- Email: [email protected]
C-reactive protein measurement and cardiovascular disease – Authors' reply
Correspondence
C-reactive protein measurement and cardiovascular disease Matthijs Boekholdt and John Kastelein state in their Comment (Jan 9, p 95)1 that measurement of C-reactive protein (CRP) might be useful in identifying individuals at risk of cardiovascular disease, but the large meta-analysis by the Emerging Risk Factors Collaboration2 (recording 28 000 cardiovascular disease events) indicates otherwise. The risk ratio for coronary heart disease between individuals with CRP in the upper and lower quintile groups (fifths) of the distribution was about 2·5, which translates to an expected detection rate (sensitivity) of about 10% for a 5% false-positive rate.3 This is poor discrimination, little better than selecting people for preventive treatment at random. The figure shows detection rate
plotted against false-positive rate for CRP and first coronary heart disease events, based on a published meta-analysis of 22 cohort studies.4 The plot barely deviates from the diagonal line (indicating a useless screening test) and the data confirm that the detection rate is only 11% for a 5% false-positive rate. The same conclusion was reached independently by Hingorani and colleagues,5 and holds even if CRP is used with other risk factors. Boekholdt and Kastelein also suggest that CRP may be useful in quantifying the efficacy of interventions for cardiovascular disease prevention,1 but this is unlikely because CRP is too nonspecific, being raised in many conditions (eg, cancer and lung disease) as the meta-analysis by the Emerging Risk Factors Collaboration shows.2 The available evidence shows that CRP measurement has no
practical value in the prediction or management of coronary heart disease or stroke. We declare that we have no conflicts of interest.
*David S Wald, Jonathan P Bestwick [email protected] Barts & the London School of Medicine and Dentistry, Queen Mary University of London, Wolfson Institute of Preventive Medicine, London EC1M 6BQ, UK 1
2
3
4
5
Boekholdt SM, Kastelein JJP. C-reactive protein and cardiovascular risk: more fuel to the fire. Lancet 2010; 375: 95–96. Emerging Risk Factors Collaboration. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010; 375: 132–40. Wald NJ, Hackshaw AK, Frost CD. When can a risk factor be used as a worthwhile screening test? BMJ 1999; 319: 1562–65. Wald DS, Kasturiratne A, Bestwick JP. The value of C-reactive protein in screening for future coronary heart disease events. J Med Screen 2009; 16: 212–14. Hingorani AD, Shah T, Casas JP, Humphries SE, Talmud PJ. C-reactive protein and coronary heart disease: predictive test or therapeutic target? Clin Chem 2009; 55: 239–55.
Authors’ reply 100
90
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Detection rate (%)
CRP 60
50
40
30
Useless test
20
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0 0
10
20
30
40
50
60
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80
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False-positive rate (%)
Figure: C-reactive protein (CRP) as a screening test for future coronary heart disease: plot of detection rate against false-positive rate, based on 22 prospective studies. Reproduced, with permission, from reference 4.
www.thelancet.com Vol 375 March 27, 2010
We do not agree with David Wald and Jonathan Bestwick’s interpretation of the clinical relevance of C-reactive protein (CRP) for several reasons. First, it remains unclear to us which statistical criteria they used to support their interpretation that the observed detection rates are clinically irrelevant. In fact, we do not agree that lack of statistical significance always implies lack of clinical relevance. Second, eFigure 5 (webappendix, p 18) of the Emerging Risk Factors Collaboration meta-analysis1 shows that the association with risk of coronary heart disease is at least as strong for CRP as it is for total cholesterol, non-HDL cholesterol, and systolic blood pressure. Following Wald and Bestwick’s reasoning, this would entail that cholesterol measures and blood pressure are useless risk factors as well and have no practical value in cardiovascular disease management—a verdict few would agree with.
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1077
Correspondence
Third, Wald and Bestwick suggest that we propose to use CRP as a screening tool, which is incorrect. In fact, CRP has only been advocated for the fine-tuning of clinical decision making in individuals estimated to be at intermediate risk. The Canadian Cardiovascular Society was the first institution to adopt the use of CRP to identify individuals at intermediate risk who may benefit from lipidlowering therapy.2 This approach is supported by clinical evidence showing that people with elevated CRP levels benefit substantially from statin treatment and that larger reductions in LDL cholesterol and CRP predict greater benefit.3,4 We agree with Wald and Bestwick that CRP is far from perfect as a risk factor. In fact, it has the same limitations as most other established risk factors. However, in the absence of perfect risk factors, physicians in clinical practice have to live with imperfect ones, including cholesterol, blood pressure, and CRP. So even if CRP is a non-specific and possibly a non-causal risk factor, we strongly believe that it may still be useful in the management of cardiovascular disease. We declare that we have no conflicts of interest.
