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(Circulation. 2005;112:2627-2633.)
© 2005 American Heart Association, Inc.

Coronary Heart Disease

Relation Between Serum Phosphate Level and Cardiovascular Event Rate in People With Coronary Disease

Marcello Tonelli, MD, SM; Frank Sacks, MD; Marc Pfeffer, MD, PhD; Zhiwei Gao, MSc; Gary Curhan, MD, ScD, for the Cholesterol And Recurrent Events (CARE) Trial Investigators

From the Department of Medicine (M.T.), Department of Critical Care (M.T.), Institute of Health Economics (M.T.), and Department of Public Health Sciences (M.T., Z.G.), University of Alberta, Edmonton, Alberta, Canada; Departments of Epidemiology (F.S., G.C.) and Nutrition (F.S.), Harvard School of Public Health, Boston, Mass; and Department of Medicine (M.P.) and Channing Laboratory (G.C.), Brigham and Women’s Hospital, Boston, Mass.

Correspondence to Dr Marcello Tonelli, University of Alberta, Division of Nephrology and Immunology, 7-129 Clinical Science Bldg, 8440 112 St, Edmonton, Alberta T6B 2B7, Canada. E-mail mtonelli{at}ualberta.ca

Received March 31, 2005; revision received June 27, 2005; accepted August 3, 2005.

Background— Higher levels of serum phosphate are associated with adverse cardiovascular outcomes, especially in the setting of overt hyperphosphatemia. Given the biological importance of phosphorus, it is plausible that higher levels of serum phosphate within the normal range may also be associated with adverse outcomes.

Methods and Results— We performed a post hoc analysis of data from the Cholesterol And Recurrent Events (CARE) study. Baseline serum phosphate levels were measured in 4127 fasting participants who were randomized to receive pravastatin 40 mg daily or placebo and followed up for a median of 59.7 months. We used Cox proportional-hazards models to examine the association between serum phosphate and adverse clinical outcomes after adjustment for potential confounders. During nearly 60 months of follow-up, 375 participants died. A significant association was noted between baseline serum phosphate level and the age-, race-, and sex-adjusted risk of all-cause death (hazard ratio per 1 mg/dL, 1.27; 95% confidence interval, 1.02 to 1.58). After categorization based on baseline phosphate level (<2.5, 2.5 to 3.4, 3.5 to 3.9, and 4 mg/dL) and further adjustment, a graded independent relation between phosphate and death was observed (P for trend=0.03). For instance, participants with serum phosphate 3.5 mg/dL had an adjusted hazard ratio for death of 1.27 (95% confidence interval, 1.02 to 1.59) compared with those with serum phosphate of <3.5 mg/dL. Higher levels of serum phosphate were also associated with increased risk of new heart failure, myocardial infarction, and the composite of coronary death or nonfatal myocardial infarction, but not the risk of stroke.

Conclusions— We found a graded independent relation between higher levels of serum phosphate and the risk of death and cardiovascular events in people with prior myocardial infarction, most of whom had serum phosphate levels within the normal range. Given the ready availability and low cost of serum phosphate assays, this finding may prove clinically useful.

Key Words: cardiovascular diseases • kidney failure • myocardial infarction • phosphates

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