Cardiology

Millions of Americans with treatment-resistant hypertension are likely not being tested to determine whether their high blood pressure is driven by primary aldosteronism (PA), despite guidelines that call for such an approach, according to findings from the first reported large-scale, multicenter study of PA testing practices.

Researchers ran a retrospective review of PA testing among 269,010 patients who met the definition as having treatment-resistant hypertension and were managed at any one of 130 Veterans Health Administration (VHA) medical centers from 2000 to 2017.

The results showed that, despite the fact that primary aldosteronism is highly prevalent among patients with treatment-resistant hypertension, only 4,277 (1.6%) underwent assessment for PA during a median of 3.3 years’ follow-up after they first met the defining criteria, Jordana B. Cohen, MD, and her associates reported in a study published in Annals of Internal Medicine on December 28.

“Testing rates also did not change meaningfully over nearly 2 decades ... despite an increasing number of guidelines recommending testing for primary aldosteronism in this population,” including the most recent recommendations from the Endocrine Society, issued in 2016, noted Dr. Cohen, a nephrologist and hypertension researcher at the University of Pennsylvania in Philadelphia, and colleagues.

Most patients in the study (almost 90%) were seen by a primary care practitioner (PCP).

The small percentage of patients seen by a nephrologist or endocrinologist were more than twice as likely to be tested for PA than those seen by a PCP or cardiologist.

Those clinicians who did order a test for PA were much more likely to treat patients with the appropriate medication, a mineralocorticoid receptor antagonist (MRA). In addition, therapy was started sooner, the researchers found.

“Our results corroborate” earlier reports from smaller health systems and suggest that dramatic underuse of PA assessment “is an issue across the US,” Dr. Cohen said in an interview.

The VHA experience “is very representative of what we think goes on across U.S. practice” and contrasts with the VHA’s reputation for “doing a pretty good job managing hypertension” in general, she noted.
 

Missed diagnosis, missed treatment

Dr. Cohen believes a number of factors likely help drive the abysmally low rate of PA testing they observed in the VHA system. She believes rates of PA testing are low elsewhere as well.

First, optimal hypertension management “is often taken for granted” but is challenging in busy primary care practices, so many of patients likely fall through the cracks, she said.

Dr. Cohen cited efforts at her institution, as well as by the VHA system, to better employ electronic health records to flag patients with treatment-resistant hypertension – defined as patients whose systolic or diastolic blood pressure remains at or above 140/90 mm Hg on at least two successive measurements at least a month apart while the patient is undergoing treatment with three conventional antihypertensive drugs – and to guide clinicians to order the right tests and treatments for these patients.

Many care providers mistakenly “see treatment-resistant hypertension as a disease of noncompliance,” although it is much more often the result of a missed diagnosis and inadequate intervention, she explained.
 

Physicians in denial; side effects of MRAs may deter prescribing

A second big cause of low PA testing rates is that doctors make the mistake of thinking a PA test result won’t change how they manage these patients.

The established treatment for most patients with treatment-resistant hypertension as well as PA is adding an MRA, either spironolactone or eplerenone (Inspra).

Many providers cling to the belief that they will start an MRA in these patients without first determining their PA status, says Dr. Cohen, but the data she and her colleagues collected show the opposite.

Overall, about 13% of all patients in the study began treatment with an MRA during follow-up. The likelihood of starting treatment with this drug class was fourfold higher among the patients tested for PA compared with those who were not tested.

PA testing also hastened the start of MRA use by more than a year, compared with untested patients.

“Providers think they prescribe an MRA” to treatment-resistant patients, “but it’s part of their denial. They are not using the evidence-based treatments [spironolactone or eplerenone], perhaps because of concerns about MRA side effects, although those have been pretty well overcome during the past 20 years,” she observed.

Dr. Cohen says gynecomastia is one adverse effect that gives pause to VHA clinicians who see a heavily male patient population. “It’s probably the biggest concern and why PA testing and MRA use is low” in the VHA system, she said.

“You can use a lower dosage of spironolactone, and the incidence is less common with eplerenone,” although using eplerenone does not completely eliminate all gynecomastia cases, she noted.

At the University of Pennsylvania hospitals, men often start on spironolactone first because it retains a significant price advantage, even though eplerenone is now generic, but “if there is a hint of gynecomastia, we quickly switch to eplerenone, which is usually well tolerated,” she explained.

And while eplerenone has a reputation of being less effective than spironolactone, “I’ve prescribed a lot of eplerenone and have had good results,” Dr. Cohen said. “Even if the blood pressure lowering is not as great compared with spironolactone, it still blunts the toxic effects of aldosterone on target organs.”

Hyperkalemia is the other big concern about spironolactone and eplerenone. Both agents cause it at roughly the same rate, although the rate is lower in patients without chronic kidney disease.

A new, nonsteroidal MRA, finerenone, caused substantially less hyperkalemia in a recent phase 3 trial, FIDELIO-DKD, and as a nonsteroidal MRA, it does not cause gynecomastia. Finerenone has promise as a potentially safer option for treating PA and treatment-resistant hypertension, noted Cohen, but so far, no advanced clinical trials have been launched to examine its efficacy for these indications.
 

PA testing allows a surgical option

A third reason to test patients with treatment-resistant hypertension for PA is that jumping straight to MRA treatment denies the patient assessment for a unilateral adrenal adenoma as the cause of excess aldosterone.

When unilateral adenomas exist, patients are candidates for adrenalectomy. Despite the potential advantage this gives patients to eliminate the cause of their PA without the need for additional drug treatment, some clinicians don’t see this as a compelling rationale to test for PA because they have a bias against surgery or have seen too many cases in which surgery failed to produce full hypertension resolution.

“It’s all about setting expectations appropriately” for the impact of this surgery, Dr. Cohen said.

“Adrenalectomy is not a cure; it just gets rid of the source of excess aldosterone.” But in patients with long-standing PA and hypertension, this is often not enough to completely resolve entrenched cardiovascular pathology.
 

PCPs, cardiologists in rural locations least likely to order PA testing

Of the 269,010 patients analyzed by Dr. Cohen and her coauthors, the average age was 65 years; 96% were men; half were obese; and 40% had diabetes. The researchers excluded patients who had already been tested for PA, as well as those who were already receiving treatment with an MRA.

For 88% of the patients, the main physician overseeing care was a PCP. A cardiologist was the main physician for 10%; a nephrologist, for 1%; and an endocrinologist, for fewer than 1%.

The rate of testing for PA varied across the 130 VHA centers that contributed data, ranging from 0% to 6%. The testing data showed that endocrinologists were most likely to order PA testing, doing it 2.48-fold more often than PCPs. Nephrologists were roughly twice as likely to order PA testing than PCPs, and cardiologists ordered testing at about the same rate as PCPs.

Patients managed at VHA centers in rural locations were nearly half as likely to undergo testing as patients managed at nonrural centers. The number of patients with treatment-resistant hypertension seen by a physician or at a center had no significant relationship to PA testing frequency.

The study received no commercial funding. Dr. Cohen has disclosed no relevant financial relationships.

A version of this story first appeared on Medscape.com.

Millions of Americans with treatment-resistant hypertension are likely not being tested to determine whether their high blood pressure is driven by primary aldosteronism (PA), despite guidelines that call for such an approach, according to findings from the first reported large-scale, multicenter study of PA testing practices.

Researchers ran a retrospective review of PA testing among 269,010 patients who met the definition as having treatment-resistant hypertension and were managed at any one of 130 Veterans Health Administration (VHA) medical centers from 2000 to 2017.

The results showed that, despite the fact that primary aldosteronism is highly prevalent among patients with treatment-resistant hypertension, only 4,277 (1.6%) underwent assessment for PA during a median of 3.3 years’ follow-up after they first met the defining criteria, Jordana B. Cohen, MD, and her associates reported in a study published in Annals of Internal Medicine on December 28.

“Testing rates also did not change meaningfully over nearly 2 decades ... despite an increasing number of guidelines recommending testing for primary aldosteronism in this population,” including the most recent recommendations from the Endocrine Society, issued in 2016, noted Dr. Cohen, a nephrologist and hypertension researcher at the University of Pennsylvania in Philadelphia, and colleagues.

Most patients in the study (almost 90%) were seen by a primary care practitioner (PCP).

The small percentage of patients seen by a nephrologist or endocrinologist were more than twice as likely to be tested for PA than those seen by a PCP or cardiologist.

Those clinicians who did order a test for PA were much more likely to treat patients with the appropriate medication, a mineralocorticoid receptor antagonist (MRA). In addition, therapy was started sooner, the researchers found.

“Our results corroborate” earlier reports from smaller health systems and suggest that dramatic underuse of PA assessment “is an issue across the US,” Dr. Cohen said in an interview.

The VHA experience “is very representative of what we think goes on across U.S. practice” and contrasts with the VHA’s reputation for “doing a pretty good job managing hypertension” in general, she noted.
 

Missed diagnosis, missed treatment

Dr. Cohen believes a number of factors likely help drive the abysmally low rate of PA testing they observed in the VHA system. She believes rates of PA testing are low elsewhere as well.

First, optimal hypertension management “is often taken for granted” but is challenging in busy primary care practices, so many of patients likely fall through the cracks, she said.

Dr. Cohen cited efforts at her institution, as well as by the VHA system, to better employ electronic health records to flag patients with treatment-resistant hypertension – defined as patients whose systolic or diastolic blood pressure remains at or above 140/90 mm Hg on at least two successive measurements at least a month apart while the patient is undergoing treatment with three conventional antihypertensive drugs – and to guide clinicians to order the right tests and treatments for these patients.

Many care providers mistakenly “see treatment-resistant hypertension as a disease of noncompliance,” although it is much more often the result of a missed diagnosis and inadequate intervention, she explained.
 

Physicians in denial; side effects of MRAs may deter prescribing

A second big cause of low PA testing rates is that doctors make the mistake of thinking a PA test result won’t change how they manage these patients.

The established treatment for most patients with treatment-resistant hypertension as well as PA is adding an MRA, either spironolactone or eplerenone (Inspra).

Many providers cling to the belief that they will start an MRA in these patients without first determining their PA status, says Dr. Cohen, but the data she and her colleagues collected show the opposite.

Overall, about 13% of all patients in the study began treatment with an MRA during follow-up. The likelihood of starting treatment with this drug class was fourfold higher among the patients tested for PA compared with those who were not tested.

PA testing also hastened the start of MRA use by more than a year, compared with untested patients.

“Providers think they prescribe an MRA” to treatment-resistant patients, “but it’s part of their denial. They are not using the evidence-based treatments [spironolactone or eplerenone], perhaps because of concerns about MRA side effects, although those have been pretty well overcome during the past 20 years,” she observed.

Dr. Cohen says gynecomastia is one adverse effect that gives pause to VHA clinicians who see a heavily male patient population. “It’s probably the biggest concern and why PA testing and MRA use is low” in the VHA system, she said.

“You can use a lower dosage of spironolactone, and the incidence is less common with eplerenone,” although using eplerenone does not completely eliminate all gynecomastia cases, she noted.

At the University of Pennsylvania hospitals, men often start on spironolactone first because it retains a significant price advantage, even though eplerenone is now generic, but “if there is a hint of gynecomastia, we quickly switch to eplerenone, which is usually well tolerated,” she explained.

And while eplerenone has a reputation of being less effective than spironolactone, “I’ve prescribed a lot of eplerenone and have had good results,” Dr. Cohen said. “Even if the blood pressure lowering is not as great compared with spironolactone, it still blunts the toxic effects of aldosterone on target organs.”

Hyperkalemia is the other big concern about spironolactone and eplerenone. Both agents cause it at roughly the same rate, although the rate is lower in patients without chronic kidney disease.

A new, nonsteroidal MRA, finerenone, caused substantially less hyperkalemia in a recent phase 3 trial, FIDELIO-DKD, and as a nonsteroidal MRA, it does not cause gynecomastia. Finerenone has promise as a potentially safer option for treating PA and treatment-resistant hypertension, noted Cohen, but so far, no advanced clinical trials have been launched to examine its efficacy for these indications.
 

PA testing allows a surgical option

A third reason to test patients with treatment-resistant hypertension for PA is that jumping straight to MRA treatment denies the patient assessment for a unilateral adrenal adenoma as the cause of excess aldosterone.

When unilateral adenomas exist, patients are candidates for adrenalectomy. Despite the potential advantage this gives patients to eliminate the cause of their PA without the need for additional drug treatment, some clinicians don’t see this as a compelling rationale to test for PA because they have a bias against surgery or have seen too many cases in which surgery failed to produce full hypertension resolution.

“It’s all about setting expectations appropriately” for the impact of this surgery, Dr. Cohen said.

“Adrenalectomy is not a cure; it just gets rid of the source of excess aldosterone.” But in patients with long-standing PA and hypertension, this is often not enough to completely resolve entrenched cardiovascular pathology.
 

PCPs, cardiologists in rural locations least likely to order PA testing

Of the 269,010 patients analyzed by Dr. Cohen and her coauthors, the average age was 65 years; 96% were men; half were obese; and 40% had diabetes. The researchers excluded patients who had already been tested for PA, as well as those who were already receiving treatment with an MRA.

For 88% of the patients, the main physician overseeing care was a PCP. A cardiologist was the main physician for 10%; a nephrologist, for 1%; and an endocrinologist, for fewer than 1%.

The rate of testing for PA varied across the 130 VHA centers that contributed data, ranging from 0% to 6%. The testing data showed that endocrinologists were most likely to order PA testing, doing it 2.48-fold more often than PCPs. Nephrologists were roughly twice as likely to order PA testing than PCPs, and cardiologists ordered testing at about the same rate as PCPs.

Patients managed at VHA centers in rural locations were nearly half as likely to undergo testing as patients managed at nonrural centers. The number of patients with treatment-resistant hypertension seen by a physician or at a center had no significant relationship to PA testing frequency.

The study received no commercial funding. Dr. Cohen has disclosed no relevant financial relationships.

A version of this story first appeared on Medscape.com.

Millions of Americans with treatment-resistant hypertension are likely not being tested to determine whether their high blood pressure is driven by primary aldosteronism (PA), despite guidelines that call for such an approach, according to findings from the first reported large-scale, multicenter study of PA testing practices.

Researchers ran a retrospective review of PA testing among 269,010 patients who met the definition as having treatment-resistant hypertension and were managed at any one of 130 Veterans Health Administration (VHA) medical centers from 2000 to 2017.

The results showed that, despite the fact that primary aldosteronism is highly prevalent among patients with treatment-resistant hypertension, only 4,277 (1.6%) underwent assessment for PA during a median of 3.3 years’ follow-up after they first met the defining criteria, Jordana B. Cohen, MD, and her associates reported in a study published in Annals of Internal Medicine on December 28.

“Testing rates also did not change meaningfully over nearly 2 decades ... despite an increasing number of guidelines recommending testing for primary aldosteronism in this population,” including the most recent recommendations from the Endocrine Society, issued in 2016, noted Dr. Cohen, a nephrologist and hypertension researcher at the University of Pennsylvania in Philadelphia, and colleagues.

Most patients in the study (almost 90%) were seen by a primary care practitioner (PCP).

The small percentage of patients seen by a nephrologist or endocrinologist were more than twice as likely to be tested for PA than those seen by a PCP or cardiologist.

Those clinicians who did order a test for PA were much more likely to treat patients with the appropriate medication, a mineralocorticoid receptor antagonist (MRA). In addition, therapy was started sooner, the researchers found.

“Our results corroborate” earlier reports from smaller health systems and suggest that dramatic underuse of PA assessment “is an issue across the US,” Dr. Cohen said in an interview.

The VHA experience “is very representative of what we think goes on across U.S. practice” and contrasts with the VHA’s reputation for “doing a pretty good job managing hypertension” in general, she noted.
 

Missed diagnosis, missed treatment

Dr. Cohen believes a number of factors likely help drive the abysmally low rate of PA testing they observed in the VHA system. She believes rates of PA testing are low elsewhere as well.

First, optimal hypertension management “is often taken for granted” but is challenging in busy primary care practices, so many of patients likely fall through the cracks, she said.

Dr. Cohen cited efforts at her institution, as well as by the VHA system, to better employ electronic health records to flag patients with treatment-resistant hypertension – defined as patients whose systolic or diastolic blood pressure remains at or above 140/90 mm Hg on at least two successive measurements at least a month apart while the patient is undergoing treatment with three conventional antihypertensive drugs – and to guide clinicians to order the right tests and treatments for these patients.

Many care providers mistakenly “see treatment-resistant hypertension as a disease of noncompliance,” although it is much more often the result of a missed diagnosis and inadequate intervention, she explained.
 

Physicians in denial; side effects of MRAs may deter prescribing

A second big cause of low PA testing rates is that doctors make the mistake of thinking a PA test result won’t change how they manage these patients.

The established treatment for most patients with treatment-resistant hypertension as well as PA is adding an MRA, either spironolactone or eplerenone (Inspra).

Many providers cling to the belief that they will start an MRA in these patients without first determining their PA status, says Dr. Cohen, but the data she and her colleagues collected show the opposite.

Overall, about 13% of all patients in the study began treatment with an MRA during follow-up. The likelihood of starting treatment with this drug class was fourfold higher among the patients tested for PA compared with those who were not tested.

PA testing also hastened the start of MRA use by more than a year, compared with untested patients.

“Providers think they prescribe an MRA” to treatment-resistant patients, “but it’s part of their denial. They are not using the evidence-based treatments [spironolactone or eplerenone], perhaps because of concerns about MRA side effects, although those have been pretty well overcome during the past 20 years,” she observed.

Dr. Cohen says gynecomastia is one adverse effect that gives pause to VHA clinicians who see a heavily male patient population. “It’s probably the biggest concern and why PA testing and MRA use is low” in the VHA system, she said.

“You can use a lower dosage of spironolactone, and the incidence is less common with eplerenone,” although using eplerenone does not completely eliminate all gynecomastia cases, she noted.

At the University of Pennsylvania hospitals, men often start on spironolactone first because it retains a significant price advantage, even though eplerenone is now generic, but “if there is a hint of gynecomastia, we quickly switch to eplerenone, which is usually well tolerated,” she explained.

And while eplerenone has a reputation of being less effective than spironolactone, “I’ve prescribed a lot of eplerenone and have had good results,” Dr. Cohen said. “Even if the blood pressure lowering is not as great compared with spironolactone, it still blunts the toxic effects of aldosterone on target organs.”

Hyperkalemia is the other big concern about spironolactone and eplerenone. Both agents cause it at roughly the same rate, although the rate is lower in patients without chronic kidney disease.

A new, nonsteroidal MRA, finerenone, caused substantially less hyperkalemia in a recent phase 3 trial, FIDELIO-DKD, and as a nonsteroidal MRA, it does not cause gynecomastia. Finerenone has promise as a potentially safer option for treating PA and treatment-resistant hypertension, noted Cohen, but so far, no advanced clinical trials have been launched to examine its efficacy for these indications.
 

PA testing allows a surgical option

A third reason to test patients with treatment-resistant hypertension for PA is that jumping straight to MRA treatment denies the patient assessment for a unilateral adrenal adenoma as the cause of excess aldosterone.

When unilateral adenomas exist, patients are candidates for adrenalectomy. Despite the potential advantage this gives patients to eliminate the cause of their PA without the need for additional drug treatment, some clinicians don’t see this as a compelling rationale to test for PA because they have a bias against surgery or have seen too many cases in which surgery failed to produce full hypertension resolution.

“It’s all about setting expectations appropriately” for the impact of this surgery, Dr. Cohen said.

“Adrenalectomy is not a cure; it just gets rid of the source of excess aldosterone.” But in patients with long-standing PA and hypertension, this is often not enough to completely resolve entrenched cardiovascular pathology.
 

PCPs, cardiologists in rural locations least likely to order PA testing

Of the 269,010 patients analyzed by Dr. Cohen and her coauthors, the average age was 65 years; 96% were men; half were obese; and 40% had diabetes. The researchers excluded patients who had already been tested for PA, as well as those who were already receiving treatment with an MRA.

For 88% of the patients, the main physician overseeing care was a PCP. A cardiologist was the main physician for 10%; a nephrologist, for 1%; and an endocrinologist, for fewer than 1%.

The rate of testing for PA varied across the 130 VHA centers that contributed data, ranging from 0% to 6%. The testing data showed that endocrinologists were most likely to order PA testing, doing it 2.48-fold more often than PCPs. Nephrologists were roughly twice as likely to order PA testing than PCPs, and cardiologists ordered testing at about the same rate as PCPs.

Patients managed at VHA centers in rural locations were nearly half as likely to undergo testing as patients managed at nonrural centers. The number of patients with treatment-resistant hypertension seen by a physician or at a center had no significant relationship to PA testing frequency.

The study received no commercial funding. Dr. Cohen has disclosed no relevant financial relationships.

A version of this story first appeared on Medscape.com.

Oxidative stress may account for the “lipid paradox,” a higher incidence of heart disease burden found in nonobese rheumatoid arthritis (RA) patients with lower levels of low-density lipoprotein (LDL). George Karpouzas, MD, an investigator at the Lundquist Institute of Biomedical Innovation, St, Torrance, Calif., discussed this exploratory finding at the virtual annual meeting of the American College of Rheumatology.

A complex dynamic exists between traditional risk factors and cardiovascular (CV) events in RA patients, said Dr. Karpouzas, professor of medicine at the University of California, Los Angeles, and chief of the division of rheumatology, Harbor-UCLA Medical Center. “Lower lipid levels, specifically total cholesterol and to a lesser extent LDL, may be associated with higher risk,” he said. One recent study found that coronary artery calcium (CAC) scores were four times higher in RA patients with lower LDL concentrations (> 70 mg/dL) than those in control groups. “This was especially true in patients who were nonobese, non-Hispanic Whites and never smokers,” said Dr. Karpouzas. Other studies have reported this association between low LDL and increased CVD risk.

