Problems With Measurements of Hemoglobin A1c

LETTERS TO THE EDITOR LETTERS TO THE EDITOR Problems With Measurements of Hemoglobin A1c To the Editor: Three months after the introduction of the turbidimetric immunoinhibition assay for hemoglobin A1c (HbA1c) (TINIA, Roche Diagnostics, Indianapolis, Ind) into our clinical practice, Mayo Clinic diabetologists noticed a discrepancy between patient-logged glucose values (above goal levels of 80-140 mg/dL) and lower than expected HbA1c levels (<6%-7%). Given the importance of HbA1c as a guide to glycemic control, the fact that this monoclonal assay is one of the most commonly used measurements of HbA1c in the United States (used in approximately 15% of laboratories reporting in the American College of Pathology Laboratory Survey in March 2006), and concerns that this discrepancy could lead to inadequate clinical care,1 we report further investigations into its performance. Mayo Clinic introduced the measure of total glycated hemoglobin by high-performance liquid chromatography (HPLC) assay in 1984. After completing validation studies showing adequate performance of the Roche assay compared to the HPLC assay, our clinical practice recently adopted the assay to harmonize reporting across the Mayo practices and in response to external pressures for reporting quality performance metrics, consistent with National Glycohemoglobin Standardization Program (NGSP) values.2 In 2002, the International Federation of Clinical Chemistry proposed a new, more specific reference method that includes an enzymatic cleavage of intact hemoglobin, reverse-phase HPLC, and mass spectrometry.3 Between the time of the Mayo evaluation of the direct assay and implementation into our practice, the manufacturer changed the assay calibration to the International Federation of Clinical Chemistry reference method expressing results in NGSP values. Based on the clinical observations of incongruence between the Roche assay and patient reports of self-monitored glucose values, comparison studies were repeated using benchmark samples from the NGSP. These studies showed adequate assay performance in the normal range (4%-6%) and higher than 8.5%. However, for values between 6% and 8.5%, the Roche assay consistently underestimated HbA1c values (by NGSP standards) by 0.4% to 0.6%. After notification and confirmation with additional NGSP controls, the manufacturer changed the standard curve algorithm to improve recovery in this clinically important range. We have repeated independent validation studies using the new assay and have found adequate performance against the NGSP benchmark. Given the importance of HbA1c as a guide to glycemic control, clinicians should remain vigilant to trends that may not reflect the clinical condition of patients and may lead to inadequate clinical care.1 Also important is the uncertainty about how economic pressures to report favorable outcomes (eg, pay for performance) may have delayed the recognition of problems in performance of the HbA1c assay. Moreover, because the HbA1c metric used most commonly in the United © 2006 Mayo Foundation for Medical Education and Research

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States has been “off” for a while, editors reviewing manuscripts for publication should be aware that before-after interventions reporting changes in HbA1c could be explained by the drift in the HbA1c measure that occurred concurrently. A systematic review of the published literature for before-and-after studies of clinical practice interventions in the United States (MEDLINE, 2002-2005) identified 253 clinical studies (excluding randomized controlled trials). The assay drift we report herein may have contributed to reported changes of HbA1c in 66 such studies. Steven A. Smith, MD Victor M. Montori, MD, MSc William L. Isley, MD Mary F. Burritt, PhD Mayo Clinic College of Medicine Rochester, Minn 1. Hanas R. Psychological impact of changing the scale of reported HbA1c results affects metabolic control [letter]. Diabetes Care. 2002;25:2110-2111. 2. Home P, Mbanya JC, Horton E. Standardisation of glycated haemoglobin [editorial]. BMJ. 2004;329:1196-1197. 3. Manley S, John WG, Marshall S. Introduction of IFCC reference method for calibration of HbA1c: implications for clinical care. Diabet Med. 2004;21: 673-676.

Health Care Reform To the Editor: In the April 2006 issue of Mayo Clinic Proceedings, Cortese and Smoldt1 provided an excellent framework for discussion of health care reform. The authors advocate a consumer-based model driven by economic principles and described the favorable economic impact of information technology, systems engineering, and research. Three additional economic efficiencies are a competitive market system, economy of scale, and appropriate health care tax policy. These economic efficiencies would substantially influence the role of providers, government, and private insurance companies in the market system for basic health care services. An efficient competitive market system requires that each health care provider choose a single price for a standard product or service.2(pp250-289) This implies that a fixed price for 1 year of basic health care would replace the complex fee-for-service system. Health care providers would compete within each medical specialty. Actual provider payment would be risk adjusted among providers to reflect the volume and type of care provided. Consumers would receive health care from the lowest-priced provider network that reflects the consumer’s preferences. The economy of scale principle states that large organizations are often more efficient than smaller organizations.2(pp174-178) This economy of scale principle explains the much greater administrative efficiency of government health care systems compared to smaller private insurance organizations.3 In an efficient health care system, a few large organizations would provide administrative functions unrelated to price competition or innovation. These organizations would replace private health care insurance. In an efficient market

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