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Electronic letters published:
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Biomarkers in Near-term vs Late-term Mortality in Patients with Peripheral Arterial Disease
Combined use of heparin and statins for preventing near-term mortality in peripheral artery disease.
Mild Inflammatory Response in Patients with Peripheral Arterial Disease
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Mary M McDermott, MD Northwestern University's Feinberg School of Medicine, Lu Tian, Kiang Liu
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mdm608{at}northwestern.edu Mary M McDermott, et al.
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First, because of relatively limited statistical power, we restricted the number of covariates included in our statistical models. Covariates in our fully adjusted models were selected in an a priori fashion, based on previously published work that identified these covariates as potential confounders of the association of biomarkers with mortality. For example, previous study demonstrates that the ankle brachial index and black race are each associated with increased mortality among persons with peripheral arterial disease (PAD) (1,2), despite the fact that these characteristics were not associated significantly with mortality in univariate analyses in the current paper. Nonetheless, we agree with Dr. Fujita that statistical adjustment for high-density lipoprotein cholesterol (HDL-C) is warranted in our analyses, since lower HDL levels were associated significantly with increased mortality in our PAD cohort. Therefore, we repeated our fully adjusted statistical analyses of biomarker levels with cardiovascular disease and all-cause mortality, adding adjustment for HDL-C. Our results were unchanged in these analyses that included adjustment for HDL-C. In all of these fully adjusted models, HDL-C was significantly or nearly significantly associated with cardiovascular disease mortality. Second, at baseline, correlation coefficients of CRP with body mass index, number of cardiovascular diseases, and HDL-C were 0.112 (p=0.0325), 0.030 (p=0.56), and -0.076 (p=0.141), respectively. Finally, we agree that some prior studies suggest that CRP may not add incrementally to traditional atherosclerotic disease risk factors in predicting cardiovascular events (3). However, the purpose of our paper was to determine whether elevated biomarker levels were more strongly associated with near-term than later -term all-cause and cardiovascular disease mortality in persons with PAD. We did not aim to address the question of whether biomarkers add to the predictive ability of traditional atherosclerotic risk factors for cardiovascular events. Similarly, there is currently insufficient data to provide recommendations on a threshold CRP or SAA value that predicts near-term risk of cardiovascular events in persons with PAD. Further study, involving a larger sample size, is needed to confirm our findings and address the question of whether a threshold biomarker level is appropriate for identifying PAD patients at high risk of near-term events. Sincerely, Mary M. McDermott, MD Lu Tian ScD Kiang Liu, PhD REFERENCS 1. Feringa HH, Bax JJ, Hoeks S, et al. A prognostic risk index for long-term mortality in patients with peripheral arterial disease. Arch Intern Med 2007; 167:2482-9. 2. Garg PK, Tian L, Criqui MH, et al. Physical activity during daily life and mortality in patients with peripheral arterial disease. Circulation 2006;114:242-248. 3. Lloyd-Jones DM, Liu K, Tian L, Greenland P. Narrative review: Assessment of C-reactive protein in risk prediction for cardiovascular disease. Ann Intern Med 2006;145:35-42. Conflict of Interest:None declared |
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Giuseppe Lippi, M.D. Sez. Chimica Clinica, Università di Verona, Osp. Policlinico, 37134 - Verona, Italy, Giovanni Targher, Gian Cesare Guidi.
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ulippi{at}tin.it Giuseppe Lippi, et al.
