Increase in Creatinine and Cardiovascular Risk in Patients with Systolic Dysfunction after Myocardial Infarction Powell Jose,* Hicham Skali,* Nagesh Anavekar, † Charles Tomson, ‡ Harlan M. Krumholz, § Jean L. Rouleau,  Lemuel Moye,* Marc A. Pfeffer,* and Scott D. Solomon;* for the SAVE Investigators *Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; † University of Melbourne, Melbourne, Australia; ‡ North Bristol NHS Trust, Bristol, United Kingdom; § Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut; and  University of Montreal, Quebec, Canada Baseline renal function is a potent independent risk factor for adverse events after acute myocardial infarction (MI). Worsening renal function (WRF) has been shown to influence outcomes in the heart failure population, but its impact on cardiovascular risk in the post-MI period has not been well defined. For assessment of the prognostic importance of WRF, 2231 patients who had left ventricular dysfunction and were enrolled in the Survival and Ventricular Enlargement (SAVE) trial were studied. Patients were randomly assigned between 3 and 16 d (average 11 d) after acute MI to receive captopril or placebo; those with a serum creatinine of >2.5 mg/dl were excluded from SAVE. WRF was defined as an increase in creatinine of >0.3 mg/dl measured from baseline to 2 wk after randomization. The predictive value of WRF on cardiovascular morbidity and mortality was examined during 42 mo of follow-up. Paired serum creatinine measurements at baseline and 2 wk were available in 1854 patients. WRF occurred in 223 (12.0%) patients and was a stronger predictor of death (hazard ratio [HR] 1.46; 95% confidence interval [CI] 1.05 to 2.02) than baseline creatinine (HR 1.31; 95% CI 1.01 to 1.70). WRF also showed an increased risk for cardiovascular death (HR 1.62; 95% CI 1.14 to 2.30) and the composite end point (HR 1.32; 95% CI 1.03 to 1.70). When stratified by treatment, 104 (5.7%) and 116 (6.4%) patients with WRF in the placebo and captopril groups had no significant association between treatment group and WRF (P  0.38). The risk for death associated with WRF was HR 1.63 (95% CI 1.05 to 2.52) in the placebo group compared with HR 1.33 (95% CI 0.81 to 2.21) in the captopril group (P  0.49 for interaction). WRF as early as 2 wk after MI was not uncommon (12.0%) and was associated with increased mortality in patients without renal dysfunction at baseline. Patients who received captopril did not demonstrate more WRF than patients who received placebo. Monitoring serum creatinine in patients during the first few weeks after MI may help to identify those who are at highest risk and guide effective long-term therapeutic choices. J Am Soc Nephrol 17: 2886 –2891, 2006. doi: 10.1681/ASN.2006010063 R enal dysfunction is a strong independent predictor of cardiovascular outcomes and mortality in the general population (1) after myocardial infarction (MI) (2– 6) and heart failure (7,8). Small increases in creatinine over a specified period, defined as worsening renal function (WRF), have been assessed in heart failure patients as an independent prognostic marker (9,10). In patients who are hospitalized for acute heart failure, WRF not only has been shown to confer additional cardiovascular risk but also has been shown to be a stronger predictor of death in patients with heart failure than the initial level of creatinine (11). Nevertheless, the prognostic value of WRF in patients after acute MI is not well defined. Furthermore, whether treatment with angiotensin-converting enzyme (ACE) inhibition in these patients is associated with WRF is unknown. We analyzed patients who were enrolled in the Survival and Ventricular Enlargement (SAVE) Trial and in whom serum creatinine was measured at baseline and at 2 wk. Our objectives were to determine the risk for all-cause and cardiovascular mortality and morbidity associated with WRF and to determine whether ACE inhibitor therapy influences this relationship. Materials and Methods Patients SAVE was a randomized, double-blind, placebo-controlled trial that examined the use of the ACE inhibitor captopril in 2231 consenting patients with acute MI and left ventricular dysfunction (left ventricular ejection fraction 40%) (12). Patients did not have overt clinical heart failure at the time of randomization. A serum creatinine of 2.5 mg/dl was part of the exclusion criteria for SAVE. All patients received a captopril test dose of 6.25 mg; patients who developed hypotensive symptoms or ischemia after initiation of study drug (n = 23) were excluded from the trial. Patients were randomly assigned to receive captopril or placebo between 3 and 16 d after MI. The titration scheme involved an initial dose of 12.5 mg, which was advanced as tolerated up Received January 21, 2006. Accepted July 6, 2006. Published online ahead of print. Publication date available at www.jasn.org. Address correspondence to: Dr. Scott D. Solomon, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. Phone: 617-732-7182; Fax: 617-277-4981; E-mail: ssolomon@rics.bwh.harvard.edu Copyright © 2006 by the American Society of Nephrology ISSN: 1046-6673/1710-2886