(Reuters Health)

NEW YORK - Progression of the coronary artery calcification (CAC) score over time predicts the risk of cardiovascular disease, but it performs no better than the most recent CAC score, according to findings from the Cooper Center Longitudinal Study (CCLS).

"I must admit that I expected to find that the change in CAC was going to provide a lot of information about cardiovascular events, and was quite surprised when it didn't add much," Dr. Benjamin D. Levine from Cooper Clinic and University of Texas Southwestern Medical Center, Dallas, Texas told Reuters Health by email. "I was then also surprised when Dr. Andre Paixao, one of our cardiology fellows at the time (now at Emory), suggested that we look at the last CAC score as the best measure for risk attributable to CAC, and he turned out to be right!"

CAC correlates with overall atherosclerotic plaque and predicts incident coronary heart disease (CHD) events, CHD mortality, and total mortality, but only a few studies have evaluated the implications of CAC progression.

Dr. Levine and colleagues used CCLS data from 5,933 participants free of cardiovascular disease (CVD) at baseline to evaluate the relative contributions of baseline CAC score, follow-up CAC score, and CAC progression rates to the risk of incident CVD events.

At baseline, 2,870 (48%) individuals had CAC. These individuals were older, more likely to be on statin therapy, and had higher systolic blood pressure and lower cardiorespiratory fitness, according to the June 29th JACC Cardiovascular Imaging online report.

Individuals with detectable CAC at baseline had significantly higher total CVD event rates than those without detectable CAC (7.70 vs 1.44 per 1,000 person-years, respectively), as well as hard CVD event rates, i.e., CVD death, nonfatal myocardial infarction, or nonfatal atherosclerotic stroke (2.68 vs 1.14 per 1,000 person-years, respectively).

Rates of total CVD and CHD events increased across quartiles of CAC progression, but there was no independent association between CAC progression and CVD outcomes after adjustment for the follow-up CAC score.

"These findings greatly simplify the interpretation of CAC scores over time," Dr. Levine said. "Because it is so difficult to quantify 'change' (a score that goes from 1 to 2 is 100% change, but from 101 to 102 is 1% change), it has been hard for clinicians to wrap their minds around the additional risk information that is contained in follow up scores. Since it is not the calcium we are worried about anyway (calcified plaque generally doesn't rupture - it is the company it keeps that is important), what matters is the overall atherosclerotic burden, as reflected by the absolute CAC score. How fast it changes doesn't matter at all!"

"Don't worry about complicated formulas for quantifying change in CAC," Dr. Levine said. "Just use the latest score to calculate the risk associated with CAC. Now that new calculators are available (and some new ones coming from our work in this space), only the latest CAC score is needed to assess risk."

In an editorial, Dr. Prediman K. Shah from Cedars Sinai Hart Institute in Los Angeles writes, "So change in CAC score may be bad, indifferent, or possibly even good depending on what causes the change: progression of underlying atherosclerosis (potentially bad) versus increased density of calcification indicating a plaque stabilizing response (potentially good)."

Dr. Shah continues. "How to distinguish potential contributors to change in CAC score remains an important and at this time an unanswered question."

"Addition of other variables that incorporate regions of change, change in regional density and other volumetric aspect of CAC change, extracoronary calcification, and epicardial fat volume may improve the value and relevance of change in CAC score," Dr. Shah said. "Further studies are needed to address these issues."

Dr. Joseph Yeboah from Wake Forest Baptist Health, Winston-Salem, North Carolina, who has also researched the association between CAC scores and cardiovascular disease risk, told Reuters Health by email, "This happens to be the first study to show that CAC progression is not informative for CVD risk assessment. At the very best, this study makes the data mixed, which is not surprising given the challenge of using a change in a variable (CAC progression) as a predictor. Some researchers have suggested that CAC density progression instead of CAC score progression may be more appropriate."

"In my opinion, these results will have very little influence on how CAC is used presently for CVD risk assessment," he said. "To my knowledge, there is presently no guideline or recommendation regarding the use of CAC progression for CVD risk assessment. This is because of the inherent challenges in assessing CAC progression and the paucity of data."

"The ACC/AHA guidelines clearly recommend the use of CAC, not CAC progression," Dr. Yeboah concluded. "The take away message here is that physicians should not use CAC progression for CVD risk assessment. More research is needed to fully understand CAC progression."

SOURCE: http://bit.ly/29rOdFM and http://bit.ly/29olMIA

J Am Coll Cardiol Imag 2016.

NEW YORK - Progression of the coronary artery calcification (CAC) score over time predicts the risk of cardiovascular disease, but it performs no better than the most recent CAC score, according to findings from the Cooper Center Longitudinal Study (CCLS).

"I must admit that I expected to find that the change in CAC was going to provide a lot of information about cardiovascular events, and was quite surprised when it didn't add much," Dr. Benjamin D. Levine from Cooper Clinic and University of Texas Southwestern Medical Center, Dallas, Texas told Reuters Health by email. "I was then also surprised when Dr. Andre Paixao, one of our cardiology fellows at the time (now at Emory), suggested that we look at the last CAC score as the best measure for risk attributable to CAC, and he turned out to be right!"

CAC correlates with overall atherosclerotic plaque and predicts incident coronary heart disease (CHD) events, CHD mortality, and total mortality, but only a few studies have evaluated the implications of CAC progression.

