficacy but better safety compared with warfarin.
He also noted that the Danish registry data document the transition that occurred during 2011 to 2015 in anticoagulant prescribing that shifted from warfarin to NOACs, with 57% of atrial fibrillation patients receiving a NOAC. In Norway, NOAC prescriptions for atrial fibrillation patients recently pulled ahead of warfarin prescription rates, Dr. Atar said. Reassuring data such as those in this report will help to further drive the shift from warfarin to NOACs, and he predicted that soon NOACs will be the anticoagulants used to treat the overwhelming majority of patients with nonvalvular atrial fibrillation.
Dr. Stærk has received research funding from Boehringer Ingelheim, the company that markets dabigatran (Pradaxa). Dr. Atar said that he has been a consultant to and has received research funding from several drug companies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @mitchelzoler
ROME – The new oral anticoagulants performed as advertised in a real-world, Danish registry of more than 40,000 patients with atrial fibrillation.
During the first year on anticoagulant treatment, patients who received a new oral anticoagulant (NOAC) had an ischemic stroke rate similar to that of patients who received the traditional oral anticoagulant, warfarin, but a significantly reduced rate of intracranial hemorrhage, Laila Stærk, MD, reported at the annual congress of the European Society of Cardiology.
These results “reinforce what we have seen in the clinical trials, but with the strength of looking in the entire Danish population,” said Dan Atar, MD, a cardiologist and professor of medicine at the University of Oslo.
“It is enlightening and very reassuring to have these real-world, unselected, registry data. They provide reassurance about safety and efficacy” when prescribing a NOAC, Dr. Atar said in an interview.
The study reported by Dr. Stærk and her associates included 43,299 Danish patients who were recently diagnosed with nonvalvular atrial fibrillation and started on treatment with an oral anticoagulant during the period August 2011 (when the first NOAC, dabigatran, became available for routine use in Denmark) through December 2015. During this period, 42% of these patients received warfarin, 29% received dabigatran (Pradaxa), 16% received apixaban (Eliquis) and 13% received rivaroxaban (Xarelto).
In a propensity-score type of analysis that controlled for baseline differences in clinical and demographic parameters, the results showed that the rate of ischemic stroke during the first year on treatment ranged from 2.0% to 2.5% in the four subgroups based on the anticoagulant received with no statistically-significant differences among the four subgroups. In other words, all three NOACs had efficacy profiles similar to those of warfarin, said Dr. Stærk, a cardiology researcher at Herlev and Gentofte University Hospitals in Hellerup, Denmark.
But on the safety side, all three NOACs were linked with lower rates of intracranial hemorrhages during the 1-year follow-up compared with the patients who received warfarin. In the cases of dabigatran and apixaban, the reduced intracranial hemorrhage rates were statistically significant, with a 0.6% rate among the patients on warfarin and rates that were reduced by a relative 34% for patients who received dabigatran and by a relative 20% among those on apixaban. Rivaroxaban linked with a 13% relative risk reduction in intracranial hemorrhage that was not statistically significant.
Dr. Atar said he would not make comparisons among the three NOACs based on these data, but rather interpreted the finding as showing that collectively the three NOACs assessed had comparable efficacy but better safety compared with warfarin.
He also noted that the Danish registry data document the transition that occurred during 2011 to 2015 in anticoagulant prescribing that shifted from warfarin to NOACs, with 57% of atrial fibrillation patients receiving a NOAC. In Norway, NOAC prescriptions for atrial fibrillation patients recently pulled ahead of warfarin prescription rates, Dr. Atar said. Reassuring data such as those in this report will help to further drive the shift from warfarin to NOACs, and he predicted that soon NOACs will be the anticoagulants used to treat the overwhelming majority of patients with nonvalvular atrial fibrillation.
Dr. Stærk has received research funding from Boehringer Ingelheim, the company that markets dabigatran (Pradaxa). Dr. Atar said that he has been a consultant to and has received research funding from several drug companies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @mitchelzoler
ROME – The new oral anticoagulants performed as advertised in a real-world, Danish registry of more than 40,000 patients with atrial fibrillation.
