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Should we measure C-reactive protein levels to ascertain the adequacy of statin therapy in patients who are at very high risk for a coronary heart disease event?
Evidence-Based Consult
Should we measure C-reactive protein levels to ascertain the adequacy of statin therapy in patients who are at very high risk for a coronary heart disease event? Abhinav Goyal, MD, and Michael Blazing, MD Durham, NC
Clinical scenario A 62-year-old man who was hospitalized 6 weeks ago with a non–ST-segment elevation myocardial infarction (MI) presents to your office for follow-up. His medications since hospital discharge include aspirin 81 mg daily, pravastatin 20 mg daily, metoprolol 25 mg twice daily, and ramipril 10 mg daily. His fasting lipid panel last week showed total cholesterol of 138 mg/dL, triglycerides 160 mg/dL, high-density lipoprotein cholesterol 38 mg/dL, and low-density lipoprotein cholesterol 68 mg/dL. He asks whether he would benefit from getting tested for C-reactive protein (CRP), which he heard from the media is a test that can bsave his lifeQ. You do a literature search to evaluate the evidence.
modifications1 to the National Cholesterol Education Program Adult Treatment Panel III guidelines2)?
Design This was a prospective cohort study (subgroups were prespecified before outcomes were ascertained) derived from a randomized, double-blind, double-dummy controlled trial (PROVE IT–TIMI 22).
Setting The setting was multicenter—349 sites in 8 countries.
Patients Combining the key words C-reactive protein and acute coronary syndromes in MEDLINE, you find 141 articles. You choose the following article which is among the first listed: Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, Pfeffer MA, Braunwald E, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 352;1:20 - 8.
The original PROVE IT–TIMI 22 study3 randomized 4162 patients with acute MI with or without ST-segment elevation, or high-risk unstable angina, to pravastatin 40 mg daily or to atorvastatin 80 mg daily and compared long-term outcomes. (The atorvastatin regimen reduced the risk of recurrent cardiovascular events at 24 months by 16%, 95% CI 5% -26%, P = .005.) This CRP substudy included 3745 patients (90% of the original cohort) who were alive and free of a recurrent coronary event at 30 days and had measurements of both LDL cholesterol and CRP levels at 30 days.
Question
Intervention
Is there a benefit to measuring CRP in a very high-risk patient who is already on statin therapy and whose LDL cholesterol level is already lowered to b 70 mg/dL (the very aggressive boptionalQ goal of the recent
Stratification of patients into 4 subgroups based on median LDL cholesterol at 30 days (70 mg/dL) and median CRP level at 30 days (2 mg/L): (1) LDL cho lesterol z70 mg/dL and CRP z2 mg/L; (2) LDL cholesterol z70 mg/dL and CRP b 2 mg/L; (3) LDL cholesterol b 70 mg/dL and CRP z2 mg/L; and (4) LDL cholesterol b 70 mg/dL and CRP b 2 mg/L.
Literature search
From the Duke Clinical Research Institute, Durham, NC. Reprint requests: Abhinav Goyal, MD, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715. E-mail: [email protected] Am Heart J 2005;150:650 -1. 0002-8703/$ - see front matter n 2005, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2005.08.001
Main outcome measures The primary end point was the age-adjusted risk of recurrent MI or death from coronary causes after a mean follow-up of 24 months.
American Heart Journal Volume 150, Number 4
Goyal and Blazing 651
Main results The rates of the primary end point by subgroup are shown below: Subgroup LDL LDL LDL LDL
z70 mg/dL, CRP z2 mg/L z70 mg/dL, CRP b 2 mg/L b 70 mg/dL, CRP z2 mg/L b 70 mg/dL, CRP b 2 mg/L
No. of patients
Event rate*
1086 899 742 1018
4.6 3.2 3.1 2.4
*Age-adjusted rate of recurrent MI or coronary death per 100 person-years. Overall P value b.001.