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We read with interest the article of Vidula et al., concluding that elevated levels of C Reactive Protein (CRP), serum amyloid A (SAA) and D- dimer are more closely associated with near-term than later-term risk for all-cause and cardiovascular disease mortality in persons with peripheral artery disease (PAD) (1). This noteworthy and innovative information deserve further scrutiny, in that it might substantiate a therapeutic approach in patients with PAD. Increased levels of D-Dimer, the primary degradation product of cross-linked fibrin, might reflect an ongoing thrombotic process or the presence of several prothrombotic conditions (2). Its association with near-term mortality suggests that the most critical risk in patients with PAD and raised D-dimer values comes from acute thrombotic complications. Therefore, antithrombotic treatments by heparin derivatives should be considered immediately upon diagnosis of PAD. Virtually every step in atherogenesis is believed to involve cells that are characteristic of inflammation and markers involved in the inflammatory response, such as CRP or SAA. Statins reduce cardiovascular events to a greater extent than can be explained by their effect on lipids (3). Besides their ability to lower Low Density Lipoprotein (LDL) cholesterol levels, statins have additional pleiotropic effects, including lowering CRP. Although prospective clinical trials are needed to verify whether the combined use of statins and heparin would be effective to prevent near-term mortality in PAD patients, the findings of Vidula et al. provide a rational basis for future research on this topic. References 1. Vidula H, Tian L, Liu K, Criqui MH, Ferrucci L, Pearce WH, et al. Biomarkers of inflammation and thrombosis as predictors of near-term mortality in patients with peripheral arterial disease: a cohort study. Ann Intern Med. 2008 Jan 15;148(2):85-93. 2. Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, et al. D -dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med. 2004 Apr 20;140(8):589-602. 3. Balk EM, Lau J, Goudas LC, Jordan HS, Kupelnick B, Kim LU, et al. Effects of statins on nonlipid serum markers associated with cardiovascular disease: a systematic review. Ann Intern Med. 2003 Oct 21;139(8):670-82 Conflict of Interest:None declared |
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Tetsuji Fujita, MD Jikei University School of Medicine
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tetsu{at}jg8.so-net.ne.jp Tetsuji Fujita
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TO THE EDITOR: I read with great interest the excellent paper by Dr Vidula and colleagues (1), in which the authors revealed that higher levels of D-dimer, C-reactive protein (CRP) and serum amyloid A (SAA) were associated with higher all-cause and cardiovascular near-term mortality among 377 patients with peripheral arterial disease (PAD), of whom 76 died during 4 years of follow-up. Of particular interest is elevation of CRP and SAA levels was a surrogate marker of death within 2 years after the determination of these protein levels. The relative risk of death within 1 year after CRP and SAA measurements in patients with higher CRP and/or SAA was 1.13 and 1.12, and the risk of death between 1 and 2 years was 1.15 and 1.13, respectively. Higher levels of these proteins were also associated higher near-term cardiovascular mortality, comprising 41 % of all deaths. These results of the study support the suggestion that each of CRP and SAA is a mediator of atherosclerosis as well as a marker for cardiovascular disease (2). I would like to address some questions. First, I wonder why the authors included insignificant factors between survivors and decedents revealed by univariate analysis such as race and ankle-brachial pressure index (ABI) in the regression analyses, and excluded high-density lipoprotein (HDL) level. As shown in Table 1, there was a significant difference in serum HDL levels (P=0.029) between survivors and non- survivors but race (P=1.00) and ABI (P=0.83) were similar in the 2 groups. In certain studies CRP was a more powerful predictor of cardiovascular risk than traditional risk factors such as low-density lipoprotein level (3), whereas a more recent study including more than 20,000 patients indicates that measuring CRP adds little to the predictive value of traditional risk factors (4) and another review suggests that many risk factors for cardiovascular disease are associated with raised serum concentration of CRP, including smoking, obesity, diabetes and depression (5). Second, I would like to ask the authors whether CRP levels were associated with body mass index, number of cardiovascular diseases, and HDL levels. As minor CRP elevation (3-10 mg/L) is associated with minor environmental irritants, common minimally inflammatory states, genetic polymorphisms and a large number of apparently non-inflammatory medical conditions such as metabolic syndrome and depression, minor elevation of CRP is found about a third of American population (5). As shown in Figure 4, mean CRP values for patients who survived and died during the year after the measurement were less than 5 mg/L. To offer CRP screening to patients with PAD, a cut-off point to discriminate a high-risk patient from others should be employed. Finally, I would like to ask the authors whether a cut-off CRP or SAA value will be determined as the threshold of high cardiovascular risk when a prospective cohort study in a larger sample is accomplished. Tetsuji Fujita, MD, Department of Surgery, Jikei University School of Medicine, Tokyo, Japan 105-8461 References 1. Vidula H, Tian L, Criqui MH, et al. Biomarkers of inflammation and thrombosis as predictors of near-term mortality in patients with peripheral arterial disease: a cohort study. Ann Intern Med. 2008; 148: 85 -93. 2. Chait A, Han CY, Oram JF, Heinecke JW. Lipoprotein-associated inflammatory proteins: markers or mediators of cardiovascular disease? J Lipid Res. 2005; 46: 389-493. 3. Ridker PM, Rifal N, Rose L, Buring JE, Cook NR. Comparison of C- reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002; 347: 1557- 65. 4. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med. 2004; 350: 1387-97. 5. Kushner I, Rzewnicki D, Samols D. What does minor elevation of C- reactive protein signify? Am J Med. 2006; 119: 166.e17-e28. Conflict of Interest:None declared |
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