C-Reactive Protein Levels and Outcomes after Statin Therapy
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《新英格兰医药杂志》
To the Editor: Ridker and colleagues (Jan. 6 issue)1 suggest that statin therapy be targeted to achieve a C-reactive protein (CRP) level of less than 2.0 mg per liter in patients with a recent acute coronary syndrome. Having examined the data presented in Table 1 of the article, we question this conclusion. After adjustment for known cardiac risk factors, the relative risk of recurrent coronary events was appreciably increased only in patients whose CRP level was in the highest quartile (>4.2 mg per liter). Patients whose CRP level was in the second or third quartile (0.9 to 4.2 mg per liter) had only moderate increases in relative risk, and after adjustment for other risk factors, those increases were not statistically significant. Although the authors found that event rates differed between patients with a CRP level of 2.0 mg per liter or greater and those with a level below 2.0 mg per liter, this difference was probably driven by data from patients with CRP levels in the highest quartile. Lowering CRP levels that are in the highest quartile may be beneficial. However, randomized clinical trials are needed to address this question. Until such trials have been conducted, we believe that it is premature to recommend aggressive use of statins to reduce CRP levels.
Beth Cohen, M.D.
David Singh, M.D.
University of California, San Francisco
San Francisco, CA 94143
References
Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352:20-28.
To the Editor: The finding that high levels of CRP are associated with a poorer outcome than low CRP levels after an acute coronary syndrome is probably due to inadequate statistical adjustment for important confounding variables. According to data from Kinjo et al.,1 high CRP levels measured 25 days after an acute coronary syndrome were associated with poorer long-term outcomes than were low CRP levels, as well as with important prognostic factors that Ridker et al. did not consider in their "fully adjusted model." These critical covariates include classic prognostic factors after an acute coronary syndrome, such as higher Killip class, a higher peak level of creatine kinase, and the use or nonuse of revascularization during the index hospitalization.1 These are true confounding variables — associated with both exposure (i.e., CRP levels) and outcome.2 Harb et al. demonstrated that the association between a high CRP level and poor outcomes after myocardial infarction was attenuated and became nonsignificant after adjustment for similar confounders, including ejection fraction.3 Thus, the weak CRP association observed (the lower level of the confidence interval for the relative risk in the highest CRP quartile was only 1.1 in the "fully-adjusted model") probably represents nothing more than residual confounding due to important prognostic factors associated with CRP in patients with an acute coronary syndrome.
Philip Greenland, M.D.
Donald M. Lloyd-Jones, M.D.
Northwestern University Feinberg School of Medicine
Chicago, IL 60611
Arthur J. Moss, M.D.
University of Rochester School of Medicine and Dentistry
Rochester, NY 14642
References
Kinjo K, Sato H, Ohnishi Y, et al. Impact of high-sensitivity C-reactive protein on predicting long-term mortality of acute myocardial infarction. Am J Cardiol 2003;91:931-935.
Moss AJ, Benhorin J. Prognosis and management after a first myocardial infarction. N Engl J Med 1990;322:743-753.
Harb TS, Zareba W, Moss AJ, et al. Association of C-reactive protein and serum amyloid A with recurrent coronary events in stable patients after healing of acute myocardial infarction. Am J Cardiol 2002;89:216-221.
To the Editor: Ridker et al. demonstrated that patients with acute coronary syndromes in whom low CRP levels are achieved after statin therapy have a decreased risk of recurrent myocardial infarction or death, regardless of the levels of low-density lipoprotein (LDL) cholesterol attained. The observed benefit was largely attributed to the antiinflammatory effects of statins, as assessed by the inflammatory biomarker CRP, thus adding to the lipid-independent, pleiotropic properties of these agents. This interpretation notwithstanding, recent work provides evidence of a direct inhibitory effect of statins on CRP biosynthesis by human hepatocytes.1 Statins also up-regulate the production of nitric oxide synthase,2 which is expressed in hepatocytes; boosting hepatic nitric oxide production might, in turn, suppress CRP synthesis.3
The nature of the CRP reduction observed after statin therapy merits some scrutiny in light of these new findings. A complementary analytical approach would be to measure other hepatic positive acute-phase reactants (e.g., ferritin) and negative acute-phase reactants (e.g., albumin), as well as more proximal inflammatory biomarkers (e.g., interleukin-6) to help decipher the direct and indirect modulatory effect of statins on the hepatic synthesis of CRP.