Although a greater proportion of patients on atorvastatin 80 mg daily achieved the dual targets specified in the study (LDL b 70 mg/dL and CRP b 2 mg/L) compared with pravastatin 40 mg daily, within each of the 4 subgroups (stratified by median LDL cholesterol and CRP levels), patients did equally well regardless of which statin regimen they followed. When the overall PROVE IT–TIMI 22 trial results were adjusted for achieved LDL cholesterol and CRP levels, there was no observed benefit of atorvastatin compared with pravastatin on clinical outcomes (hazard ratio 1.00, 95% CI 0.75 -1.34, P = .90), suggesting that the achievement of dual targets was more important than the choice of statin regimen. The relationship between achieved CRP and LDL cholesterol levels at 30 days yielded a Spearman correlation coefficient of 0.16 (r = 0.16, or r 2 = 0.03), indicating that only 3% of the variation in achieved CRP levels could be explained by the variation in achieved LDL cholesterol levels (ie, one cannot predict the degree of reduction of CRP levels based on the degree of LDL cholesterol lowering), and that measuring both markers would be necessary to predict risk accurately.
Commentary Numerous studies have supported the utility of CRP in predicting the risk of future coronary events. This is the first study to report that reducing CRP levels below a certain threshold is associated with improved clinical outcomes. The study is provocative, but with important limitations. First, although the survival analyses were prespecified, the comparison groups (stratification by median LDL cholesterol and CRP levels at 1 month) were defined post-randomization. Therefore, the data demonstrate only an association, not a direct link, between reduced CRP and reduced mortality. Second, in the analysis comparing 4 subgroups based on median achieved LDL cholesterol and CRP levels, the outcomes were adjusted only for age, and not for other cardiovascular risk factors that were ascertained at baseline (including sex, smoking status, diabetes, hypertension, and body mass index). This is a major limitation of an analysis that seeks to establish the benefit of lowering CRP levels independent of other known predictors of
future coronary heart disease events. Third, the authors reported the lack of correlation between the LDL cholesterol and CRP levels achieved after 30 days of statin therapy. However, their analysis did not account for the starting level of both of these markers before statin therapy. (PROVE IT–TIMI 22 did not allow for a reliable analysis of the correlation between the change in LDL cholesterol and the change in CRP levels because the baseline levels of these markers were obtained after an acute coronary syndrome, after which CRP levels are markedly elevated and LDL cholesterol levels are suppressed. When determining risk for future cardiovascular disease events, these markers should be obtained only in subjects who are not acutely ill.) Despite these limitations, the authors are to be congratulated for generating this interesting hypothesis.
Expert opinion Evidence continues to accumulate supporting the association between elevated CRP levels and higher risk of cardiovascular events. However, whether mitigating the process of inflammation will improve clinical outcomes independent of lipid lowering pathways is a matter of intense debate and study. It is challenging to separate lipid-lowering and anti-inflammatory pathways, as LDL particles, possibly through their oxidation, are intimately tied to inflammatory processes in the arterial wall and in atherosclerotic plaques. Furthermore, CRP’s precise role in the inflammation cascade has not yet been elucidated, and whether it is truly the best marker of inflammation in the arterial wall is uncertain. Establishing CRP as an independent therapeutic target would require randomized clinical trial protocols testing two different lipid-lowering regimens that aim a priori for similar degrees of LDL cholesterol lowering but different degrees of CRP reduction in each treatment arm, or placebocontrolled protocols that test therapies that reduce only CRP and not LDL cholesterol levels. Until such randomized trials are designed, the CRP substudies of several other lipid-lowering trials, including the A to Z trial, the TNT study, the IDEAL trial, and the SEARCH study, should shed additional light on this area of intense interest.
References 1. Grundy SM, Cleeman JI, Merz CN, et al, Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227 - 39. 2. Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol on adults (adult treatment panel III). JAMA 2001;285:2486 - 97. 3. Cannon CP, Braunwald E, McCabe CH, et al, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) – Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495 - 504.