These paradoxes led to several questions: Does obesity modify the effect of LDL on cardiovascular disease (CVD) risk in RA and does it moderate the effect of LDL on coronary plaque burden and progression? Do LDL particle composition and oxidation variations underlie the paradoxical association of low LDL with higher coronary atherosclerosis burden in RA? To find answers, Dr. Karpouzas’ team in the Prospective Evaluation of Latent Coronary Atherosclerosis in Rheumatoid Arthritis (PROTECT-RA) trial studied a cohort of 150 established RA patients without symptoms or diagnosis of CV disease.

Dr. Karpouzas presented two oral abstracts that summarized this research during the ACR 2020 session, “RA, diagnosis, manifestations and outcomes: heart of the matter,” which was held virtually.
 

Higher plaque burden seen in nonobese patients

In one part of the study, patients underwent baseline cardiac coronary CT angiography (CTA) over 1 year (2010-2011). Investigators evaluated CAC scores, segment involvement scores (SIS), segment stenosis scores (SSS), and extensive and obstructive disease. Low LDL was defined as < 70 mg/dL, obesity as a waist to height ratio of > 0.58 squared.

Investigators in follow-up work (2017-2018) evaluated for plaque progression, prospectively recording all cardiovascular disease events such as cardiac death, myocardial infarction, unstable angina, stroke, and heart failure hospitalization. Multivariable models assessed the effects of LDL lower than 70 mg/dL, obesity, and their interaction, accounting for factors such as age, sex, statin use, diabetes and hypertension.
 

Four LDL obesity cohorts

Nonobese RA patients with low LDL exhibited the highest plaque burden. “Despite no differences in RA inflammation, patients in this group were more likely to exhibit high levels of LDL oxidation,” Dr. Karpouzas said in an interview. “Nonobese patients with low LDL more likely exhibited new coronary plaque formation as well as increased stenotic severity of prevalent plaque after adjustments for relevant covariates,” he added.

The study’s observational nature exposed it to biases and unmeasured confounding, Dr. Karpouzas emphasized. Because it took place in a single center, the results might not be generalizable to ethnically and racially diverse cohorts. Patients with calcifications, extensive or obstructive coronary plaque at baseline scan received more aggressive treatments, which could have slowed CVD event risk and plaque progression. Investigators cautioned that the results should be seen as “exploratory,” given that CVD event analysis wasn’t applied to the original study design.
 

The oxidation-LDL connection

Another arm of the study examined the oxidation association question. Investigators did a similar analysis of the same patients but also evaluated for cholesterol content, Lp(a) mass, OxLDL levels, IgG and IgM anti-OxLDL and apoB100 immune complexes and proinflammatory cytokines.

RA patients with LDL lower than 70 mg/dL had higher SSS and CAC scores and were more likely to have extensive or obstructive plaque. Statin-naive patients with lower LDL exhibited greater LDL oxidation than higher LDL groups. In addition, those with lower LDL had higher anti-OxLDL and apoB100 than patients with higher LDL.

“Oxidation makes the cholesterol more ‘sticky,’ allowing it to penetrate into the walls of the endothelium, and changes macrophages to foam cells. This malignant process is very powerful and can potentially increase atheroma burden,” study coauthor Matthew Budoff, MD, professor of medicine at UCLA and endowed chair of preventive cardiology at the Lundquist Institute, said in an interview.

Investigators also found an independent association between Lp(a) content and LDL oxidation. This association seemed strong in patients with lower LDL compared to higher LDL groups. In addition, “greater oxidation and immune recognition of oxLDL further associated with higher IL-6 elaboration which may in turn augment atherosclerosis burden in the low LDL group,” said Dr. Karpouzas.

The analysis did not explore alternate mechanisms such as increased cholesterol loading capacity, lower efflux capacity or increased hepatocyte uptake through LDL-R upregulation, a key limitation. Dr. Karpouzas also acknowledged that higher cumulative inflammatory burden incurred before evaluating low LDL patients at baseline may have led to greater coronary plaque burden.

Overall, the study shows that low LDL is not protective in this population, said Dr. Budoff. “Low LDL patients who have atherosclerosis should be treated with statins and other therapies to lower their CV risk.”
 

Larger studies to confirm associations

Attendees of the ACR 2020 session called for additional studies to confirm that LDL oxidation leads to increased coronary atherosclerotic burden in RA patients.

The study provides “mechanistic insight into this important problem for patients with RA,” noted Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine at Harvard Medical School and associate physician at Brigham and Women’s Hospital, Boston.

Some of the patients studied were on lipid-lowering drugs such as statins, though the statistical analysis adjusted for use of these medications, noted Dr. Sparks. “It is possible that excess systemic inflammation alone is responsible for changes in LDL oxidation that may ultimately lead to cardiovascular disease,” he offered.

Future mechanistic and interventional studies related specifically to LDL oxidation “should establish the importance of this pathway in the development of cardiovascular disease in patients with RA,” said Dr. Sparks.

Large studies of patients with different BMI and LDL values followed prospectively for CV events would be ideal, said Joel M. Kremer, MD, president of the Corrona Research Foundation and founder of Corrona, a biopharma data solutions firm. Investigators would need to follow patients for several years. And, such a venture might face some obstacles. “The practical impediments and cost would be substantial. Also, as LDL oxidation may be related to disease activity, there would be ethical and pragmatic issues associated with controlling disease activity in these patients. This would obscure these outcomes of interest,” said Dr. Kremer.

Dr. Karpouzas receives grant and research support from the American Heart Association and Pfizer-Aspire. Dr. Budoff receives grant support from General Electric.

rhnews@mdedge.com

SOURCE: Karpouzas G et al. ACR 2020. Abstract 0485 and Abstract 0486.

Oxidative stress may account for the “lipid paradox,” a higher incidence of heart disease burden found in nonobese rheumatoid arthritis (RA) patients with lower levels of low-density lipoprotein (LDL). George Karpouzas, MD, an investigator at the Lundquist Institute of Biomedical Innovation, St, Torrance, Calif., discussed this exploratory finding at the virtual annual meeting of the American College of Rheumatology.

A complex dynamic exists between traditional risk factors and cardiovascular (CV) events in RA patients, said Dr. Karpouzas, professor of medicine at the University of California, Los Angeles, and chief of the division of rheumatology, Harbor-UCLA Medical Center. “Lower lipid levels, specifically total cholesterol and to a lesser extent LDL, may be associated with higher risk,” he said. One recent study found that coronary artery calcium (CAC) scores were four times higher in RA patients with lower LDL concentrations (> 70 mg/dL) than those in control groups. “This was especially true in patients who were nonobese, non-Hispanic Whites and never smokers,” said Dr. Karpouzas. Other studies have reported this association between low LDL and increased CVD risk.

These paradoxes led to several questions: Does obesity modify the effect of LDL on cardiovascular disease (CVD) risk in RA and does it moderate the effect of LDL on coronary plaque burden and progression? Do LDL particle composition and oxidation variations underlie the paradoxical association of low LDL with higher coronary atherosclerosis burden in RA? To find answers, Dr. Karpouzas’ team in the Prospective Evaluation of Latent Coronary Atherosclerosis in Rheumatoid Arthritis (PROTECT-RA) trial studied a cohort of 150 established RA patients without symptoms or diagnosis of CV disease.

Dr. Karpouzas presented two oral abstracts that summarized this research during the ACR 2020 session, “RA, diagnosis, manifestations and outcomes: heart of the matter,” which was held virtually.
 

Higher plaque burden seen in nonobese patients

In one part of the study, patients underwent baseline cardiac coronary CT angiography (CTA) over 1 year (2010-2011). Investigators evaluated CAC scores, segment involvement scores (SIS), segment stenosis scores (SSS), and extensive and obstructive disease. Low LDL was defined as < 70 mg/dL, obesity as a waist to height ratio of > 0.58 squared.

Investigators in follow-up work (2017-2018) evaluated for plaque progression, prospectively recording all cardiovascular disease events such as cardiac death, myocardial infarction, unstable angina, stroke, and heart failure hospitalization. Multivariable models assessed the effects of LDL lower than 70 mg/dL, obesity, and their interaction, accounting for factors such as age, sex, statin use, diabetes and hypertension.
 

Four LDL obesity cohorts

Nonobese RA patients with low LDL exhibited the highest plaque burden. “Despite no differences in RA inflammation, patients in this group were more likely to exhibit high levels of LDL oxidation,” Dr. Karpouzas said in an interview. “Nonobese patients with low LDL more likely exhibited new coronary plaque formation as well as increased stenotic severity of prevalent plaque after adjustments for relevant covariates,” he added.

The study’s observational nature exposed it to biases and unmeasured confounding, Dr. Karpouzas emphasized. Because it took place in a single center, the results might not be generalizable to ethnically and racially diverse cohorts. Patients with calcifications, extensive or obstructive coronary plaque at baseline scan received more aggressive treatments, which could have slowed CVD event risk and plaque progression. Investigators cautioned that the results should be seen as “exploratory,” given that CVD event analysis wasn’t applied to the original study design.
 

The oxidation-LDL connection

Another arm of the study examined the oxidation association question. Investigators did a similar analysis of the same patients but also evaluated for cholesterol content, Lp(a) mass, OxLDL levels, IgG and IgM anti-OxLDL and apoB100 immune complexes and proinflammatory cytokines.

RA patients with LDL lower than 70 mg/dL had higher SSS and CAC scores and were more likely to have extensive or obstructive plaque. Statin-naive patients with lower LDL exhibited greater LDL oxidation than higher LDL groups. In addition, those with lower LDL had higher anti-OxLDL and apoB100 than patients with higher LDL.

“Oxidation makes the cholesterol more ‘sticky,’ allowing it to penetrate into the walls of the endothelium, and changes macrophages to foam cells. This malignant process is very powerful and can potentially increase atheroma burden,” study coauthor Matthew Budoff, MD, professor of medicine at UCLA and endowed chair of preventive cardiology at the Lundquist Institute, said in an interview.

Investigators also found an independent association between Lp(a) content and LDL oxidation. This association seemed strong in patients with lower LDL compared to higher LDL groups. In addition, “greater oxidation and immune recognition of oxLDL further associated with higher IL-6 elaboration which may in turn augment atherosclerosis burden in the low LDL group,” said Dr. Karpouzas.

The analysis did not explore alternate mechanisms such as increased cholesterol loading capacity, lower efflux capacity or increased hepatocyte uptake through LDL-R upregulation, a key limitation. Dr. Karpouzas also acknowledged that higher cumulative inflammatory burden incurred before evaluating low LDL patients at baseline may have led to greater coronary plaque burden.

Overall, the study shows that low LDL is not protective in this population, said Dr. Budoff. “Low LDL patients who have atherosclerosis should be treated with statins and other therapies to lower their CV risk.”
 

Larger studies to confirm associations

Attendees of the ACR 2020 session called for additional studies to confirm that LDL oxidation leads to increased coronary atherosclerotic burden in RA patients.

The study provides “mechanistic insight into this important problem for patients with RA,” noted Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine at Harvard Medical School and associate physician at Brigham and Women’s Hospital, Boston.

Some of the patients studied were on lipid-lowering drugs such as statins, though the statistical analysis adjusted for use of these medications, noted Dr. Sparks. “It is possible that excess systemic inflammation alone is responsible for changes in LDL oxidation that may ultimately lead to cardiovascular disease,” he offered.

Future mechanistic and interventional studies related specifically to LDL oxidation “should establish the importance of this pathway in the development of cardiovascular disease in patients with RA,” said Dr. Sparks.

Large studies of patients with different BMI and LDL values followed prospectively for CV events would be ideal, said Joel M. Kremer, MD, president of the Corrona Research Foundation and founder of Corrona, a biopharma data solutions firm. Investigators would need to follow patients for several years. And, such a venture might face some obstacles. “The practical impediments and cost would be substantial. Also, as LDL oxidation may be related to disease activity, there would be ethical and pragmatic issues associated with controlling disease activity in these patients. This would obscure these outcomes of interest,” said Dr. Kremer.

Dr. Karpouzas receives grant and research support from the American Heart Association and Pfizer-Aspire. Dr. Budoff receives grant support from General Electric.

rhnews@mdedge.com

SOURCE: Karpouzas G et al. ACR 2020. Abstract 0485 and Abstract 0486.

Oxidative stress may account for the “lipid paradox,” a higher incidence of heart disease burden found in nonobese rheumatoid arthritis (RA) patients with lower levels of low-density lipoprotein (LDL). George Karpouzas, MD, an investigator at the Lundquist Institute of Biomedical Innovation, St, Torrance, Calif., discussed this exploratory finding at the virtual annual meeting of the American College of Rheumatology.

A complex dynamic exists between traditional risk factors and cardiovascular (CV) events in RA patients, said Dr. Karpouzas, professor of medicine at the University of California, Los Angeles, and chief of the division of rheumatology, Harbor-UCLA Medical Center. “Lower lipid levels, specifically total cholesterol and to a lesser extent LDL, may be associated with higher risk,” he said. One recent study found that coronary artery calcium (CAC) scores were four times higher in RA patients with lower LDL concentrations (> 70 mg/dL) than those in control groups. “This was especially true in patients who were nonobese, non-Hispanic Whites and never smokers,” said Dr. Karpouzas. Other studies have reported this association between low LDL and increased CVD risk.

These paradoxes led to several questions: Does obesity modify the effect of LDL on cardiovascular disease (CVD) risk in RA and does it moderate the effect of LDL on coronary plaque burden and progression? Do LDL particle composition and oxidation variations underlie the paradoxical association of low LDL with higher coronary atherosclerosis burden in RA? To find answers, Dr. Karpouzas’ team in the Prospective Evaluation of Latent Coronary Atherosclerosis in Rheumatoid Arthritis (PROTECT-RA) trial studied a cohort of 150 established RA patients without symptoms or diagnosis of CV disease.

Dr. Karpouzas presented two oral abstracts that summarized this research during the ACR 2020 session, “RA, diagnosis, manifestations and outcomes: heart of the matter,” which was held virtually.
 

Higher plaque burden seen in nonobese patients

In one part of the study, patients underwent baseline cardiac coronary CT angiography (CTA) over 1 year (2010-2011). Investigators evaluated CAC scores, segment involvement scores (SIS), segment stenosis scores (SSS), and extensive and obstructive disease. Low LDL was defined as < 70 mg/dL, obesity as a waist to height ratio of > 0.58 squared.

Investigators in follow-up work (2017-2018) evaluated for plaque progression, prospectively recording all cardiovascular disease events such as cardiac death, myocardial infarction, unstable angina, stroke, and heart failure hospitalization. Multivariable models assessed the effects of LDL lower than 70 mg/dL, obesity, and their interaction, accounting for factors such as age, sex, statin use, diabetes and hypertension.
 

Four LDL obesity cohorts

Nonobese RA patients with low LDL exhibited the highest plaque burden. “Despite no differences in RA inflammation, patients in this group were more likely to exhibit high levels of LDL oxidation,” Dr. Karpouzas said in an interview. “Nonobese patients with low LDL more likely exhibited new coronary plaque formation as well as increased stenotic severity of prevalent plaque after adjustments for relevant covariates,” he added.

The study’s observational nature exposed it to biases and unmeasured confounding, Dr. Karpouzas emphasized. Because it took place in a single center, the results might not be generalizable to ethnically and racially diverse cohorts. Patients with calcifications, extensive or obstructive coronary plaque at baseline scan received more aggressive treatments, which could have slowed CVD event risk and plaque progression. Investigators cautioned that the results should be seen as “exploratory,” given that CVD event analysis wasn’t applied to the original study design.
 

The oxidation-LDL connection

Another arm of the study examined the oxidation association question. Investigators did a similar analysis of the same patients but also evaluated for cholesterol content, Lp(a) mass, OxLDL levels, IgG and IgM anti-OxLDL and apoB100 immune complexes and proinflammatory cytokines.

RA patients with LDL lower than 70 mg/dL had higher SSS and CAC scores and were more likely to have extensive or obstructive plaque. Statin-naive patients with lower LDL exhibited greater LDL oxidation than higher LDL groups. In addition, those with lower LDL had higher anti-OxLDL and apoB100 than patients with higher LDL.

“Oxidation makes the cholesterol more ‘sticky,’ allowing it to penetrate into the walls of the endothelium, and changes macrophages to foam cells. This malignant process is very powerful and can potentially increase atheroma burden,” study coauthor Matthew Budoff, MD, professor of medicine at UCLA and endowed chair of preventive cardiology at the Lundquist Institute, said in an interview.

Investigators also found an independent association between Lp(a) content and LDL oxidation. This association seemed strong in patients with lower LDL compared to higher LDL groups. In addition, “greater oxidation and immune recognition of oxLDL further associated with higher IL-6 elaboration which may in turn augment atherosclerosis burden in the low LDL group,” said Dr. Karpouzas.

The analysis did not explore alternate mechanisms such as increased cholesterol loading capacity, lower efflux capacity or increased hepatocyte uptake through LDL-R upregulation, a key limitation. Dr. Karpouzas also acknowledged that higher cumulative inflammatory burden incurred before evaluating low LDL patients at baseline may have led to greater coronary plaque burden.

Overall, the study shows that low LDL is not protective in this population, said Dr. Budoff. “Low LDL patients who have atherosclerosis should be treated with statins and other therapies to lower their CV risk.”
 

Larger studies to confirm associations

Attendees of the ACR 2020 session called for additional studies to confirm that LDL oxidation leads to increased coronary atherosclerotic burden in RA patients.

The study provides “mechanistic insight into this important problem for patients with RA,” noted Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine at Harvard Medical School and associate physician at Brigham and Women’s Hospital, Boston.

Some of the patients studied were on lipid-lowering drugs such as statins, though the statistical analysis adjusted for use of these medications, noted Dr. Sparks. “It is possible that excess systemic inflammation alone is responsible for changes in LDL oxidation that may ultimately lead to cardiovascular disease,” he offered.

Future mechanistic and interventional studies related specifically to LDL oxidation “should establish the importance of this pathway in the development of cardiovascular disease in patients with RA,” said Dr. Sparks.

Large studies of patients with different BMI and LDL values followed prospectively for CV events would be ideal, said Joel M. Kremer, MD, president of the Corrona Research Foundation and founder of Corrona, a biopharma data solutions firm. Investigators would need to follow patients for several years. And, such a venture might face some obstacles. “The practical impediments and cost would be substantial. Also, as LDL oxidation may be related to disease activity, there would be ethical and pragmatic issues associated with controlling disease activity in these patients. This would obscure these outcomes of interest,” said Dr. Kremer.

Dr. Karpouzas receives grant and research support from the American Heart Association and Pfizer-Aspire. Dr. Budoff receives grant support from General Electric.

rhnews@mdedge.com

SOURCE: Karpouzas G et al. ACR 2020. Abstract 0485 and Abstract 0486.

Elite American soccer players have, on average, larger, thicker, and heavier hearts than the general population, according to a new study that provides clinicians with normative echocardiogram and electrocardiogram (ECG) cutoffs to use when assessing the heart health of competitive athletes.

Nikada/Getty Images

To provide these age- and sex-specific reference values, a team from Massachusetts General Hospital, Boston, led by Timothy W. Churchill, MD, and Aaron L. Baggish, MD, analyzed data from 122 female and 116 male soccer players from the American national teams preparing for World Cup play and undergoing FIFA-mandated preparticipation screening.

The athletes frequently exceeded normal echocardiographic ranges for left ventricular (LV) mass, volume, and wall thickness – structural cardiac parameters responsive to exercise-induced remodeling – but with none showing pathologic findings that might indicate the need to restrict their participation in the sport.

Almost one-third (30%) of female athletes and 41% of male athletes exceeded the American Society of Echocardiography’s upper limit of normal for LV wall thickness, with a measure greater than 12 mm seen in 12% of men and 1% of women.

The majority (51% of females and 59% of males) exceeded normal ranges for body surface area–indexed LV mass, with 77% and 68%, respectively, having LV volumes above the normal range.

Dr. Baggish stressed in an interview, however, that these data tell a story about healthy hearts, not at-risk hearts.

“These are the healthiest, highest-performing elite soccer players that we have in the United States, and this is really a look at how adaptive the heart can be, how much it can grow and change in size, shape, structure, and function in response to sport,” said Dr. Baggish.

The mean age of screened athletes was 20 years (range, 15-40 years). The majority of the female players were White (71%), whereas the male players were more evenly divided between Black (34%), Hispanic (33%), and White (32%).

Screening was performed at U.S. Soccer training sites by experienced clinicians affiliated with the Massachusetts General Hospital cardiovascular performance program.

Interestingly, the study debunks the idea that women, on average, have smaller chamber sizes. “When we did body-size correction, the men and women actually looked pretty similar with respect to their ability to adapt to strenuous exercise,” noted Dr. Baggish.

They did see, however, that women were more likely than men to have abnormal ECG findings. Male athletes showed a higher prevalence of “normal” training-related ECG findings, whereas female athletes were more likely to have abnormal ECG patterns (11.5% vs. 0.0% in the male cohort), most often pathologic T-wave inversions (TWI) confined to the anterior precordial lead distribution.

“This is important because ECGs are the most common screening tool used and we wanted to alert people to the fact that these women who showed some abnormalities on ECG went on to have a total healthy-looking echo, so a false-positive ECG is something to consider,” said Dr. Baggish.

This excess in anterior TWIs has been seen in previous studies and is thought to be benign, although the mechanism remains unclear. Four of the nine female athletes with abnormal ECG findings on initial evaluation had normalized on repeat testing 2-4 years later. Serial data were available in only a subset of athletes.
 

Clarity needed after COVID

The data, published recently in JAMA Cardiology, are particularly valuable these days given concern over the effects of COVID-19 on the heart and return-to-play recommendations.

