American Association for Clinical Chemistry
Better health through laboratory medicine
August 2007 Clinical Laboratory News: Diagnostic Profiles

August 2007: Volume 33, Number 8

Neopterin Levels Aid Prognosis in ACS

A newly published study in Circulation (2007; 115: 3071–3078) found that increased monocyte activation detected by an elevated plasma neopterin level identifies patients at long-term risk of death or recurrent acute coronary events after an initial episode of acute coronary syndrome (ACS), but intense statin therapy can significantly diminish the risk of recurrent events in these patients. Neopterin, a pteridine derivative produced by activated monocytes, is a soluble marker of immune activation that may precede recurrent acute coronary events. Investigators from University of Cambridge (U.K.), Brigham and Women’s Hospital (Boston, Mass.) and Children’s Hospital Boston assessed the relationship between plasma neopterin levels and the risk of death, acute coronary events including nonfatal myocardial infarction or unstable angina, and actual mortality, at hospital discharge. The investigators checked neopterin levels and these risks and at 7 days in 3,946 patients and at 4 months in 3,369 patients after acute coronary events, over a 2-year period. Seven days after an ACS event, neopterin levels ≥12.1 nmol/L (upper quartile, derived from a post hoc analysis) were associated with an increased risk of death and an increased risk of death or acute coronary events after adjustment for age, sex, history of diabetes, history of hypertension, history of smoking, type of ACS presentation, use of percutaneous coronary intervention for the index event, statin regimen, LDL cholesterol, and hs CRP level (HR 1.86, 95% CI, 1.24–2.77 and HR 1.33, 95% CI, 1.09–1.63, respectively). Neopterin levels ≥12.11 nmol/L after 4 months remained a predictor of death alone and of death or acute coronary events after multivariable adjustment including month 4 LDL cholesterol, hs CRP, and statin regimen (HR 2.39, 95% CI 1.43–3.99 and HR 1.60, 95% CI 1.21–2.11, respectively). High-dose atovastatin significantly attenuated the risk among subjects with neopterin levels ≥12.11 nmol/L at baseline. These findings suggest that elevated neopterin levels may reflect atherosclerotic disease activity and vulnerability to development of ACS, and that high levels provide additional prognostic information, researchers wrote.

Anti-Cyclic Citrullinated Peptide Antibody May Diagnose RA

Anti-cyclic citrullinated peptide (CCP) antibodies are more specific than rheumatoid factor (RF) for diagnosing rheumatoid arthritis (RA) and may better predict erosive disease, authors of a recently published paper concluded (Ann Intern Med 2007; 146: 797–808). To determine if antibodies against CCP are better serum markers than RF for diagnosing RA, researchers from the Harvard School of Public Health in Boston and Hyogo College of Medicine and Kobe University Graduate School of Medicine in Hyogo, Japan conducted an analysis of published papers that described studies with at least 10 patients and examined the role of anti-CCP antibody and RF in the diagnosis or prognosis of known or suspected RA. The researchers analyzed 37 studies of anti-CCP antibody and 50 studies of RF. The pooled sensitivity, specificity, and positive and negative likelihood ratios for anti-CCP antibody were 67% (95% CI, 62%–72%), 95% (CI, 94%–97%), 12.46 (CI, 9.72–15.98), and 0.36 (CI, 0.31–0.42), respectively. For IgM RF, the values were 69% (CI, 65%–73%), 85% (CI, 82%–88%), 4.86 (CI, 3.95–5.97), and 0.38 (CI, 0.33–0.44), respectively. Likelihood ratios among IgM, RF, and IgA seemed to be similar, researchers wrote. Results from studies on early RA were similar to those from all studies. Some studies found that risk for radiographic progression was greater with anti-CCP antibody positivity than with IgM RF positivity. The authors cautioned that fewer studies evaluated anti-CCP antibody than RF, and noted possible publication bias for reporting positive findings regarding anti-CCP antibody. But their results corroborate the results of two published systematic reviews, the authors added. They suggested that positivity for anti-CCP antibodies be added to the American College of Rheumatology criteria for RA.