During the first year on anticoagulant treatment, patients who received a new oral anticoagulant (NOAC) had an ischemic stroke rate similar to that of patients who received the traditional oral anticoagulant, warfarin, but a significantly reduced rate of intracranial hemorrhage, Laila Stærk, MD, reported at the annual congress of the European Society of Cardiology.
These results “reinforce what we have seen in the clinical trials, but with the strength of looking in the entire Danish population,” said Dan Atar, MD, a cardiologist and professor of medicine at the University of Oslo.
“It is enlightening and very reassuring to have these real-world, unselected, registry data. They provide reassurance about safety and efficacy” when prescribing a NOAC, Dr. Atar said in an interview.
The study reported by Dr. Stærk and her associates included 43,299 Danish patients who were recently diagnosed with nonvalvular atrial fibrillation and started on treatment with an oral anticoagulant during the period August 2011 (when the first NOAC, dabigatran, became available for routine use in Denmark) through December 2015. During this period, 42% of these patients received warfarin, 29% received dabigatran (Pradaxa), 16% received apixaban (Eliquis) and 13% received rivaroxaban (Xarelto).
In a propensity-score type of analysis that controlled for baseline differences in clinical and demographic parameters, the results showed that the rate of ischemic stroke during the first year on treatment ranged from 2.0% to 2.5% in the four subgroups based on the anticoagulant received with no statistically-significant differences among the four subgroups. In other words, all three NOACs had efficacy profiles similar to those of warfarin, said Dr. Stærk, a cardiology researcher at Herlev and Gentofte University Hospitals in Hellerup, Denmark.
But on the safety side, all three NOACs were linked with lower rates of intracranial hemorrhages during the 1-year follow-up compared with the patients who received warfarin. In the cases of dabigatran and apixaban, the reduced intracranial hemorrhage rates were statistically significant, with a 0.6% rate among the patients on warfarin and rates that were reduced by a relative 34% for patients who received dabigatran and by a relative 20% among those on apixaban. Rivaroxaban linked with a 13% relative risk reduction in intracranial hemorrhage that was not statistically significant.
Dr. Atar said he would not make comparisons among the three NOACs based on these data, but rather interpreted the finding as showing that collectively the three NOACs assessed had comparable efficacy but better safety compared with warfarin.
He also noted that the Danish registry data document the transition that occurred during 2011 to 2015 in anticoagulant prescribing that shifted from warfarin to NOACs, with 57% of atrial fibrillation patients receiving a NOAC. In Norway, NOAC prescriptions for atrial fibrillation patients recently pulled ahead of warfarin prescription rates, Dr. Atar said. Reassuring data such as those in this report will help to further drive the shift from warfarin to NOACs, and he predicted that soon NOACs will be the anticoagulants used to treat the overwhelming majority of patients with nonvalvular atrial fibrillation.
Dr. Stærk has received research funding from Boehringer Ingelheim, the company that markets dabigatran (Pradaxa). Dr. Atar said that he has been a consultant to and has received research funding from several drug companies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @mitchelzoler
AT THE ESC CONGRESS 2016
Inadequate diversity snags hypertrophic cardiomyopathy genetic linkages
The genetic tests used for more than a decade to identify patients or family members who carry genetic mutations linked to hypertrophic cardiomyopathy are seriously flawed.
The tests have been erroneously flagging people as genetically positive for hypertrophic cardiomyopathy (HC) when they actually carried benign genetic variants, according to a new reassessment of the genetic linkages by researchers using a more genetically diverse database. Five genetic variants now reclassified as benign were collectively responsible for flagging 74% of people flagged at genetic risk for HC in the more than 8,500 cases examined.
The results call into question any genetic diagnosis of HC made since genetic testing entered the mainstream in 2003, especially among African Americans who seem to have been disproportionately affected by these mislabeled genetic markers because of inadequate population diversity when the markers were first established.