“Athletes who have had COVID are being sent for echocardiograms before they can return to play to check for COVID-induced heart disease – which is real – but what we’re seeing is that there’s confusion out there in terms of what is a COVID-related abnormality and what is a normal, adapted athletic heart,” said Dr. Baggish.

“In this paper, we provide a dataset of normal values – generated before COVID was on anyone’s radar – to let cardiologists know what’s ‘big good’ and not ‘big bad.’ ”
 

More sport-specific data needed

“Although these numbers are still small, this dataset is an important step forward in our understanding of athletic adaptations,” said Matthew Martinez, MD, in an interview. “Many factors impact physiologic athletic changes, and the study aids in our understanding of gender- and sport-specific changes in athletes.”

Dr. Martinez, who is the director of sports cardiology at Atlantic Health–Morristown (N.J.) Medical Center and the Gagnon Cardiovascular Institute, also in Morristown, and the chair of Sports and Exercise Cardiology Section Leadership Council for the American College of Cardiology, noted the relatively young mean age of screened athletes.

“The data represent collegiate-age athletes with some older groups mixed in, but it does not represent older established elite athlete changes,” he said.

Mean age was 21 years in the female players but only 18 years in the males because the men’s senior national team failed to qualify for the World Cup during the study period and was therefore not screened. The authors acknowledged the “dearth of older men in the cohort.”

There is, overall, little age-, sport-, and sex-specific normative data for differentiating training-related cardiovascular adaptations from potentially pathologic phenotypes, wrote the authors.

It exists for men playing in the National Football League and for both sexes participating in the National Basketball Association, but most other studies have mixed the sports and focused mainly on men. That said, Dr. Baggish does not consider these data to be applicable to all elite athletes.

“Soccer is kind of in a league of its own with respect to the mixed amount of explosive or resistant and aerobic work that these athletes have to do, and also it’s the most popular sport in the world, so we really wanted to focus on them,” said Dr. Baggish.

Although the findings are perhaps applicable to athletes from other team sports characterized by explosive spurts of high-intensity activity – like hockey, lacrosse, and field hockey – he would not suggest they be applied to, say, long-distance runners, cyclists, or other sports that require a similar type of aerobic output.

Dr. Baggish reported no relevant conflict of interest. Dr. Martinez is league cardiologist for Major League Soccer.

A version of this article first appeared on Medscape.com.

Elite American soccer players have, on average, larger, thicker, and heavier hearts than the general population, according to a new study that provides clinicians with normative echocardiogram and electrocardiogram (ECG) cutoffs to use when assessing the heart health of competitive athletes.

Nikada/Getty Images

To provide these age- and sex-specific reference values, a team from Massachusetts General Hospital, Boston, led by Timothy W. Churchill, MD, and Aaron L. Baggish, MD, analyzed data from 122 female and 116 male soccer players from the American national teams preparing for World Cup play and undergoing FIFA-mandated preparticipation screening.

The athletes frequently exceeded normal echocardiographic ranges for left ventricular (LV) mass, volume, and wall thickness – structural cardiac parameters responsive to exercise-induced remodeling – but with none showing pathologic findings that might indicate the need to restrict their participation in the sport.

Almost one-third (30%) of female athletes and 41% of male athletes exceeded the American Society of Echocardiography’s upper limit of normal for LV wall thickness, with a measure greater than 12 mm seen in 12% of men and 1% of women.

The majority (51% of females and 59% of males) exceeded normal ranges for body surface area–indexed LV mass, with 77% and 68%, respectively, having LV volumes above the normal range.

Dr. Baggish stressed in an interview, however, that these data tell a story about healthy hearts, not at-risk hearts.

“These are the healthiest, highest-performing elite soccer players that we have in the United States, and this is really a look at how adaptive the heart can be, how much it can grow and change in size, shape, structure, and function in response to sport,” said Dr. Baggish.

The mean age of screened athletes was 20 years (range, 15-40 years). The majority of the female players were White (71%), whereas the male players were more evenly divided between Black (34%), Hispanic (33%), and White (32%).

Screening was performed at U.S. Soccer training sites by experienced clinicians affiliated with the Massachusetts General Hospital cardiovascular performance program.

Interestingly, the study debunks the idea that women, on average, have smaller chamber sizes. “When we did body-size correction, the men and women actually looked pretty similar with respect to their ability to adapt to strenuous exercise,” noted Dr. Baggish.

They did see, however, that women were more likely than men to have abnormal ECG findings. Male athletes showed a higher prevalence of “normal” training-related ECG findings, whereas female athletes were more likely to have abnormal ECG patterns (11.5% vs. 0.0% in the male cohort), most often pathologic T-wave inversions (TWI) confined to the anterior precordial lead distribution.

“This is important because ECGs are the most common screening tool used and we wanted to alert people to the fact that these women who showed some abnormalities on ECG went on to have a total healthy-looking echo, so a false-positive ECG is something to consider,” said Dr. Baggish.

This excess in anterior TWIs has been seen in previous studies and is thought to be benign, although the mechanism remains unclear. Four of the nine female athletes with abnormal ECG findings on initial evaluation had normalized on repeat testing 2-4 years later. Serial data were available in only a subset of athletes.
 

Clarity needed after COVID

The data, published recently in JAMA Cardiology, are particularly valuable these days given concern over the effects of COVID-19 on the heart and return-to-play recommendations.

“Athletes who have had COVID are being sent for echocardiograms before they can return to play to check for COVID-induced heart disease – which is real – but what we’re seeing is that there’s confusion out there in terms of what is a COVID-related abnormality and what is a normal, adapted athletic heart,” said Dr. Baggish.

“In this paper, we provide a dataset of normal values – generated before COVID was on anyone’s radar – to let cardiologists know what’s ‘big good’ and not ‘big bad.’ ”
 

More sport-specific data needed

“Although these numbers are still small, this dataset is an important step forward in our understanding of athletic adaptations,” said Matthew Martinez, MD, in an interview. “Many factors impact physiologic athletic changes, and the study aids in our understanding of gender- and sport-specific changes in athletes.”

Dr. Martinez, who is the director of sports cardiology at Atlantic Health–Morristown (N.J.) Medical Center and the Gagnon Cardiovascular Institute, also in Morristown, and the chair of Sports and Exercise Cardiology Section Leadership Council for the American College of Cardiology, noted the relatively young mean age of screened athletes.

“The data represent collegiate-age athletes with some older groups mixed in, but it does not represent older established elite athlete changes,” he said.

Mean age was 21 years in the female players but only 18 years in the males because the men’s senior national team failed to qualify for the World Cup during the study period and was therefore not screened. The authors acknowledged the “dearth of older men in the cohort.”

There is, overall, little age-, sport-, and sex-specific normative data for differentiating training-related cardiovascular adaptations from potentially pathologic phenotypes, wrote the authors.

It exists for men playing in the National Football League and for both sexes participating in the National Basketball Association, but most other studies have mixed the sports and focused mainly on men. That said, Dr. Baggish does not consider these data to be applicable to all elite athletes.

“Soccer is kind of in a league of its own with respect to the mixed amount of explosive or resistant and aerobic work that these athletes have to do, and also it’s the most popular sport in the world, so we really wanted to focus on them,” said Dr. Baggish.

Although the findings are perhaps applicable to athletes from other team sports characterized by explosive spurts of high-intensity activity – like hockey, lacrosse, and field hockey – he would not suggest they be applied to, say, long-distance runners, cyclists, or other sports that require a similar type of aerobic output.

Dr. Baggish reported no relevant conflict of interest. Dr. Martinez is league cardiologist for Major League Soccer.

A version of this article first appeared on Medscape.com.

Elite American soccer players have, on average, larger, thicker, and heavier hearts than the general population, according to a new study that provides clinicians with normative echocardiogram and electrocardiogram (ECG) cutoffs to use when assessing the heart health of competitive athletes.

Nikada/Getty Images

To provide these age- and sex-specific reference values, a team from Massachusetts General Hospital, Boston, led by Timothy W. Churchill, MD, and Aaron L. Baggish, MD, analyzed data from 122 female and 116 male soccer players from the American national teams preparing for World Cup play and undergoing FIFA-mandated preparticipation screening.

The athletes frequently exceeded normal echocardiographic ranges for left ventricular (LV) mass, volume, and wall thickness – structural cardiac parameters responsive to exercise-induced remodeling – but with none showing pathologic findings that might indicate the need to restrict their participation in the sport.

Almost one-third (30%) of female athletes and 41% of male athletes exceeded the American Society of Echocardiography’s upper limit of normal for LV wall thickness, with a measure greater than 12 mm seen in 12% of men and 1% of women.

The majority (51% of females and 59% of males) exceeded normal ranges for body surface area–indexed LV mass, with 77% and 68%, respectively, having LV volumes above the normal range.

Dr. Baggish stressed in an interview, however, that these data tell a story about healthy hearts, not at-risk hearts.

“These are the healthiest, highest-performing elite soccer players that we have in the United States, and this is really a look at how adaptive the heart can be, how much it can grow and change in size, shape, structure, and function in response to sport,” said Dr. Baggish.

The mean age of screened athletes was 20 years (range, 15-40 years). The majority of the female players were White (71%), whereas the male players were more evenly divided between Black (34%), Hispanic (33%), and White (32%).

Screening was performed at U.S. Soccer training sites by experienced clinicians affiliated with the Massachusetts General Hospital cardiovascular performance program.

Interestingly, the study debunks the idea that women, on average, have smaller chamber sizes. “When we did body-size correction, the men and women actually looked pretty similar with respect to their ability to adapt to strenuous exercise,” noted Dr. Baggish.

They did see, however, that women were more likely than men to have abnormal ECG findings. Male athletes showed a higher prevalence of “normal” training-related ECG findings, whereas female athletes were more likely to have abnormal ECG patterns (11.5% vs. 0.0% in the male cohort), most often pathologic T-wave inversions (TWI) confined to the anterior precordial lead distribution.

“This is important because ECGs are the most common screening tool used and we wanted to alert people to the fact that these women who showed some abnormalities on ECG went on to have a total healthy-looking echo, so a false-positive ECG is something to consider,” said Dr. Baggish.

This excess in anterior TWIs has been seen in previous studies and is thought to be benign, although the mechanism remains unclear. Four of the nine female athletes with abnormal ECG findings on initial evaluation had normalized on repeat testing 2-4 years later. Serial data were available in only a subset of athletes.
 

Clarity needed after COVID

The data, published recently in JAMA Cardiology, are particularly valuable these days given concern over the effects of COVID-19 on the heart and return-to-play recommendations.

“Athletes who have had COVID are being sent for echocardiograms before they can return to play to check for COVID-induced heart disease – which is real – but what we’re seeing is that there’s confusion out there in terms of what is a COVID-related abnormality and what is a normal, adapted athletic heart,” said Dr. Baggish.

“In this paper, we provide a dataset of normal values – generated before COVID was on anyone’s radar – to let cardiologists know what’s ‘big good’ and not ‘big bad.’ ”
 

More sport-specific data needed

“Although these numbers are still small, this dataset is an important step forward in our understanding of athletic adaptations,” said Matthew Martinez, MD, in an interview. “Many factors impact physiologic athletic changes, and the study aids in our understanding of gender- and sport-specific changes in athletes.”

Dr. Martinez, who is the director of sports cardiology at Atlantic Health–Morristown (N.J.) Medical Center and the Gagnon Cardiovascular Institute, also in Morristown, and the chair of Sports and Exercise Cardiology Section Leadership Council for the American College of Cardiology, noted the relatively young mean age of screened athletes.

“The data represent collegiate-age athletes with some older groups mixed in, but it does not represent older established elite athlete changes,” he said.

Mean age was 21 years in the female players but only 18 years in the males because the men’s senior national team failed to qualify for the World Cup during the study period and was therefore not screened. The authors acknowledged the “dearth of older men in the cohort.”

There is, overall, little age-, sport-, and sex-specific normative data for differentiating training-related cardiovascular adaptations from potentially pathologic phenotypes, wrote the authors.

It exists for men playing in the National Football League and for both sexes participating in the National Basketball Association, but most other studies have mixed the sports and focused mainly on men. That said, Dr. Baggish does not consider these data to be applicable to all elite athletes.

“Soccer is kind of in a league of its own with respect to the mixed amount of explosive or resistant and aerobic work that these athletes have to do, and also it’s the most popular sport in the world, so we really wanted to focus on them,” said Dr. Baggish.

Although the findings are perhaps applicable to athletes from other team sports characterized by explosive spurts of high-intensity activity – like hockey, lacrosse, and field hockey – he would not suggest they be applied to, say, long-distance runners, cyclists, or other sports that require a similar type of aerobic output.

Dr. Baggish reported no relevant conflict of interest. Dr. Martinez is league cardiologist for Major League Soccer.

A version of this article first appeared on Medscape.com.

Heart transplant recipients infected with SARS-CoV-2 are about twice as likely to die from COVID-19 and should be immediately referred to a transplant center for care, according to transplant experts from Northern Italy.

In a COVID Rapid Report published Dec. 9 in JACC Heart Failure, a group led by Tomaso Bottio, MD, PhD, from the University of Padua, Italy, presented findings on 47 heart transplant recipients who tested positive for SARS-Cov-2 between Feb. 21 and June 30.

The investigators found a case fatality rate of 29.7%, compared with 15.4% in the general population. Prevalence of infection was also much higher at 18 cases (vs. 7) per 1,000 population.

“In our opinion, prompt referral to a heart transplant center is crucial for immunosuppressive therapy optimization and cardiologic follow-up,” Dr. Bottio said in an interview.

Beyond the need for careful adjustment of immunosuppression, graft function should be assessed to “avoid acute rejection or decompensation,” he added.

Dr. Bottio and colleagues tracked COVID-19 cases from among the 2,676 heart transplant recipients alive before the onset of the pandemic at seven heart transplant centers in Northern Italy.

Of the 47 recipients who contracted SARS-CoV-2, 38 required hospitalization while 9 remained at home and 14 died. Mean length of stay in hospital was 17.8 days, much longer in survivors than nonsurvivors (23.2 days vs. 8.5 days; P < .001).  

Nonsurvivors were significantly older than survivors (72 vs. 58 years; P = .002). Nonsurvivors were also more likely to present with diabetes (P = .04), extra-cardiac arteriopathy (P = .04), previous percutaneous coronary intervention (P = .04), more allograft vasculopathy (P = .04), and more symptoms of heart failure (P = .02).

Although the authors said the high case fatality rate was, unfortunately, expected, they did not expect so many patients to do well at home.

“What most surprised us was the proportion of a- or pauci-symptomatic heart transplanted patients who did well being treated at home without any therapy modifications,” Dr. Bottio shared. They were also surprised to see there were no cases of graft failure caused by infection-related myocarditis.

These findings from Northern Italy are not dissimilar from the 25% case fatality rate seen in a cohort of heart transplant recipients who caught COVID-19 in New York City early in the pandemic.

In another study, this time looking at a wider group of solid organ transplant recipients with SARS-CoV-2 infection at two centers during the first 3 weeks of the outbreak in New York City, 16 of 90 patients (18%) died.
 

Treatment recommendations?

Recognizing that there is no randomized trial data informing the treatment of this vulnerable patient population, Dr. Bottio and colleagues suggested that, based on their experience, no change in immunosuppression is needed in those who are “pauci-symptomatic” (mildly symptomatic).

“On the other hand, in hospitalized patients a partial reduction in immunosuppressive therapy avoiding full discontinuation and risk of graft rejection seems to be a common strategy in facing the viral infection,” he said. “In addition, the introduction of corticosteroids could help to suspend the onset of the inflammatory cascade responsible for severe forms of the disease.”

Antibiotic prophylaxis appears to be “fundamental,” he added, particularly in hospitalized patients, but “the role of specific antiviral therapies is still not fully understood in our population.”

Since July 1, they’ve seen an additional six patients with a positive test for SARS-CoV-2. Five were asymptomatic and quarantined at home without changing their immunosuppressive therapy. One patient was hospitalized for pneumonia and had immunosuppressive therapy reduced.

Dr. Bottio and the study coauthors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Heart transplant recipients infected with SARS-CoV-2 are about twice as likely to die from COVID-19 and should be immediately referred to a transplant center for care, according to transplant experts from Northern Italy.

In a COVID Rapid Report published Dec. 9 in JACC Heart Failure, a group led by Tomaso Bottio, MD, PhD, from the University of Padua, Italy, presented findings on 47 heart transplant recipients who tested positive for SARS-Cov-2 between Feb. 21 and June 30.

The investigators found a case fatality rate of 29.7%, compared with 15.4% in the general population. Prevalence of infection was also much higher at 18 cases (vs. 7) per 1,000 population.

“In our opinion, prompt referral to a heart transplant center is crucial for immunosuppressive therapy optimization and cardiologic follow-up,” Dr. Bottio said in an interview.

Beyond the need for careful adjustment of immunosuppression, graft function should be assessed to “avoid acute rejection or decompensation,” he added.

Dr. Bottio and colleagues tracked COVID-19 cases from among the 2,676 heart transplant recipients alive before the onset of the pandemic at seven heart transplant centers in Northern Italy.

Of the 47 recipients who contracted SARS-CoV-2, 38 required hospitalization while 9 remained at home and 14 died. Mean length of stay in hospital was 17.8 days, much longer in survivors than nonsurvivors (23.2 days vs. 8.5 days; P < .001).  

Nonsurvivors were significantly older than survivors (72 vs. 58 years; P = .002). Nonsurvivors were also more likely to present with diabetes (P = .04), extra-cardiac arteriopathy (P = .04), previous percutaneous coronary intervention (P = .04), more allograft vasculopathy (P = .04), and more symptoms of heart failure (P = .02).

Although the authors said the high case fatality rate was, unfortunately, expected, they did not expect so many patients to do well at home.

“What most surprised us was the proportion of a- or pauci-symptomatic heart transplanted patients who did well being treated at home without any therapy modifications,” Dr. Bottio shared. They were also surprised to see there were no cases of graft failure caused by infection-related myocarditis.

These findings from Northern Italy are not dissimilar from the 25% case fatality rate seen in a cohort of heart transplant recipients who caught COVID-19 in New York City early in the pandemic.

In another study, this time looking at a wider group of solid organ transplant recipients with SARS-CoV-2 infection at two centers during the first 3 weeks of the outbreak in New York City, 16 of 90 patients (18%) died.
 

Treatment recommendations?

Recognizing that there is no randomized trial data informing the treatment of this vulnerable patient population, Dr. Bottio and colleagues suggested that, based on their experience, no change in immunosuppression is needed in those who are “pauci-symptomatic” (mildly symptomatic).

“On the other hand, in hospitalized patients a partial reduction in immunosuppressive therapy avoiding full discontinuation and risk of graft rejection seems to be a common strategy in facing the viral infection,” he said. “In addition, the introduction of corticosteroids could help to suspend the onset of the inflammatory cascade responsible for severe forms of the disease.”

Antibiotic prophylaxis appears to be “fundamental,” he added, particularly in hospitalized patients, but “the role of specific antiviral therapies is still not fully understood in our population.”

Since July 1, they’ve seen an additional six patients with a positive test for SARS-CoV-2. Five were asymptomatic and quarantined at home without changing their immunosuppressive therapy. One patient was hospitalized for pneumonia and had immunosuppressive therapy reduced.

Dr. Bottio and the study coauthors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Heart transplant recipients infected with SARS-CoV-2 are about twice as likely to die from COVID-19 and should be immediately referred to a transplant center for care, according to transplant experts from Northern Italy.

In a COVID Rapid Report published Dec. 9 in JACC Heart Failure, a group led by Tomaso Bottio, MD, PhD, from the University of Padua, Italy, presented findings on 47 heart transplant recipients who tested positive for SARS-Cov-2 between Feb. 21 and June 30.

The investigators found a case fatality rate of 29.7%, compared with 15.4% in the general population. Prevalence of infection was also much higher at 18 cases (vs. 7) per 1,000 population.

“In our opinion, prompt referral to a heart transplant center is crucial for immunosuppressive therapy optimization and cardiologic follow-up,” Dr. Bottio said in an interview.

Beyond the need for careful adjustment of immunosuppression, graft function should be assessed to “avoid acute rejection or decompensation,” he added.

Dr. Bottio and colleagues tracked COVID-19 cases from among the 2,676 heart transplant recipients alive before the onset of the pandemic at seven heart transplant centers in Northern Italy.

Of the 47 recipients who contracted SARS-CoV-2, 38 required hospitalization while 9 remained at home and 14 died. Mean length of stay in hospital was 17.8 days, much longer in survivors than nonsurvivors (23.2 days vs. 8.5 days; P < .001).  

Nonsurvivors were significantly older than survivors (72 vs. 58 years; P = .002). Nonsurvivors were also more likely to present with diabetes (P = .04), extra-cardiac arteriopathy (P = .04), previous percutaneous coronary intervention (P = .04), more allograft vasculopathy (P = .04), and more symptoms of heart failure (P = .02).

Although the authors said the high case fatality rate was, unfortunately, expected, they did not expect so many patients to do well at home.

“What most surprised us was the proportion of a- or pauci-symptomatic heart transplanted patients who did well being treated at home without any therapy modifications,” Dr. Bottio shared. They were also surprised to see there were no cases of graft failure caused by infection-related myocarditis.

These findings from Northern Italy are not dissimilar from the 25% case fatality rate seen in a cohort of heart transplant recipients who caught COVID-19 in New York City early in the pandemic.

In another study, this time looking at a wider group of solid organ transplant recipients with SARS-CoV-2 infection at two centers during the first 3 weeks of the outbreak in New York City, 16 of 90 patients (18%) died.
 

Treatment recommendations?

Recognizing that there is no randomized trial data informing the treatment of this vulnerable patient population, Dr. Bottio and colleagues suggested that, based on their experience, no change in immunosuppression is needed in those who are “pauci-symptomatic” (mildly symptomatic).