*S Matthijs Boekholdt, John J Kastelein [email protected] Department of Cardiology, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, Netherlands 1
2
3
4
1078
Emerging Risk Factors Collaboration. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010; 375: 132–40. Genest J, McPherson R, Frohlich J, et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult—2009 recommendations. Can J Cardiol 2009; 25: 567–79. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195–207. Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009; 373: 1175–82.
The Emerging Risk Factors Collaboration (Jan 9, p 132)1 reports the results of an extensive meta-analysis in an ongoing effort to understand the relation between circulating C-reactive protein (CRP) and cardiovascular risk. The collaborators conclude that CRP’s association with cardiovascular risk is driven predominantly by systemic inflammation and that CRP is unlikely to contribute directly to cardiovascular disease as a pathogenic factor. Similar conclusions were drawn from recent Mendelian randomisation studies.2 We would like to point out that these conclusions are based on the assumption that there is only one biologically active isoform of CRP, on which the authors base their relation studies. However, along with the well recognised pentameric form of CRP (pCRP), which is currently measured in the circulation, a plausible biological mechanism for the formation of monomeric CRP (mCRP) has also been identified.3 There is growing evidence that mCRP may have novel proinflammatory4 and thrombotic5 properties. The conversion of pCRP to mCRP has been described as being mediated by activated platelets,4 which are clearly associated with cardiovascular risk. This hypothesis is attractive because it could provide a link between atherosclerosis and CRP, with important therapeutic implications. The currently discussed association studies1,2 are missing this potential inflammatory “activation” of pCRP, an intermediary step which has not been considered in the interpretation of these data. Conclusions made while our understanding of the biology of the CRP system is incomplete potentially leave an important part of the story untold. We declare that we have no conflicts of interest.
*Jonathon Habersberger, Steffen Eisenhardt, Karlheinz Peter [email protected] Baker IDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia (JH, KP); and Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Freiburg, Germany (SE)
1
2
3
4
5
The Emerging Risk Factors Collaboration. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010; 375: 132–40. Elliott P, Chambers JC, Zhang W, et al. Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA 2009; 302: 37–48. Ji SR, Wu Y, Zhu L, et al. Cell membranes and liposomes dissociate C-reactive protein (CRP) to form a new, biologically active structural intermediate: mCRP(m). FASEB J 2007; 21: 284–94. Eisenhardt SU, Habersberger J, Murphy A, et al. Dissociation of pentameric to monomeric C-reactive protein on activated platelets localizes inflammation to atherosclerotic plaques. Circ Res 2009; 105: 128–37. Molins B, Peña E, Vilahur G, Mendieta C, Slevin M, Badimon L. C-reactive protein isoforms differ in their effects on thrombus growth. Arterioscler Thromb Vasc Biol 2008; 28: 2239–46.
American Medical Association and patients’ autonomy In his discussion of patients’ right to decline some kinds of information, Charles Foster (Jan 30, p 368)1 has not completely and accurately interpreted the substance and intent of American Medical Association (AMA) policy. Although AMA policy does not explicitly address a “right not to know”, it does emphasise that physicians have an obligation to individualise consent. The Code of Medical Ethics provides that “Physicians should sensitively and respectfully disclose all relevant medical information to patients. The quantity and specificity of this information should be tailored to meet the preferences and needs of individual patients”.2 I declare that I have no conflicts of interest.
