Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Studies Examine Inflammatory Biomarker in Prevention and Prediction of Heart Disease

Studies Examine Inflammatory Biomarker in Prevention and Prediction of Heart Disease New Orleans—Researchers have demonstrated that a new primary prevention strategy may reduce cardiovascular events in certain patients at risk of cardiovascular disease. At the Scientific Sessions of the American Heart Association (AHA) held here in November, scientists reported that among apparently healthy patients with elevated levels of high-sensitivity C-reactive protein (hsCRP, an inflammatory biomarker) but without elevated low-density lipoprotein cholesterol (LDL-C) levels (< 130 mg/dL), using a statin reduced the LDL-C levels and significantly reduced the risk of myocardial infarction, stroke, and death. Levels of C-reactive protein increase during inflammation, making its measurement a potentially useful biomarker for improving cardiovascular risk stratification. In addition, findings from other studies presented at the meeting suggested that hsCRP may improve cardiovascular risk stratification beyond such traditional factors as age, blood pressure, total cholesterol, smoking status, and diabetes mellitus. These results about the potential utility of hsCRP in risk assessment most likely will be considered in updates of guidelines for the assessment and management of cardiovascular risk factors. Committees writing such updates are already convening and are expected to publish their revisions in early 2010. Reducing cardiovascular events Generating the greatest interest at the meeting were the results from the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which were presented in a late-breaking clinical trials session and published concurrently (Ridker PM et al. N Engl J Med. 2008;359[21]:2195-2207). The trial was supported by AstraZeneca, London, England, and Paul M Ridker, MD, the lead author and director of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital in Boston, reported receiving grant support from the company. Ridker is also listed as a coinventor on patents held by Brigham and Women's relating to the use of inflammatory biomarkers in cardiovascular disease, including hsCRP. In this randomized double-blinded placebo-controlled trial, researchers screened 89 890 “apparently healthy” individuals at 1315 sites in 26 countries; 17 802 men (aged ≥50 years) and women (aged ≥60 years) with LDL-C levels of less than 130 mg/dL and hsCRP levels of 2.0 mg/L or higher were then randomly assigned to receive 20 mg of rosuvastatin daily or placebo. The combined primary end point was myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. The JUPITER researchers found that LDL-C levels in participants who received rosuvastatin decreased almost 50% from a median of 108 mg/dL to 55 mg/dL and remained stable in participants in the placebo group. At 12-month follow-up, hsCRP levels had fallen from a median 4.2 mg/L at baseline in the rosuvastatin group to 2.2 mg/L while in the placebo group, hsCRP declined from 4.3 mg/L to 3.5 mg/L. The primary end point event rates were 0.77 per 100 person-years of follow-up for those who received rosuvastatin vs 1.36 per 100 person-years of follow-up for those who received placebo—a 44% relative risk reduction (approximately 1% absolute risk reduction). Trial participants were observed for only a median of 1.9 years rather than for 5 years as planned after an independent data and safety monitoring board recommended terminating the study and placing all enrollees on statins because of the benefits seen in the rosuvastatin group. However, the study left unresolved whether only those with high hsCRP benefit and whether only rosuvastatin works or whether other statins might also have similar effects. Sydney C. Smith Jr, MD, professor of medicine at the University of North Carolina at Chapel Hill School of Medicine and a past president of the American Heart Association, was impressed with the study results. “Whenever anybody talks about a better way to identify risk and couples it with information that treatment based on that identification improves outcomes, I’m interested,” said Smith. Some caveats Timothy J. Gardner MD, AHA president and medical director of Christiana Care's Center for Heart & Vascular Health in Wilmington, Del, was struck by the trial results but noted that there are unanswered questions about who should be treated. While the trial participants were “apparently healthy” at enrollment, he said, their median body mass index was 28.3 for men and 28.4 for women; median systolic/diastolic blood pressure for men and women was 134/80 mm Hg (within the prehypertensive range). Also, about 16% were smokers, about 11.5% had a family history of premature cardiovascular disease, and about 41% were considered to have the metabolic syndrome. “In JUPITER, some people, despite having LDL-C at or below the normal range, were overweight, some had hypertension, and some metabolic syndrome so it's not black and white as to who should get