In addition, the results more broadly cast a shadow over the full spectrum of genetic tests for disease-linked variants now in routine medical practice because of the possibility that other linkage determinations derived from an inadequately-representative reference population, reported Arjun K. Manrai, PhD, and his associates (N Engl J Med. 2016 Aug 18;375[7]:655-65). The researchers call the HC experience they document a “cautionary tale of broad relevance to genetic diagnosis.”
The findings “powerfully illustrate the importance of racial and genetic diversity” when running linkage studies aimed at validating genetic markers for widespread clinical use, Isaac S. Kohane, MD, senior author of the study, said in a written statement. “Racial and ethnic inclusiveness improves the validity and accuracy” of genetic tests, said Dr. Kohane, professor of biomedical informatics and pediatrics at Harvard Medical School in Boston.
“We believe that what we’re seeing in the case of hypertrophic cardiomyopathy may be the tip of the iceberg of a larger problem that transcends a single genetic disease,” Dr. Manrai, a biomedical informatics researcher at Harvard, said in the same statement. “Much genetic assessment today relies on historical links between a disorder and variant, sometimes decades old. We believe our findings illustrate the critical need to systematically reevaluate prior assertions about genetic variants,” Dr. Manrai added in an interview.
The two researchers and their associates reexamined the link between genetic variants and HC in three genetic databases that involved a total of more than 8,500 people. One database included 4,300 white Americans and 2,203 black Americans. A second database included genetic data from 1,092 people from 14 worldwide populations, and the third had genetic data from 938 people from 51 worldwide populations.
The analysis showed that although 94 distinct genetic variants that had previously been reported as associated with HC were confirmed as linked, just 5 met the study’s definition of a “high-frequency” variant with an allele frequent of more than 1%. These five variants together accounted for 74% of the overall total of linkages seen in these 8,533 people. Further analysis classified all five of these high-frequency genetic variants as benign with no discernible link to HC.
These five high-frequency variants occurred disproportionately higher among black Americans, and the consequences of this showed up in the patient records the researchers reviewed from one large U.S. genetic testing laboratory. They examined in detail HC genetic test results during 2004-2013 from 2,912 unrelated people. The records showed seven people had been labeled as carrying either a pathogenic or “presumed pathogenic” variant when in fact they had one of the five high-frequency variants now declared benign. Five of the seven mislabeled people were of African ancestry; the other two had unknown ancestry.
The researchers called for reevaluating known variants for all genetic diseases in more diverse populations and to immediately release the results of updated linkage assessments. This has the potential to meaningfully rewrite current gospel for many genetic variants and linkages.
“Our findings point to the value of patients staying in contact with their genetic counselors and physicians, even years after genetic testing,” Dr. Manrai said. Reassessments using more diverse populations will take time, he acknowledged, but tools are available to allow clinical geneticists to update old variants and apply new ones in real time, as soon as a new assessment completes.
Dr. Manrai and Dr. Kohane had no disclosures.
On Twitter @mitchelzoler
The genetic tests used for more than a decade to identify patients or family members who carry genetic mutations linked to hypertrophic cardiomyopathy are seriously flawed.
The tests have been erroneously flagging people as genetically positive for hypertrophic cardiomyopathy (HC) when they actually carried benign genetic variants, according to a new reassessment of the genetic linkages by researchers using a more genetically diverse database. Five genetic variants now reclassified as benign were collectively responsible for flagging 74% of people flagged at genetic risk for HC in the more than 8,500 cases examined.
The results call into question any genetic diagnosis of HC made since genetic testing entered the mainstream in 2003, especially among African Americans who seem to have been disproportionately affected by these mislabeled genetic markers because of inadequate population diversity when the markers were first established.
In addition, the results more broadly cast a shadow over the full spectrum of genetic tests for disease-linked variants now in routine medical practice because of the possibility that other linkage determinations derived from an inadequately-representative reference population, reported Arjun K. Manrai, PhD, and his associates (N Engl J Med. 2016 Aug 18;375[7]:655-65). The researchers call the HC experience they document a “cautionary tale of broad relevance to genetic diagnosis.”