John W McMahon Snr [email protected] Council on Ethical and Judicial Affairs, American Medical Association, Chicago, IL 60654, USA 1 2
Foster C. Autonomy should chair, not rule. Lancet 2010; 375: 368–69. American Medical Association. Opinion 8.08: informed consent. AMA Code of Medical Ethics. Chicago: American Medical Association, 2008. http://www.ama-assn.org/ama/pub/ physician-resources/medical-ethics/codemedical-ethics/opinion808.shtml (accessed March 2, 2010).
www.thelancet.com Vol 375 March 27, 2010
C-reactive protein measurement and cardiovascular disease Matthijs Boekholdt and John Kastelein state in their Comment (Jan 9, p 95)1 that measurement of C-reactive protein (CRP) might be useful in identifying individuals at risk of cardiovascular disease, but the large meta-analysis by the Emerging Risk Factors Collaboration2 (recording 28 000 cardiovascular disease events) indicates otherwise. The risk ratio for coronary heart disease between individuals with CRP in the upper and lower quintile groups (fifths) of the distribution was about 2·5, which translates to an expected detection rate (sensitivity) of about 10% for a 5% false-positive rate.3 This is poor discrimination, little better than selecting people for preventive treatment at random. The figure shows detection rate
plotted against false-positive rate for CRP and first coronary heart disease events, based on a published meta-analysis of 22 cohort studies.4 The plot barely deviates from the diagonal line (indicating a useless screening test) and the data confirm that the detection rate is only 11% for a 5% false-positive rate. The same conclusion was reached independently by Hingorani and colleagues,5 and holds even if CRP is used with other risk factors. Boekholdt and Kastelein also suggest that CRP may be useful in quantifying the efficacy of interventions for cardiovascular disease prevention,1 but this is unlikely because CRP is too nonspecific, being raised in many conditions (eg, cancer and lung disease) as the meta-analysis by the Emerging Risk Factors Collaboration shows.2 The available evidence shows that CRP measurement has no
practical value in the prediction or management of coronary heart disease or stroke. We declare that we have no conflicts of interest.
*David S Wald, Jonathan P Bestwick [email protected] Barts & the London School of Medicine and Dentistry, Queen Mary University of London, Wolfson Institute of Preventive Medicine, London EC1M 6BQ, UK 1
2
3
4
5
Boekholdt SM, Kastelein JJP. C-reactive protein and cardiovascular risk: more fuel to the fire. Lancet 2010; 375: 95–96. Emerging Risk Factors Collaboration. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010; 375: 132–40. Wald NJ, Hackshaw AK, Frost CD. When can a risk factor be used as a worthwhile screening test? BMJ 1999; 319: 1562–65. Wald DS, Kasturiratne A, Bestwick JP. The value of C-reactive protein in screening for future coronary heart disease events. J Med Screen 2009; 16: 212–14. Hingorani AD, Shah T, Casas JP, Humphries SE, Talmud PJ. C-reactive protein and coronary heart disease: predictive test or therapeutic target? Clin Chem 2009; 55: 239–55.
Authors’ reply 100
90
80
70
Detection rate (%)
CRP 60
50
40
30
Useless test
20
10
0 0
10
20
30
40
50
60
70
80
90
100
False-positive rate (%)
Figure: C-reactive protein (CRP) as a screening test for future coronary heart disease: plot of detection rate against false-positive rate, based on 22 prospective studies. Reproduced, with permission, from reference 4.
www.thelancet.com Vol 375 March 27, 2010
We do not agree with David Wald and Jonathan Bestwick’s interpretation of the clinical relevance of C-reactive protein (CRP) for several reasons. First, it remains unclear to us which statistical criteria they used to support their interpretation that the observed detection rates are clinically irrelevant. In fact, we do not agree that lack of statistical significance always implies lack of clinical relevance. Second, eFigure 5 (webappendix, p 18) of the Emerging Risk Factors Collaboration meta-analysis1 shows that the association with risk of coronary heart disease is at least as strong for CRP as it is for total cholesterol, non-HDL cholesterol, and systolic blood pressure. Following Wald and Bestwick’s reasoning, this would entail that cholesterol measures and blood pressure are useless risk factors as well and have no practical value in cardiovascular disease management—a verdict few would agree with.
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1077
Correspondence
Third, Wald and Bestwick suggest that we propose to use CRP as a screening tool, which is incorrect. In fact, CRP has only been advocated for the fine-tuning of clinical decision making in individuals estimated to be at intermediate risk. The Canadian Cardiovascular Society was the first institution to adopt the use of CRP to identify individuals at intermediate risk who may benefit from lipidlowering therapy.2 This approach is supported by clinical evidence showing that people with elevated CRP levels benefit substantially from statin treatment and that larger reductions in LDL cholesterol and CRP predict greater benefit.3,4 We agree with Wald and Bestwick that CRP is far from perfect as a risk factor. In fact, it has the same limitations as most other established risk factors. However, in the absence of perfect risk factors, physicians in clinical practice have to live with imperfect ones, including cholesterol, blood pressure, and CRP. So even if CRP is a non-specific and possibly a non-causal risk factor, we strongly believe that it may still be useful in the management of cardiovascular disease. We declare that we have no conflicts of interest.