Dr. Levine and colleagues used CCLS data from 5,933 participants free of cardiovascular disease (CVD) at baseline to evaluate the relative contributions of baseline CAC score, follow-up CAC score, and CAC progression rates to the risk of incident CVD events.

At baseline, 2,870 (48%) individuals had CAC. These individuals were older, more likely to be on statin therapy, and had higher systolic blood pressure and lower cardiorespiratory fitness, according to the June 29th JACC Cardiovascular Imaging online report.

Individuals with detectable CAC at baseline had significantly higher total CVD event rates than those without detectable CAC (7.70 vs 1.44 per 1,000 person-years, respectively), as well as hard CVD event rates, i.e., CVD death, nonfatal myocardial infarction, or nonfatal atherosclerotic stroke (2.68 vs 1.14 per 1,000 person-years, respectively).

Rates of total CVD and CHD events increased across quartiles of CAC progression, but there was no independent association between CAC progression and CVD outcomes after adjustment for the follow-up CAC score.

"These findings greatly simplify the interpretation of CAC scores over time," Dr. Levine said. "Because it is so difficult to quantify 'change' (a score that goes from 1 to 2 is 100% change, but from 101 to 102 is 1% change), it has been hard for clinicians to wrap their minds around the additional risk information that is contained in follow up scores. Since it is not the calcium we are worried about anyway (calcified plaque generally doesn't rupture - it is the company it keeps that is important), what matters is the overall atherosclerotic burden, as reflected by the absolute CAC score. How fast it changes doesn't matter at all!"

"Don't worry about complicated formulas for quantifying change in CAC," Dr. Levine said. "Just use the latest score to calculate the risk associated with CAC. Now that new calculators are available (and some new ones coming from our work in this space), only the latest CAC score is needed to assess risk."

In an editorial, Dr. Prediman K. Shah from Cedars Sinai Hart Institute in Los Angeles writes, "So change in CAC score may be bad, indifferent, or possibly even good depending on what causes the change: progression of underlying atherosclerosis (potentially bad) versus increased density of calcification indicating a plaque stabilizing response (potentially good)."

Dr. Shah continues. "How to distinguish potential contributors to change in CAC score remains an important and at this time an unanswered question."

"Addition of other variables that incorporate regions of change, change in regional density and other volumetric aspect of CAC change, extracoronary calcification, and epicardial fat volume may improve the value and relevance of change in CAC score," Dr. Shah said. "Further studies are needed to address these issues."

Dr. Joseph Yeboah from Wake Forest Baptist Health, Winston-Salem, North Carolina, who has also researched the association between CAC scores and cardiovascular disease risk, told Reuters Health by email, "This happens to be the first study to show that CAC progression is not informative for CVD risk assessment. At the very best, this study makes the data mixed, which is not surprising given the challenge of using a change in a variable (CAC progression) as a predictor. Some researchers have suggested that CAC density progression instead of CAC score progression may be more appropriate."

"In my opinion, these results will have very little influence on how CAC is used presently for CVD risk assessment," he said. "To my knowledge, there is presently no guideline or recommendation regarding the use of CAC progression for CVD risk assessment. This is because of the inherent challenges in assessing CAC progression and the paucity of data."

"The ACC/AHA guidelines clearly recommend the use of CAC, not CAC progression," Dr. Yeboah concluded. "The take away message here is that physicians should not use CAC progression for CVD risk assessment. More research is needed to fully understand CAC progression."

SOURCE: http://bit.ly/29rOdFM and http://bit.ly/29olMIA

J Am Coll Cardiol Imag 2016.

NEW YORK - Progression of the coronary artery calcification (CAC) score over time predicts the risk of cardiovascular disease, but it performs no better than the most recent CAC score, according to findings from the Cooper Center Longitudinal Study (CCLS).

"I must admit that I expected to find that the change in CAC was going to provide a lot of information about cardiovascular events, and was quite surprised when it didn't add much," Dr. Benjamin D. Levine from Cooper Clinic and University of Texas Southwestern Medical Center, Dallas, Texas told Reuters Health by email. "I was then also surprised when Dr. Andre Paixao, one of our cardiology fellows at the time (now at Emory), suggested that we look at the last CAC score as the best measure for risk attributable to CAC, and he turned out to be right!"

CAC correlates with overall atherosclerotic plaque and predicts incident coronary heart disease (CHD) events, CHD mortality, and total mortality, but only a few studies have evaluated the implications of CAC progression.

Dr. Levine and colleagues used CCLS data from 5,933 participants free of cardiovascular disease (CVD) at baseline to evaluate the relative contributions of baseline CAC score, follow-up CAC score, and CAC progression rates to the risk of incident CVD events.

At baseline, 2,870 (48%) individuals had CAC. These individuals were older, more likely to be on statin therapy, and had higher systolic blood pressure and lower cardiorespiratory fitness, according to the June 29th JACC Cardiovascular Imaging online report.

Individuals with detectable CAC at baseline had significantly higher total CVD event rates than those without detectable CAC (7.70 vs 1.44 per 1,000 person-years, respectively), as well as hard CVD event rates, i.e., CVD death, nonfatal myocardial infarction, or nonfatal atherosclerotic stroke (2.68 vs 1.14 per 1,000 person-years, respectively).

Rates of total CVD and CHD events increased across quartiles of CAC progression, but there was no independent association between CAC progression and CVD outcomes after adjustment for the follow-up CAC score.