treatment,” Gardner said. Indeed, researchers estimated that only 4% to 7% of the US population would qualify for treatment based on the criteria for eligibility in JUPITER. Still, that 4% to 7% may be just the patients who are especially at risk for cardiovascular disease but who may be missed by their physicians because they appear healthy, said James H. Stein, MD, a professor of medicine at the University of Wisconsin School of Medicine in Madison. “The real neat thing is JUPITER found the sweet spot of cardiovascular risk—it's the prototypical patient that every physician sees,” said Stein. Experts point out that there are caveats attached to the JUPITER results. While the relative risk reduction appears great, some observers calculated the actual results suggest that it would require the treatment of 120 individuals for nearly 2 years to prevent 1 “hard” cardiac event (myocardial infarction, stroke, or cardiovascular death) (Hlatky MA. N Engl J Med. 2008;359[21]:2280-2282). And rosuvastatin is still under patent protection and costs an estimated $3.45 a day, suggesting it will cost about $285 000 to prevent 1 cardiovascular event using the drug. If a generic statin had been tested and found to be as effective as rosuvastatin, the cost to prevent a cardiovascular event could be about $50 000. Stein admitted that cost will be a factor for him to consider when treating patients who meet the JUPITER criteria. “I personally think that any other statin that gets the same levels of LDL-C and CRP found in JUPITER will be good,” he said. Long-term safety of statin therapy for patients with very low LDL-C levels is another concern, especially because the trial’s early termination resulted in less than 2 years of follow-up for JUPITER participants. The researchers did note a slight, but statistically significant, increase in glycated hemoglobin at 24 months and a 25% increase in physician-reported newly diagnosed diabetes in patients taking rosuvastatin compared with placebo. Marker or cause? Another question left unanswered by the trial is whether the lowering of LDL-C, the decrease in hsCRP, or a combination of the two reduced cardiovascular events. Although further research will be needed to sort this out, findings from other studies presented at the meeting suggest that CRP may be gaining some credibility as a biomarker associated with increased risk for cardiovascular events. In a study of 3006 participants from the Framingham Offspring Study (the children [and their spouses] of participants in the original Framingham study), researchers found that measurement of circulating levels of CRP offered moderate improvement in reclassification of cardiovascular risk and may be used most effectively in individuals at intermediate risk for vascular events (Wilson PWF et al. Circ Cardiovasc Qual Outcomes. 2008;1[2]:92-97). Including CRP with traditional risk factors resulted in a net reclassification improvement of 11.8% for hard coronary heart disease (CHD) outcomes (myocardial infarction and CHD-related death) and 5.6% for total cardiovascular disease (hard CHD events plus angina pectoris, transient ischemic attack, stroke, and intermittent claudication). In a second study, involving 10 724 initially healthy US men, investigators found that using a prediction model incorporating hsCRP levels and parental history of myocardial infarction before age 60 years (the Reynolds Risk Score) resulted in global cardiovascular risk prediction that was significantly better than that generated by the traditional model (Ridker PM et al. Circulation. 2008;118[22]:2243-2251). The Reynolds Risk Score reclassified 17.8% of the men into higher risk or lower risk categories for the end point of all cardiovascular events, with improved accuracy among those reclassified. Last year, researchers suggested that a similar model improved cardiovascular risk assessment in women (Ridker PM et al. JAMA. 2007;297[6]:611-619). Guidelines updates Smith, who is also the senior advisor for cardiovascular research translation and application with the National Heart, Lung, and Blood Institute (NHLBI), said these 3 studies will be under consideration as NHLBI moves forward in developing guidelines. Work is proceeding on the fourth report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel [ATP] IV). The NHLBI is also preparing to publish the Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8). Also, in the works is an update on the agency's Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. “The efforts under way at NHLBI are designed to focus on a uniform application of assessing risk and understanding how the existing approach, which relies on the Framingham Risk Assessment score, adjusted for ethnicity, can be improved,” said Smith. “So the question becomes ‘At what point should we apply hsCRP to the screening process and how might that compare to other new screening methods such as imaging?’” http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Studies Examine Inflammatory Biomarker in Prevention and Prediction of Heart Disease

