American Association for Clinical Chemistry
Better health through laboratory medicine
May 2008 Clinical Laboratory News: Diagnostics Profiles

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May 2008: Volume 34, Number 5


Elevated Uric Acid Linked to CHF, Stroke Death


Serum uric acid levels are independently associated with mortality from congestive heart failure (CHF) and stroke, results of a large prospective trial show (Clin Chem 2008; 54: 273–284). Researchers from the National Institute on Aging joined a multinational team of investigators in determining the association of serum uric acid and CHD mortality and stroke in apparently healthy men of various ages. The team followed a cohort of 83,683 Austrian men of mean age 41.6 years for a median of 13 years. Uric acid concentration >398.81 µmol/L was significantly related to mortality from CHF and stroke. Researchers found no association between elevated uric acid and mortality from acute, subacute, or chronic forms of CHD after adjusting for potential confounding factors, but uric acid elevation in younger men had a strong association with fatal CHD. The data demonstrate the clinical importance of basing medical interventions on uric acid levels determined during routine monitoring, researchers wrote.


VKORC1 Is the Stronger Factor in Warfarin Response


Initial variability in the international normalized ratio (INR) response to warfarin is more strongly associated with variability in the pharmacologic target of warfarin, VKORC1, than with CYP2C9, the enzyme that metabolizes it, according to a recent paper (NEJM 2008; 358: 999–1008). Researchers from Vanderbilt School of Medicine sought to better understand the role of these variants during initial coagulation by assessing CYP2C9 genotypes (CYP2C9 *1, *2, and *3) and VKORC1 haplotypes (designated A and non-A), clinical characteristics, response to therapy as determined by INR, and bleeding events in 297 patients starting warfarin therapy. Outcomes were time to the first INR within the therapeutic range, the time to the first INR of more than 4.0, the time above the therapeutic INR range, the INR response over time, and the warfarin dose requirement. As compared with patients with the non-A/non-A haplotype, patients with the A/A haplotype of VKORC1 had a decreased time to the first INR of more than 4. In contrast, the CYP2C9 genotype was not a significant predictor of the time to the first INR within the therapeutic range but was a significant predictor of the time to the first INR of more than 4. Both the CYP2C9 genotype and the VKORC1 haplotype had a significant influence on the required warfarin dose after the first 2 weeks of therapy.


Study Finds HbA1c Reference System Valid


International comparison studies performed over a 5-year period confirm the robustness of the IFCC’s anchor for its reference system for HbA1c measurement and the network of laboratories that maintain the system, according to a recent paper (Clin Chem 54: 240–248). A multinational team of researchers at 14 reference laboratories examined the outcomes of 12 periodic evaluations to control essential elements of the IFCC Reference Measurement System (IFCC-RMS) for HbA1c conducted between 2001 and 2006 and to confirm that IFCC-RMS is robust enough to guarantee the stability and continuity of the analytical reference method. Each study included unknown samples used to test individual network laboratories and known samples that served as controls, as well as recently manufactured calibrators to check calculated assigned value, stored calibrators to test stability, and a set used to calibrate the IFCC-RMS. To determine the stability of the master equation that describes the relationship between the IFCC-RMS and these direct comparison methods, researchers measured the unknown samples with the IFCC-RMS and designated comparison methods, including those developed by the U.S. National Glycohemoglobin Standardization Program (NGSP), the Japanese Diabetes Society and the Japanese Society for Clinical Chemistry (JDS/JSCC), and the Swedish Mono-S. Trend analysis of the master equation, expressed as change in percentage HbA1c per year, was insignificant in 95 data sets. The overall change was 0.0% for NGSP, -0.03 for JDS/JSCC, and -0.016 for Mono-S. Evaluation of long-term performance revealed no systematic change over time, with two laboratories showing significant bias and one showed poor reproducibility. The mean HbA1c determined by laboratories performing mass spectrometry was the same as that determined by laboratories using capillary electrophoresis (CE), but the reproducibility at laboratories using CE was better. One batch of new calibrators wasn’t approved. All stored calibrators were stable.


NT-proBNP Provides Incremental Prognostic Information in Some ACS Cases


In patients with suspected ACS who are considered to be low risk because of normal troponin values, NT-proBNP above 474 pg/mL can identify who should be considered for risk stratification (J Am Coll Cardiology 2008; 51: 1188-1195). To determine the clinical relevance of NT-proBNP values in patients with ACS symptoms and normal TnT values, a team of researchers studied 2,614 patients from two independent registries, one serving as a derivation cohort that included patients with evident ACS and another with chest pain patients serving as the validation cohort. All patients had NT-proBNP and TnT values measured upon admission and outcomes assessed over the next 6 months. In both cohorts, the mortality rate was significantly lower among TnT-negative patients: 3.8% versus 8.2% in the derivation cohort, and 2.8% versus 8.6% in the validation cohort. Among TnT negative patients, ROC curve analysis yielded an optimal cutoff value of 474 pg/mL for NT-proBNP for discriminating patients at higher risk in the derivation and validation cohorts (mortality rate 12.3% vs. 1.3%, and 8.5% vs. 1.5%, respectively). By Kaplan-Meier analysis, patients with NT-proBNP values over 474 pg/mL were at higher risk for death in both cohorts.


POC cTnI is Useful in Emergency NSTE-ACS Patients


Testing for cTnI in the emergency department (ED) might be clinically relevant for patients with suspected non-ST-segment elevation acute coronary syndrome (NSTE-ACS), especially those high-risk patients for whom there is a low suspicion of ACS (Academic Emergency Medicine 2008; 15: 216-224). To assess the impact of POC cTnI measurement on the time to anti-ischemic therapy (TAIT) for patients with suspected NSTE-ACS presenting to the ED, French researchers in a university-affiliated hospital conducted an open-label, randomized, single-center trial. After randomly allocating cTnI measurement of patients with suspicion of NSTE-ACS coming to the ED to either POCT or central hospital laboratory testing (CHLT), the authors compared baseline characteristics, time to anti-ischemic therapy, and medical outcomes between the randomized groups, in all study participants, in high-risk NSTE-ACS patients with cTnI level ≥ 0.10 μg/mL, and in those with low suspicion ACS (no chest pain and no ST deviation). Of the 860 patients enrolled, 113 were high-risk NSTE-ACS patients, including 53 (46.9%) allocated to POCT and 60 (53.1%) assigned to CHLT. POCT was associated with decreased time to anti-ischemic therapy of about three-quarters of an hour, which was due to a shorter time to physician notification of cTnI level in both groups. In contrast, neither ED length of stay nor medical outcomes differed between the study groups.


Lp-PLA2 Predicts CHD Events in Healthy Older Adults


Lipoprotein-associated phospholipase A2 (Lp-PLA2) levels predict coronary heart disease (CHD) events in apparently healthy older adults, independent of CHD risk factors, new research concludes (J Am Coll Cardiol 208; 51: 913–919). To determine if a previously observed independent association of Lp-PLA2 levels and CHD is apparent in older adults, researchers from the University of California San Diego and diaDexus followed 1,077 community-dwelling men and women of median age 72 for a mean of 16 years. The subjects had no known CHD at baseline. The researchers used Cox proportional hazard regression models to examine the association of serum levels of Lp-PLA2 with incidence of myocardial infarction, angina, or coronary revascularization. Lp-PLA2 levels correlated positively with age, BMI, and levels of LDL-C and CRP, and but negatively with LDL-C. Lp-PLA2 levels in the second, third, and fourth quartiles predicted an increased risk of CHD, compared with the lowest quartile. The association persisted after adjusting for CRP and other CHD risk factors.