"These findings greatly simplify the interpretation of CAC scores over time," Dr. Levine said. "Because it is so difficult to quantify 'change' (a score that goes from 1 to 2 is 100% change, but from 101 to 102 is 1% change), it has been hard for clinicians to wrap their minds around the additional risk information that is contained in follow up scores. Since it is not the calcium we are worried about anyway (calcified plaque generally doesn't rupture - it is the company it keeps that is important), what matters is the overall atherosclerotic burden, as reflected by the absolute CAC score. How fast it changes doesn't matter at all!"

"Don't worry about complicated formulas for quantifying change in CAC," Dr. Levine said. "Just use the latest score to calculate the risk associated with CAC. Now that new calculators are available (and some new ones coming from our work in this space), only the latest CAC score is needed to assess risk."

In an editorial, Dr. Prediman K. Shah from Cedars Sinai Hart Institute in Los Angeles writes, "So change in CAC score may be bad, indifferent, or possibly even good depending on what causes the change: progression of underlying atherosclerosis (potentially bad) versus increased density of calcification indicating a plaque stabilizing response (potentially good)."

Dr. Shah continues. "How to distinguish potential contributors to change in CAC score remains an important and at this time an unanswered question."

"Addition of other variables that incorporate regions of change, change in regional density and other volumetric aspect of CAC change, extracoronary calcification, and epicardial fat volume may improve the value and relevance of change in CAC score," Dr. Shah said. "Further studies are needed to address these issues."

Dr. Joseph Yeboah from Wake Forest Baptist Health, Winston-Salem, North Carolina, who has also researched the association between CAC scores and cardiovascular disease risk, told Reuters Health by email, "This happens to be the first study to show that CAC progression is not informative for CVD risk assessment. At the very best, this study makes the data mixed, which is not surprising given the challenge of using a change in a variable (CAC progression) as a predictor. Some researchers have suggested that CAC density progression instead of CAC score progression may be more appropriate."

"In my opinion, these results will have very little influence on how CAC is used presently for CVD risk assessment," he said. "To my knowledge, there is presently no guideline or recommendation regarding the use of CAC progression for CVD risk assessment. This is because of the inherent challenges in assessing CAC progression and the paucity of data."

"The ACC/AHA guidelines clearly recommend the use of CAC, not CAC progression," Dr. Yeboah concluded. "The take away message here is that physicians should not use CAC progression for CVD risk assessment. More research is needed to fully understand CAC progression."

SOURCE: http://bit.ly/29rOdFM and http://bit.ly/29olMIA

J Am Coll Cardiol Imag 2016.

NEW YORK - Patients with persistent nonalcoholic fatty liver disease (NAFLD) face a significantly elevated risk of carotid atherosclerosis, according to a new study of Korean men.

"The most interesting finding of our research is that regression of fatty liver is associated with reduced risk of subclinical carotid atherosclerosis compared to persistent fatty liver," said Dr. Geum-Youn Gwak from Sungkyunkwan University School of Medicine in Seoul.

"So, if somebody has fatty liver at one point, he or she should try hard to resolve fatty liver. Otherwise, it is highly likely that he or she would get cardiovascular disease one day," Dr. Gwak told Reuters Health by email.

NAFLD is associated with metabolic syndrome, diabetes, and cardiovascular disease morbidity and mortality, and several studies have shown that fatty liver is associated with markers of subclinical atherosclerosis.

Dr. Gwak's team conducted a retrospective longitudinal study of 8,020 men to assess the independent association of NAFLD with the development of subclinical carotid atherosclerosis identified by ultrasound, as defined by the development of an abnormally increased carotid intima-media thickness (CIMT) or of carotid plaque.

At baseline, 39.7% of the men had NAFLD, and 17.6% of these showed regression of NAFLD during follow-up. Nearly a quarter of men (23.1%) without NAFLD at baseline had developed it by the end of follow-up, which lasted a median of 3.3 years.

The three-year cumulative incidence of subclinical carotid atherosclerosis was 14.3%, the researchers report in Gastroenterology, online June 6.

The risk of developing carotid atherosclerosis was 23% higher among men with persistent NAFLD than among those without the condition (p<0.001). This association persisted after adjusting for smoking, alcohol use, body mass index, and weight change but disappeared after adjustment for metabolic variables.

This suggests that metabolic factors mediate the association between NAFLD and the development of carotid atherosclerosis, the researchers note.

Men whose NAFLD regressed had an 18% lower risk of carotid atherosclerosis, compared with men who had persistent NAFLD (p<0.013).

Other factors associated with the development of carotid atherosclerosis included higher baseline NAFLD fibrosis score and baseline or persistent elevations of alanine aminotransferase (ALT) or gamma-glutamyltransferase (GGT).

"Once fatty liver is successfully resolved, the cardiovascular disease risk becomes similar to those without fatty liver at baseline," Dr. Gwak concluded. "That's the key message that physicians should deliver to their fatty liver patients."

SOURCE: http://bit.ly/28ODruY

Gastroenterology 2016.

NEW YORK - Patients with persistent nonalcoholic fatty liver disease (NAFLD) face a significantly elevated risk of carotid atherosclerosis, according to a new study of Korean men.

"The most interesting finding of our research is that regression of fatty liver is associated with reduced risk of subclinical carotid atherosclerosis compared to persistent fatty liver," said Dr. Geum-Youn Gwak from Sungkyunkwan University School of Medicine in Seoul.