The findings “powerfully illustrate the importance of racial and genetic diversity” when running linkage studies aimed at validating genetic markers for widespread clinical use, Isaac S. Kohane, MD, senior author of the study, said in a written statement. “Racial and ethnic inclusiveness improves the validity and accuracy” of genetic tests, said Dr. Kohane, professor of biomedical informatics and pediatrics at Harvard Medical School in Boston.
“We believe that what we’re seeing in the case of hypertrophic cardiomyopathy may be the tip of the iceberg of a larger problem that transcends a single genetic disease,” Dr. Manrai, a biomedical informatics researcher at Harvard, said in the same statement. “Much genetic assessment today relies on historical links between a disorder and variant, sometimes decades old. We believe our findings illustrate the critical need to systematically reevaluate prior assertions about genetic variants,” Dr. Manrai added in an interview.
The two researchers and their associates reexamined the link between genetic variants and HC in three genetic databases that involved a total of more than 8,500 people. One database included 4,300 white Americans and 2,203 black Americans. A second database included genetic data from 1,092 people from 14 worldwide populations, and the third had genetic data from 938 people from 51 worldwide populations.
The analysis showed that although 94 distinct genetic variants that had previously been reported as associated with HC were confirmed as linked, just 5 met the study’s definition of a “high-frequency” variant with an allele frequent of more than 1%. These five variants together accounted for 74% of the overall total of linkages seen in these 8,533 people. Further analysis classified all five of these high-frequency genetic variants as benign with no discernible link to HC.
These five high-frequency variants occurred disproportionately higher among black Americans, and the consequences of this showed up in the patient records the researchers reviewed from one large U.S. genetic testing laboratory. They examined in detail HC genetic test results during 2004-2013 from 2,912 unrelated people. The records showed seven people had been labeled as carrying either a pathogenic or “presumed pathogenic” variant when in fact they had one of the five high-frequency variants now declared benign. Five of the seven mislabeled people were of African ancestry; the other two had unknown ancestry.
The researchers called for reevaluating known variants for all genetic diseases in more diverse populations and to immediately release the results of updated linkage assessments. This has the potential to meaningfully rewrite current gospel for many genetic variants and linkages.
“Our findings point to the value of patients staying in contact with their genetic counselors and physicians, even years after genetic testing,” Dr. Manrai said. Reassessments using more diverse populations will take time, he acknowledged, but tools are available to allow clinical geneticists to update old variants and apply new ones in real time, as soon as a new assessment completes.
Dr. Manrai and Dr. Kohane had no disclosures.
On Twitter @mitchelzoler
The genetic tests used for more than a decade to identify patients or family members who carry genetic mutations linked to hypertrophic cardiomyopathy are seriously flawed.
The tests have been erroneously flagging people as genetically positive for hypertrophic cardiomyopathy (HC) when they actually carried benign genetic variants, according to a new reassessment of the genetic linkages by researchers using a more genetically diverse database. Five genetic variants now reclassified as benign were collectively responsible for flagging 74% of people flagged at genetic risk for HC in the more than 8,500 cases examined.
The results call into question any genetic diagnosis of HC made since genetic testing entered the mainstream in 2003, especially among African Americans who seem to have been disproportionately affected by these mislabeled genetic markers because of inadequate population diversity when the markers were first established.
In addition, the results more broadly cast a shadow over the full spectrum of genetic tests for disease-linked variants now in routine medical practice because of the possibility that other linkage determinations derived from an inadequately-representative reference population, reported Arjun K. Manrai, PhD, and his associates (N Engl J Med. 2016 Aug 18;375[7]:655-65). The researchers call the HC experience they document a “cautionary tale of broad relevance to genetic diagnosis.”