“On the other hand, in hospitalized patients a partial reduction in immunosuppressive therapy avoiding full discontinuation and risk of graft rejection seems to be a common strategy in facing the viral infection,” he said. “In addition, the introduction of corticosteroids could help to suspend the onset of the inflammatory cascade responsible for severe forms of the disease.”

Antibiotic prophylaxis appears to be “fundamental,” he added, particularly in hospitalized patients, but “the role of specific antiviral therapies is still not fully understood in our population.”

Since July 1, they’ve seen an additional six patients with a positive test for SARS-CoV-2. Five were asymptomatic and quarantined at home without changing their immunosuppressive therapy. One patient was hospitalized for pneumonia and had immunosuppressive therapy reduced.

Dr. Bottio and the study coauthors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Each year in the United States, approximately one to two out of every thousand people suffer from venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. The American Society of Hematology (ASH) issued new guidelines for the management of VTE, including primary treatment, secondary prevention, and treatment of recurrent events, earlier this year.

These guidelines, which were recently published in Blood Advances (Ortel T L et al. Blood Adv 2020 doi: 10.1182/bloodadvances.2020001830), include 28 recommendations.

How to treat uncomplicated patients

For uncomplicated deep vein thrombosis (DVT) and/or pulmonary embolism (PE), the guidelines suggest treating patients at home rather than in the hospital. This is especially important for family physicians to note as many of these patients will now be the responsibility of the primary care doctor to treat and follow. Patients treated at home can avoid the risk of nosocomial infections, especially in the days of COVID-19. Evidence also suggests that being treated at home was shown to reduce the risk of PE versus being treated in the hospital. It is, therefore, crucial that family physicians know which patients are low versus high risk.

Further, the guidelines suggest that these patients with low risk of complications are better treated with direct oral anticoagulants (DOACs) instead of vitamin K antagonists, such as Coumadin.

Medication-related suggestions

The guidelines also suggest that no DOAC is preferred over another. Since DOACs are relatively newer agents, family doctors need to become comfortable with their use. For proximal DVTs, anticoagulation alone can be used without thrombolytics.

Family physicians are often tasked with the decision on when to stop anticoagulation. The authors recommend against using diagnostic tests such as D-Dimer or ultrasound to decide when to stop these medications in low-risk patients. In patients at risk of recurrent VTE due to chronic medical conditions, it is suggested to continue anti-coagulants indefinitely. While anticoagulant therapy effectively reduces risk of VTE, it does increase the risk of bleeding events.

The guidelines are quite extensive and specific in their recommendations and family physicians need to understand them. We are often the first ones in the medical system to diagnose VTE, and it is quite possible to keep these patients home, thereby eliminating risks they may encounter by being hospitalized. In addition, the recommendation regarding the use of DOACs may ease some of the burden of monitoring patients on long-term Coumadin. These medications do not come without risks, and we must be comfortable evaluating for any complications. In our current health care system, different insurance companies have different formularies making it necessary for us to know all these medications.

In the past, the diagnosis of PE and even a DVT would mean a hospital stay. We now know, and these guidelines reaffirm, that this is not necessary in uncomplicated cases.

In addition to diagnosing VTE, family physicians are also tasked with following up with patients who were hospitalized or started on treatment by other physicians. We need to know the plan on when to stop the medication or when to reevaluate its use. Patients often bring this question to us, and these guidelines will help us answer that question.

Many patients who have more complicated medical conditions often see multiple specialists. The ASH recommendations help standardize the care of these patients across specialties.

What the recommendations are missing

As family doctors, we often treat patients with multiple comorbidities. These guidelines do not make recommendations for patients with cancer, who are at high risk of VTE events. Some patients also have conditions that increase their risk of bleeding or have contraindications to the use of anticoagulants. It would be helpful to have more recommendations for both of these types of patients in addition to the use of inferior vena cava filter in patients with proximal DVT. The document is also missing recommendations for pregnant patients, which would be useful.

Overall, these guidelines include much of what we already do in our practices while doing a great job of incorporating the newer DOACs. These guidelines are easy for family physicians to put into practice.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at fpnews@mdedge.com.

Each year in the United States, approximately one to two out of every thousand people suffer from venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. The American Society of Hematology (ASH) issued new guidelines for the management of VTE, including primary treatment, secondary prevention, and treatment of recurrent events, earlier this year.

These guidelines, which were recently published in Blood Advances (Ortel T L et al. Blood Adv 2020 doi: 10.1182/bloodadvances.2020001830), include 28 recommendations.

How to treat uncomplicated patients

For uncomplicated deep vein thrombosis (DVT) and/or pulmonary embolism (PE), the guidelines suggest treating patients at home rather than in the hospital. This is especially important for family physicians to note as many of these patients will now be the responsibility of the primary care doctor to treat and follow. Patients treated at home can avoid the risk of nosocomial infections, especially in the days of COVID-19. Evidence also suggests that being treated at home was shown to reduce the risk of PE versus being treated in the hospital. It is, therefore, crucial that family physicians know which patients are low versus high risk.

Further, the guidelines suggest that these patients with low risk of complications are better treated with direct oral anticoagulants (DOACs) instead of vitamin K antagonists, such as Coumadin.

Medication-related suggestions

The guidelines also suggest that no DOAC is preferred over another. Since DOACs are relatively newer agents, family doctors need to become comfortable with their use. For proximal DVTs, anticoagulation alone can be used without thrombolytics.

Family physicians are often tasked with the decision on when to stop anticoagulation. The authors recommend against using diagnostic tests such as D-Dimer or ultrasound to decide when to stop these medications in low-risk patients. In patients at risk of recurrent VTE due to chronic medical conditions, it is suggested to continue anti-coagulants indefinitely. While anticoagulant therapy effectively reduces risk of VTE, it does increase the risk of bleeding events.

The guidelines are quite extensive and specific in their recommendations and family physicians need to understand them. We are often the first ones in the medical system to diagnose VTE, and it is quite possible to keep these patients home, thereby eliminating risks they may encounter by being hospitalized. In addition, the recommendation regarding the use of DOACs may ease some of the burden of monitoring patients on long-term Coumadin. These medications do not come without risks, and we must be comfortable evaluating for any complications. In our current health care system, different insurance companies have different formularies making it necessary for us to know all these medications.

In the past, the diagnosis of PE and even a DVT would mean a hospital stay. We now know, and these guidelines reaffirm, that this is not necessary in uncomplicated cases.

In addition to diagnosing VTE, family physicians are also tasked with following up with patients who were hospitalized or started on treatment by other physicians. We need to know the plan on when to stop the medication or when to reevaluate its use. Patients often bring this question to us, and these guidelines will help us answer that question.

Many patients who have more complicated medical conditions often see multiple specialists. The ASH recommendations help standardize the care of these patients across specialties.

What the recommendations are missing

As family doctors, we often treat patients with multiple comorbidities. These guidelines do not make recommendations for patients with cancer, who are at high risk of VTE events. Some patients also have conditions that increase their risk of bleeding or have contraindications to the use of anticoagulants. It would be helpful to have more recommendations for both of these types of patients in addition to the use of inferior vena cava filter in patients with proximal DVT. The document is also missing recommendations for pregnant patients, which would be useful.

Overall, these guidelines include much of what we already do in our practices while doing a great job of incorporating the newer DOACs. These guidelines are easy for family physicians to put into practice.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at fpnews@mdedge.com.

Each year in the United States, approximately one to two out of every thousand people suffer from venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. The American Society of Hematology (ASH) issued new guidelines for the management of VTE, including primary treatment, secondary prevention, and treatment of recurrent events, earlier this year.

These guidelines, which were recently published in Blood Advances (Ortel T L et al. Blood Adv 2020 doi: 10.1182/bloodadvances.2020001830), include 28 recommendations.

How to treat uncomplicated patients

For uncomplicated deep vein thrombosis (DVT) and/or pulmonary embolism (PE), the guidelines suggest treating patients at home rather than in the hospital. This is especially important for family physicians to note as many of these patients will now be the responsibility of the primary care doctor to treat and follow. Patients treated at home can avoid the risk of nosocomial infections, especially in the days of COVID-19. Evidence also suggests that being treated at home was shown to reduce the risk of PE versus being treated in the hospital. It is, therefore, crucial that family physicians know which patients are low versus high risk.

Further, the guidelines suggest that these patients with low risk of complications are better treated with direct oral anticoagulants (DOACs) instead of vitamin K antagonists, such as Coumadin.

Medication-related suggestions

The guidelines also suggest that no DOAC is preferred over another. Since DOACs are relatively newer agents, family doctors need to become comfortable with their use. For proximal DVTs, anticoagulation alone can be used without thrombolytics.

Family physicians are often tasked with the decision on when to stop anticoagulation. The authors recommend against using diagnostic tests such as D-Dimer or ultrasound to decide when to stop these medications in low-risk patients. In patients at risk of recurrent VTE due to chronic medical conditions, it is suggested to continue anti-coagulants indefinitely. While anticoagulant therapy effectively reduces risk of VTE, it does increase the risk of bleeding events.

The guidelines are quite extensive and specific in their recommendations and family physicians need to understand them. We are often the first ones in the medical system to diagnose VTE, and it is quite possible to keep these patients home, thereby eliminating risks they may encounter by being hospitalized. In addition, the recommendation regarding the use of DOACs may ease some of the burden of monitoring patients on long-term Coumadin. These medications do not come without risks, and we must be comfortable evaluating for any complications. In our current health care system, different insurance companies have different formularies making it necessary for us to know all these medications.

In the past, the diagnosis of PE and even a DVT would mean a hospital stay. We now know, and these guidelines reaffirm, that this is not necessary in uncomplicated cases.

In addition to diagnosing VTE, family physicians are also tasked with following up with patients who were hospitalized or started on treatment by other physicians. We need to know the plan on when to stop the medication or when to reevaluate its use. Patients often bring this question to us, and these guidelines will help us answer that question.

Many patients who have more complicated medical conditions often see multiple specialists. The ASH recommendations help standardize the care of these patients across specialties.

What the recommendations are missing

As family doctors, we often treat patients with multiple comorbidities. These guidelines do not make recommendations for patients with cancer, who are at high risk of VTE events. Some patients also have conditions that increase their risk of bleeding or have contraindications to the use of anticoagulants. It would be helpful to have more recommendations for both of these types of patients in addition to the use of inferior vena cava filter in patients with proximal DVT. The document is also missing recommendations for pregnant patients, which would be useful.

Overall, these guidelines include much of what we already do in our practices while doing a great job of incorporating the newer DOACs. These guidelines are easy for family physicians to put into practice.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at fpnews@mdedge.com.

A Food and Drug Administration advisory committee lit a long-standing fuse, recommending that evidence from the controversial TOPCAT trial can be used to support a new indication for spironolactone.

The generic aldosterone blocker is already approved for the treatment of heart failure with reduced ejection fraction (HFrEF). 

Hopes that it could be the first therapy to show improved outcomes in HF with preserved EF (HFpEF) were dashed in 2013 when TOPCAT failed to show a significant benefit over placebo for the primary endpoint of cardiovascular (CV) death, HF hospitalization, or aborted cardiac arrest.

Regional differences in the data, however, aroused concerns about the findings early on. Patients enrolled in Russia and the Republic of Georgia were younger, less likely to qualify on the basis of elevated natriuretic peptide levels, and had more evidence of ischemic heart disease than those in the Americas.

Event rates were also substantially lower in Russia/Georgia than in the Americas and in previous HFpEF trials, suggesting that many of these patients may not have had heart failure, the trialists argued.

In the Americas, results for the primary endpoint favor spironolactone over placebo (10.4 vs. 12.6 events per 100 patient-years; P = .026), whereas the rate in Russia/Georgia was much lower than in the Americas and slightly favors placebo (2.5 vs. 2.3 events/100 patient-years).

Medication noncompliance also may have been more common in Russia/Georgia based on pharmacodynamic studies and a 2017 analysis showing undetectable levels of canrenone, an active metabolite of spironolactone, in 30% of Russian versus 3% of North American patients who reported using the drug at 1 year.

TOPCAT investigator Marc Pfeffer, MD, PhD, from Brigham and Women’s Hospital and Harvard Medical School, Boston, said no trial is without flaws but that the observations represent serious misconduct. “Really we’re talking about a cancer, a cancer that has clear margins. The margins are Russia, Georgia that warrant censoring their data.”

The FDA’s own review of the National Institutes of Health–sponsored study, however, showed no significant interaction between treatment and region (P = .12) and “insufficient evidence to conclude the two regions are different enough such that overall results should not be considered,” said FDA statistician Ququan Liu, MD, MS.

She cautioned against removing data from a whole region that constituted almost half the study population and said it would set a precedent on what is considered substantial evidence for approval.

Several advisors concurred but, ultimately, the Cardiovascular and Renal Drugs Advisory Committee voted 8 to 4, with 1 abstention, that TOPCAT provides “sufficient evidence to support any indication.”

The same committee voted yesterday in support of an expanded role for sacubitril/valsartan (Entresto, Novartis) in select patients with HFpEF. In casting a “no” vote, panelist Steven E. Nissen, MD, from the Cleveland Clinic, said that decisions made by the panel set precedent.

Catherine Hackett

“If the pharmaceutical industry came to us with a study like this and said the P value was .14 but we think a bunch of our sites weren’t very good and so we’re going to throw those data out and just look at the sites we like, the FDA would not have even brought that before us,” he said. “I cannot hold other sponsors, including our own government, to a different standard.”

Dr. Nissen argued that the primary endpoint failed by a significant margin (P = .138), the study was marginally powered, there was a troubling amount of missing data in the two regions, and spironolactone is also not without side effects. “Poor study conduct cannot be an excuse for a result we don’t like.”

Panel chair Julia B. Lewis, MD, from Vanderbilt University Medical Center in Nashville, Tenn., said she would love to support a cheap, generic drug to keep HF patients out of the hospital but was troubled by the egregious conduct of the trial and concerns about cherry-picking results. “My heart says this would be a great place for us to go but I can’t say that my head thinks this is an acceptable body of data.”

Several panelists, however, highlighted the benefits with spironolactone over placebo in the Americas including an 18% reduction in hospitalization for HF (21% vs. 25%; hazard ratio, 0.82; P = .04) and a 25% reduction in cumulative HF hospitalizations (361 vs. 438 events; incidence rate ratio, 0.75; P = .024).

There was also a reduction in CV mortality with spironolactone (11% vs. 14%; HR, 0.74; P = .027) – something, it was noted, not observed during the prior day’s proceeding on sacubitril/valsartan.

Panelist Christopher M. O’Connor, MD, from Inova Heart and Vascular Institute in Falls Church, Va., and Duke University, Durham, N.C., said he voted “yes” because of the totality of the information and that the investigators provided “compelling evidence” with or without the Russia/Georgia cohort on the efficacy on HF hospitalization reduction. “I think this is the augmented sweet spot of this data set.”

C. Michael Gibson, MD, said his decision to vote yes was not based on analyses that excluded half the patients but rather on the totality of the evidence, particularly the benefit on cumulative HF hospitalizations and in those with an EF lower than 56%.

Several panelists and members of the public cited for treatments among patients with HFpEF. Edward K. Kasper, MD, from Johns Hopkins University, Baltimore, said he found both sides of the argument persuasive but that he already uses spironolactone in this setting. “Somehow I’ve become convinced that this drug worked, so I voted yes.”

Dr. Kasper said the FDA may ultimately find there isn’t an indication for spironolactone in HFpEF but that it will likely move from a IIb to IIa recommendation in the next iteration of the American College of Cardiology guidelines.

Paul Ridker, MD, MPH, from Brigham and Women’s Hospital and Harvard Medical School, said he shared concerns about the precedent of dropping half the data, “even though, in this case, I believe half the data is wrong.”

Dr. Ridker noted that he would have been comfortable using the secondary endpoint of HF reduction as an indication in patients with mildly reduced EF but abstained because that data was not presented today, although it may be available from TOPCAT and the RALES trial.

The panel took up other nonvoting questions, including what additional data would be needed to augment support for approval. Suggestions ranged from additional analyses to a new trial, with TOPCAT serving as “pilot data,” but no recommendation was made.

A version of this article first appeared on Medscape.com.

A Food and Drug Administration advisory committee lit a long-standing fuse, recommending that evidence from the controversial TOPCAT trial can be used to support a new indication for spironolactone.

The generic aldosterone blocker is already approved for the treatment of heart failure with reduced ejection fraction (HFrEF). 

Hopes that it could be the first therapy to show improved outcomes in HF with preserved EF (HFpEF) were dashed in 2013 when TOPCAT failed to show a significant benefit over placebo for the primary endpoint of cardiovascular (CV) death, HF hospitalization, or aborted cardiac arrest.

Regional differences in the data, however, aroused concerns about the findings early on. Patients enrolled in Russia and the Republic of Georgia were younger, less likely to qualify on the basis of elevated natriuretic peptide levels, and had more evidence of ischemic heart disease than those in the Americas.

Event rates were also substantially lower in Russia/Georgia than in the Americas and in previous HFpEF trials, suggesting that many of these patients may not have had heart failure, the trialists argued.

In the Americas, results for the primary endpoint favor spironolactone over placebo (10.4 vs. 12.6 events per 100 patient-years; P = .026), whereas the rate in Russia/Georgia was much lower than in the Americas and slightly favors placebo (2.5 vs. 2.3 events/100 patient-years).

Medication noncompliance also may have been more common in Russia/Georgia based on pharmacodynamic studies and a 2017 analysis showing undetectable levels of canrenone, an active metabolite of spironolactone, in 30% of Russian versus 3% of North American patients who reported using the drug at 1 year.

TOPCAT investigator Marc Pfeffer, MD, PhD, from Brigham and Women’s Hospital and Harvard Medical School, Boston, said no trial is without flaws but that the observations represent serious misconduct. “Really we’re talking about a cancer, a cancer that has clear margins. The margins are Russia, Georgia that warrant censoring their data.”

The FDA’s own review of the National Institutes of Health–sponsored study, however, showed no significant interaction between treatment and region (P = .12) and “insufficient evidence to conclude the two regions are different enough such that overall results should not be considered,” said FDA statistician Ququan Liu, MD, MS.

She cautioned against removing data from a whole region that constituted almost half the study population and said it would set a precedent on what is considered substantial evidence for approval.

Several advisors concurred but, ultimately, the Cardiovascular and Renal Drugs Advisory Committee voted 8 to 4, with 1 abstention, that TOPCAT provides “sufficient evidence to support any indication.”

The same committee voted yesterday in support of an expanded role for sacubitril/valsartan (Entresto, Novartis) in select patients with HFpEF. In casting a “no” vote, panelist Steven E. Nissen, MD, from the Cleveland Clinic, said that decisions made by the panel set precedent.

Catherine Hackett

“If the pharmaceutical industry came to us with a study like this and said the P value was .14 but we think a bunch of our sites weren’t very good and so we’re going to throw those data out and just look at the sites we like, the FDA would not have even brought that before us,” he said. “I cannot hold other sponsors, including our own government, to a different standard.”

Dr. Nissen argued that the primary endpoint failed by a significant margin (P = .138), the study was marginally powered, there was a troubling amount of missing data in the two regions, and spironolactone is also not without side effects. “Poor study conduct cannot be an excuse for a result we don’t like.”

Panel chair Julia B. Lewis, MD, from Vanderbilt University Medical Center in Nashville, Tenn., said she would love to support a cheap, generic drug to keep HF patients out of the hospital but was troubled by the egregious conduct of the trial and concerns about cherry-picking results. “My heart says this would be a great place for us to go but I can’t say that my head thinks this is an acceptable body of data.”

Several panelists, however, highlighted the benefits with spironolactone over placebo in the Americas including an 18% reduction in hospitalization for HF (21% vs. 25%; hazard ratio, 0.82; P = .04) and a 25% reduction in cumulative HF hospitalizations (361 vs. 438 events; incidence rate ratio, 0.75; P = .024).

There was also a reduction in CV mortality with spironolactone (11% vs. 14%; HR, 0.74; P = .027) – something, it was noted, not observed during the prior day’s proceeding on sacubitril/valsartan.

Panelist Christopher M. O’Connor, MD, from Inova Heart and Vascular Institute in Falls Church, Va., and Duke University, Durham, N.C., said he voted “yes” because of the totality of the information and that the investigators provided “compelling evidence” with or without the Russia/Georgia cohort on the efficacy on HF hospitalization reduction. “I think this is the augmented sweet spot of this data set.”

C. Michael Gibson, MD, said his decision to vote yes was not based on analyses that excluded half the patients but rather on the totality of the evidence, particularly the benefit on cumulative HF hospitalizations and in those with an EF lower than 56%.

Several panelists and members of the public cited for treatments among patients with HFpEF. Edward K. Kasper, MD, from Johns Hopkins University, Baltimore, said he found both sides of the argument persuasive but that he already uses spironolactone in this setting. “Somehow I’ve become convinced that this drug worked, so I voted yes.”

Dr. Kasper said the FDA may ultimately find there isn’t an indication for spironolactone in HFpEF but that it will likely move from a IIb to IIa recommendation in the next iteration of the American College of Cardiology guidelines.

Paul Ridker, MD, MPH, from Brigham and Women’s Hospital and Harvard Medical School, said he shared concerns about the precedent of dropping half the data, “even though, in this case, I believe half the data is wrong.”

Dr. Ridker noted that he would have been comfortable using the secondary endpoint of HF reduction as an indication in patients with mildly reduced EF but abstained because that data was not presented today, although it may be available from TOPCAT and the RALES trial.

The panel took up other nonvoting questions, including what additional data would be needed to augment support for approval. Suggestions ranged from additional analyses to a new trial, with TOPCAT serving as “pilot data,” but no recommendation was made.

A version of this article first appeared on Medscape.com.

A Food and Drug Administration advisory committee lit a long-standing fuse, recommending that evidence from the controversial TOPCAT trial can be used to support a new indication for spironolactone.