JAMA , Volume 301 (1) – Jan 7, 2009

Loading next page...
 
/lp/american-medical-association/studies-examine-inflammatory-biomarker-in-prevention-and-prediction-of-XWGf2LF10Y

References (0)

References for this paper are not available at this time. We will be adding them shortly, thank you for your patience.

Publisher
American Medical Association
Copyright
Copyright © 2009 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.2008.876
Publisher site
See Article on Publisher Site

Abstract

New Orleans—Researchers have demonstrated that a new primary prevention strategy may reduce cardiovascular events in certain patients at risk of cardiovascular disease. At the Scientific Sessions of the American Heart Association (AHA) held here in November, scientists reported that among apparently healthy patients with elevated levels of high-sensitivity C-reactive protein (hsCRP, an inflammatory biomarker) but without elevated low-density lipoprotein cholesterol (LDL-C) levels (< 130 mg/dL), using a statin reduced the LDL-C levels and significantly reduced the risk of myocardial infarction, stroke, and death. Levels of C-reactive protein increase during inflammation, making its measurement a potentially useful biomarker for improving cardiovascular risk stratification. In addition, findings from other studies presented at the meeting suggested that hsCRP may improve cardiovascular risk stratification beyond such traditional factors as age, blood pressure, total cholesterol, smoking status, and diabetes mellitus. These results about the potential utility of hsCRP in risk assessment most likely will be considered in updates of guidelines for the assessment and management of cardiovascular risk factors. Committees writing such updates are already convening and are expected to publish their revisions in early 2010. Reducing cardiovascular events Generating the greatest interest at the meeting were the results from the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which were presented in a late-breaking clinical trials session and published concurrently (Ridker PM et al. N Engl J Med. 2008;359[21]:2195-2207). The trial was supported by AstraZeneca, London, England, and Paul M Ridker, MD, the lead author and director of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital in Boston, reported receiving grant support from the company. Ridker is also listed as a coinventor on patents held by Brigham and Women's relating to the use of inflammatory biomarkers in cardiovascular disease, including hsCRP. In this randomized double-blinded placebo-controlled trial, researchers screened 89 890 “apparently healthy” individuals at 1315 sites in 26 countries; 17 802 men (aged ≥50 years) and women (aged ≥60 years) with LDL-C levels of less than 130 mg/dL and hsCRP levels of 2.0 mg/L or higher were then randomly assigned to receive 20 mg of rosuvastatin daily or placebo. The combined primary end point was myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. The JUPITER researchers found that LDL-C levels in participants who received rosuvastatin decreased almost 50% from a median of 108 mg/dL to 55 mg/dL and remained stable in participants in the placebo group. At 12-month follow-up, hsCRP levels had fallen from a median 4.2 mg/L at baseline in the rosuvastatin group to 2.2 mg/L while in the placebo group, hsCRP declined from 4.3 mg/L to 3.5 mg/L. The primary end point event rates were 0.77 per 100 person-years of follow-up for those who received rosuvastatin vs 1.36 per 100 person-years of follow-up for those who received placebo—a 44% relative risk reduction (approximately 1% absolute risk reduction). Trial participants were observed for only a median of 1.9 years rather than for 5 years as planned after an independent data and safety monitoring board recommended terminating the study and placing all enrollees on statins because of the benefits seen in the rosuvastatin group. However, the study left unresolved whether only those with high hsCRP benefit and whether only rosuvastatin works or whether other statins might also have similar effects. Sydney C. Smith Jr, MD, professor of medicine at the University of North Carolina at Chapel Hill School of Medicine and a past president of the American Heart Association, was impressed with the study results. “Whenever anybody talks about a better way to identify risk and couples it with information that treatment based on that identification improves outcomes, I’m interested,” said Smith. Some caveats Timothy J. Gardner MD, AHA president and medical director of Christiana Care's Center for Heart & Vascular Health in Wilmington, Del, was struck by the trial results but noted that there are unanswered questions about who should be treated. While the trial participants were “apparently healthy” at enrollment, he said, their median body mass index was 28.3 for men and 28.4 for women; median systolic/diastolic blood pressure for men and women was 134/80 mm Hg (within the prehypertensive range). Also, about 16% were smokers, about 11.5% had a family history of premature cardiovascular disease, and about 41% were considered to have the metabolic syndrome. “In JUPITER, some people, despite having LDL-C at or below the normal