Should we measure C-reactive protein levels to ascertain the adequacy of statin therapy in patients who are at very high risk for a coronary heart disease event? Abhinav Goyal, MD, and Michael Blazing, MD Durham, NC
Clinical scenario A 62-year-old man who was hospitalized 6 weeks ago with a non–ST-segment elevation myocardial infarction (MI) presents to your office for follow-up. His medications since hospital discharge include aspirin 81 mg daily, pravastatin 20 mg daily, metoprolol 25 mg twice daily, and ramipril 10 mg daily. His fasting lipid panel last week showed total cholesterol of 138 mg/dL, triglycerides 160 mg/dL, high-density lipoprotein cholesterol 38 mg/dL, and low-density lipoprotein cholesterol 68 mg/dL. He asks whether he would benefit from getting tested for C-reactive protein (CRP), which he heard from the media is a test that can bsave his lifeQ. You do a literature search to evaluate the evidence.
modifications1 to the National Cholesterol Education Program Adult Treatment Panel III guidelines2)?
Design This was a prospective cohort study (subgroups were prespecified before outcomes were ascertained) derived from a randomized, double-blind, double-dummy controlled trial (PROVE IT–TIMI 22).
Setting The setting was multicenter—349 sites in 8 countries.
Patients Combining the key words C-reactive protein and acute coronary syndromes in MEDLINE, you find 141 articles. You choose the following article which is among the first listed: Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, Pfeffer MA, Braunwald E, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 352;1:20 - 8.
The original PROVE IT–TIMI 22 study3 randomized 4162 patients with acute MI with or without ST-segment elevation, or high-risk unstable angina, to pravastatin 40 mg daily or to atorvastatin 80 mg daily and compared long-term outcomes. (The atorvastatin regimen reduced the risk of recurrent cardiovascular events at 24 months by 16%, 95% CI 5% -26%, P = .005.) This CRP substudy included 3745 patients (90% of the original cohort) who were alive and free of a recurrent coronary event at 30 days and had measurements of both LDL cholesterol and CRP levels at 30 days.
Question
Intervention
Is there a benefit to measuring CRP in a very high-risk patient who is already on statin therapy and whose LDL cholesterol level is already lowered to b 70 mg/dL (the very aggressive boptionalQ goal of the recent
Stratification of patients into 4 subgroups based on median LDL cholesterol at 30 days (70 mg/dL) and median CRP level at 30 days (2 mg/L): (1) LDL cho lesterol z70 mg/dL and CRP z2 mg/L; (2) LDL cholesterol z70 mg/dL and CRP b 2 mg/L; (3) LDL cholesterol b 70 mg/dL and CRP z2 mg/L; and (4) LDL cholesterol b 70 mg/dL and CRP b 2 mg/L.
Literature search
From the Duke Clinical Research Institute, Durham, NC. Reprint requests: Abhinav Goyal, MD, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715. E-mail: [email protected] Am Heart J 2005;150:650 -1. 0002-8703/$ - see front matter n 2005, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2005.08.001
Main outcome measures The primary end point was the age-adjusted risk of recurrent MI or death from coronary causes after a mean follow-up of 24 months.
American Heart Journal Volume 150, Number 4
Goyal and Blazing 651
Main results The rates of the primary end point by subgroup are shown below: Subgroup LDL LDL LDL LDL
z70 mg/dL, CRP z2 mg/L z70 mg/dL, CRP b 2 mg/L b 70 mg/dL, CRP z2 mg/L b 70 mg/dL, CRP b 2 mg/L
No. of patients
Event rate*
1086 899 742 1018
4.6 3.2 3.1 2.4
*Age-adjusted rate of recurrent MI or coronary death per 100 person-years. Overall P value b.001.