The findings “powerfully illustrate the importance of racial and genetic diversity” when running linkage studies aimed at validating genetic markers for widespread clinical use, Isaac S. Kohane, MD, senior author of the study, said in a written statement. “Racial and ethnic inclusiveness improves the validity and accuracy” of genetic tests, said Dr. Kohane, professor of biomedical informatics and pediatrics at Harvard Medical School in Boston.
“We believe that what we’re seeing in the case of hypertrophic cardiomyopathy may be the tip of the iceberg of a larger problem that transcends a single genetic disease,” Dr. Manrai, a biomedical informatics researcher at Harvard, said in the same statement. “Much genetic assessment today relies on historical links between a disorder and variant, sometimes decades old. We believe our findings illustrate the critical need to systematically reevaluate prior assertions about genetic variants,” Dr. Manrai added in an interview.
The two researchers and their associates reexamined the link between genetic variants and HC in three genetic databases that involved a total of more than 8,500 people. One database included 4,300 white Americans and 2,203 black Americans. A second database included genetic data from 1,092 people from 14 worldwide populations, and the third had genetic data from 938 people from 51 worldwide populations.
The analysis showed that although 94 distinct genetic variants that had previously been reported as associated with HC were confirmed as linked, just 5 met the study’s definition of a “high-frequency” variant with an allele frequent of more than 1%. These five variants together accounted for 74% of the overall total of linkages seen in these 8,533 people. Further analysis classified all five of these high-frequency genetic variants as benign with no discernible link to HC.
These five high-frequency variants occurred disproportionately higher among black Americans, and the consequences of this showed up in the patient records the researchers reviewed from one large U.S. genetic testing laboratory. They examined in detail HC genetic test results during 2004-2013 from 2,912 unrelated people. The records showed seven people had been labeled as carrying either a pathogenic or “presumed pathogenic” variant when in fact they had one of the five high-frequency variants now declared benign. Five of the seven mislabeled people were of African ancestry; the other two had unknown ancestry.
The researchers called for reevaluating known variants for all genetic diseases in more diverse populations and to immediately release the results of updated linkage assessments. This has the potential to meaningfully rewrite current gospel for many genetic variants and linkages.
“Our findings point to the value of patients staying in contact with their genetic counselors and physicians, even years after genetic testing,” Dr. Manrai said. Reassessments using more diverse populations will take time, he acknowledged, but tools are available to allow clinical geneticists to update old variants and apply new ones in real time, as soon as a new assessment completes.
Dr. Manrai and Dr. Kohane had no disclosures.
On Twitter @mitchelzoler
Key clinical point: Five high-frequency genetic variants that collectively had been linked to 74% of hypertrophic cardiomyopathy cases are actually benign with no detectable pathologic linkage.
Major finding: Inaccurate linkage data mislabeled seven people as having a hypertrophic cardiomyopathy–causing genetic variant.
Data source: Three genomic sequence databases that included 8,533 people and a genetic laboratory’s records for 2,912 clients.
Disclosures: Dr. Manrai and Dr. Kohane had no disclosures.
Ankylosing spondylitis patients develop multiple comorbidities after diagnosis
DENVER – Evidence continues to mount that ankylosing spondylitis patients are at increased risk for developing various comorbidities, compared with the general adult population.
Patients newly diagnosed with ankylosing spondylitis (AS) had twice the rate of new-onset depression during the first 3 years following diagnosis, compared with matched people from the general population in a study of more than 21,000 American adults. Patients with newly diagnosed AS also had a 60% higher rate of developing a new cardiovascular disease, compared with the matched general population, Jessica A. Walsh, MD, said at the annual meeting of the Spondyloarthritis Research and Treatment Network.
“We need to figure out what to do about all the comorbidities. Rheumatologists need to either screen their AS patients for comorbidities, or they need to be sure their patients are plugged in with another physician who will screen them,” said Dr. Walsh, director of the spondyloarthritis clinic at the University of Utah in Salt Lake City.