The generic aldosterone blocker is already approved for the treatment of heart failure with reduced ejection fraction (HFrEF). 

Hopes that it could be the first therapy to show improved outcomes in HF with preserved EF (HFpEF) were dashed in 2013 when TOPCAT failed to show a significant benefit over placebo for the primary endpoint of cardiovascular (CV) death, HF hospitalization, or aborted cardiac arrest.

Regional differences in the data, however, aroused concerns about the findings early on. Patients enrolled in Russia and the Republic of Georgia were younger, less likely to qualify on the basis of elevated natriuretic peptide levels, and had more evidence of ischemic heart disease than those in the Americas.

Event rates were also substantially lower in Russia/Georgia than in the Americas and in previous HFpEF trials, suggesting that many of these patients may not have had heart failure, the trialists argued.

In the Americas, results for the primary endpoint favor spironolactone over placebo (10.4 vs. 12.6 events per 100 patient-years; P = .026), whereas the rate in Russia/Georgia was much lower than in the Americas and slightly favors placebo (2.5 vs. 2.3 events/100 patient-years).

Medication noncompliance also may have been more common in Russia/Georgia based on pharmacodynamic studies and a 2017 analysis showing undetectable levels of canrenone, an active metabolite of spironolactone, in 30% of Russian versus 3% of North American patients who reported using the drug at 1 year.

TOPCAT investigator Marc Pfeffer, MD, PhD, from Brigham and Women’s Hospital and Harvard Medical School, Boston, said no trial is without flaws but that the observations represent serious misconduct. “Really we’re talking about a cancer, a cancer that has clear margins. The margins are Russia, Georgia that warrant censoring their data.”

The FDA’s own review of the National Institutes of Health–sponsored study, however, showed no significant interaction between treatment and region (P = .12) and “insufficient evidence to conclude the two regions are different enough such that overall results should not be considered,” said FDA statistician Ququan Liu, MD, MS.

She cautioned against removing data from a whole region that constituted almost half the study population and said it would set a precedent on what is considered substantial evidence for approval.

Several advisors concurred but, ultimately, the Cardiovascular and Renal Drugs Advisory Committee voted 8 to 4, with 1 abstention, that TOPCAT provides “sufficient evidence to support any indication.”

The same committee voted yesterday in support of an expanded role for sacubitril/valsartan (Entresto, Novartis) in select patients with HFpEF. In casting a “no” vote, panelist Steven E. Nissen, MD, from the Cleveland Clinic, said that decisions made by the panel set precedent.

Catherine Hackett

“If the pharmaceutical industry came to us with a study like this and said the P value was .14 but we think a bunch of our sites weren’t very good and so we’re going to throw those data out and just look at the sites we like, the FDA would not have even brought that before us,” he said. “I cannot hold other sponsors, including our own government, to a different standard.”

Dr. Nissen argued that the primary endpoint failed by a significant margin (P = .138), the study was marginally powered, there was a troubling amount of missing data in the two regions, and spironolactone is also not without side effects. “Poor study conduct cannot be an excuse for a result we don’t like.”

Panel chair Julia B. Lewis, MD, from Vanderbilt University Medical Center in Nashville, Tenn., said she would love to support a cheap, generic drug to keep HF patients out of the hospital but was troubled by the egregious conduct of the trial and concerns about cherry-picking results. “My heart says this would be a great place for us to go but I can’t say that my head thinks this is an acceptable body of data.”

Several panelists, however, highlighted the benefits with spironolactone over placebo in the Americas including an 18% reduction in hospitalization for HF (21% vs. 25%; hazard ratio, 0.82; P = .04) and a 25% reduction in cumulative HF hospitalizations (361 vs. 438 events; incidence rate ratio, 0.75; P = .024).

There was also a reduction in CV mortality with spironolactone (11% vs. 14%; HR, 0.74; P = .027) – something, it was noted, not observed during the prior day’s proceeding on sacubitril/valsartan.

Panelist Christopher M. O’Connor, MD, from Inova Heart and Vascular Institute in Falls Church, Va., and Duke University, Durham, N.C., said he voted “yes” because of the totality of the information and that the investigators provided “compelling evidence” with or without the Russia/Georgia cohort on the efficacy on HF hospitalization reduction. “I think this is the augmented sweet spot of this data set.”

C. Michael Gibson, MD, said his decision to vote yes was not based on analyses that excluded half the patients but rather on the totality of the evidence, particularly the benefit on cumulative HF hospitalizations and in those with an EF lower than 56%.

Several panelists and members of the public cited for treatments among patients with HFpEF. Edward K. Kasper, MD, from Johns Hopkins University, Baltimore, said he found both sides of the argument persuasive but that he already uses spironolactone in this setting. “Somehow I’ve become convinced that this drug worked, so I voted yes.”

Dr. Kasper said the FDA may ultimately find there isn’t an indication for spironolactone in HFpEF but that it will likely move from a IIb to IIa recommendation in the next iteration of the American College of Cardiology guidelines.

Paul Ridker, MD, MPH, from Brigham and Women’s Hospital and Harvard Medical School, said he shared concerns about the precedent of dropping half the data, “even though, in this case, I believe half the data is wrong.”

Dr. Ridker noted that he would have been comfortable using the secondary endpoint of HF reduction as an indication in patients with mildly reduced EF but abstained because that data was not presented today, although it may be available from TOPCAT and the RALES trial.

The panel took up other nonvoting questions, including what additional data would be needed to augment support for approval. Suggestions ranged from additional analyses to a new trial, with TOPCAT serving as “pilot data,” but no recommendation was made.

A version of this article first appeared on Medscape.com.

Two new studies suggest that LDL cholesterol (LDL-C) may be not the main driver of atherosclerotic cardiovascular disease (ASCVD).

The findings instead implicate remnant cholesterol (remnant-C) and very-low-density lipoprotein (VLDL) cholesterol in the development of cardiovascular disease (CVD) and MI.

The PREDIMED study, conducted in Spain, examined the association of triglycerides and remnant-C with major cardiovascular events (MACE) in older individuals with high CVD risk. It found that levels of triglycerides and remnant-C were associated with MACE independently of other risk factors, but there was no similar association with LDL-C.

“These findings lead [clinicians] to consider in the clinical management of dyslipidemias a greater control of the lipid profiles as a whole, including remnant-cholesterol and/or triglycerides,” Montserrat Fitó Colomer, MD, PhD, of the Cardiovascular Risk and Nutrition Research Group, Hospital del Mar Medical Research Institute, Barcelona, said in an interview.

In a separate analysis, the Copenhagen General Population Study, which focused on 25,000 individuals who were not taking lipid-lowering therapy, looked at the role of VLDL cholesterol and triglycerides in driving MI risk from apolipoprotein B (apoB)–containing lipoproteins.

Bruce Jancin/Frontline Medical News

“Elevated VLDL cholesterol explained a larger fraction of risk than did elevated LDL cholesterol, or elevated VLDL triglycerides,” Børge G. Nordestgaard, MD, DMSc, professor, University of Copenhagen, said in an interview.

Both studies were published online Nov. 30 in the Journal of the American College of Cardiology.

But in an editorial accompanying both reports, John Burnett, MD, PhD, from the University of Western Australia, Perth, and colleagues cautioned that it would be “premature to discard LDL-C based on PREDIMED.”

The findings are “insufficient to offset the mountain of literally hundreds of studies that uphold the value of LDL-C in prediction and intervention of ASCVD,” Dr. Burnett and coauthors wrote.

Similarly, the editorialists cautioned that, although the findings from the study by Dr. Nordestgaard and colleagues indicate that VLDL cholesterol is the “new kid in town for prediction, LDL cholesterol retains predictive power.” Clinical cardiologists should not “shelve LDL cholesterol and embrace VLDL and remnant cholesterol as the new oracles of ASCVD risk.” 

In a comment, Dr. Burnett said, “The take-home message for clinicians in both papers is that LDL-C is the main lipid measurement to guide clinical decisions; however, residual risk of atherosclerotic cardiovascular disease remains, even after LCL-C is treated.

“Assessment of residual ASCVD risk with nontraditional lipid biomarkers, including VLDL cholesterol and remnant cholesterol, as well as lipoprotein (a) and apoB, may improve prognostication and help guide preventive treatments,” he added.
 

“Affordable and inexpensive”

In their report, the PREDIMED study authors explained that atherogenic dyslipidemia is characterized by “an excess of serum triglycerides” contained in VLDL cholesterol, intermediate-density lipoproteins, and their remnants, all of which are called “triglyceride-rich lipoproteins (TRLs).”

TRLs and remnant-C “have the capacity to cross the arterial wall,” and may therefore play a causal role in atherosclerosis development, they wrote.

The main PREDIMED trial compared a low-fat diet with the Mediterranean diet for the primary prevention of CVD in high-risk participants. Those enrolled in the trial “had a high prevalence of diabetes, obesity, and metabolic syndrome, conditions that are associated with insulin resistance, hypertriglyceridemia, and atherogenic dyslipidemia,” the authors wrote. “Thus, this cohort of subjects at high cardiovascular risk was well suited to investigate the association of triglycerides and TRLs with cardiovascular outcomes.” 

The researchers investigated the role of triglycerides and remnant-C in incident CVD among these high-risk individuals, particularly those with chronic cardiometabolic disorders (prediabetes, type 2 diabetes, and poorly controlled diabetes), overweight and obesity, metabolic syndrome, and renal failure.

Their 6,901 participants (42.6% male, mean age 67 years, mean BMI 30.0 kg/m2) had a diagnosis of type 2 diabetes or at least three CVD risk factors including current smoking, hypertension, elevated LDL-C levels, low HDL cholesterol levels, elevated body mass index, or family history of premature coronary heart disease.

The primary study endpoint was a composite of adverse cardiovascular events (MACE): MI, stroke, or cardiovascular death. Participants were followed for a mean of 4.8 years, during which there was a total of 263 MACE events.

Multivariable-adjusted analyses showed that levels of triglycerides and remnant-C were both associated with MACE independent of other risk factors (hazard ratio, 1.04; 95% confidence interval, 1.02-1.06; and HR, 1.21; 95% CI, 1.10-1.33 per 10 mg/dl, respectively, both P < .001). Non–HDL cholesterol was also associated with MACE (HR, 1.05; 95% CI, 1.01-1.10 per 10 mg/dl, P = .026).

In particular, elevated remnant-C (≥30 mg/dL), compared with lower concentrations, flagged subjects at a higher risk of MACE, even if their LDL-C levels were at target (defined as ≤ 100 mg/dL).

Levels of LDL-C and HDL cholesterol were not associated with MACE.

“The indirect calculation of remnant-C is an affordable and inexpensive method, which could provide valuable data for clinical management,” Dr. Fitó Colomer said.

“The results of this study suggest that, in individuals at high cardiovascular risk with well-controlled LDL-C, triglycerides and mainly remnant-C should be considered as a treatment target,” she proposed.
 

New oracles?

Evidence has pointed to triglyceride-rich remnants or VLDL cholesterol as contributing to atherosclerotic CVD, together with LDL-C, but it is “unclear which fraction of risk is explained by, respectively, cholesterol and triglycerides in VLDL,” write the authors of the Copenhagen population study.

Dr. Nordestgaard said their study was motivated by an awareness that “in clinical practice, the focus for lipid-related risk is almost solely on reduction of LDL-C for prevention of ASCVD,” so the current focus needs to be reevaluated because patients with low LDL-C but elevated VLDL cholesterol and plasma triglycerides “may not be offered adequate preventive lipid-lowering therapy in order to prevent future MI and ASCVD.”

His group therefore tested the hypothesis that VLDL cholesterol and triglycerides may each explain part of the MI risk from apoB-containing lipoproteins.

They used measurements of plasma apoB and cholesterol and triglyceride content of VLDL cholesterol, intermediate-density-lipoprotein cholesterol, and LDL-C in the study participants (N = 25,480, median age 61 years, 53% female), who were required to be free of MI and not receiving lipid-lowering therapy at baseline.

During a median 11-year follow-up period, 1,816 participants experienced an MI. They tended to be older, compared with those who did not experience an MI, and also more likely to be male, to smoke, and to have higher systolic blood pressure.

Each 39-mg/dL increase in lipid level was found to be associated with higher MI risk.

The researchers looked at MI-associated risk of specific subfractions of apoB-containing lipoproteins. “VLDL cholesterol explained half of the MI risk from elevated apoB-containing lipoproteins, and [intermediate-density-lipoprotein] and LDL-C together accounted for only 29% of the risk,” Dr. Nordestgaard said.

“If LDL cholesterol is adequately reduced, clinicians need to evaluate possible elevated triglyceride-rich lipoproteins, either as elevated plasma triglycerides, remnant cholesterol, or elevated VLDL cholesterol; and, if elevated, consideration should also be given to reduction of triglyceride-rich lipoproteins,” he advised.

The Copenhagen General Population study was funded by the Danish Heart Foundation and the Novo Nordisk Foundation. Dr. Nordestgaard disclosed consulting for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka Seiken, Amarin, Novartis, Novo Nordisk, and Silence Therapeutrics. PREDIMED was supported by grants from the Instituto de Salud Carlos III- FEDER, Fundació La Marató de TV3, and Agència de Gestió d’Ajuts Universitaris i de Recerca. Dr. Fitó Colomer disclosed no relevant financial relationships. Dr. Burnett disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Two new studies suggest that LDL cholesterol (LDL-C) may be not the main driver of atherosclerotic cardiovascular disease (ASCVD).

The findings instead implicate remnant cholesterol (remnant-C) and very-low-density lipoprotein (VLDL) cholesterol in the development of cardiovascular disease (CVD) and MI.

The PREDIMED study, conducted in Spain, examined the association of triglycerides and remnant-C with major cardiovascular events (MACE) in older individuals with high CVD risk. It found that levels of triglycerides and remnant-C were associated with MACE independently of other risk factors, but there was no similar association with LDL-C.

“These findings lead [clinicians] to consider in the clinical management of dyslipidemias a greater control of the lipid profiles as a whole, including remnant-cholesterol and/or triglycerides,” Montserrat Fitó Colomer, MD, PhD, of the Cardiovascular Risk and Nutrition Research Group, Hospital del Mar Medical Research Institute, Barcelona, said in an interview.

In a separate analysis, the Copenhagen General Population Study, which focused on 25,000 individuals who were not taking lipid-lowering therapy, looked at the role of VLDL cholesterol and triglycerides in driving MI risk from apolipoprotein B (apoB)–containing lipoproteins.

Bruce Jancin/Frontline Medical News

“Elevated VLDL cholesterol explained a larger fraction of risk than did elevated LDL cholesterol, or elevated VLDL triglycerides,” Børge G. Nordestgaard, MD, DMSc, professor, University of Copenhagen, said in an interview.

Both studies were published online Nov. 30 in the Journal of the American College of Cardiology.

But in an editorial accompanying both reports, John Burnett, MD, PhD, from the University of Western Australia, Perth, and colleagues cautioned that it would be “premature to discard LDL-C based on PREDIMED.”

The findings are “insufficient to offset the mountain of literally hundreds of studies that uphold the value of LDL-C in prediction and intervention of ASCVD,” Dr. Burnett and coauthors wrote.

Similarly, the editorialists cautioned that, although the findings from the study by Dr. Nordestgaard and colleagues indicate that VLDL cholesterol is the “new kid in town for prediction, LDL cholesterol retains predictive power.” Clinical cardiologists should not “shelve LDL cholesterol and embrace VLDL and remnant cholesterol as the new oracles of ASCVD risk.” 

In a comment, Dr. Burnett said, “The take-home message for clinicians in both papers is that LDL-C is the main lipid measurement to guide clinical decisions; however, residual risk of atherosclerotic cardiovascular disease remains, even after LCL-C is treated.

“Assessment of residual ASCVD risk with nontraditional lipid biomarkers, including VLDL cholesterol and remnant cholesterol, as well as lipoprotein (a) and apoB, may improve prognostication and help guide preventive treatments,” he added.
 

“Affordable and inexpensive”

In their report, the PREDIMED study authors explained that atherogenic dyslipidemia is characterized by “an excess of serum triglycerides” contained in VLDL cholesterol, intermediate-density lipoproteins, and their remnants, all of which are called “triglyceride-rich lipoproteins (TRLs).”

TRLs and remnant-C “have the capacity to cross the arterial wall,” and may therefore play a causal role in atherosclerosis development, they wrote.

The main PREDIMED trial compared a low-fat diet with the Mediterranean diet for the primary prevention of CVD in high-risk participants. Those enrolled in the trial “had a high prevalence of diabetes, obesity, and metabolic syndrome, conditions that are associated with insulin resistance, hypertriglyceridemia, and atherogenic dyslipidemia,” the authors wrote. “Thus, this cohort of subjects at high cardiovascular risk was well suited to investigate the association of triglycerides and TRLs with cardiovascular outcomes.” 

The researchers investigated the role of triglycerides and remnant-C in incident CVD among these high-risk individuals, particularly those with chronic cardiometabolic disorders (prediabetes, type 2 diabetes, and poorly controlled diabetes), overweight and obesity, metabolic syndrome, and renal failure.

Their 6,901 participants (42.6% male, mean age 67 years, mean BMI 30.0 kg/m2) had a diagnosis of type 2 diabetes or at least three CVD risk factors including current smoking, hypertension, elevated LDL-C levels, low HDL cholesterol levels, elevated body mass index, or family history of premature coronary heart disease.

The primary study endpoint was a composite of adverse cardiovascular events (MACE): MI, stroke, or cardiovascular death. Participants were followed for a mean of 4.8 years, during which there was a total of 263 MACE events.

Multivariable-adjusted analyses showed that levels of triglycerides and remnant-C were both associated with MACE independent of other risk factors (hazard ratio, 1.04; 95% confidence interval, 1.02-1.06; and HR, 1.21; 95% CI, 1.10-1.33 per 10 mg/dl, respectively, both P < .001). Non–HDL cholesterol was also associated with MACE (HR, 1.05; 95% CI, 1.01-1.10 per 10 mg/dl, P = .026).

In particular, elevated remnant-C (≥30 mg/dL), compared with lower concentrations, flagged subjects at a higher risk of MACE, even if their LDL-C levels were at target (defined as ≤ 100 mg/dL).

Levels of LDL-C and HDL cholesterol were not associated with MACE.

“The indirect calculation of remnant-C is an affordable and inexpensive method, which could provide valuable data for clinical management,” Dr. Fitó Colomer said.

“The results of this study suggest that, in individuals at high cardiovascular risk with well-controlled LDL-C, triglycerides and mainly remnant-C should be considered as a treatment target,” she proposed.
 

New oracles?

Evidence has pointed to triglyceride-rich remnants or VLDL cholesterol as contributing to atherosclerotic CVD, together with LDL-C, but it is “unclear which fraction of risk is explained by, respectively, cholesterol and triglycerides in VLDL,” write the authors of the Copenhagen population study.

Dr. Nordestgaard said their study was motivated by an awareness that “in clinical practice, the focus for lipid-related risk is almost solely on reduction of LDL-C for prevention of ASCVD,” so the current focus needs to be reevaluated because patients with low LDL-C but elevated VLDL cholesterol and plasma triglycerides “may not be offered adequate preventive lipid-lowering therapy in order to prevent future MI and ASCVD.”

His group therefore tested the hypothesis that VLDL cholesterol and triglycerides may each explain part of the MI risk from apoB-containing lipoproteins.

They used measurements of plasma apoB and cholesterol and triglyceride content of VLDL cholesterol, intermediate-density-lipoprotein cholesterol, and LDL-C in the study participants (N = 25,480, median age 61 years, 53% female), who were required to be free of MI and not receiving lipid-lowering therapy at baseline.

During a median 11-year follow-up period, 1,816 participants experienced an MI. They tended to be older, compared with those who did not experience an MI, and also more likely to be male, to smoke, and to have higher systolic blood pressure.

Each 39-mg/dL increase in lipid level was found to be associated with higher MI risk.

The researchers looked at MI-associated risk of specific subfractions of apoB-containing lipoproteins. “VLDL cholesterol explained half of the MI risk from elevated apoB-containing lipoproteins, and [intermediate-density-lipoprotein] and LDL-C together accounted for only 29% of the risk,” Dr. Nordestgaard said.

“If LDL cholesterol is adequately reduced, clinicians need to evaluate possible elevated triglyceride-rich lipoproteins, either as elevated plasma triglycerides, remnant cholesterol, or elevated VLDL cholesterol; and, if elevated, consideration should also be given to reduction of triglyceride-rich lipoproteins,” he advised.

The Copenhagen General Population study was funded by the Danish Heart Foundation and the Novo Nordisk Foundation. Dr. Nordestgaard disclosed consulting for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka Seiken, Amarin, Novartis, Novo Nordisk, and Silence Therapeutrics. PREDIMED was supported by grants from the Instituto de Salud Carlos III- FEDER, Fundació La Marató de TV3, and Agència de Gestió d’Ajuts Universitaris i de Recerca. Dr. Fitó Colomer disclosed no relevant financial relationships. Dr. Burnett disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Two new studies suggest that LDL cholesterol (LDL-C) may be not the main driver of atherosclerotic cardiovascular disease (ASCVD).

The findings instead implicate remnant cholesterol (remnant-C) and very-low-density lipoprotein (VLDL) cholesterol in the development of cardiovascular disease (CVD) and MI.

The PREDIMED study, conducted in Spain, examined the association of triglycerides and remnant-C with major cardiovascular events (MACE) in older individuals with high CVD risk. It found that levels of triglycerides and remnant-C were associated with MACE independently of other risk factors, but there was no similar association with LDL-C.

“These findings lead [clinicians] to consider in the clinical management of dyslipidemias a greater control of the lipid profiles as a whole, including remnant-cholesterol and/or triglycerides,” Montserrat Fitó Colomer, MD, PhD, of the Cardiovascular Risk and Nutrition Research Group, Hospital del Mar Medical Research Institute, Barcelona, said in an interview.