Although a greater proportion of patients on atorvastatin 80 mg daily achieved the dual targets specified in the study (LDL b 70 mg/dL and CRP b 2 mg/L) compared with pravastatin 40 mg daily, within each of the 4 subgroups (stratified by median LDL cholesterol and CRP levels), patients did equally well regardless of which statin regimen they followed. When the overall PROVE IT–TIMI 22 trial results were adjusted for achieved LDL cholesterol and CRP levels, there was no observed benefit of atorvastatin compared with pravastatin on clinical outcomes (hazard ratio 1.00, 95% CI 0.75 -1.34, P = .90), suggesting that the achievement of dual targets was more important than the choice of statin regimen. The relationship between achieved CRP and LDL cholesterol levels at 30 days yielded a Spearman correlation coefficient of 0.16 (r = 0.16, or r 2 = 0.03), indicating that only 3% of the variation in achieved CRP levels could be explained by the variation in achieved LDL cholesterol levels (ie, one cannot predict the degree of reduction of CRP levels based on the degree of LDL cholesterol lowering), and that measuring both markers would be necessary to predict risk accurately.
Commentary Numerous studies have supported the utility of CRP in predicting the risk of future coronary events. This is the first study to report that reducing CRP levels below a certain threshold is associated with improved clinical outcomes. The study is provocative, but with important limitations. First, although the survival analyses were prespecified, the comparison groups (stratification by median LDL cholesterol and CRP levels at 1 month) were defined post-randomization. Therefore, the data demonstrate only an association, not a direct link, between reduced CRP and reduced mortality. Second, in the analysis comparing 4 subgroups based on median achieved LDL cholesterol and CRP levels, the outcomes were adjusted only for age, and not for other cardiovascular risk factors that were ascertained at baseline (including sex, smoking status, diabetes, hypertension, and body mass index). This is a major limitation of an analysis that seeks to establish the benefit of lowering CRP levels independent of other known predictors of
future coronary heart disease events. Third, the authors reported the lack of correlation between the LDL cholesterol and CRP levels achieved after 30 days of statin therapy. However, their analysis did not account for the starting level of both of these markers before statin therapy. (PROVE IT–TIMI 22 did not allow for a reliable analysis of the correlation between the change in LDL cholesterol and the change in CRP levels because the baseline levels of these markers were obtained after an acute coronary syndrome, after which CRP levels are markedly elevated and LDL cholesterol levels are suppressed. When determining risk for future cardiovascular disease events, these markers should be obtained only in subjects who are not acutely ill.) Despite these limitations, the authors are to be congratulated for generating this interesting hypothesis.
Expert opinion Evidence continues to accumulate supporting the association between elevated CRP levels and higher risk of cardiovascular events. However, whether mitigating the process of inflammation will improve clinical outcomes independent of lipid lowering pathways is a matter of intense debate and study. It is challenging to separate lipid-lowering and anti-inflammatory pathways, as LDL particles, possibly through their oxidation, are intimately tied to inflammatory processes in the arterial wall and in atherosclerotic plaques. Furthermore, CRP’s precise role in the inflammation cascade has not yet been elucidated, and whether it is truly the best marker of inflammation in the arterial wall is uncertain. Establishing CRP as an independent therapeutic target would require randomized clinical trial protocols testing two different lipid-lowering regimens that aim a priori for similar degrees of LDL cholesterol lowering but different degrees of CRP reduction in each treatment arm, or placebocontrolled protocols that test therapies that reduce only CRP and not LDL cholesterol levels. Until such randomized trials are designed, the CRP substudies of several other lipid-lowering trials, including the A to Z trial, the TNT study, the IDEAL trial, and the SEARCH study, should shed additional light on this area of intense interest.
References 1. Grundy SM, Cleeman JI, Merz CN, et al, Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227 - 39. 2. Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol on adults (adult treatment panel III). JAMA 2001;285:2486 - 97. 3. Cannon CP, Braunwald E, McCabe CH, et al, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) – Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495 - 504.