American Association for Clinical Chemistry
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January 2010 Clinical Laboratory News: Diagnostic Profiles

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January 2009: Volume 36, Number 1

Alkaline Phosphatase, Serum Phosphate Linked to Excess Mortality in Patients without Known Kidney Disease

New research has identified a link between alkaline phosphatase (AlkP), serum phosphate, and all-cause and cardiovascular (CV) mortality in patients without evidence of kidney disease (Circulation 2009;120:1784–92). The study suggests that AlkP, particularly in combination with serum phosphate, may provide not only pathophysiological insight, but also prognostic information.

The investigators initiated the study in response to recent research reporting a strong independent association between AlkP and the risk of adverse outcomes in patients with kidney failure. The authors of those studies speculated that the association was due to abnormal bone metabolism, possibly mediated by vascular calcification, which is common in dialysis patients. However, little is known about whether vascular calcification also may contribute to CV risk in people with normal kidney function, so the researchers sought to explore whether higher levels of AlkP are associated with increased risk of all-cause mortality and adverse CV outcome.

The initial phase of research involved a post hoc analysis of data from the Cholesterol and Recurrent Events (CARE) trial, a study of pravastatin versus placebo in 4,159 patients with hyperlipidemia and a history of myocardial infarction. Of these participants, 4,115 had AlkP measured at baseline and were included in the post hoc analysis. The primary outcome was all-cause mortality; secondary outcomes included death due to coronary disease, and development of symptomatic heart failure, among others.

The researchers placed participants in tertiles based on AlkP levels, including <80 IU/L, 80-99 IU/L, and >99 IU/L. After adjustment for age, sex, and race, higher levels of AlkP were associated with increased risk of all-cause death, with a 1.62 hazard ratio for risk of death in the highest versus lowest AlkP tertile. The researchers performed a multivariate sensitivity analysis and found no appreciable effect on the association between higher AlkP levels and increased risk of death or new heart failure. The hazard ratio was highest in participants with both elevated AlkP and serum phosphate, and there was a graded risk relationship from lowest to highest levels of the two analytes.

The second phase of research involved validation of these findings in an apparently healthy population from the Third National Health and Nutrition Examination Survey (NHANES III). As in the CARE analysis, researchers found that higher levels of AlkP and serum phosphate were associated with an increased risk for both all-cause and cardiovascular morality. Findings from both the CARE and NHANES data sets were similar among both individuals with and without evidence of kidney disease.

The investigators offered several theories as to why higher levels of AlkP were associated with excess mortality, even in participants with normal kidney function. For example, vascular calcification, once considered a passive process in which calcium and phosphate ions are deposited, may actually be an active, cell-mediated process to which multiple circulating promoters and inhibitors also contribute. The authors called for further research to confirm the findings and elucidate the factors underlying increased levels of AlkP and serum phosphate and excess mortality.

Study Outlines NT-proBNP Threshold for Statin Efficacy in Heart Failure Patients

New research indicates that heart failure patients with N-terminal proB-type natriuretic peptide (NT-proBNP) levels of 868 pg/mL or less may benefit from rosuvastatin, while treatment may be futile in patients with markedly elevated concentrations (J Am Coll Cardiol 2009;54:1850–9). The study builds on previous research that suggested there might be a transition point for NT-proBNP levels beyond which statins are no longer effective at improving outcomes in patients with heart failure.

The researchers conducted a post hoc analysis of data from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) study, a multicenter trial of more than 5,000 patients that explored the effect of statins in heart failure patients. Patients were at least 60 years old, had stable, symptomatic heart failure, ischemic heart disease, and reduced left ventricular ejection fraction. They were randomly assigned to receive either 10 mg rosuvastatin or placebo once daily. Of these participants, NT-proBNP was measured in 3,664 (73%), and this was the group included in the post hoc analysis. The primary outcome was a composite of cardiovascular mortality or nonfatal myocardial infarction (MI) or stroke. Secondary outcomes included all-cause mortality, any coronary event, cardiovascular mortality and total number of hospitalizations. Two additional post hoc composite outcomes included death from any cause or hospitalization for worsening heart failure, and an atherothrombotic endpoint encompassing fatal or non-fatal MI or fatal or nonfatal hemorrhagic stroke.

Patients were assigned to three tertiles based on NT-proBNP levels, including >2,347 pg/mL, 868-2,347 pg/mL, and <868 pg/mL. Those in the lowest tertile had the best prognosis, and were younger, more likely to have mild symptoms, higher body mass index, systolic blood pressure and cholesterol, and less likely to have rhythm disturbances, renal dysfunction or increased hs C-reactive protein. If they were assigned to rosuvastatin rather than placebo, these patients also had a greater reduction in the primary end point than patients in other tertiles. Patients in the highest tertile had many other markers of a worse prognosis. With the exception of nonfatal vascular events, there was a marked and progressive increase in the rate of each outcome of interest with each increasing tertile of NT-proBNP.

The researchers emphasized that their findings should be confirmed in a prospective study. In the meantime, NT-proBNP levels should be used for general guidance rather than a strict decision point for determining whether to prescribe rosuvastatin in patients with advanced heart failure, according to the authors.