Bertrand L. Jaber, M.D.
Nicolaos E. Madias, M.D.
Caritas St. Elizabeth's Medical Center
Boston, MA 02135
bertrand_jaber@cchcs.org
References
Kleemann R, Verschuren L, de Rooij BJ, et al. Evidence for anti-inflammatory activity of statins and PPARalpha activators in human C-reactive protein transgenic mice in vivo and in cultured human hepatocytes in vitro. Blood 2004;103:4188-4194.
Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998;97:1129-1135.
McCarty MF. AMPK activation may suppress hepatic production of C-reactive protein by stimulating nitric oxide synthase. Med Hypotheses 2004;63:328-333.
The authors reply: Drs. Jaber and Madias correctly note that multiple mechanisms have been proposed for the statin-lowering effect of CRP, and they seek information regarding proximal inflammatory markers. In this regard, our data and those of others have indicated that statins lower CRP levels but do not consistently reduce levels of interleukin-6.1
Drs. Cohen and Singh interpret our data to suggest that only patients with the highest CRP levels benefited from statin therapy. However, as shown in Table 1 of our article, we observed a linear relationship between inflammation and hard clinical outcomes across the full spectrum of CRP levels — a finding compatible with data from studies of primary prevention.2 Furthermore, as shown in Table 2, additional benefits were observed among patients who not only had LDL cholesterol levels below 70 mg per liter but who also had CRP levels that were reduced to less than 1 mg per liter.
Dr. Greenland and colleagues speculate that the strong relationship in our data between CRP levels measured at 30 days and subsequent vascular events might be due to residual confounding by the Killip class, peak creatine kinase level, and use or nonuse of early revascularization. In our study, we reported a relative risk of 1.8 for patients with a CRP level in the top quartile in a multivariate analysis adjusted for sex, smoking status, the presence or absence of diabetes, the presence or absence of a history of hypertension, body-mass index, achieved LDL cholesterol level, and assignment to antibiotic therapy or placebo (95 percent confidence interval, 1.2 to 2.7; P=0.003). After additional adjustment for the Killip class, peak level of creatine kinase, and use or nonuse of early revascularization, the relative risk was 1.9 (95 percent confidence interval, 1.3 to 2.9; P=0.004).
We cannot agree with Dr. Greenland and colleagues that the data reported by Kinjo et al. support a role of residual confounding, when that study showed a statistically significant, ninefold increase in the risk of death from cardiovascular causes among patients in stable condition after a myocardial infarction who had elevated levels of CRP, even after adjustment for usual risk factors and for use or nonuse of revascularization, Killip class, creatine kinase level, infarct location, and use or nonuse of adjunctive medical therapies.3 Moreover, in their discussion of the THROMBO study,4 in which CRP levels were a univariate but not multivariate predictor of recurrent events, Dr. Greenland and colleagues do not point out that in the same data set, the LDL cholesterol level was not predictive at all, even in univariate analyses.5 Thus, if it is concluded on the basis of the THROMBO study that CRP levels after myocardial infarction have little clinical utility, then it must also be concluded that there is no utility in measuring LDL cholesterol, a position at odds with all current recommendations6 and one we do not accept.
Paul M Ridker, M.D.
Christopher P. Cannon, M.D.
Eugene Braunwald, M.D.
Brigham and Women's Hospital
Boston, MA 02115
pridker@partners.org
References
Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S. Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation 2001;103:1933-1935.
Ridker PM, Cook N. Clinical usefulness of very high and very low levels of C-reactive protein across the full range of Framingham risk scores. Circulation 2004;109:1955-1959.