range, were overweight, some had hypertension, and some metabolic syndrome so it's not black and white as to who should get treatment,” Gardner said. Indeed, researchers estimated that only 4% to 7% of the US population would qualify for treatment based on the criteria for eligibility in JUPITER. Still, that 4% to 7% may be just the patients who are especially at risk for cardiovascular disease but who may be missed by their physicians because they appear healthy, said James H. Stein, MD, a professor of medicine at the University of Wisconsin School of Medicine in Madison. “The real neat thing is JUPITER found the sweet spot of cardiovascular risk—it's the prototypical patient that every physician sees,” said Stein. Experts point out that there are caveats attached to the JUPITER results. While the relative risk reduction appears great, some observers calculated the actual results suggest that it would require the treatment of 120 individuals for nearly 2 years to prevent 1 “hard” cardiac event (myocardial infarction, stroke, or cardiovascular death) (Hlatky MA. N Engl J Med. 2008;359[21]:2280-2282). And rosuvastatin is still under patent protection and costs an estimated $3.45 a day, suggesting it will cost about $285 000 to prevent 1 cardiovascular event using the drug. If a generic statin had been tested and found to be as effective as rosuvastatin, the cost to prevent a cardiovascular event could be about $50 000. Stein admitted that cost will be a factor for him to consider when treating patients who meet the JUPITER criteria. “I personally think that any other statin that gets the same levels of LDL-C and CRP found in JUPITER will be good,” he said. Long-term safety of statin therapy for patients with very low LDL-C levels is another concern, especially because the trial’s early termination resulted in less than 2 years of follow-up for JUPITER participants. The researchers did note a slight, but statistically significant, increase in glycated hemoglobin at 24 months and a 25% increase in physician-reported newly diagnosed diabetes in patients taking rosuvastatin compared with placebo. Marker or cause? Another question left unanswered by the trial is whether the lowering of LDL-C, the decrease in hsCRP, or a combination of the two reduced cardiovascular events. Although further research will be needed to sort this out, findings from other studies presented at the meeting suggest that CRP may be gaining some credibility as a biomarker associated with increased risk for cardiovascular events. In a study of 3006 participants from the Framingham Offspring Study (the children [and their spouses] of participants in the original Framingham study), researchers found that measurement of circulating levels of CRP offered moderate improvement in reclassification of cardiovascular risk and may be used most effectively in individuals at intermediate risk for vascular events (Wilson PWF et al. Circ Cardiovasc Qual Outcomes. 2008;1[2]:92-97). Including CRP with traditional risk factors resulted in a net reclassification improvement of 11.8% for hard coronary heart disease (CHD) outcomes (myocardial infarction and CHD-related death) and 5.6% for total cardiovascular disease (hard CHD events plus angina pectoris, transient ischemic attack, stroke, and intermittent claudication). In a second study, involving 10 724 initially healthy US men, investigators found that using a prediction model incorporating hsCRP levels and parental history of myocardial infarction before age 60 years (the Reynolds Risk Score) resulted in global cardiovascular risk prediction that was significantly better than that generated by the traditional model (Ridker PM et al. Circulation. 2008;118[22]:2243-2251). The Reynolds Risk Score reclassified 17.8% of the men into higher risk or lower risk categories for the end point of all cardiovascular events, with improved accuracy among those reclassified. Last year, researchers suggested that a similar model improved cardiovascular risk assessment in women (Ridker PM et al. JAMA. 2007;297[6]:611-619). Guidelines updates Smith, who is also the senior advisor for cardiovascular research translation and application with the National Heart, Lung, and Blood Institute (NHLBI), said these 3 studies will be under consideration as NHLBI moves forward in developing guidelines. Work is proceeding on the fourth report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel [ATP] IV). The NHLBI is also preparing to publish the Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8). Also, in the works is an update on the agency's Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. “The efforts under way at NHLBI are designed to focus on a uniform application of assessing risk and understanding how the existing approach, which relies on the Framingham Risk Assessment score, adjusted for ethnicity, can be improved,” said Smith. “So the question becomes ‘At what point should we apply hsCRP to the screening process and how might that compare to other new screening methods such as imaging?’”

Journal

JAMAAmerican Medical Association

Published: Jan 7, 2009

Keywords: inflammatory markers,heart diseases,cardiovascular event

There are no references for this article.