"So, if somebody has fatty liver at one point, he or she should try hard to resolve fatty liver. Otherwise, it is highly likely that he or she would get cardiovascular disease one day," Dr. Gwak told Reuters Health by email.

NAFLD is associated with metabolic syndrome, diabetes, and cardiovascular disease morbidity and mortality, and several studies have shown that fatty liver is associated with markers of subclinical atherosclerosis.

Dr. Gwak's team conducted a retrospective longitudinal study of 8,020 men to assess the independent association of NAFLD with the development of subclinical carotid atherosclerosis identified by ultrasound, as defined by the development of an abnormally increased carotid intima-media thickness (CIMT) or of carotid plaque.

At baseline, 39.7% of the men had NAFLD, and 17.6% of these showed regression of NAFLD during follow-up. Nearly a quarter of men (23.1%) without NAFLD at baseline had developed it by the end of follow-up, which lasted a median of 3.3 years.

The three-year cumulative incidence of subclinical carotid atherosclerosis was 14.3%, the researchers report in Gastroenterology, online June 6.

The risk of developing carotid atherosclerosis was 23% higher among men with persistent NAFLD than among those without the condition (p<0.001). This association persisted after adjusting for smoking, alcohol use, body mass index, and weight change but disappeared after adjustment for metabolic variables.

This suggests that metabolic factors mediate the association between NAFLD and the development of carotid atherosclerosis, the researchers note.

Men whose NAFLD regressed had an 18% lower risk of carotid atherosclerosis, compared with men who had persistent NAFLD (p<0.013).

Other factors associated with the development of carotid atherosclerosis included higher baseline NAFLD fibrosis score and baseline or persistent elevations of alanine aminotransferase (ALT) or gamma-glutamyltransferase (GGT).

"Once fatty liver is successfully resolved, the cardiovascular disease risk becomes similar to those without fatty liver at baseline," Dr. Gwak concluded. "That's the key message that physicians should deliver to their fatty liver patients."

SOURCE: http://bit.ly/28ODruY

Gastroenterology 2016.

NEW YORK - Patients with persistent nonalcoholic fatty liver disease (NAFLD) face a significantly elevated risk of carotid atherosclerosis, according to a new study of Korean men.

"The most interesting finding of our research is that regression of fatty liver is associated with reduced risk of subclinical carotid atherosclerosis compared to persistent fatty liver," said Dr. Geum-Youn Gwak from Sungkyunkwan University School of Medicine in Seoul.

"So, if somebody has fatty liver at one point, he or she should try hard to resolve fatty liver. Otherwise, it is highly likely that he or she would get cardiovascular disease one day," Dr. Gwak told Reuters Health by email.

NAFLD is associated with metabolic syndrome, diabetes, and cardiovascular disease morbidity and mortality, and several studies have shown that fatty liver is associated with markers of subclinical atherosclerosis.

Dr. Gwak's team conducted a retrospective longitudinal study of 8,020 men to assess the independent association of NAFLD with the development of subclinical carotid atherosclerosis identified by ultrasound, as defined by the development of an abnormally increased carotid intima-media thickness (CIMT) or of carotid plaque.

At baseline, 39.7% of the men had NAFLD, and 17.6% of these showed regression of NAFLD during follow-up. Nearly a quarter of men (23.1%) without NAFLD at baseline had developed it by the end of follow-up, which lasted a median of 3.3 years.

The three-year cumulative incidence of subclinical carotid atherosclerosis was 14.3%, the researchers report in Gastroenterology, online June 6.

The risk of developing carotid atherosclerosis was 23% higher among men with persistent NAFLD than among those without the condition (p<0.001). This association persisted after adjusting for smoking, alcohol use, body mass index, and weight change but disappeared after adjustment for metabolic variables.

This suggests that metabolic factors mediate the association between NAFLD and the development of carotid atherosclerosis, the researchers note.

Men whose NAFLD regressed had an 18% lower risk of carotid atherosclerosis, compared with men who had persistent NAFLD (p<0.013).

Other factors associated with the development of carotid atherosclerosis included higher baseline NAFLD fibrosis score and baseline or persistent elevations of alanine aminotransferase (ALT) or gamma-glutamyltransferase (GGT).

"Once fatty liver is successfully resolved, the cardiovascular disease risk becomes similar to those without fatty liver at baseline," Dr. Gwak concluded. "That's the key message that physicians should deliver to their fatty liver patients."

SOURCE: http://bit.ly/28ODruY

Gastroenterology 2016.

NEW YORK - A new protein-based risk score outperforms the Framingham model for predicting cardiovascular outcomes in patients with stable coronary heart disease.

"Patients who carry the diagnosis of stable coronary heart disease have been viewed traditionally as a homogeneous population within which all individuals tend to be treated similarly," Dr. Peter Ganz, from the University of California, San Francisco, told Reuters Health by email.

"Instead, we found that individuals who all carried the same clinical diagnosis of stable coronary heart disease had a risk of adverse events (heart attacks, strokes, heart failure, and death) that varied by as much as 10-fold, as revealed by analysis of the levels of nine proteins in their blood," he said.

Dr. Ganz and colleagues sought to derive and validate a score to predict the risk of cardiovascular outcomes among patients with coronary heart disease, using modified aptamers to measure 1,130 proteins in plasma samples.

Aptamers are small nucleic acids that can form secondary and tertiary structures capable of specifically binding proteins and thus can be considered the chemical equivalent of antibodies.