Kinjo K, Sato H, Ohnishi Y, et al. Impact of high-sensitivity C-reactive protein on predicting long-term mortality of acute myocardial infarction. Am J Cardiol 2003;91:931-935.
Harb TS, Zareba W, Moss AJ, et al. Association of C-reactive protein and serum amyloid A with recurrent coronary events in stable patients after healing of acute myocardial infarction. Am J Cardiol 2002;89:216-221.
Moss AJ, Goldstein RE, Marder VJ, et al. Thrombogenic factors and recurrent coronary events. Circulation 1999;99:2517-2522.
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;110:227-239.
Beth Cohen, M.D.
David Singh, M.D.
University of California, San Francisco
San Francisco, CA 94143
References
Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352:20-28.
To the Editor: The finding that high levels of CRP are associated with a poorer outcome than low CRP levels after an acute coronary syndrome is probably due to inadequate statistical adjustment for important confounding variables. According to data from Kinjo et al.,1 high CRP levels measured 25 days after an acute coronary syndrome were associated with poorer long-term outcomes than were low CRP levels, as well as with important prognostic factors that Ridker et al. did not consider in their "fully adjusted model." These critical covariates include classic prognostic factors after an acute coronary syndrome, such as higher Killip class, a higher peak level of creatine kinase, and the use or nonuse of revascularization during the index hospitalization.1 These are true confounding variables — associated with both exposure (i.e., CRP levels) and outcome.2 Harb et al. demonstrated that the association between a high CRP level and poor outcomes after myocardial infarction was attenuated and became nonsignificant after adjustment for similar confounders, including ejection fraction.3 Thus, the weak CRP association observed (the lower level of the confidence interval for the relative risk in the highest CRP quartile was only 1.1 in the "fully-adjusted model") probably represents nothing more than residual confounding due to important prognostic factors associated with CRP in patients with an acute coronary syndrome.
Philip Greenland, M.D.
Donald M. Lloyd-Jones, M.D.
Northwestern University Feinberg School of Medicine
Chicago, IL 60611
Arthur J. Moss, M.D.
University of Rochester School of Medicine and Dentistry
Rochester, NY 14642
References
Kinjo K, Sato H, Ohnishi Y, et al. Impact of high-sensitivity C-reactive protein on predicting long-term mortality of acute myocardial infarction. Am J Cardiol 2003;91:931-935.
Moss AJ, Benhorin J. Prognosis and management after a first myocardial infarction. N Engl J Med 1990;322:743-753.
Harb TS, Zareba W, Moss AJ, et al. Association of C-reactive protein and serum amyloid A with recurrent coronary events in stable patients after healing of acute myocardial infarction. Am J Cardiol 2002;89:216-221.
To the Editor: Ridker et al. demonstrated that patients with acute coronary syndromes in whom low CRP levels are achieved after statin therapy have a decreased risk of recurrent myocardial infarction or death, regardless of the levels of low-density lipoprotein (LDL) cholesterol attained. The observed benefit was largely attributed to the antiinflammatory effects of statins, as assessed by the inflammatory biomarker CRP, thus adding to the lipid-independent, pleiotropic properties of these agents. This interpretation notwithstanding, recent work provides evidence of a direct inhibitory effect of statins on CRP biosynthesis by human hepatocytes.1 Statins also up-regulate the production of nitric oxide synthase,2 which is expressed in hepatocytes; boosting hepatic nitric oxide production might, in turn, suppress CRP synthesis.3
The nature of the CRP reduction observed after statin therapy merits some scrutiny in light of these new findings. A complementary analytical approach would be to measure other hepatic positive acute-phase reactants (e.g., ferritin) and negative acute-phase reactants (e.g., albumin), as well as more proximal inflammatory biomarkers (e.g., interleukin-6) to help decipher the direct and indirect modulatory effect of statins on the hepatic synthesis of CRP.
Bertrand L. Jaber, M.D.
Nicolaos E. Madias, M.D.