Her analysis used data from the Truven Health MarketScan databases for U.S. patients covered by Medicare or commercial health insurance, and included 6,370 patients with newly diagnosed AS and 14,988 adults matched by age and sex. The analysis only included AS patients who were free from comorbidities during the 2 years prior to their AS diagnosis. The average age of the people in the study was 52 years, and 54% were men.
During an average follow-up of 2.9 years following initial AS diagnosis, the most common comorbidity among the AS patients was uveitis, which occurred nearly 15-fold more frequently among the AS patients than in the controls. Other common incident comorbidities included inflammatory bowel disease, nearly sixfold more common among the AS patients, and osteoporosis, which was nearly threefold more common during follow-up after AS diagnosis, compared with the controls.
Other comorbidities with increased incidence in the AS patients included sleep apnea (80% more common among the AS patients during follow-up), asthma (50% more often), hypertension (44% more common), malignancy (23% more common), diabetes (20% more common), and dyslipidemia (11% more common). All these incidence rates represented statistically significant increases in the AS patients, compared with the controls.
A related analysis reported by Dr. Walsh also used data from the Truven Health databases for a somewhat larger group of AS patients, 6,679 followed for 1 year after their AS diagnosis, and 19,951 matched controls. The AS patients had a significantly higher rate of hospital admissions – 12%, compared with 6% among the controls – and a significantly higher rate of emergency department visits, at 23%, compared with 15% among the controls. The AS patients also had double the rate of physician office visits and prescribed medications.
“Obviously, the AS patients are not as healthy,” Dr. Walsh said in an interview. “We adjusted for their comorbidities, but that did not affect the hospitalization rates. We need to look into this more; I don’t know why the AS patients are being hospitalized. Typically AS itself does not lead to hospitalization, so I suspect it’s because of comorbidities, or perhaps because of adverse events from treatment.”
Dr. Walsh is a consultant to AbbVie and Novartis.
On Twitter @mitchelzoler
DENVER – Evidence continues to mount that ankylosing spondylitis patients are at increased risk for developing various comorbidities, compared with the general adult population.
Patients newly diagnosed with ankylosing spondylitis (AS) had twice the rate of new-onset depression during the first 3 years following diagnosis, compared with matched people from the general population in a study of more than 21,000 American adults. Patients with newly diagnosed AS also had a 60% higher rate of developing a new cardiovascular disease, compared with the matched general population, Jessica A. Walsh, MD, said at the annual meeting of the Spondyloarthritis Research and Treatment Network.
“We need to figure out what to do about all the comorbidities. Rheumatologists need to either screen their AS patients for comorbidities, or they need to be sure their patients are plugged in with another physician who will screen them,” said Dr. Walsh, director of the spondyloarthritis clinic at the University of Utah in Salt Lake City.
Her analysis used data from the Truven Health MarketScan databases for U.S. patients covered by Medicare or commercial health insurance, and included 6,370 patients with newly diagnosed AS and 14,988 adults matched by age and sex. The analysis only included AS patients who were free from comorbidities during the 2 years prior to their AS diagnosis. The average age of the people in the study was 52 years, and 54% were men.
During an average follow-up of 2.9 years following initial AS diagnosis, the most common comorbidity among the AS patients was uveitis, which occurred nearly 15-fold more frequently among the AS patients than in the controls. Other common incident comorbidities included inflammatory bowel disease, nearly sixfold more common among the AS patients, and osteoporosis, which was nearly threefold more common during follow-up after AS diagnosis, compared with the controls.
Other comorbidities with increased incidence in the AS patients included sleep apnea (80% more common among the AS patients during follow-up), asthma (50% more often), hypertension (44% more common), malignancy (23% more common), diabetes (20% more common), and dyslipidemia (11% more common). All these incidence rates represented statistically significant increases in the AS patients, compared with the controls.
