Clinical Laboratory Strategies: May 22, 2008

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Finding New Uses for an Old Assay
Tests for Hematologic Disorders May Help Diagnose Coronary Diseases
By Deborah Levenson

Laboratorians and physicians agree on the need for new diagnostic and prognostic markers for CVD. A growing body of evidence shows that certain common hematology tests—especially hemoglobin—can help predict risk of mortality and poor outcomes. Various studies have linked anemia and CVD, but hemoglobin levels associated with adverse cardiac outcomes have been poorly defined. Now a recent paper shows an independent association between specific hemoglobin levels and risk of new cardiac events. This issue of Strategies examines its findings.

Hemoglobin is important to oxygen carrying capacity, blood flow, and inflammatory processes. Some researchers have postulated that having too much or too little hemoglobin could be associated with adverse cardiac outcomes, while chronic anemia has been recognized as an important cause of increased cardiac output in response to low hemoglobin levels. Now researchers from the University of Colorado Health Sciences Center, University of Nevada Reno School of Medicine, and the Veterans Affairs Medical Center in Reno, Nev., have linked specific hemoglobin levels with increased risk for new cardiac events (American Heart Journal 2008; 155: 494–498).

Hemoglobin levels ≥ 17 g/dL or less <15 g/dL are independently associated with increased risk for new cardiac events, independent of kidney dysfunction, major comorbidities, and use of statins or β-blockers, the researchers found. They based their conclusion on a historical cohort study of 25,622 patients from eight Veterans Affairs medical centers. They evaluated these patients’ baseline hemoglobin determinations from 1994 through 2003, comparing patients with baseline hemoglobin levels of 15 to 17 g/dL to those with hemoglobin levels of 9–11 g/dL, 11–13 g/dL, 13–15 g/dL, and ≥17 g/dL with respect to risk for new diagnosis of CAD. In their comparisons, the researchers used Cox proportional hazards regressions models and Kaplan-Meier survival analysis. The researchers adjusted models for age, sex, BMI, smoking, blood pressure, fasting glucose levels, LDL-C, HDL-C, triglycerides, creatinine clearance, and use of statins or β-blockers.

Just over 20% of the cohort—5,297 patients—developed CAD over 73,895 person-years of follow-up. The multivariable-adjusted risk of CAD increased with lower hemoglobin levels. For hemoglobin levels of 9.0–11.0 g/dL, the HR was 1.47 (95% CI, 1.18–1.84); for levels of 11.0–13.0, the HR was 1.34 (95% CI, 1.20–1.49); and for hemoglobin level of 13.0 to 15.0, the HR was 1.07 (95% CI, 1.01–1.13). Hemoglobin levels ≥17.0 g/dL were also associated with increased risk for CAD, with a HR of 1.22 (95% CI, 1.08–1.37).

Expanding the Findings

The researchers write that their paper supports previous findings that patients with both low and high hemoglobin levels have an increased risk of developing new cardiac events, and note that their own study population was primarily male. One of the study’s authors identified a need for a similar study in women. “Actually, the more research we have on this topic across gender, and different ethnicities and races the better, so these differences can be better understood,” said Michel Chonchol, MD, Associate Professor of Medicine at University of Colorado Health Sciences Center’s Division of Renal Diseases and Hypertension.

The definition of anemia differs by gender, noted a physician who studies hemoglobin as a marker of ACS. David Sane, Associate Professor of Internal Medicine and Cardiology at Wake Forest University School of Medicine. WHO defines it as hemoglobin <12 g/dL in women and <13 g/dL in men, he pointed out. “Prior to menopause, women are more likely to have iron-deficiency anemia. In some studies, women have higher C-reactive protein, possibly reflecting higher inflammatory status. Chronic inflammation can cause anemia. Anemia is associated with higher brain natriuretic peptide levels in women. So evaluating the gender-dependent difference in prevalence, cause, and consequences of anemia could be useful for learning more about differences in coronary heart disease in men and women.”

Impact Will Be Minimal

This paper is interesting but probably won’t have any impact on hemoglobin test volume, according to the chair of the National Academy of Clinical Biochemistry’s (NACB) 2007 guidelines on ACS. “The study population is mostly older men, and most physicians are already checking their hemoglobin routinely. The test is easy and cheap, so I’d be shocked if they weren’t measuring hemoglobin at virtually every visit,” said Robert Christenson, PhD, Director, and Clinical Chemistry Laboratories at University of Maryland Medical Center in Baltimore and Professor of Pathology and Medical and Research Technology at University of Maryland Medical School.

He noted that the hazard ratios reported in the paper are only “modestly strong. That sapped my enthusiasm for this research being a leap forward in risk stratification for these patients,” he noted.

A colleague from the NACB committee agreed with the point on hazard ratios. They ranged only from 1.07 to 1.47, explained Alan Wu, Chief of Clinical Chemistry and Toxicology at San Francisco General Hospital and Professor of Laboratory Medicine at University of California San Francisco. “How do those ratios change practice? There’s no clinical value to using the test in ACS because the odds ratio is so close to a coin flip,” he explained.

“Even though the patients don’t qualify as clinically anemic, the paper does underscore the importance of monitoring hemoglobin levels routinely,” Christenson concluded.

A New Look at Other Hematology Tests

Other recent papers examine how other established tests might be newly used in determining prognosis of heart patients. Sane is an author of one such study, which explains how common tests including white blood cell count, hemoglobin and hematocrit, and platelet count might be used to identify ACS patients at high risk for adverse events (American Heart Journal 2008; 55: 808–816).  It cites eight studies that tested hematocrit as a prognostic marker in ACS and showed increased mortality in patients with lower hemoglobin or hematocrit values. Five of these studies showed low values are associated with short-term mortality.

Sane’s paper also notes 11 studies demonstrating that an elevated white blood cell count during ACS is associated with a variety of adverse clinical outcomes. The two largest both showed that a higher WBC count on admission was associated with increased short-term mortality, as did several of the smaller studies.


Dr. Christenson has received grants from Biosite, Dade Behring, Response Biomedical, and Roche. Dr. Wu has received grants from Abbott, Nanosphere, and Response Biomedical.  

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