The researchers' unbiased statistical approach identified nine proteins, from which they derived a risk score that reflects the probability of a cardiovascular event occurring within four years.

In both the derivation and validation cohorts, participants had four-year cumulative event rates of 60% to 80% in the highest risk score decile and less than 10% in the lowest risk score decile, according to the June 21 JAMA report.

Compared with the Framingham model, the protein-based risk score showed an absolute increase of 12% in average risk for participants with events compared with participants without events.

The protein-based risk score was within two percentage points of the observed event rate in the external validation cohort.

Moreover, the protein-based risk score changed more than the Framingham model among participants approaching new events, and the protein-based risk score at follow-up was a stronger predictor of subsequent outcomes than the preceding baseline risk score.

"We may now be able to tell individual patients with coronary heart disease, 'You are at a very high risk, medium risk, or a very low risk,' and they may opt to be treated differently from other patients with the same diagnosis," Dr. Ganz said.

"In addition to the results described in the JAMA paper that apply to patients with coronary heart disease, we have an ongoing discovery program to identify proteins that can predict the risk of cardiovascular disease in additional patient populations, including lower-risk individuals who appear healthy but may actually be at high risk of coronary heart disease due to high cholesterol, high blood pressure, diabetes, or smoking, or among individuals who may be at high risk due to kidney disease or HIV infection," Dr. Ganz said.

"Although more accurate risk prediction is always welcome, clinicians more readily embrace measuring a prognostic biomarker or calculating a risk score if the results could alter therapeutic decision making," writes Dr. Marc S. Sabatine from Brigham and Women's Hospital, Boston, in an accompanying editorial.

"To that end, it would be interesting to apply these arrays to samples from patients in randomized clinical trials of therapies," he said. "If a gradient of treatment benefit existed, such data would make measurement of the relevant proteins in clinical practice more compelling (which, for the current list, is impractical). Furthermore, part of the long-term value of this sort of proteomics work may come from exploring the basic pathways that underline some of the novel associations described."

Dr. Matthew Sherwood, from Duke University Medical Center, Durham, North Carolina, who recently described multimarker risk stratification in patients with acute myocardial infarction, told Reuters Health by email, "While the results are impressive, their scope is limited. Since the population studied is already at high risk for further cardiovascular events, more refined risk stratification may not have significant clinical import. These patients have indications for treatment of CAD at present, thus changes in medical management are unlikely."

"Our ability to use proteomic signatures to predict cardiovascular risk continues to expand, and may become available to a broad cohort of patients in the future," Dr. Sherwood said. "The clinical utility of these platforms remains uncertain, and further investigation is needed to determine if proteomic based risk scores could help to modify therapeutic management in lower risk populations."

SomaLogic provided funding for protein assays and employed two coauthors. Four coauthors and the editorialist reported disclosures.

SOURCE: http://bit.ly/28L6oEy and http://bit.ly/28NgaJg

JAMA 2016.

NEW YORK - A new protein-based risk score outperforms the Framingham model for predicting cardiovascular outcomes in patients with stable coronary heart disease.

"Patients who carry the diagnosis of stable coronary heart disease have been viewed traditionally as a homogeneous population within which all individuals tend to be treated similarly," Dr. Peter Ganz, from the University of California, San Francisco, told Reuters Health by email.

"Instead, we found that individuals who all carried the same clinical diagnosis of stable coronary heart disease had a risk of adverse events (heart attacks, strokes, heart failure, and death) that varied by as much as 10-fold, as revealed by analysis of the levels of nine proteins in their blood," he said.

Dr. Ganz and colleagues sought to derive and validate a score to predict the risk of cardiovascular outcomes among patients with coronary heart disease, using modified aptamers to measure 1,130 proteins in plasma samples.

Aptamers are small nucleic acids that can form secondary and tertiary structures capable of specifically binding proteins and thus can be considered the chemical equivalent of antibodies.

The researchers' unbiased statistical approach identified nine proteins, from which they derived a risk score that reflects the probability of a cardiovascular event occurring within four years.

In both the derivation and validation cohorts, participants had four-year cumulative event rates of 60% to 80% in the highest risk score decile and less than 10% in the lowest risk score decile, according to the June 21 JAMA report.

Compared with the Framingham model, the protein-based risk score showed an absolute increase of 12% in average risk for participants with events compared with participants without events.

The protein-based risk score was within two percentage points of the observed event rate in the external validation cohort.

Moreover, the protein-based risk score changed more than the Framingham model among participants approaching new events, and the protein-based risk score at follow-up was a stronger predictor of subsequent outcomes than the preceding baseline risk score.

"We may now be able to tell individual patients with coronary heart disease, 'You are at a very high risk, medium risk, or a very low risk,' and they may opt to be treated differently from other patients with the same diagnosis," Dr. Ganz said.

"In addition to the results described in the JAMA paper that apply to patients with coronary heart disease, we have an ongoing discovery program to identify proteins that can predict the risk of cardiovascular disease in additional patient populations, including lower-risk individuals who appear healthy but may actually be at high risk of coronary heart disease due to high cholesterol, high blood pressure, diabetes, or smoking, or among individuals who may be at high risk due to kidney disease or HIV infection," Dr. Ganz said.