In a separate analysis, the Copenhagen General Population Study, which focused on 25,000 individuals who were not taking lipid-lowering therapy, looked at the role of VLDL cholesterol and triglycerides in driving MI risk from apolipoprotein B (apoB)–containing lipoproteins.

Bruce Jancin/Frontline Medical News

“Elevated VLDL cholesterol explained a larger fraction of risk than did elevated LDL cholesterol, or elevated VLDL triglycerides,” Børge G. Nordestgaard, MD, DMSc, professor, University of Copenhagen, said in an interview.

Both studies were published online Nov. 30 in the Journal of the American College of Cardiology.

But in an editorial accompanying both reports, John Burnett, MD, PhD, from the University of Western Australia, Perth, and colleagues cautioned that it would be “premature to discard LDL-C based on PREDIMED.”

The findings are “insufficient to offset the mountain of literally hundreds of studies that uphold the value of LDL-C in prediction and intervention of ASCVD,” Dr. Burnett and coauthors wrote.

Similarly, the editorialists cautioned that, although the findings from the study by Dr. Nordestgaard and colleagues indicate that VLDL cholesterol is the “new kid in town for prediction, LDL cholesterol retains predictive power.” Clinical cardiologists should not “shelve LDL cholesterol and embrace VLDL and remnant cholesterol as the new oracles of ASCVD risk.” 

In a comment, Dr. Burnett said, “The take-home message for clinicians in both papers is that LDL-C is the main lipid measurement to guide clinical decisions; however, residual risk of atherosclerotic cardiovascular disease remains, even after LCL-C is treated.

“Assessment of residual ASCVD risk with nontraditional lipid biomarkers, including VLDL cholesterol and remnant cholesterol, as well as lipoprotein (a) and apoB, may improve prognostication and help guide preventive treatments,” he added.
 

“Affordable and inexpensive”

In their report, the PREDIMED study authors explained that atherogenic dyslipidemia is characterized by “an excess of serum triglycerides” contained in VLDL cholesterol, intermediate-density lipoproteins, and their remnants, all of which are called “triglyceride-rich lipoproteins (TRLs).”

TRLs and remnant-C “have the capacity to cross the arterial wall,” and may therefore play a causal role in atherosclerosis development, they wrote.

The main PREDIMED trial compared a low-fat diet with the Mediterranean diet for the primary prevention of CVD in high-risk participants. Those enrolled in the trial “had a high prevalence of diabetes, obesity, and metabolic syndrome, conditions that are associated with insulin resistance, hypertriglyceridemia, and atherogenic dyslipidemia,” the authors wrote. “Thus, this cohort of subjects at high cardiovascular risk was well suited to investigate the association of triglycerides and TRLs with cardiovascular outcomes.” 

The researchers investigated the role of triglycerides and remnant-C in incident CVD among these high-risk individuals, particularly those with chronic cardiometabolic disorders (prediabetes, type 2 diabetes, and poorly controlled diabetes), overweight and obesity, metabolic syndrome, and renal failure.

Their 6,901 participants (42.6% male, mean age 67 years, mean BMI 30.0 kg/m2) had a diagnosis of type 2 diabetes or at least three CVD risk factors including current smoking, hypertension, elevated LDL-C levels, low HDL cholesterol levels, elevated body mass index, or family history of premature coronary heart disease.

The primary study endpoint was a composite of adverse cardiovascular events (MACE): MI, stroke, or cardiovascular death. Participants were followed for a mean of 4.8 years, during which there was a total of 263 MACE events.

Multivariable-adjusted analyses showed that levels of triglycerides and remnant-C were both associated with MACE independent of other risk factors (hazard ratio, 1.04; 95% confidence interval, 1.02-1.06; and HR, 1.21; 95% CI, 1.10-1.33 per 10 mg/dl, respectively, both P < .001). Non–HDL cholesterol was also associated with MACE (HR, 1.05; 95% CI, 1.01-1.10 per 10 mg/dl, P = .026).

In particular, elevated remnant-C (≥30 mg/dL), compared with lower concentrations, flagged subjects at a higher risk of MACE, even if their LDL-C levels were at target (defined as ≤ 100 mg/dL).

Levels of LDL-C and HDL cholesterol were not associated with MACE.

“The indirect calculation of remnant-C is an affordable and inexpensive method, which could provide valuable data for clinical management,” Dr. Fitó Colomer said.

“The results of this study suggest that, in individuals at high cardiovascular risk with well-controlled LDL-C, triglycerides and mainly remnant-C should be considered as a treatment target,” she proposed.
 

New oracles?

Evidence has pointed to triglyceride-rich remnants or VLDL cholesterol as contributing to atherosclerotic CVD, together with LDL-C, but it is “unclear which fraction of risk is explained by, respectively, cholesterol and triglycerides in VLDL,” write the authors of the Copenhagen population study.

Dr. Nordestgaard said their study was motivated by an awareness that “in clinical practice, the focus for lipid-related risk is almost solely on reduction of LDL-C for prevention of ASCVD,” so the current focus needs to be reevaluated because patients with low LDL-C but elevated VLDL cholesterol and plasma triglycerides “may not be offered adequate preventive lipid-lowering therapy in order to prevent future MI and ASCVD.”

His group therefore tested the hypothesis that VLDL cholesterol and triglycerides may each explain part of the MI risk from apoB-containing lipoproteins.

They used measurements of plasma apoB and cholesterol and triglyceride content of VLDL cholesterol, intermediate-density-lipoprotein cholesterol, and LDL-C in the study participants (N = 25,480, median age 61 years, 53% female), who were required to be free of MI and not receiving lipid-lowering therapy at baseline.

During a median 11-year follow-up period, 1,816 participants experienced an MI. They tended to be older, compared with those who did not experience an MI, and also more likely to be male, to smoke, and to have higher systolic blood pressure.

Each 39-mg/dL increase in lipid level was found to be associated with higher MI risk.

The researchers looked at MI-associated risk of specific subfractions of apoB-containing lipoproteins. “VLDL cholesterol explained half of the MI risk from elevated apoB-containing lipoproteins, and [intermediate-density-lipoprotein] and LDL-C together accounted for only 29% of the risk,” Dr. Nordestgaard said.

“If LDL cholesterol is adequately reduced, clinicians need to evaluate possible elevated triglyceride-rich lipoproteins, either as elevated plasma triglycerides, remnant cholesterol, or elevated VLDL cholesterol; and, if elevated, consideration should also be given to reduction of triglyceride-rich lipoproteins,” he advised.

The Copenhagen General Population study was funded by the Danish Heart Foundation and the Novo Nordisk Foundation. Dr. Nordestgaard disclosed consulting for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka Seiken, Amarin, Novartis, Novo Nordisk, and Silence Therapeutrics. PREDIMED was supported by grants from the Instituto de Salud Carlos III- FEDER, Fundació La Marató de TV3, and Agència de Gestió d’Ajuts Universitaris i de Recerca. Dr. Fitó Colomer disclosed no relevant financial relationships. Dr. Burnett disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Individuals who have hypertension at any age are more likely to experience more rapid cognitive decline compared with their counterparts with normal blood pressure, new research shows. In a retrospective study of more than 15,000 participants, hypertension during middle age was associated with memory decline, and onset at later ages was linked to worsening memory and global cognition.

The investigators found that prehypertension, defined as systolic pressure of 120-139 mm Hg or diastolic pressure of 80-89 mm Hg, was also linked to accelerated cognitive decline.

Although duration of hypertension was not associated with any marker of cognitive decline, blood pressure control “can substantially reduce hypertension’s deleterious effect on the pace of cognitive decline,” said study investigator Sandhi M. Barreto, MD, PhD, professor of medicine at Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

The findings were published online Dec. 14 in Hypertension.
 

Unanswered questions

Hypertension is an established and highly prevalent risk factor for cognitive decline, but the age at which it begins to affect cognition is unclear. Previous research suggests that onset during middle age is associated with more harmful cognitive effects than onset in later life. One reason for this apparent difference may be that the duration of hypertension influences the magnitude of cognitive decline, the researchers noted.

Other studies have shown that prehypertension is associated with damage to certain organs, but its effects on cognition are uncertain. In addition, the effect of good blood pressure control with antihypertensive medications and the impact on cognition are also unclear.

To investigate, the researchers examined data from the ongoing, multicenter ELSA-Brasil study. ELSA-Brasil follows 15,105 civil servants between the ages of 35 and 74 years. Dr. Barreto and team assessed data from visit 1, which was conducted between 2008 and 2010, and visit 2, which was conducted between 2012 and 2014.

At each visit, participants underwent a memory test, a verbal fluency test, and the Trail Making Test Part B. The investigators calculated Z scores for these tests to derive a global cognitive score.

Blood pressure was measured on the right arm, and hypertension status, age at the time of hypertension diagnosis, duration of hypertension diagnosis, hypertension treatment, and control status were recorded. Other covariables included sex, education, race, smoking status, physical activity, body mass index, and total cholesterol level.

The researchers excluded patients who did not undergo cognitive testing at visit 2, those who had a history of stroke at baseline, and those who initiated antihypertensive medications despite having normotension. After exclusions, the analysis included 7,063 participants (approximately 55% were women, 15% were Black).

At visit 1, the mean age of the group was 58.9 years, and 53.4% of participants had 14 or more years of education. In addition, 22% had prehypertension, and 46.8% had hypertension. The median duration of hypertension was 7 years; 29.8% of participants with hypertension were diagnosed with the condition during middle age.

Of those who reported having hypertension at visit 1, 7.3% were not taking any antihypertensive medication. Among participants with hypertension who were taking antihypertensives, 31.2% had uncontrolled blood pressure.
 

Independent predictor

Results showed that prehypertension independently predicted a significantly greater decline in verbal fluency (Z score, –0.0095; P < .01) and global cognitive score (Z score, –0.0049; P < .05) compared with normal blood pressure.

At middle age, hypertension was associated with a steeper decline in memory (Z score, –0.0072; P < .05) compared with normal blood pressure. At older ages, hypertension was linked to a steeper decline in both memory (Z score, –0.0151; P < .001) and global cognitive score (Z score, –0.0080; P < .01). Duration of hypertension, however, did not significantly predict changes in cognition (P < .109).

Among those with hypertension who were taking antihypertensive medications, those with uncontrolled blood pressure experienced greater declines in rapid memory (Z score, –0.0126; P < .01) and global cognitive score (Z score, –0.0074; P < .01) than did those with controlled blood pressure.

The investigators noted that the study participants had a comparatively high level of education, which has been shown to “boost cognitive reserve and lessen the speed of age-related cognitive decline,” Dr. Barreto said. However, “our results indicate that the effect of hypertension on cognitive decline affects individuals of all educational levels similarly,” she said.

Dr. Barreto noted that the findings have two major clinical implications. First, “maintaining blood pressure below prehypertension levels is important to preserve cognitive function or delay cognitive decline,” she said. Secondly, “in hypertensive individuals, keeping blood pressure under control is essential to reduce the speed of cognitive decline.”

The researchers plan to conduct further analyses of the data to clarify the observed relationship between memory and verbal fluency. They also plan to examine how hypertension affects long-term executive function.
 

‘Continuum of risk’

Commenting on the study, Philip B. Gorelick, MD, MPH, adjunct professor of neurology (stroke and neurocritical care) at Northwestern University, Chicago, noted that, so far, research suggests that the risk for stroke associated with blood pressure levels should be understood as representing a continuum rather than as being associated with several discrete points.

“The same may hold true for cognitive decline and dementia. There may be a continuum of risk whereby persons even at so-called elevated but relatively lower levels of blood pressure based on a continuous scale are at risk,” said Dr. Gorelick, who was not involved with the current study.

The investigators relied on a large and well-studied population of civil servants. However, the population’s relative youth and high level of education may limit the generalizability of the findings, he noted. In addition, the follow-up time was relatively short.

“The hard endpoint of dementia was not studied but would be of interest to enhance our understanding of the influence of blood pressure elevation on cognitive decline or dementia during a longer follow-up of the cohort,” Dr. Gorelick said.

The findings also suggest the need to better understand mechanisms that link blood pressure elevation with cognitive decline, he added.

They indicate “the need for additional clinical trials to better elucidate blood pressure lowering targets for cognitive preservation in different groups of persons at risk,” such as those with normal cognition, those with mild cognitive impairment, and those with dementia, said Dr. Gorelick. “For example, is it safe and efficacious to lower blood pressure in persons with more advanced cognitive impairment or dementia?” he asked.

The study was funded by the Brazilian Coordination for the Improvement of Higher Education Personnel. Dr. Barreto has received support from the Research Agency of the State of Minas Gerais. Although Dr. Gorelick was not involved in the ELSA-Brasil cohort study, he serves on a data monitoring committee for a trial of a blood pressure–lowering agent in the preservation of cognition.

A version of this article first appeared on Medscape.com.

Individuals who have hypertension at any age are more likely to experience more rapid cognitive decline compared with their counterparts with normal blood pressure, new research shows. In a retrospective study of more than 15,000 participants, hypertension during middle age was associated with memory decline, and onset at later ages was linked to worsening memory and global cognition.

The investigators found that prehypertension, defined as systolic pressure of 120-139 mm Hg or diastolic pressure of 80-89 mm Hg, was also linked to accelerated cognitive decline.

Although duration of hypertension was not associated with any marker of cognitive decline, blood pressure control “can substantially reduce hypertension’s deleterious effect on the pace of cognitive decline,” said study investigator Sandhi M. Barreto, MD, PhD, professor of medicine at Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

The findings were published online Dec. 14 in Hypertension.
 

Unanswered questions

Hypertension is an established and highly prevalent risk factor for cognitive decline, but the age at which it begins to affect cognition is unclear. Previous research suggests that onset during middle age is associated with more harmful cognitive effects than onset in later life. One reason for this apparent difference may be that the duration of hypertension influences the magnitude of cognitive decline, the researchers noted.

Other studies have shown that prehypertension is associated with damage to certain organs, but its effects on cognition are uncertain. In addition, the effect of good blood pressure control with antihypertensive medications and the impact on cognition are also unclear.

To investigate, the researchers examined data from the ongoing, multicenter ELSA-Brasil study. ELSA-Brasil follows 15,105 civil servants between the ages of 35 and 74 years. Dr. Barreto and team assessed data from visit 1, which was conducted between 2008 and 2010, and visit 2, which was conducted between 2012 and 2014.

At each visit, participants underwent a memory test, a verbal fluency test, and the Trail Making Test Part B. The investigators calculated Z scores for these tests to derive a global cognitive score.

Blood pressure was measured on the right arm, and hypertension status, age at the time of hypertension diagnosis, duration of hypertension diagnosis, hypertension treatment, and control status were recorded. Other covariables included sex, education, race, smoking status, physical activity, body mass index, and total cholesterol level.

The researchers excluded patients who did not undergo cognitive testing at visit 2, those who had a history of stroke at baseline, and those who initiated antihypertensive medications despite having normotension. After exclusions, the analysis included 7,063 participants (approximately 55% were women, 15% were Black).

At visit 1, the mean age of the group was 58.9 years, and 53.4% of participants had 14 or more years of education. In addition, 22% had prehypertension, and 46.8% had hypertension. The median duration of hypertension was 7 years; 29.8% of participants with hypertension were diagnosed with the condition during middle age.

Of those who reported having hypertension at visit 1, 7.3% were not taking any antihypertensive medication. Among participants with hypertension who were taking antihypertensives, 31.2% had uncontrolled blood pressure.
 

Independent predictor

Results showed that prehypertension independently predicted a significantly greater decline in verbal fluency (Z score, –0.0095; P < .01) and global cognitive score (Z score, –0.0049; P < .05) compared with normal blood pressure.

At middle age, hypertension was associated with a steeper decline in memory (Z score, –0.0072; P < .05) compared with normal blood pressure. At older ages, hypertension was linked to a steeper decline in both memory (Z score, –0.0151; P < .001) and global cognitive score (Z score, –0.0080; P < .01). Duration of hypertension, however, did not significantly predict changes in cognition (P < .109).

Among those with hypertension who were taking antihypertensive medications, those with uncontrolled blood pressure experienced greater declines in rapid memory (Z score, –0.0126; P < .01) and global cognitive score (Z score, –0.0074; P < .01) than did those with controlled blood pressure.

The investigators noted that the study participants had a comparatively high level of education, which has been shown to “boost cognitive reserve and lessen the speed of age-related cognitive decline,” Dr. Barreto said. However, “our results indicate that the effect of hypertension on cognitive decline affects individuals of all educational levels similarly,” she said.

Dr. Barreto noted that the findings have two major clinical implications. First, “maintaining blood pressure below prehypertension levels is important to preserve cognitive function or delay cognitive decline,” she said. Secondly, “in hypertensive individuals, keeping blood pressure under control is essential to reduce the speed of cognitive decline.”

The researchers plan to conduct further analyses of the data to clarify the observed relationship between memory and verbal fluency. They also plan to examine how hypertension affects long-term executive function.
 

‘Continuum of risk’

Commenting on the study, Philip B. Gorelick, MD, MPH, adjunct professor of neurology (stroke and neurocritical care) at Northwestern University, Chicago, noted that, so far, research suggests that the risk for stroke associated with blood pressure levels should be understood as representing a continuum rather than as being associated with several discrete points.

“The same may hold true for cognitive decline and dementia. There may be a continuum of risk whereby persons even at so-called elevated but relatively lower levels of blood pressure based on a continuous scale are at risk,” said Dr. Gorelick, who was not involved with the current study.

The investigators relied on a large and well-studied population of civil servants. However, the population’s relative youth and high level of education may limit the generalizability of the findings, he noted. In addition, the follow-up time was relatively short.

“The hard endpoint of dementia was not studied but would be of interest to enhance our understanding of the influence of blood pressure elevation on cognitive decline or dementia during a longer follow-up of the cohort,” Dr. Gorelick said.

The findings also suggest the need to better understand mechanisms that link blood pressure elevation with cognitive decline, he added.

They indicate “the need for additional clinical trials to better elucidate blood pressure lowering targets for cognitive preservation in different groups of persons at risk,” such as those with normal cognition, those with mild cognitive impairment, and those with dementia, said Dr. Gorelick. “For example, is it safe and efficacious to lower blood pressure in persons with more advanced cognitive impairment or dementia?” he asked.

The study was funded by the Brazilian Coordination for the Improvement of Higher Education Personnel. Dr. Barreto has received support from the Research Agency of the State of Minas Gerais. Although Dr. Gorelick was not involved in the ELSA-Brasil cohort study, he serves on a data monitoring committee for a trial of a blood pressure–lowering agent in the preservation of cognition.

A version of this article first appeared on Medscape.com.

Individuals who have hypertension at any age are more likely to experience more rapid cognitive decline compared with their counterparts with normal blood pressure, new research shows. In a retrospective study of more than 15,000 participants, hypertension during middle age was associated with memory decline, and onset at later ages was linked to worsening memory and global cognition.

The investigators found that prehypertension, defined as systolic pressure of 120-139 mm Hg or diastolic pressure of 80-89 mm Hg, was also linked to accelerated cognitive decline.

Although duration of hypertension was not associated with any marker of cognitive decline, blood pressure control “can substantially reduce hypertension’s deleterious effect on the pace of cognitive decline,” said study investigator Sandhi M. Barreto, MD, PhD, professor of medicine at Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

The findings were published online Dec. 14 in Hypertension.
 

Unanswered questions

Hypertension is an established and highly prevalent risk factor for cognitive decline, but the age at which it begins to affect cognition is unclear. Previous research suggests that onset during middle age is associated with more harmful cognitive effects than onset in later life. One reason for this apparent difference may be that the duration of hypertension influences the magnitude of cognitive decline, the researchers noted.

Other studies have shown that prehypertension is associated with damage to certain organs, but its effects on cognition are uncertain. In addition, the effect of good blood pressure control with antihypertensive medications and the impact on cognition are also unclear.

To investigate, the researchers examined data from the ongoing, multicenter ELSA-Brasil study. ELSA-Brasil follows 15,105 civil servants between the ages of 35 and 74 years. Dr. Barreto and team assessed data from visit 1, which was conducted between 2008 and 2010, and visit 2, which was conducted between 2012 and 2014.

At each visit, participants underwent a memory test, a verbal fluency test, and the Trail Making Test Part B. The investigators calculated Z scores for these tests to derive a global cognitive score.

Blood pressure was measured on the right arm, and hypertension status, age at the time of hypertension diagnosis, duration of hypertension diagnosis, hypertension treatment, and control status were recorded. Other covariables included sex, education, race, smoking status, physical activity, body mass index, and total cholesterol level.

The researchers excluded patients who did not undergo cognitive testing at visit 2, those who had a history of stroke at baseline, and those who initiated antihypertensive medications despite having normotension. After exclusions, the analysis included 7,063 participants (approximately 55% were women, 15% were Black).

At visit 1, the mean age of the group was 58.9 years, and 53.4% of participants had 14 or more years of education. In addition, 22% had prehypertension, and 46.8% had hypertension. The median duration of hypertension was 7 years; 29.8% of participants with hypertension were diagnosed with the condition during middle age.

Of those who reported having hypertension at visit 1, 7.3% were not taking any antihypertensive medication. Among participants with hypertension who were taking antihypertensives, 31.2% had uncontrolled blood pressure.
 

Independent predictor

Results showed that prehypertension independently predicted a significantly greater decline in verbal fluency (Z score, –0.0095; P < .01) and global cognitive score (Z score, –0.0049; P < .05) compared with normal blood pressure.

At middle age, hypertension was associated with a steeper decline in memory (Z score, –0.0072; P < .05) compared with normal blood pressure. At older ages, hypertension was linked to a steeper decline in both memory (Z score, –0.0151; P < .001) and global cognitive score (Z score, –0.0080; P < .01). Duration of hypertension, however, did not significantly predict changes in cognition (P < .109).