A related analysis reported by Dr. Walsh also used data from the Truven Health databases for a somewhat larger group of AS patients, 6,679 followed for 1 year after their AS diagnosis, and 19,951 matched controls. The AS patients had a significantly higher rate of hospital admissions – 12%, compared with 6% among the controls – and a significantly higher rate of emergency department visits, at 23%, compared with 15% among the controls. The AS patients also had double the rate of physician office visits and prescribed medications.
“Obviously, the AS patients are not as healthy,” Dr. Walsh said in an interview. “We adjusted for their comorbidities, but that did not affect the hospitalization rates. We need to look into this more; I don’t know why the AS patients are being hospitalized. Typically AS itself does not lead to hospitalization, so I suspect it’s because of comorbidities, or perhaps because of adverse events from treatment.”
Dr. Walsh is a consultant to AbbVie and Novartis.
On Twitter @mitchelzoler
DENVER – Evidence continues to mount that ankylosing spondylitis patients are at increased risk for developing various comorbidities, compared with the general adult population.
Patients newly diagnosed with ankylosing spondylitis (AS) had twice the rate of new-onset depression during the first 3 years following diagnosis, compared with matched people from the general population in a study of more than 21,000 American adults. Patients with newly diagnosed AS also had a 60% higher rate of developing a new cardiovascular disease, compared with the matched general population, Jessica A. Walsh, MD, said at the annual meeting of the Spondyloarthritis Research and Treatment Network.
“We need to figure out what to do about all the comorbidities. Rheumatologists need to either screen their AS patients for comorbidities, or they need to be sure their patients are plugged in with another physician who will screen them,” said Dr. Walsh, director of the spondyloarthritis clinic at the University of Utah in Salt Lake City.
Her analysis used data from the Truven Health MarketScan databases for U.S. patients covered by Medicare or commercial health insurance, and included 6,370 patients with newly diagnosed AS and 14,988 adults matched by age and sex. The analysis only included AS patients who were free from comorbidities during the 2 years prior to their AS diagnosis. The average age of the people in the study was 52 years, and 54% were men.
During an average follow-up of 2.9 years following initial AS diagnosis, the most common comorbidity among the AS patients was uveitis, which occurred nearly 15-fold more frequently among the AS patients than in the controls. Other common incident comorbidities included inflammatory bowel disease, nearly sixfold more common among the AS patients, and osteoporosis, which was nearly threefold more common during follow-up after AS diagnosis, compared with the controls.
Other comorbidities with increased incidence in the AS patients included sleep apnea (80% more common among the AS patients during follow-up), asthma (50% more often), hypertension (44% more common), malignancy (23% more common), diabetes (20% more common), and dyslipidemia (11% more common). All these incidence rates represented statistically significant increases in the AS patients, compared with the controls.
A related analysis reported by Dr. Walsh also used data from the Truven Health databases for a somewhat larger group of AS patients, 6,679 followed for 1 year after their AS diagnosis, and 19,951 matched controls. The AS patients had a significantly higher rate of hospital admissions – 12%, compared with 6% among the controls – and a significantly higher rate of emergency department visits, at 23%, compared with 15% among the controls. The AS patients also had double the rate of physician office visits and prescribed medications.
“Obviously, the AS patients are not as healthy,” Dr. Walsh said in an interview. “We adjusted for their comorbidities, but that did not affect the hospitalization rates. We need to look into this more; I don’t know why the AS patients are being hospitalized. Typically AS itself does not lead to hospitalization, so I suspect it’s because of comorbidities, or perhaps because of adverse events from treatment.”
Dr. Walsh is a consultant to AbbVie and Novartis.
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AT THE 2016 SPARTAN ANNUAL MEETING
Key clinical point: In the 3 years after initial ankylosing spondylitis diagnosis, the incidence of several comorbidities rises significantly above those in the general population.
Major finding: The incidence of new-onset depression among newly diagnosed ankylosing spondylitis patients was twice as high as it was among matched controls.
Data source: Observational data collected by Truven Health MarketScan, with a total of 21,358 patients and controls.
Disclosures: Dr. Walsh is a consultant to AbbVie and Novartis.