"Although more accurate risk prediction is always welcome, clinicians more readily embrace measuring a prognostic biomarker or calculating a risk score if the results could alter therapeutic decision making," writes Dr. Marc S. Sabatine from Brigham and Women's Hospital, Boston, in an accompanying editorial.

"To that end, it would be interesting to apply these arrays to samples from patients in randomized clinical trials of therapies," he said. "If a gradient of treatment benefit existed, such data would make measurement of the relevant proteins in clinical practice more compelling (which, for the current list, is impractical). Furthermore, part of the long-term value of this sort of proteomics work may come from exploring the basic pathways that underline some of the novel associations described."

Dr. Matthew Sherwood, from Duke University Medical Center, Durham, North Carolina, who recently described multimarker risk stratification in patients with acute myocardial infarction, told Reuters Health by email, "While the results are impressive, their scope is limited. Since the population studied is already at high risk for further cardiovascular events, more refined risk stratification may not have significant clinical import. These patients have indications for treatment of CAD at present, thus changes in medical management are unlikely."

"Our ability to use proteomic signatures to predict cardiovascular risk continues to expand, and may become available to a broad cohort of patients in the future," Dr. Sherwood said. "The clinical utility of these platforms remains uncertain, and further investigation is needed to determine if proteomic based risk scores could help to modify therapeutic management in lower risk populations."

SomaLogic provided funding for protein assays and employed two coauthors. Four coauthors and the editorialist reported disclosures.

SOURCE: http://bit.ly/28L6oEy and http://bit.ly/28NgaJg

JAMA 2016.

NEW YORK - A new protein-based risk score outperforms the Framingham model for predicting cardiovascular outcomes in patients with stable coronary heart disease.

"Patients who carry the diagnosis of stable coronary heart disease have been viewed traditionally as a homogeneous population within which all individuals tend to be treated similarly," Dr. Peter Ganz, from the University of California, San Francisco, told Reuters Health by email.

"Instead, we found that individuals who all carried the same clinical diagnosis of stable coronary heart disease had a risk of adverse events (heart attacks, strokes, heart failure, and death) that varied by as much as 10-fold, as revealed by analysis of the levels of nine proteins in their blood," he said.

Dr. Ganz and colleagues sought to derive and validate a score to predict the risk of cardiovascular outcomes among patients with coronary heart disease, using modified aptamers to measure 1,130 proteins in plasma samples.

Aptamers are small nucleic acids that can form secondary and tertiary structures capable of specifically binding proteins and thus can be considered the chemical equivalent of antibodies.

The researchers' unbiased statistical approach identified nine proteins, from which they derived a risk score that reflects the probability of a cardiovascular event occurring within four years.

In both the derivation and validation cohorts, participants had four-year cumulative event rates of 60% to 80% in the highest risk score decile and less than 10% in the lowest risk score decile, according to the June 21 JAMA report.

Compared with the Framingham model, the protein-based risk score showed an absolute increase of 12% in average risk for participants with events compared with participants without events.

The protein-based risk score was within two percentage points of the observed event rate in the external validation cohort.

Moreover, the protein-based risk score changed more than the Framingham model among participants approaching new events, and the protein-based risk score at follow-up was a stronger predictor of subsequent outcomes than the preceding baseline risk score.

"We may now be able to tell individual patients with coronary heart disease, 'You are at a very high risk, medium risk, or a very low risk,' and they may opt to be treated differently from other patients with the same diagnosis," Dr. Ganz said.

"In addition to the results described in the JAMA paper that apply to patients with coronary heart disease, we have an ongoing discovery program to identify proteins that can predict the risk of cardiovascular disease in additional patient populations, including lower-risk individuals who appear healthy but may actually be at high risk of coronary heart disease due to high cholesterol, high blood pressure, diabetes, or smoking, or among individuals who may be at high risk due to kidney disease or HIV infection," Dr. Ganz said.

"Although more accurate risk prediction is always welcome, clinicians more readily embrace measuring a prognostic biomarker or calculating a risk score if the results could alter therapeutic decision making," writes Dr. Marc S. Sabatine from Brigham and Women's Hospital, Boston, in an accompanying editorial.

"To that end, it would be interesting to apply these arrays to samples from patients in randomized clinical trials of therapies," he said. "If a gradient of treatment benefit existed, such data would make measurement of the relevant proteins in clinical practice more compelling (which, for the current list, is impractical). Furthermore, part of the long-term value of this sort of proteomics work may come from exploring the basic pathways that underline some of the novel associations described."

Dr. Matthew Sherwood, from Duke University Medical Center, Durham, North Carolina, who recently described multimarker risk stratification in patients with acute myocardial infarction, told Reuters Health by email, "While the results are impressive, their scope is limited. Since the population studied is already at high risk for further cardiovascular events, more refined risk stratification may not have significant clinical import. These patients have indications for treatment of CAD at present, thus changes in medical management are unlikely."

"Our ability to use proteomic signatures to predict cardiovascular risk continues to expand, and may become available to a broad cohort of patients in the future," Dr. Sherwood said. "The clinical utility of these platforms remains uncertain, and further investigation is needed to determine if proteomic based risk scores could help to modify therapeutic management in lower risk populations."

SomaLogic provided funding for protein assays and employed two coauthors. Four coauthors and the editorialist reported disclosures.

SOURCE: http://bit.ly/28L6oEy and http://bit.ly/28NgaJg

JAMA 2016.