Caritas St. Elizabeth's Medical Center
Boston, MA 02135
bertrand_jaber@cchcs.org
References
Kleemann R, Verschuren L, de Rooij BJ, et al. Evidence for anti-inflammatory activity of statins and PPARalpha activators in human C-reactive protein transgenic mice in vivo and in cultured human hepatocytes in vitro. Blood 2004;103:4188-4194.
Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998;97:1129-1135.
McCarty MF. AMPK activation may suppress hepatic production of C-reactive protein by stimulating nitric oxide synthase. Med Hypotheses 2004;63:328-333.
The authors reply: Drs. Jaber and Madias correctly note that multiple mechanisms have been proposed for the statin-lowering effect of CRP, and they seek information regarding proximal inflammatory markers. In this regard, our data and those of others have indicated that statins lower CRP levels but do not consistently reduce levels of interleukin-6.1
Drs. Cohen and Singh interpret our data to suggest that only patients with the highest CRP levels benefited from statin therapy. However, as shown in Table 1 of our article, we observed a linear relationship between inflammation and hard clinical outcomes across the full spectrum of CRP levels — a finding compatible with data from studies of primary prevention.2 Furthermore, as shown in Table 2, additional benefits were observed among patients who not only had LDL cholesterol levels below 70 mg per liter but who also had CRP levels that were reduced to less than 1 mg per liter.
Dr. Greenland and colleagues speculate that the strong relationship in our data between CRP levels measured at 30 days and subsequent vascular events might be due to residual confounding by the Killip class, peak creatine kinase level, and use or nonuse of early revascularization. In our study, we reported a relative risk of 1.8 for patients with a CRP level in the top quartile in a multivariate analysis adjusted for sex, smoking status, the presence or absence of diabetes, the presence or absence of a history of hypertension, body-mass index, achieved LDL cholesterol level, and assignment to antibiotic therapy or placebo (95 percent confidence interval, 1.2 to 2.7; P=0.003). After additional adjustment for the Killip class, peak level of creatine kinase, and use or nonuse of early revascularization, the relative risk was 1.9 (95 percent confidence interval, 1.3 to 2.9; P=0.004).
We cannot agree with Dr. Greenland and colleagues that the data reported by Kinjo et al. support a role of residual confounding, when that study showed a statistically significant, ninefold increase in the risk of death from cardiovascular causes among patients in stable condition after a myocardial infarction who had elevated levels of CRP, even after adjustment for usual risk factors and for use or nonuse of revascularization, Killip class, creatine kinase level, infarct location, and use or nonuse of adjunctive medical therapies.3 Moreover, in their discussion of the THROMBO study,4 in which CRP levels were a univariate but not multivariate predictor of recurrent events, Dr. Greenland and colleagues do not point out that in the same data set, the LDL cholesterol level was not predictive at all, even in univariate analyses.5 Thus, if it is concluded on the basis of the THROMBO study that CRP levels after myocardial infarction have little clinical utility, then it must also be concluded that there is no utility in measuring LDL cholesterol, a position at odds with all current recommendations6 and one we do not accept.
Paul M Ridker, M.D.
Christopher P. Cannon, M.D.
Eugene Braunwald, M.D.
Brigham and Women's Hospital
Boston, MA 02115
pridker@partners.org
References
Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S. Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation 2001;103:1933-1935.
Ridker PM, Cook N. Clinical usefulness of very high and very low levels of C-reactive protein across the full range of Framingham risk scores. Circulation 2004;109:1955-1959.
Kinjo K, Sato H, Ohnishi Y, et al. Impact of high-sensitivity C-reactive protein on predicting long-term mortality of acute myocardial infarction. Am J Cardiol 2003;91:931-935.
Harb TS, Zareba W, Moss AJ, et al. Association of C-reactive protein and serum amyloid A with recurrent coronary events in stable patients after healing of acute myocardial infarction. Am J Cardiol 2002;89:216-221.
Moss AJ, Goldstein RE, Marder VJ, et al. Thrombogenic factors and recurrent coronary events. Circulation 1999;99:2517-2522.
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;110:227-239.