Among those with hypertension who were taking antihypertensive medications, those with uncontrolled blood pressure experienced greater declines in rapid memory (Z score, –0.0126; P < .01) and global cognitive score (Z score, –0.0074; P < .01) than did those with controlled blood pressure.

The investigators noted that the study participants had a comparatively high level of education, which has been shown to “boost cognitive reserve and lessen the speed of age-related cognitive decline,” Dr. Barreto said. However, “our results indicate that the effect of hypertension on cognitive decline affects individuals of all educational levels similarly,” she said.

Dr. Barreto noted that the findings have two major clinical implications. First, “maintaining blood pressure below prehypertension levels is important to preserve cognitive function or delay cognitive decline,” she said. Secondly, “in hypertensive individuals, keeping blood pressure under control is essential to reduce the speed of cognitive decline.”

The researchers plan to conduct further analyses of the data to clarify the observed relationship between memory and verbal fluency. They also plan to examine how hypertension affects long-term executive function.
 

‘Continuum of risk’

Commenting on the study, Philip B. Gorelick, MD, MPH, adjunct professor of neurology (stroke and neurocritical care) at Northwestern University, Chicago, noted that, so far, research suggests that the risk for stroke associated with blood pressure levels should be understood as representing a continuum rather than as being associated with several discrete points.

“The same may hold true for cognitive decline and dementia. There may be a continuum of risk whereby persons even at so-called elevated but relatively lower levels of blood pressure based on a continuous scale are at risk,” said Dr. Gorelick, who was not involved with the current study.

The investigators relied on a large and well-studied population of civil servants. However, the population’s relative youth and high level of education may limit the generalizability of the findings, he noted. In addition, the follow-up time was relatively short.

“The hard endpoint of dementia was not studied but would be of interest to enhance our understanding of the influence of blood pressure elevation on cognitive decline or dementia during a longer follow-up of the cohort,” Dr. Gorelick said.

The findings also suggest the need to better understand mechanisms that link blood pressure elevation with cognitive decline, he added.

They indicate “the need for additional clinical trials to better elucidate blood pressure lowering targets for cognitive preservation in different groups of persons at risk,” such as those with normal cognition, those with mild cognitive impairment, and those with dementia, said Dr. Gorelick. “For example, is it safe and efficacious to lower blood pressure in persons with more advanced cognitive impairment or dementia?” he asked.

The study was funded by the Brazilian Coordination for the Improvement of Higher Education Personnel. Dr. Barreto has received support from the Research Agency of the State of Minas Gerais. Although Dr. Gorelick was not involved in the ELSA-Brasil cohort study, he serves on a data monitoring committee for a trial of a blood pressure–lowering agent in the preservation of cognition.

A version of this article first appeared on Medscape.com.

Although guidelines generally recommend ambulatory over home blood pressure monitoring for diagnosing hypertension, new research questions home BP monitoring’s role as second fiddle.

One week of home BP monitoring (HBPM) was more reliable than one 24-hour ambulatory BP or nine mercury readings across three office visits among younger, untreated participants in the Improving the Detection of Hypertension study.

The reliability coefficients were 0.938, 0.846, and 0.894 for systolic BP and 0.918, 0.843, and 0.847 for diastolic BP, respectively.

Further, HBPM had the strongest association with left ventricular mass index (LVMI), a predictor of adverse cardiovascular events, according to researchers led by Joseph E. Schwartz, PhD, Stony Brook (N.Y.) University and Columbia University Irving Medical Center, New York.

The association with LVMI also remained after multivariate adjustment and after correcting for regression dilution bias, indicating the results were not a result of differences in the number of readings, they write in the study, published online in the Journal of the American College of Cardiology.

Whenever patients have an elevated blood pressure for the first time or even borderline elevated BP, guidelines recommend clinicians request a 24-hour ambulatory recording or home monitoring, Dr. Schwartz said in an interview. “I think this has the potential, for that purpose, to put ambulatory blood pressure monitoring out of business, even though that’s what I’ve done for 30 years.”

Previous studies have shown that home and ambulatory BP monitoring (ABPM) correlate more strongly with target-organ damage and cardiovascular outcomes than office BP, but head-to-head outcomes trials of the two techniques are lacking. A recent systematic review also found scant evidence supporting one approach over the other for predicting cardiovascular events or mortality.

An accompanying editorial notes that ABPM is largely unavailable to primary care physicians in the United States and poorly reimbursed. “Thus the demonstration that HBPM is more reliable and associates more closely with LVMI than ABPM, if confirmed, would carry the potential to change clinical practice,” wrote Robert M. Carey, MD, University of Virginia Health System in Charlottesville, and Thomas H. Marwick, MBBS, PhD, MPH, Baker Heart and Diabetes Institute, Melbourne.

In a comment, ABPM proponent Raymond R. Townsend, MD, said, “Honestly, it may be that we’ll need to act on this. I’m not quite ready to do that and change my practice patterns but, on the other hand, I can’t sweep this under the rug.”

He noted that it’s ironic the study is coauthored by the late Thomas Pickering, MD, a maven of ABPM who coined the term “white-coat hypertension” and pointed out masked hypertension.

That said, “it raised the bar on ambulatory blood pressure monitoring: Is it really worth our public health dollars? So I think it’s a very good call to arms,” said Dr. Townsend, who directs the hypertension program at the University of Pennsylvania, Philadelphia.

Ambulatory BP monitoring has long been considered the preferred method but, from a cost standpoint, HBPM is more attractive because the devices can be used more than once and track more than one person in a household, he said. The Center for Medicare Management also has a code in the 2020 bundle to reimburse physicians $15 for training patients and has a monthly charge for communicating with those filing regularly. “You’re not going to get rich doing monitoring of home BP, but at least the government is recognizing we are moving more and more to the home base in terms of our managing common conditions like blood pressure.”

One of the attractions of ABPM is the ability to do every half hour to every hour nocturnal pressures, but at least one home monitor, manufactured by Microlife, has added a nocturnal feature, Dr. Townsend noted. “So that’s just one more incoming against the ABPM defenses about why ABPMs are still better.”

The study enrolled a community-based sample of 408 participants who had office BP assessed at three visits (three readings per visit) using a mercury sphygmomanometer, a BpTRU (VSM MedTech) automated oscillometric device, and a home-validated Omron Healthcare oscillometric device.

After 5 minutes of in-office training and receipt of a reference sheet, participants also completed 3 weeks of HBPM with the Omron device as well as two 24-hour ambulatory measurements (Spacelabs Healthcare, Model 90207). Cardiovascular evaluations, including two-dimensional echocardiograms, were performed during the fifth office visit.

The 400 participants who completed all five visits had a mean age of 41 years, mean LVMI of 79.3 g/m², and mean office systolic BP ranging from 116.0 to 117.2 mm Hg and diastolic BP from 75.6 to 76.5 mm Hg.

Both before and after correction for regression dilution bias, home systolic and diastolic BP were more highly correlated with LVMI than 24-hour ambulatory or office mercury readings. The corrected correlations for systolic BP were 0.501, 0.430, and 0.389, respectively.

After multivariable adjustment including office and 24-hour ambulatory BP, 10 mm Hg higher systolic and diastolic home BP were associated with 5.07 g/m² (P = .001) and 3.92 g/m² (P = .07) higher LVMI, respectively. After adjustment for home BP, however, neither systolic or diastolic office BP nor ambulatory BP was associated with LVMI.

Dr. Townsend and editorialists Dr. Carey and Dr. Marwick pointed out the study included a younger population in whom just 30% to 50% would have been classified as having hypertension by the 2017 American College of Cardiology/American Heart Association guidelines, which Dr. Carey helped to pen.

“These people are young and older people have a different kind of blood pressure driven more by the stiffness in their circulation and less by the resistance to blood flow that you find more characteristic in younger people,” Dr. Townsend observed.

“I don’t know that you can extrapolate the findings from this study in healthy, younger untreated people to older, perhaps sicker, and more diabetic people where the real action is and where the endpoints like heart attack, death, and stroke actually occur,” he said.

The results suggest measurement of resting daytime BP may be relatively more important than dynamic daytime and/or nocturnal parameters in predicting subclinical cardiac target organ damage, but this requires further study, Dr. Carey and Dr. Marwick noted.

Commenting further, they wrote that the results suggest “HBPM could be especially important for detecting elevated BP and hypertension early in life, when adults are relatively healthy, but those with hypertension have a high lifetime risk of CVD.”

Dr. Schwartz acknowledged the study didn’t include the typical hypertensive patient but said it goes to the central question of whether the risk associated with blood pressure is because of the heart’s cumulative exposure over its lifetime and, thus, best measured with multiple readings taken under a variety of circumstances or with readings taken only at rest. 

“I’ve been posing that question at a conceptual level for 15 years, never in print, and this paper is the first hint, at least with respect to the left ventricular mass index … that getting a better measure of resting blood pressure is more important for controlling risk than the heart’s cumulative exposure to blood pressure, as measured by ambulatory,” he said.

The Improving the Detection of Hypertension study was supported by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The authors disclosed no relevant financial relationships. Dr. Townsend reported receiving royalties as a writer for UpToDate and serving as an unpaid reviewer for ValidateBP.org. Dr. Carey is principal investigator and project director of a NIH R01 and P01 grant, respectively; vice chair of the 2017 ACC/AHA hypertension guideline writing committee; and chair of the AHA Resistant Hypertension Scientific Statement writing committee. Dr. Marwick disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Although guidelines generally recommend ambulatory over home blood pressure monitoring for diagnosing hypertension, new research questions home BP monitoring’s role as second fiddle.

One week of home BP monitoring (HBPM) was more reliable than one 24-hour ambulatory BP or nine mercury readings across three office visits among younger, untreated participants in the Improving the Detection of Hypertension study.

The reliability coefficients were 0.938, 0.846, and 0.894 for systolic BP and 0.918, 0.843, and 0.847 for diastolic BP, respectively.

Further, HBPM had the strongest association with left ventricular mass index (LVMI), a predictor of adverse cardiovascular events, according to researchers led by Joseph E. Schwartz, PhD, Stony Brook (N.Y.) University and Columbia University Irving Medical Center, New York.

The association with LVMI also remained after multivariate adjustment and after correcting for regression dilution bias, indicating the results were not a result of differences in the number of readings, they write in the study, published online in the Journal of the American College of Cardiology.

Whenever patients have an elevated blood pressure for the first time or even borderline elevated BP, guidelines recommend clinicians request a 24-hour ambulatory recording or home monitoring, Dr. Schwartz said in an interview. “I think this has the potential, for that purpose, to put ambulatory blood pressure monitoring out of business, even though that’s what I’ve done for 30 years.”

Previous studies have shown that home and ambulatory BP monitoring (ABPM) correlate more strongly with target-organ damage and cardiovascular outcomes than office BP, but head-to-head outcomes trials of the two techniques are lacking. A recent systematic review also found scant evidence supporting one approach over the other for predicting cardiovascular events or mortality.

An accompanying editorial notes that ABPM is largely unavailable to primary care physicians in the United States and poorly reimbursed. “Thus the demonstration that HBPM is more reliable and associates more closely with LVMI than ABPM, if confirmed, would carry the potential to change clinical practice,” wrote Robert M. Carey, MD, University of Virginia Health System in Charlottesville, and Thomas H. Marwick, MBBS, PhD, MPH, Baker Heart and Diabetes Institute, Melbourne.

In a comment, ABPM proponent Raymond R. Townsend, MD, said, “Honestly, it may be that we’ll need to act on this. I’m not quite ready to do that and change my practice patterns but, on the other hand, I can’t sweep this under the rug.”

He noted that it’s ironic the study is coauthored by the late Thomas Pickering, MD, a maven of ABPM who coined the term “white-coat hypertension” and pointed out masked hypertension.

That said, “it raised the bar on ambulatory blood pressure monitoring: Is it really worth our public health dollars? So I think it’s a very good call to arms,” said Dr. Townsend, who directs the hypertension program at the University of Pennsylvania, Philadelphia.

Ambulatory BP monitoring has long been considered the preferred method but, from a cost standpoint, HBPM is more attractive because the devices can be used more than once and track more than one person in a household, he said. The Center for Medicare Management also has a code in the 2020 bundle to reimburse physicians $15 for training patients and has a monthly charge for communicating with those filing regularly. “You’re not going to get rich doing monitoring of home BP, but at least the government is recognizing we are moving more and more to the home base in terms of our managing common conditions like blood pressure.”

One of the attractions of ABPM is the ability to do every half hour to every hour nocturnal pressures, but at least one home monitor, manufactured by Microlife, has added a nocturnal feature, Dr. Townsend noted. “So that’s just one more incoming against the ABPM defenses about why ABPMs are still better.”

The study enrolled a community-based sample of 408 participants who had office BP assessed at three visits (three readings per visit) using a mercury sphygmomanometer, a BpTRU (VSM MedTech) automated oscillometric device, and a home-validated Omron Healthcare oscillometric device.

After 5 minutes of in-office training and receipt of a reference sheet, participants also completed 3 weeks of HBPM with the Omron device as well as two 24-hour ambulatory measurements (Spacelabs Healthcare, Model 90207). Cardiovascular evaluations, including two-dimensional echocardiograms, were performed during the fifth office visit.

The 400 participants who completed all five visits had a mean age of 41 years, mean LVMI of 79.3 g/m², and mean office systolic BP ranging from 116.0 to 117.2 mm Hg and diastolic BP from 75.6 to 76.5 mm Hg.

Both before and after correction for regression dilution bias, home systolic and diastolic BP were more highly correlated with LVMI than 24-hour ambulatory or office mercury readings. The corrected correlations for systolic BP were 0.501, 0.430, and 0.389, respectively.

After multivariable adjustment including office and 24-hour ambulatory BP, 10 mm Hg higher systolic and diastolic home BP were associated with 5.07 g/m² (P = .001) and 3.92 g/m² (P = .07) higher LVMI, respectively. After adjustment for home BP, however, neither systolic or diastolic office BP nor ambulatory BP was associated with LVMI.

Dr. Townsend and editorialists Dr. Carey and Dr. Marwick pointed out the study included a younger population in whom just 30% to 50% would have been classified as having hypertension by the 2017 American College of Cardiology/American Heart Association guidelines, which Dr. Carey helped to pen.

“These people are young and older people have a different kind of blood pressure driven more by the stiffness in their circulation and less by the resistance to blood flow that you find more characteristic in younger people,” Dr. Townsend observed.

“I don’t know that you can extrapolate the findings from this study in healthy, younger untreated people to older, perhaps sicker, and more diabetic people where the real action is and where the endpoints like heart attack, death, and stroke actually occur,” he said.

The results suggest measurement of resting daytime BP may be relatively more important than dynamic daytime and/or nocturnal parameters in predicting subclinical cardiac target organ damage, but this requires further study, Dr. Carey and Dr. Marwick noted.

Commenting further, they wrote that the results suggest “HBPM could be especially important for detecting elevated BP and hypertension early in life, when adults are relatively healthy, but those with hypertension have a high lifetime risk of CVD.”

Dr. Schwartz acknowledged the study didn’t include the typical hypertensive patient but said it goes to the central question of whether the risk associated with blood pressure is because of the heart’s cumulative exposure over its lifetime and, thus, best measured with multiple readings taken under a variety of circumstances or with readings taken only at rest. 

“I’ve been posing that question at a conceptual level for 15 years, never in print, and this paper is the first hint, at least with respect to the left ventricular mass index … that getting a better measure of resting blood pressure is more important for controlling risk than the heart’s cumulative exposure to blood pressure, as measured by ambulatory,” he said.

The Improving the Detection of Hypertension study was supported by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The authors disclosed no relevant financial relationships. Dr. Townsend reported receiving royalties as a writer for UpToDate and serving as an unpaid reviewer for ValidateBP.org. Dr. Carey is principal investigator and project director of a NIH R01 and P01 grant, respectively; vice chair of the 2017 ACC/AHA hypertension guideline writing committee; and chair of the AHA Resistant Hypertension Scientific Statement writing committee. Dr. Marwick disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Although guidelines generally recommend ambulatory over home blood pressure monitoring for diagnosing hypertension, new research questions home BP monitoring’s role as second fiddle.

One week of home BP monitoring (HBPM) was more reliable than one 24-hour ambulatory BP or nine mercury readings across three office visits among younger, untreated participants in the Improving the Detection of Hypertension study.

The reliability coefficients were 0.938, 0.846, and 0.894 for systolic BP and 0.918, 0.843, and 0.847 for diastolic BP, respectively.

Further, HBPM had the strongest association with left ventricular mass index (LVMI), a predictor of adverse cardiovascular events, according to researchers led by Joseph E. Schwartz, PhD, Stony Brook (N.Y.) University and Columbia University Irving Medical Center, New York.

The association with LVMI also remained after multivariate adjustment and after correcting for regression dilution bias, indicating the results were not a result of differences in the number of readings, they write in the study, published online in the Journal of the American College of Cardiology.

Whenever patients have an elevated blood pressure for the first time or even borderline elevated BP, guidelines recommend clinicians request a 24-hour ambulatory recording or home monitoring, Dr. Schwartz said in an interview. “I think this has the potential, for that purpose, to put ambulatory blood pressure monitoring out of business, even though that’s what I’ve done for 30 years.”

Previous studies have shown that home and ambulatory BP monitoring (ABPM) correlate more strongly with target-organ damage and cardiovascular outcomes than office BP, but head-to-head outcomes trials of the two techniques are lacking. A recent systematic review also found scant evidence supporting one approach over the other for predicting cardiovascular events or mortality.

An accompanying editorial notes that ABPM is largely unavailable to primary care physicians in the United States and poorly reimbursed. “Thus the demonstration that HBPM is more reliable and associates more closely with LVMI than ABPM, if confirmed, would carry the potential to change clinical practice,” wrote Robert M. Carey, MD, University of Virginia Health System in Charlottesville, and Thomas H. Marwick, MBBS, PhD, MPH, Baker Heart and Diabetes Institute, Melbourne.

In a comment, ABPM proponent Raymond R. Townsend, MD, said, “Honestly, it may be that we’ll need to act on this. I’m not quite ready to do that and change my practice patterns but, on the other hand, I can’t sweep this under the rug.”

He noted that it’s ironic the study is coauthored by the late Thomas Pickering, MD, a maven of ABPM who coined the term “white-coat hypertension” and pointed out masked hypertension.

That said, “it raised the bar on ambulatory blood pressure monitoring: Is it really worth our public health dollars? So I think it’s a very good call to arms,” said Dr. Townsend, who directs the hypertension program at the University of Pennsylvania, Philadelphia.

Ambulatory BP monitoring has long been considered the preferred method but, from a cost standpoint, HBPM is more attractive because the devices can be used more than once and track more than one person in a household, he said. The Center for Medicare Management also has a code in the 2020 bundle to reimburse physicians $15 for training patients and has a monthly charge for communicating with those filing regularly. “You’re not going to get rich doing monitoring of home BP, but at least the government is recognizing we are moving more and more to the home base in terms of our managing common conditions like blood pressure.”

One of the attractions of ABPM is the ability to do every half hour to every hour nocturnal pressures, but at least one home monitor, manufactured by Microlife, has added a nocturnal feature, Dr. Townsend noted. “So that’s just one more incoming against the ABPM defenses about why ABPMs are still better.”

The study enrolled a community-based sample of 408 participants who had office BP assessed at three visits (three readings per visit) using a mercury sphygmomanometer, a BpTRU (VSM MedTech) automated oscillometric device, and a home-validated Omron Healthcare oscillometric device.

After 5 minutes of in-office training and receipt of a reference sheet, participants also completed 3 weeks of HBPM with the Omron device as well as two 24-hour ambulatory measurements (Spacelabs Healthcare, Model 90207). Cardiovascular evaluations, including two-dimensional echocardiograms, were performed during the fifth office visit.

The 400 participants who completed all five visits had a mean age of 41 years, mean LVMI of 79.3 g/m², and mean office systolic BP ranging from 116.0 to 117.2 mm Hg and diastolic BP from 75.6 to 76.5 mm Hg.

Both before and after correction for regression dilution bias, home systolic and diastolic BP were more highly correlated with LVMI than 24-hour ambulatory or office mercury readings. The corrected correlations for systolic BP were 0.501, 0.430, and 0.389, respectively.

After multivariable adjustment including office and 24-hour ambulatory BP, 10 mm Hg higher systolic and diastolic home BP were associated with 5.07 g/m² (P = .001) and 3.92 g/m² (P = .07) higher LVMI, respectively. After adjustment for home BP, however, neither systolic or diastolic office BP nor ambulatory BP was associated with LVMI.

Dr. Townsend and editorialists Dr. Carey and Dr. Marwick pointed out the study included a younger population in whom just 30% to 50% would have been classified as having hypertension by the 2017 American College of Cardiology/American Heart Association guidelines, which Dr. Carey helped to pen.

“These people are young and older people have a different kind of blood pressure driven more by the stiffness in their circulation and less by the resistance to blood flow that you find more characteristic in younger people,” Dr. Townsend observed.

“I don’t know that you can extrapolate the findings from this study in healthy, younger untreated people to older, perhaps sicker, and more diabetic people where the real action is and where the endpoints like heart attack, death, and stroke actually occur,” he said.

The results suggest measurement of resting daytime BP may be relatively more important than dynamic daytime and/or nocturnal parameters in predicting subclinical cardiac target organ damage, but this requires further study, Dr. Carey and Dr. Marwick noted.

Commenting further, they wrote that the results suggest “HBPM could be especially important for detecting elevated BP and hypertension early in life, when adults are relatively healthy, but those with hypertension have a high lifetime risk of CVD.”