NEW YORK - Several hepatitis C virus core antigen (HCVcAg) tests accurately diagnose hepatitis C virus (HCV) infection and could replace nucleic acid testing (NAT) in settings where HCV is prevalent, according to a systematic review and meta-analysis.

"Overall, several of the tests perform very well and while they are not equal to NAT, the lower costs may improve diagnostic capacity in the appropriate setting," Dr. J. Morgan Freiman from Boston Medical Center in Massachusetts told Reuters Health by email.

The current two-step diagnostic procedure for diagnosing HCV infection -- screening for antibodies to HCV followed by NAT for those with anti-HCV antibodies -- is a major bottleneck for addressing the HCV elimination strategy proposed by the World Health Organization. Currently, there are five tests for HCVcAg commercially available.

Dr. Freiman and colleagues evaluated the accuracy of diagnosis of active HCV infection among adults and children for these five commercially available tests compared with NAT in their systematic review and meta-analysis of 44 published reports.

The pooled sensitivity and specificity were 93.4% and 98.8% for the Abbott ARCHITECT assay, 93.2% and 99.2% for the Ortho HCV Ag ELISA, and 59.5% and 82.9% for the Hunan Jynda HCV Ag ELISA. There was insufficient information for a pooled analysis of the Eiken Lumispot HCV Ag and the Fujirebio Lumipulse Ortho HCV Ag assays.

Three reports showed that the HCVcAg correlated well with RNA when levels were at least 3000 IU/mL when the Abbott ARCHITECT assay was used, according to the June 21 Annals of Internal Medicine report.

"Although even tests with the highest performance are not as sensitive as NAT, well-performing HCVcAg tests with an analytic sensitivity reaching into the femtomolar range (equal to 3000 IU/mL) could replace NAT for HCV detection, particularly if a lower cost per test allows more patients to be served," the researchers conclude. "Therefore, HCVcAg should be explored for point-of-care (POC) testing to increase the number of patients diagnosed and streamline the HCV cascade of care."

"There is much more work to be done to determine at what sensitivity threshold a POC test would be clinically useful," Dr. Freiman said. "In settings with reliable access to centralized laboratory processing and higher diagnostic capacity, a POC test may still prove to be useful as a screening tool, but would be less likely to replace confirmatory nucleic acid testing (NAT)."

"We have the technology to detect circulating HCV RNA down to 15 IU/mL - amazing -- but how clinically relevant is that threshold when access to testing is equally as important as accuracy in resource limited settings?" he wondered.

Dr. Jose-Manuel Echevarria, from Carlos III Health Institute, Madrid, Spain, who recently reported that HCV core-specific antibody may represent occult HCV infection among blood donors, told Reuters Health by email, "Physicians should conclude from the report that HCVcAg testing provides trustful diagnostic results for the characterization of their anti-HCV positive patients as viremic or non-viremic before deciding about antiviral treatment."

"I would add that HCVcAg testing is particularly useful for the purpose of transfusion centers," he said. "Chronically infected blood donors are detected by anti-HCV screening, and HCVcAg will detect efficiently almost every blood unit obtained from donors experiencing the window period of the acute HCV infection, who test negative for anti-HCV."

"At present, high-resource settings will for sure use NAT testing because of its higher sensitivity, and because automatic equipment has reduced the chance for false-positive results because sample-to-sample contamination (is kept) to a minimum," Dr. Echevarria concluded. "However, HCVcAg testing is extremely useful and convenient for low-resource settings, and also for emergency units everywhere."

The National Institutes of Health funded this research. Three coauthors reported disclosures.

SOURCE: http://bit.ly/28LpRcU Ann Intern Med 2016.

NEW YORK - Several hepatitis C virus core antigen (HCVcAg) tests accurately diagnose hepatitis C virus (HCV) infection and could replace nucleic acid testing (NAT) in settings where HCV is prevalent, according to a systematic review and meta-analysis.

"Overall, several of the tests perform very well and while they are not equal to NAT, the lower costs may improve diagnostic capacity in the appropriate setting," Dr. J. Morgan Freiman from Boston Medical Center in Massachusetts told Reuters Health by email.

The current two-step diagnostic procedure for diagnosing HCV infection -- screening for antibodies to HCV followed by NAT for those with anti-HCV antibodies -- is a major bottleneck for addressing the HCV elimination strategy proposed by the World Health Organization. Currently, there are five tests for HCVcAg commercially available.

Dr. Freiman and colleagues evaluated the accuracy of diagnosis of active HCV infection among adults and children for these five commercially available tests compared with NAT in their systematic review and meta-analysis of 44 published reports.

The pooled sensitivity and specificity were 93.4% and 98.8% for the Abbott ARCHITECT assay, 93.2% and 99.2% for the Ortho HCV Ag ELISA, and 59.5% and 82.9% for the Hunan Jynda HCV Ag ELISA. There was insufficient information for a pooled analysis of the Eiken Lumispot HCV Ag and the Fujirebio Lumipulse Ortho HCV Ag assays.

Three reports showed that the HCVcAg correlated well with RNA when levels were at least 3000 IU/mL when the Abbott ARCHITECT assay was used, according to the June 21 Annals of Internal Medicine report.

"Although even tests with the highest performance are not as sensitive as NAT, well-performing HCVcAg tests with an analytic sensitivity reaching into the femtomolar range (equal to 3000 IU/mL) could replace NAT for HCV detection, particularly if a lower cost per test allows more patients to be served," the researchers conclude. "Therefore, HCVcAg should be explored for point-of-care (POC) testing to increase the number of patients diagnosed and streamline the HCV cascade of care."