NT-proBNP Testing Improves Care of Suspected Acute Heart Failure Patients

N-terminal pro-B-type natriurectic peptide (NT-proBNP) testing improves management of patients presenting to emergency departments with dysnea through improved diagnosis, cost savings, and improvement in selected outcomes for the Canadian universal coverage healthcare system, which emphasizes judicious use of healthcare resources, according to a recently published study in Circulation (2007; 115: 3101–3110). Canadian researchers from University of Toronto, McGill University (Montreal, Quebec) and Dalhousie University (Halifax, Nova Scotia) and American researchers from Harvard Medical School (Boston, Mass.) tested the hypothesis that NT-proBNP testing improves the management of patients presenting with dyspnea to Canadian emergency departments by prospectively comparing the clinical and economic impact of a randomized management strategy guided by either NT-proBNP results to impact of a strategy that does not include knowledge of these concentrations. The investigators studied 500 patients who presented with dyspnea to seven emergency departments and compared the median NT-proBNP level among 230 subjects with a final diagnosis of heart failure to 270 patients without such a diagnosis. Those figures were 3,697 pg/mL and 212 pg/mL, respectively. The knowledge of patients’ NT-proBNP results reduced both the duration of emergency department visits by 21%, from 6.3 hours to 5.6 hours, and the number of patients readmitted to hospitals within 60 days by 35%, from 51 to 33. Knowledge of NT-proBNP level also reduced direct medical costs of all emergency department visits, hospitalizations, and subsequent outpatient services, from U.S. $6,129 to $5,180 per patient. Furthermore, adding NT-pro-BNP to clinical judgment enhanced the accuracy of diagnosis. The area under the ROC curve for the logistic model combining NT-proBNP and clinical judgment increased from 0.83 to 0.90 and was superior to either component in isolation. Researchers pointed out that their research was the first prospective randomized analysis to definitively address the question of the additive value of natriuretic peptide testing from both a diagnostic and a cost perspective in a universal healthcare system.

UGT1A1 Polymorphism Can Predict Toxicity in Irinotecan Patients

Identification of UGT1A1 promoter polymorphisms in high-risk stage III colon cancer patients before treatment with 5-fluoroacil (LV5FU) and CPT- 11 adjuvant chemotherapy predicts early hematologic toxicity, while the -3156G>A polymorphism seems to be a better predictor than the UGT1A1 (TA)6TAA>(TA)7TAA polymorphism, a recent study suggests (Clin Cancer Res 2007; 13: 3269–3275). French researchers from Institut National de la Santa et de la Recherche Medicale, Paris, and Service d’Oncologie, Montpelier, and Service d’Anatomie-Pathologique in St. Herblain, Bordeaux, Rennes, and Toulouse prospectively randomized 400 patients with high-risk stage III colon cancer into a phase III trial comparing LV5FU2 to LV5FU2+CPT-11. The researchers extracted DNA from 184 patients to detect the nucleotide polymorphism 3435c>T for ABCB1, 6986A>G for CYP3A5, UT1A1*28, and -3156g>A for UGT1A1. Genotype frequencies were similar in both treatment arms. Researchers observed no significant difference in toxicity or disease-free survival for ABCB1 and CYP3A5 polymorphisms in the test arm. UGT1A1*28 homozygous patients showed more frequent severe hematologic toxicity (50%) than UGT1A1*1 homozygous patients (16.2%) for wild-type allele (12.5%). This toxicity occurred significantly earlier in homozygous mutant patients than wild-type homozygous counterparts. In a Cox model, the hazard ratio for severe hematologic toxicity was significantly higher for patient with the A/A genotype than the G/G genotype (HR 8.4, 95% CI, 1.9–37.2). Multivariate analysis showed a strong independent role of sex in the occurrence of severe hematolgoic toxicity, researchers wrote, noting that drugs metabolized by phase II enzymes are usually cleared faster in men than in women. The study team called for more research to explore the role of the UGT1A1 haplotype in the occurrence of severe side effects and the relative predictive weight of each of the UGT1A1 promoter polymorphisms.