*S Matthijs Boekholdt, John J Kastelein [email protected] Department of Cardiology, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, Netherlands 1
2
3
4
1078
Emerging Risk Factors Collaboration. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010; 375: 132–40. Genest J, McPherson R, Frohlich J, et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult—2009 recommendations. Can J Cardiol 2009; 25: 567–79. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195–207. Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009; 373: 1175–82.
The Emerging Risk Factors Collaboration (Jan 9, p 132)1 reports the results of an extensive meta-analysis in an ongoing effort to understand the relation between circulating C-reactive protein (CRP) and cardiovascular risk. The collaborators conclude that CRP’s association with cardiovascular risk is driven predominantly by systemic inflammation and that CRP is unlikely to contribute directly to cardiovascular disease as a pathogenic factor. Similar conclusions were drawn from recent Mendelian randomisation studies.2 We would like to point out that these conclusions are based on the assumption that there is only one biologically active isoform of CRP, on which the authors base their relation studies. However, along with the well recognised pentameric form of CRP (pCRP), which is currently measured in the circulation, a plausible biological mechanism for the formation of monomeric CRP (mCRP) has also been identified.3 There is growing evidence that mCRP may have novel proinflammatory4 and thrombotic5 properties. The conversion of pCRP to mCRP has been described as being mediated by activated platelets,4 which are clearly associated with cardiovascular risk. This hypothesis is attractive because it could provide a link between atherosclerosis and CRP, with important therapeutic implications. The currently discussed association studies1,2 are missing this potential inflammatory “activation” of pCRP, an intermediary step which has not been considered in the interpretation of these data. Conclusions made while our understanding of the biology of the CRP system is incomplete potentially leave an important part of the story untold. We declare that we have no conflicts of interest.
*Jonathon Habersberger, Steffen Eisenhardt, Karlheinz Peter [email protected] Baker IDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia (JH, KP); and Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Freiburg, Germany (SE)
1
2
3
4
5
The Emerging Risk Factors Collaboration. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010; 375: 132–40. Elliott P, Chambers JC, Zhang W, et al. Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA 2009; 302: 37–48. Ji SR, Wu Y, Zhu L, et al. Cell membranes and liposomes dissociate C-reactive protein (CRP) to form a new, biologically active structural intermediate: mCRP(m). FASEB J 2007; 21: 284–94. Eisenhardt SU, Habersberger J, Murphy A, et al. Dissociation of pentameric to monomeric C-reactive protein on activated platelets localizes inflammation to atherosclerotic plaques. Circ Res 2009; 105: 128–37. Molins B, Peña E, Vilahur G, Mendieta C, Slevin M, Badimon L. C-reactive protein isoforms differ in their effects on thrombus growth. Arterioscler Thromb Vasc Biol 2008; 28: 2239–46.
American Medical Association and patients’ autonomy In his discussion of patients’ right to decline some kinds of information, Charles Foster (Jan 30, p 368)1 has not completely and accurately interpreted the substance and intent of American Medical Association (AMA) policy. Although AMA policy does not explicitly address a “right not to know”, it does emphasise that physicians have an obligation to individualise consent. The Code of Medical Ethics provides that “Physicians should sensitively and respectfully disclose all relevant medical information to patients. The quantity and specificity of this information should be tailored to meet the preferences and needs of individual patients”.2 I declare that I have no conflicts of interest.
John W McMahon Snr [email protected] Council on Ethical and Judicial Affairs, American Medical Association, Chicago, IL 60654, USA 1 2
Foster C. Autonomy should chair, not rule. Lancet 2010; 375: 368–69. American Medical Association. Opinion 8.08: informed consent. AMA Code of Medical Ethics. Chicago: American Medical Association, 2008. http://www.ama-assn.org/ama/pub/ physician-resources/medical-ethics/codemedical-ethics/opinion808.shtml (accessed March 2, 2010).
www.thelancet.com Vol 375 March 27, 2010