"There is much more work to be done to determine at what sensitivity threshold a POC test would be clinically useful," Dr. Freiman said. "In settings with reliable access to centralized laboratory processing and higher diagnostic capacity, a POC test may still prove to be useful as a screening tool, but would be less likely to replace confirmatory nucleic acid testing (NAT)."

"We have the technology to detect circulating HCV RNA down to 15 IU/mL - amazing -- but how clinically relevant is that threshold when access to testing is equally as important as accuracy in resource limited settings?" he wondered.

Dr. Jose-Manuel Echevarria, from Carlos III Health Institute, Madrid, Spain, who recently reported that HCV core-specific antibody may represent occult HCV infection among blood donors, told Reuters Health by email, "Physicians should conclude from the report that HCVcAg testing provides trustful diagnostic results for the characterization of their anti-HCV positive patients as viremic or non-viremic before deciding about antiviral treatment."

"I would add that HCVcAg testing is particularly useful for the purpose of transfusion centers," he said. "Chronically infected blood donors are detected by anti-HCV screening, and HCVcAg will detect efficiently almost every blood unit obtained from donors experiencing the window period of the acute HCV infection, who test negative for anti-HCV."

"At present, high-resource settings will for sure use NAT testing because of its higher sensitivity, and because automatic equipment has reduced the chance for false-positive results because sample-to-sample contamination (is kept) to a minimum," Dr. Echevarria concluded. "However, HCVcAg testing is extremely useful and convenient for low-resource settings, and also for emergency units everywhere."

The National Institutes of Health funded this research. Three coauthors reported disclosures.

SOURCE: http://bit.ly/28LpRcU Ann Intern Med 2016.

NEW YORK - Several hepatitis C virus core antigen (HCVcAg) tests accurately diagnose hepatitis C virus (HCV) infection and could replace nucleic acid testing (NAT) in settings where HCV is prevalent, according to a systematic review and meta-analysis.

"Overall, several of the tests perform very well and while they are not equal to NAT, the lower costs may improve diagnostic capacity in the appropriate setting," Dr. J. Morgan Freiman from Boston Medical Center in Massachusetts told Reuters Health by email.

The current two-step diagnostic procedure for diagnosing HCV infection -- screening for antibodies to HCV followed by NAT for those with anti-HCV antibodies -- is a major bottleneck for addressing the HCV elimination strategy proposed by the World Health Organization. Currently, there are five tests for HCVcAg commercially available.

Dr. Freiman and colleagues evaluated the accuracy of diagnosis of active HCV infection among adults and children for these five commercially available tests compared with NAT in their systematic review and meta-analysis of 44 published reports.

The pooled sensitivity and specificity were 93.4% and 98.8% for the Abbott ARCHITECT assay, 93.2% and 99.2% for the Ortho HCV Ag ELISA, and 59.5% and 82.9% for the Hunan Jynda HCV Ag ELISA. There was insufficient information for a pooled analysis of the Eiken Lumispot HCV Ag and the Fujirebio Lumipulse Ortho HCV Ag assays.

Three reports showed that the HCVcAg correlated well with RNA when levels were at least 3000 IU/mL when the Abbott ARCHITECT assay was used, according to the June 21 Annals of Internal Medicine report.

"Although even tests with the highest performance are not as sensitive as NAT, well-performing HCVcAg tests with an analytic sensitivity reaching into the femtomolar range (equal to 3000 IU/mL) could replace NAT for HCV detection, particularly if a lower cost per test allows more patients to be served," the researchers conclude. "Therefore, HCVcAg should be explored for point-of-care (POC) testing to increase the number of patients diagnosed and streamline the HCV cascade of care."

"There is much more work to be done to determine at what sensitivity threshold a POC test would be clinically useful," Dr. Freiman said. "In settings with reliable access to centralized laboratory processing and higher diagnostic capacity, a POC test may still prove to be useful as a screening tool, but would be less likely to replace confirmatory nucleic acid testing (NAT)."

"We have the technology to detect circulating HCV RNA down to 15 IU/mL - amazing -- but how clinically relevant is that threshold when access to testing is equally as important as accuracy in resource limited settings?" he wondered.

Dr. Jose-Manuel Echevarria, from Carlos III Health Institute, Madrid, Spain, who recently reported that HCV core-specific antibody may represent occult HCV infection among blood donors, told Reuters Health by email, "Physicians should conclude from the report that HCVcAg testing provides trustful diagnostic results for the characterization of their anti-HCV positive patients as viremic or non-viremic before deciding about antiviral treatment."

"I would add that HCVcAg testing is particularly useful for the purpose of transfusion centers," he said. "Chronically infected blood donors are detected by anti-HCV screening, and HCVcAg will detect efficiently almost every blood unit obtained from donors experiencing the window period of the acute HCV infection, who test negative for anti-HCV."

"At present, high-resource settings will for sure use NAT testing because of its higher sensitivity, and because automatic equipment has reduced the chance for false-positive results because sample-to-sample contamination (is kept) to a minimum," Dr. Echevarria concluded. "However, HCVcAg testing is extremely useful and convenient for low-resource settings, and also for emergency units everywhere."

The National Institutes of Health funded this research. Three coauthors reported disclosures.

SOURCE: http://bit.ly/28LpRcU Ann Intern Med 2016.