American Association for Clinical Chemistry
Better health through laboratory medicine
May 2011 Clinical Laboratory News: Diagnostic Profiles

Study Chronicles the Clinical Utility of High-Sensitivity cTn Assay

Use of a new high-sensitivity cardiac troponin I (cTn) assay in patients with suspected acute coronary syndrome (ACS) increased detection of myocardial infarction (MI) by 29% and identified patients who were at high risk for recurrent MI and death (JAMA 2011;305:1210–16). The authors found that reclassification of patients based on the results of the assay led to improved clinical management, fewer deaths, and fewer hospitalizations for recurrent MI.

The study, conducted by Scottish researchers, involved 2,092 consecutive patients admitted with suspected ACS. Although researchers measured cTn for all patients in both the validation and implementation phases of the study using a new, high-sensitivity assay, only concentrations above the original diagnostic threshold ≥0.20 ng/mL were reported to physicians in the validation phase. However, concentrations above the revised diagnostic threshold ≥0.05 ng/mL were reported during the implementation phase. The investigators classified patients into three groups based on peak cTn levels: <0.05 ng/mL, 0.05–0.19 ng/mL, and ≥0.20 ng/mL.

The researchers had three aims in conducting the study, including evaluating the effect of the new assay on the diagnosis rate of MI, determining whether small increases in cTn I would predict future risk of adverse clinical outcomes, and assessing how lowering diagnostic thresholds would affect clinical outcomes.

During the validation phase of the trial, patients with undisclosed cTn levels between 0.05–0.19 ng/mL (above the new diagnostic threshold but below the original), were two-to-three times more likely to have an adverse outcome than those with elevations above the original diagnostic threshold (≥0.20 ng/mL). The authors speculate that these patients had worse outcomes because their attending physicians were not made aware of the slightly elevated levels, and therefore did not modify patient management for ACS.

Anti-drug Antibodies Linked to Improved Rheumatoid Arthritis Drug Response

Rheumatoid arthritis (RA) patients without anti-drug antibodies against a first tumor necrosis factor (TNF) inhibitor had a diminished response to a second TNF inhibitor, etanercept. However, those who developed anti-drug antibodies after their first TNF inhibitor had responses to etanercept that were similar to patients who took etanercept without having tried other TNF inhibitors (Ann Rheum Dis 2011;70:284–88). The findings suggest that determining RA patients’ immunogenic status can help physicians decide whether switching to another TNF inhibitor will be beneficial, an important consideration given the high costs of anti-TNF treatment, according to the authors.

TNF is a pro-inflammatory cytokine important in RA and other chronic inflammatory diseases, and the TNF inhibitors infliximab, adalimumab, and etanercept are widely used to treat RA. However, while prior research has shown that switching between TNF inhibitors can help patients, treatment responses in switchers tends to be lower than in patients who have never taken anti-TNF agents.

The study involved 203 consecutive patients treated with etanercept, 30% of whom had been treated previously with either infliximab or adalimumab. Before starting the patients on entanercept, the researchers tested them for antibodies to the other two anti-TNF agents.

The investigators assessed disease activity using change in Disease Activity Score in 28 joints (DAS28), C-reactive protein, and erythrocyte sedimentation rate levels. They found that patients who switched to etanercept and did not have anti-drug antibodies had statistically significant lower changes in DAS28 compared with patients who previously had not taken anti-TNF medications. 

Serum Glucose Levels Predict Mortality in Hospitalized Elderly

A study of elderly, non-diabetic patients hospitalized for acute illness found that serum glucose concentration is an important and independent predictor of hospital mortality also associated with mean in-hospital survival time (Int J Clin Pract 2011;65:308–13). Although prior studies have explored the link between hyperglycemia and hospital mortality, few have characterized this association specifically in elderly patients. The findings could help clinicians identify patients at “high vital risk during hospitalization in order to intensify therapy for improving prognosis,” according to the authors.

The study involved hospitalized patients with a mean age of 61 years, whom researchers categorized into three groups based on serum glucose levels obtained the morning after admission following an overnight fast, including Group 1, <126 mg/dL, Group 2, 126–180 mg/dL, and Group 3, >180 mg/dL. Overall, one-quarter of patients had a history of diabetes, while 55.9% were in Group 1, 15% in Group 2, and 3.5% in Group 3. Mortality rates were 8.4%, 18%, and 32.1% in Groups 1, 2 and 3, respectively, and mean hospital survival time declined from 40.5 days in Group 1 to 28.5 days in Group 3. 

Novel Risk Factors for Post-CABG Thrombosis Described

Researchers recently reported that aspirin-insensitive thromboxane generation and shear-dependent platelet hyper-reactivity are novel independent risk factors for early saphenous vein graft (SVG) thrombosis following coronary artery bypass graft (CABG) surgery (J Am Coll Cardiol 2011;57:1069–77).

Aspirin has been the medication most convincingly shown to prevent SVG occlusions, based on its effect of irreversibly inhibiting platelet cyclooxygenase-1 (COX-1), an enzyme critical to generating thromboxane A2 (TXA2) from arachidonic acid. Recently, however, research has shown that some patients exhibit an incomplete or inadequate antiplatelet effect from aspirin, with persistent TXA2 generation and high platelet reactivity. These patients are at increased risk for adverse cardiac events compared with those who have suppressed platelet reactivity and TXA2 generation. This led the researchers to investigate whether an incomplete response to or inadequate antiplatelet effect from aspirin, or both, might contribute to early post-CABG SVG thrombosis.

The analysis was part of the Reduction in Graft Occlusion Rates (RIGOR) study, a multicenter study of first-time CABG patients that looked at the effects of antiplatelet factor 4/heparin antibody induction on SVG occlusion. A second prospectively described objective of RIGOR was to explore the role of aspirin resistance.

The researchers used several different measures of platelet reactivity and aspirin responsiveness, including: platelet aggregation response to arachidonic acid, adenosine diphosphate, epinephrine, and collagen; collagen/epinephrine and collagen/adenosine diphosphate closure times of whole blood (CEPI CT and CADP CT); arachidonic acid-induced platelet aggregation in whole blood; and TXA2 generation measured by the concentration of its stable metabolite 11-dehydro-thromboxane B2 (UTBX2) in urine. They found inhibited arachidonic acid-induced platelet aggregation, an indicator of aspirin-mediated COX-1 suppression, in 95% and >99% of patients 3 days and 6 months post-surgery, respectively. However, nearly three-quarters and one-third of patients at these respective time points still had elevated UTXB2, and only UTXB2 and CADP CT correlated with outcomes.

The findings raise the question of whether aspirin-insensitive TXA2 generation in patients with cardiovascular disease indicates that aspirin failed to inhibit platelet COX-1-mediated TXA2 biosynthesis, or whether alternate pathways of TXA2 production exist that aspirin does not effectively inhibit.