Dr. Schwartz acknowledged the study didn’t include the typical hypertensive patient but said it goes to the central question of whether the risk associated with blood pressure is because of the heart’s cumulative exposure over its lifetime and, thus, best measured with multiple readings taken under a variety of circumstances or with readings taken only at rest. 

“I’ve been posing that question at a conceptual level for 15 years, never in print, and this paper is the first hint, at least with respect to the left ventricular mass index … that getting a better measure of resting blood pressure is more important for controlling risk than the heart’s cumulative exposure to blood pressure, as measured by ambulatory,” he said.

The Improving the Detection of Hypertension study was supported by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The authors disclosed no relevant financial relationships. Dr. Townsend reported receiving royalties as a writer for UpToDate and serving as an unpaid reviewer for ValidateBP.org. Dr. Carey is principal investigator and project director of a NIH R01 and P01 grant, respectively; vice chair of the 2017 ACC/AHA hypertension guideline writing committee; and chair of the AHA Resistant Hypertension Scientific Statement writing committee. Dr. Marwick disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

UPDATED DECEMBER 17

A panel of federal advisers on Tuesday effectively backed a bid to expand approval of sacubitril/valsartan for use in a form of heart failure for which there is not yet an approved medication.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The U.S. Food and Drug Administration asked its Cardiovascular and Renal Drugs Advisory Committee to broadly consider whether new analyses of data from the PARAGON-HF trial, combined with other information, could support use of sacubitril/valsartan (Entresto, Novartis) in heart failure with preserved ejection fraction (HFpEF).

The advisory committee voted 12-1 on this question, which can be seen as a marker for an expanded approval: “Does PARAGON-HF, perhaps supported by previous studies, provide sufficient evidence to support any indication?”

The dissenting vote was cast by the panel’s chairperson, Julia B. Lewis, MD, a professor of medicine from Vanderbilt University. In explaining her vote, Dr. Lewis cited concerns about expanding use of the drug, which has a potential for hypotension. But she noted that the rest of the panelists were “impressed by the totality of the evidence” presented, including a willingness to take a new look at the PARAGON-HF trial. This study was perceived at first pass as having failed to prove a benefit for people with HFpEF.

The 2019 initial unveiling of the PARAGON-HF results had dampened hopes for an evidence-based drug therapy for HFpEF. Patients treated with the first-of-its-kind renin-angiotensin system (RAS) inhibitor, compared with those who received standard valsartan, had 13% fewer heart failure hospitalizations or cardiovascular (CV) deaths over an average of about 3 years, but the difference missed significance at a P value of .059.

“Everybody agreed that the P value of .05 was not written in stone,” Dr. Lewis said in summarizing the panelists’ views on the voting question.

At the FDA’s request, the panel also addressed several other questions without voting on them. The agency asked the panel to describe the patient population for whom an expanded approval would be appropriate. The FDA initially approved sacubitril/valsartan in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

Novartis in April submitted an application to the FDA, seeking to expand the use of sacubitril/valsartan from the currently approved indication for the treatment of chronic heart failure (CHF) patients with reduced ejection fraction (HFrEF) to include what the company terms “the adjacent population of patients with preserved ejection fraction (HFpEF) who have a left ventricular ejection fraction (LVEF) below normal.” The American Society of Echocardiography and European Association of Cardiovascular Imaging define normal LVEF and normal range (±2 standard deviations) as 62% (range, 52%-72%) in men and 64% (range, 54%-74%) in women, Novartis said in its briefing materials for the meeting.

FDA panelist Christopher M. O’Connor, MD, for example, suggested that an expanded approval could allow for use of sacubitril/valsartan for the reduction of heart failure or hospitalization in patients with mildly reduced ejection fraction as defined by greater than 45% through 55%. FDA panelist C. Noel Bairey Merz, MD, director of the Barbra Streisand Women’s Heart Center at Cedars-Sinai Medical Center in Los Angeles, suggested extending this to 57% to acknowledge the higher threshold for women.

Another FDA panelist, Steven E. Nissen, MD, of the Cleveland Clinic, argued against use of imprecise terms in defining an expanded patient population for sacubitril/valsartan. If used in the right patient population, the drug could provide a benefit for people who have active heart failure with symptoms, including preventing hospitalizations and renal disease, he said.

“If you are symptomatic with a syndrome that’s consistent with heart failure and you have an ejection fraction below the lower limits of normal, I believe it’s in the public interest for you to get sacubitril/valsartan,” Dr. Nissen said.

The FDA usually follows the advice of its panels, but is not obligated to. But in this case, the agency staff were clearly seeking a path for an expanded approval of sacubitril/valsartan.


 

Challenging a standard

The FDA had encouraged Novartis to submit the supplementary application for the HFpEF indication and even suggested some of the post-hoc analyses, the agency staff said in a briefing document for the meeting.

PARAGON-HF illustrated some of the agency’s concerns about missed opportunities in general in large research trials. Some events of interest in studies may be miscounted due to a lack of information such as a requirement for the presence of physical examination findings that are not documented in the patient’s dossier, the FDA staff said.

“We would like to consider giving ‘partial credit’ to events based on the level of evidence provided, e.g., use of an ordinal variable rather than a dichotomous ‘yes’ or ‘no,’ ” the staff said in the briefing document.

At the panel meeting, Norman Stockbridge, MD, PhD, director of the Division of Cardiology and Nephrology in the FDA’s Center for Drug Evaluation and Research, told the panelists there is no basis in law for setting a P value of .05 as the benchmark on whether to declare a trial a success or failure.

“I wanted to take a few minutes and make sure that you on the committee understands what flexibility you have in addressing the case study in question,” Dr. Stockbridge said at the start of the meeting.

He then reviewed cases where the FDA had approved claims for cardiac medicines that had not shown desired results in key tests. These include approval of enalapril for use in asymptomatic left ventricular dysfunction on the basis of the SOLVD-Prevention trial, approval of digoxin for heart failure on the basis of the DIG study, and approval of carvedilol for reduced ejection fraction following myocardial infarction on

the basis of the CAPRICORN study, Dr. Stockbridge said.

In reviewing the data for sacubitril/valsartan, FDA staff noted a similarity between investigator-reported and adjudicated results, Stockbridge said.

“This suggested that there were events that did not need all evidentiary criteria as qualified events, but likely were nonetheless,” he said. “This is an example of dichotomization of events being wasteful of information.”

Post-hoc exploratory analyses in PARAGON-HF were able to meet the commonly used standard, according to the FDA briefing document. Among the key findings of these analyses were:

• An analysis of investigator-reported events for the primary composite endpoint of total hospitalizations for heart failure (HHF) and cardiovascular (CV) death demonstrated a rate ratio (RR) of 0.84 (95% confidence interval 0.74- 0.97; P = .01).
• Investigator-reported events added 226 and 290 HHF events but decreased CV death by 56 and 58 events in the sacubitril/valsartan and valsartan arms, respectively. Hence, a net 170 and 232 events were added to the clinical endpoint committee–reported primary composite endpoint leading to a P value of .01, without a significant change in RR.
• Analysis of investigator-reported expanded primary composite endpoint events including total HHF, urgent HF visits, and CV death demonstrated a RR of 0.83 (95% CI, 0.73-0.95; P = .006. There were 136 and 173 investigator-reported urgent HF events in sacubitril/valsartan and valsartan arms, respectively.

Opening a floodgate?

Cynthia L. Chauhan, MSW, of Wichita, Kansas, who served as the consumer representative on the panel, questioned whether a decision to revisit the data on PARAGON-HF might lead drugmakers to seek to repurpose other failed trials.

“Are we opening any kind of floodgate for other researchers to go back and see this is an invitation to try to, for want of a better term, back-door their way into some approvals?” Ms. Chauhan asked.

Dr. Nissen assured her that this concern was valid and would be considered. The goal would be to allow some flexibility in cases that merit further consideration, while preventing companies from data mining until they find some evidence to support an FDA application, he said.

Re-analyzing trials “should be done carefully, conservatively, and only when it really is compelling that the public interest supports it,” Dr. Nissen stressed.

Panelists reported no conflicts of interest related to the topic of the meeting.
 

UPDATED DECEMBER 17

A panel of federal advisers on Tuesday effectively backed a bid to expand approval of sacubitril/valsartan for use in a form of heart failure for which there is not yet an approved medication.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The U.S. Food and Drug Administration asked its Cardiovascular and Renal Drugs Advisory Committee to broadly consider whether new analyses of data from the PARAGON-HF trial, combined with other information, could support use of sacubitril/valsartan (Entresto, Novartis) in heart failure with preserved ejection fraction (HFpEF).

The advisory committee voted 12-1 on this question, which can be seen as a marker for an expanded approval: “Does PARAGON-HF, perhaps supported by previous studies, provide sufficient evidence to support any indication?”

The dissenting vote was cast by the panel’s chairperson, Julia B. Lewis, MD, a professor of medicine from Vanderbilt University. In explaining her vote, Dr. Lewis cited concerns about expanding use of the drug, which has a potential for hypotension. But she noted that the rest of the panelists were “impressed by the totality of the evidence” presented, including a willingness to take a new look at the PARAGON-HF trial. This study was perceived at first pass as having failed to prove a benefit for people with HFpEF.

The 2019 initial unveiling of the PARAGON-HF results had dampened hopes for an evidence-based drug therapy for HFpEF. Patients treated with the first-of-its-kind renin-angiotensin system (RAS) inhibitor, compared with those who received standard valsartan, had 13% fewer heart failure hospitalizations or cardiovascular (CV) deaths over an average of about 3 years, but the difference missed significance at a P value of .059.

“Everybody agreed that the P value of .05 was not written in stone,” Dr. Lewis said in summarizing the panelists’ views on the voting question.

At the FDA’s request, the panel also addressed several other questions without voting on them. The agency asked the panel to describe the patient population for whom an expanded approval would be appropriate. The FDA initially approved sacubitril/valsartan in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

Novartis in April submitted an application to the FDA, seeking to expand the use of sacubitril/valsartan from the currently approved indication for the treatment of chronic heart failure (CHF) patients with reduced ejection fraction (HFrEF) to include what the company terms “the adjacent population of patients with preserved ejection fraction (HFpEF) who have a left ventricular ejection fraction (LVEF) below normal.” The American Society of Echocardiography and European Association of Cardiovascular Imaging define normal LVEF and normal range (±2 standard deviations) as 62% (range, 52%-72%) in men and 64% (range, 54%-74%) in women, Novartis said in its briefing materials for the meeting.

FDA panelist Christopher M. O’Connor, MD, for example, suggested that an expanded approval could allow for use of sacubitril/valsartan for the reduction of heart failure or hospitalization in patients with mildly reduced ejection fraction as defined by greater than 45% through 55%. FDA panelist C. Noel Bairey Merz, MD, director of the Barbra Streisand Women’s Heart Center at Cedars-Sinai Medical Center in Los Angeles, suggested extending this to 57% to acknowledge the higher threshold for women.

Another FDA panelist, Steven E. Nissen, MD, of the Cleveland Clinic, argued against use of imprecise terms in defining an expanded patient population for sacubitril/valsartan. If used in the right patient population, the drug could provide a benefit for people who have active heart failure with symptoms, including preventing hospitalizations and renal disease, he said.

“If you are symptomatic with a syndrome that’s consistent with heart failure and you have an ejection fraction below the lower limits of normal, I believe it’s in the public interest for you to get sacubitril/valsartan,” Dr. Nissen said.

The FDA usually follows the advice of its panels, but is not obligated to. But in this case, the agency staff were clearly seeking a path for an expanded approval of sacubitril/valsartan.


 

Challenging a standard

The FDA had encouraged Novartis to submit the supplementary application for the HFpEF indication and even suggested some of the post-hoc analyses, the agency staff said in a briefing document for the meeting.

PARAGON-HF illustrated some of the agency’s concerns about missed opportunities in general in large research trials. Some events of interest in studies may be miscounted due to a lack of information such as a requirement for the presence of physical examination findings that are not documented in the patient’s dossier, the FDA staff said.

“We would like to consider giving ‘partial credit’ to events based on the level of evidence provided, e.g., use of an ordinal variable rather than a dichotomous ‘yes’ or ‘no,’ ” the staff said in the briefing document.

At the panel meeting, Norman Stockbridge, MD, PhD, director of the Division of Cardiology and Nephrology in the FDA’s Center for Drug Evaluation and Research, told the panelists there is no basis in law for setting a P value of .05 as the benchmark on whether to declare a trial a success or failure.

“I wanted to take a few minutes and make sure that you on the committee understands what flexibility you have in addressing the case study in question,” Dr. Stockbridge said at the start of the meeting.

He then reviewed cases where the FDA had approved claims for cardiac medicines that had not shown desired results in key tests. These include approval of enalapril for use in asymptomatic left ventricular dysfunction on the basis of the SOLVD-Prevention trial, approval of digoxin for heart failure on the basis of the DIG study, and approval of carvedilol for reduced ejection fraction following myocardial infarction on

the basis of the CAPRICORN study, Dr. Stockbridge said.

In reviewing the data for sacubitril/valsartan, FDA staff noted a similarity between investigator-reported and adjudicated results, Stockbridge said.

“This suggested that there were events that did not need all evidentiary criteria as qualified events, but likely were nonetheless,” he said. “This is an example of dichotomization of events being wasteful of information.”

Post-hoc exploratory analyses in PARAGON-HF were able to meet the commonly used standard, according to the FDA briefing document. Among the key findings of these analyses were:

• An analysis of investigator-reported events for the primary composite endpoint of total hospitalizations for heart failure (HHF) and cardiovascular (CV) death demonstrated a rate ratio (RR) of 0.84 (95% confidence interval 0.74- 0.97; P = .01).
• Investigator-reported events added 226 and 290 HHF events but decreased CV death by 56 and 58 events in the sacubitril/valsartan and valsartan arms, respectively. Hence, a net 170 and 232 events were added to the clinical endpoint committee–reported primary composite endpoint leading to a P value of .01, without a significant change in RR.
• Analysis of investigator-reported expanded primary composite endpoint events including total HHF, urgent HF visits, and CV death demonstrated a RR of 0.83 (95% CI, 0.73-0.95; P = .006. There were 136 and 173 investigator-reported urgent HF events in sacubitril/valsartan and valsartan arms, respectively.

Opening a floodgate?

Cynthia L. Chauhan, MSW, of Wichita, Kansas, who served as the consumer representative on the panel, questioned whether a decision to revisit the data on PARAGON-HF might lead drugmakers to seek to repurpose other failed trials.

“Are we opening any kind of floodgate for other researchers to go back and see this is an invitation to try to, for want of a better term, back-door their way into some approvals?” Ms. Chauhan asked.

Dr. Nissen assured her that this concern was valid and would be considered. The goal would be to allow some flexibility in cases that merit further consideration, while preventing companies from data mining until they find some evidence to support an FDA application, he said.

Re-analyzing trials “should be done carefully, conservatively, and only when it really is compelling that the public interest supports it,” Dr. Nissen stressed.

Panelists reported no conflicts of interest related to the topic of the meeting.
 

UPDATED DECEMBER 17

A panel of federal advisers on Tuesday effectively backed a bid to expand approval of sacubitril/valsartan for use in a form of heart failure for which there is not yet an approved medication.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The U.S. Food and Drug Administration asked its Cardiovascular and Renal Drugs Advisory Committee to broadly consider whether new analyses of data from the PARAGON-HF trial, combined with other information, could support use of sacubitril/valsartan (Entresto, Novartis) in heart failure with preserved ejection fraction (HFpEF).

The advisory committee voted 12-1 on this question, which can be seen as a marker for an expanded approval: “Does PARAGON-HF, perhaps supported by previous studies, provide sufficient evidence to support any indication?”

The dissenting vote was cast by the panel’s chairperson, Julia B. Lewis, MD, a professor of medicine from Vanderbilt University. In explaining her vote, Dr. Lewis cited concerns about expanding use of the drug, which has a potential for hypotension. But she noted that the rest of the panelists were “impressed by the totality of the evidence” presented, including a willingness to take a new look at the PARAGON-HF trial. This study was perceived at first pass as having failed to prove a benefit for people with HFpEF.

The 2019 initial unveiling of the PARAGON-HF results had dampened hopes for an evidence-based drug therapy for HFpEF. Patients treated with the first-of-its-kind renin-angiotensin system (RAS) inhibitor, compared with those who received standard valsartan, had 13% fewer heart failure hospitalizations or cardiovascular (CV) deaths over an average of about 3 years, but the difference missed significance at a P value of .059.

“Everybody agreed that the P value of .05 was not written in stone,” Dr. Lewis said in summarizing the panelists’ views on the voting question.

At the FDA’s request, the panel also addressed several other questions without voting on them. The agency asked the panel to describe the patient population for whom an expanded approval would be appropriate. The FDA initially approved sacubitril/valsartan in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

Novartis in April submitted an application to the FDA, seeking to expand the use of sacubitril/valsartan from the currently approved indication for the treatment of chronic heart failure (CHF) patients with reduced ejection fraction (HFrEF) to include what the company terms “the adjacent population of patients with preserved ejection fraction (HFpEF) who have a left ventricular ejection fraction (LVEF) below normal.” The American Society of Echocardiography and European Association of Cardiovascular Imaging define normal LVEF and normal range (±2 standard deviations) as 62% (range, 52%-72%) in men and 64% (range, 54%-74%) in women, Novartis said in its briefing materials for the meeting.

FDA panelist Christopher M. O’Connor, MD, for example, suggested that an expanded approval could allow for use of sacubitril/valsartan for the reduction of heart failure or hospitalization in patients with mildly reduced ejection fraction as defined by greater than 45% through 55%. FDA panelist C. Noel Bairey Merz, MD, director of the Barbra Streisand Women’s Heart Center at Cedars-Sinai Medical Center in Los Angeles, suggested extending this to 57% to acknowledge the higher threshold for women.

Another FDA panelist, Steven E. Nissen, MD, of the Cleveland Clinic, argued against use of imprecise terms in defining an expanded patient population for sacubitril/valsartan. If used in the right patient population, the drug could provide a benefit for people who have active heart failure with symptoms, including preventing hospitalizations and renal disease, he said.

“If you are symptomatic with a syndrome that’s consistent with heart failure and you have an ejection fraction below the lower limits of normal, I believe it’s in the public interest for you to get sacubitril/valsartan,” Dr. Nissen said.

The FDA usually follows the advice of its panels, but is not obligated to. But in this case, the agency staff were clearly seeking a path for an expanded approval of sacubitril/valsartan.


 

Challenging a standard

The FDA had encouraged Novartis to submit the supplementary application for the HFpEF indication and even suggested some of the post-hoc analyses, the agency staff said in a briefing document for the meeting.

PARAGON-HF illustrated some of the agency’s concerns about missed opportunities in general in large research trials. Some events of interest in studies may be miscounted due to a lack of information such as a requirement for the presence of physical examination findings that are not documented in the patient’s dossier, the FDA staff said.

“We would like to consider giving ‘partial credit’ to events based on the level of evidence provided, e.g., use of an ordinal variable rather than a dichotomous ‘yes’ or ‘no,’ ” the staff said in the briefing document.

At the panel meeting, Norman Stockbridge, MD, PhD, director of the Division of Cardiology and Nephrology in the FDA’s Center for Drug Evaluation and Research, told the panelists there is no basis in law for setting a P value of .05 as the benchmark on whether to declare a trial a success or failure.

“I wanted to take a few minutes and make sure that you on the committee understands what flexibility you have in addressing the case study in question,” Dr. Stockbridge said at the start of the meeting.

He then reviewed cases where the FDA had approved claims for cardiac medicines that had not shown desired results in key tests. These include approval of enalapril for use in asymptomatic left ventricular dysfunction on the basis of the SOLVD-Prevention trial, approval of digoxin for heart failure on the basis of the DIG study, and approval of carvedilol for reduced ejection fraction following myocardial infarction on

the basis of the CAPRICORN study, Dr. Stockbridge said.

In reviewing the data for sacubitril/valsartan, FDA staff noted a similarity between investigator-reported and adjudicated results, Stockbridge said.

“This suggested that there were events that did not need all evidentiary criteria as qualified events, but likely were nonetheless,” he said. “This is an example of dichotomization of events being wasteful of information.”

Post-hoc exploratory analyses in PARAGON-HF were able to meet the commonly used standard, according to the FDA briefing document. Among the key findings of these analyses were:

• An analysis of investigator-reported events for the primary composite endpoint of total hospitalizations for heart failure (HHF) and cardiovascular (CV) death demonstrated a rate ratio (RR) of 0.84 (95% confidence interval 0.74- 0.97; P = .01).
• Investigator-reported events added 226 and 290 HHF events but decreased CV death by 56 and 58 events in the sacubitril/valsartan and valsartan arms, respectively. Hence, a net 170 and 232 events were added to the clinical endpoint committee–reported primary composite endpoint leading to a P value of .01, without a significant change in RR.
• Analysis of investigator-reported expanded primary composite endpoint events including total HHF, urgent HF visits, and CV death demonstrated a RR of 0.83 (95% CI, 0.73-0.95; P = .006. There were 136 and 173 investigator-reported urgent HF events in sacubitril/valsartan and valsartan arms, respectively.

Opening a floodgate?

Cynthia L. Chauhan, MSW, of Wichita, Kansas, who served as the consumer representative on the panel, questioned whether a decision to revisit the data on PARAGON-HF might lead drugmakers to seek to repurpose other failed trials.

“Are we opening any kind of floodgate for other researchers to go back and see this is an invitation to try to, for want of a better term, back-door their way into some approvals?” Ms. Chauhan asked.

Dr. Nissen assured her that this concern was valid and would be considered. The goal would be to allow some flexibility in cases that merit further consideration, while preventing companies from data mining until they find some evidence to support an FDA application, he said.

Re-analyzing trials “should be done carefully, conservatively, and only when it really is compelling that the public interest supports it,” Dr. Nissen stressed.

Panelists reported no conflicts of interest related to the topic of the meeting.