CORRESPONDENCE: RESEARCH CORRESPONDENCE
Influence of Proteinuria on Cardiovascular Risk and Response to Angiotensin-Converting Enzyme Inhibition After Myocardial Infarction
Powell Jose, BS,
Charles Tomson, BM, BCh,
Hicham Skali, MD, MSc,
Jean Rouleau, MD, FACC,
Eugene Braunwald, MD, MACC,
J. Malcolm Arnold, MD, FACC,
Thomas Cuddy, MD, FACC,
Bruce Sussex, MD, FACC,
Victoria Bernstein, MD,
Marc Pfeffer, MD, PhD, FACC and
Scott Solomon, MD*
* Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115 (Email: ssolomon{at}rics.bwh.harvard.edu).
To the Editor: Proteinuria is a known predictor of cardiovascular (CV) morbidity and mortality in diabetics, hypertensive patients, and the general population (1–3), but the impact of proteinuria as a risk factor after acute myocardial infarction (MI) is less well-defined. We analyzed a subset of patients enrolled in the Survival And Ventricular Enlargement (SAVE) trial in whom dipstick urinalyses were recorded to determine the prognostic importance of baseline proteinuria on outcomes, and to evaluate whether the response to angiotensin-converting enzyme (ACE) inhibition is affected by the presence of proteinuria.
The SAVE trial was a randomized, double-blind, placebo-controlled trial examining the use of ACE inhibition in 2,231 patients with acute MI and left ventricular dysfunction (left ventricular ejection fraction [LVEF]  40%) (4). Patients with serum creatinine <2.5 mg/dl were randomized to captopril (50 mg three times a day) or placebo on average 10 days post-MI. A total of 658 patients from the Canadian cohort underwent dipstick urinalyses because of safety concerns, and baseline dipstick measures were available in 583 patients. Dipstick classification included none, trace, 1+, 2+, 3+, 4+, corresponding to protein concentrations of <10 mg/dl, 10 to 30, 30 to 100, 100 to 300, and >1,000 mg/dl, respectively (5). The four-variable Modification of Diet in Renal Disease equation was used to estimate glomerular filtration rate (eGFR) (6). Univariate and multivariate estimates of risk for outcomes were derived using Cox proportional hazards models, and the interaction between proteinuria and treatment effect was assessed. All-cause mortality, CV mortality, and a composite outcome of death, stroke, recurrent MI, and hospitalization for congestive heart failure over 42 months of follow-up were primary end points.
Of 583 subjects, 122 (20.9%) had trace or greater proteinuria (trace, 14.9%; greater-than-trace, 6.0%). Proteinuric subjects were older, more often hypertensive (p = 0.03), with higher baseline serum creatinine (p < 0.001) Killip class (p < 0.001), and lower LVEF (p < 0.001). Diabetes prevalence (p = 0.18), use of lipid-lowering agents (p = 0.21), or use of aspirin (p = 0.90) did not significantly differ between patients groups. Proteinuria increased with decreasing eGFR, with lower eGFR in proteinuric subjects (60.9 vs. 69.9 ml/min/1.73 m2, p < 0.001).
Proteinuria was an independent predictor of all-cause mortality (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.20 to 2.82), CV mortality (HR 1.87, 95% CI 1.18 to 2.98), and the composite end point (HR 1.41, 95% CI 0.99 to 2.02) after adjusting for known covariates including age, gender, previous MI, history of hypertension, history of diabetes, history of congestive heart failure, body mass index, systolic/diastolic blood pressure, LVEF, baseline eGFR, use of diuretics, and treatment assignment. The combination of an eGFR <60 ml/min/1.73 m2 and proteinuria conferred nearly a three-fold increased risk of death (HR 2.74, 95% CI 1.68 to 4.45) compared to having neither risk factor. Mortality in patients with no, trace, or greater than trace proteinuria was 20.0%, 25.3%, and 45.7%, respectively (p trend = 0.002).
Subjects with proteinuria appeared to have the greatest reduction in all-cause and CV mortality with captopril therapy, with a significant interaction between proteinuria and treatment assignment (p = 0.02) (Fig. 1). Captopril provided a greater mortality benefit in patients with proteinuria (HR 0.46, 95% CI 0.24 to 0.89) compared to patients without (HR 0.83, 95% CI 0.55 to 1.25). A similar reduction in risk was seen for the composite end point (proteinuria: HR 0.41, 95% CI 0.21 to 0.73; no proteinuria: HR 0.87, 95% CI 0.63 to 1.19).
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Figure 1 Kaplan-Meier curves for the composite end point stratified by presence of proteinuria (P) and treatment assignment (placebo vs. captopril). MI = myocardial infarction.
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Proteinuria measured by standard urine dipstick at baseline in patients with acute MI and systolic dysfunction was associated with an increased risk for all-cause and CV mortality in patients after MI with left ventricular dysfunction. Moreover, proteinuria modified the benefit of captopril therapy.
That common dipstick urinalysis is such a potent predictor of mortality reinforces the importance of proteinuria as a risk factor for CV disease. Proteinuria, and specifically albuminuria, may reflect early inflammation accompanying coronary artery disease and MI. C-reactive protein and white blood cell counts are increased in patients with albuminuria, suggesting that inflammation plays a role in glomerular and renal damage (7,8). Albuminuria is also associated with elevations of neurohormonal markers in heart failure (9).
We previously showed that eGFR independently predicted CV risk in the overall SAVE cohort (10). In this analysis, proteinuria was associated with increased mortality irrespective of eGFR, with the combination showing additive increased mortality. Whether these risk factors influence outcomes by the same or separate mechanisms requires further study.
Post-MI subjects with trace or higher proteinuria derived the greatest absolute benefit from captopril treatment. The added benefit seen in proteinuric patients most likely reflects the increased risk observed in this population. It is important to note that dipstick urinalysis provides only a crude estimate of protein excretion, and may not be as accurate an indicator of CV risk as tests with a higher sensitivity and specificity for quantifying microalbuminuria. Although hypothesis-generating, proteinuria may define a subgroup of patients who are more sensitive to the protective effects of captopril.
In summary, we observed that proteinuria, measured with dipstick urinalysis at baseline in patients with systolic dysfunction post-MI, is predictive of all-cause and CV mortality, independently of baseline renal function, as assessed by eGFR. The benefit of captopril in reducing CV morbidity and mortality was greatest in patients with proteinuria, suggesting that this measure may help identify a group of patients who are at higher risk, and who may receive additional benefit from ACE inhibitor therapy after acute MI.
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Footnotes
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Please note: the SAVE trial was originally supported by a grant from Bristol-Myers Squibb. Mr. Jose was a research fellow supported by the Stanley J. Sarnoff Endowment for Cardiovascular Science Inc.
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References
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1. Gerstein HC, Mann JF, Yi Q, et al. HOPE Study Investigators Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals JAMA 2001;286:421-426.[Abstract/Free Full Text]2. Berton G, Cordiano R, Mbaso S, De Toni R, Mormino P, Palatini P. Prognostic significance of hypertension and albuminuria for early mortality after acute myocardial infarction J Hypertens 1998;16:525-530.[CrossRef][Web of Science][Medline] 3. Culleton BF, Larson MG, Parfrey PS, Kannel WB, Levy D. Proteinuria as a risk factor for cardiovascular disease and mortality in older peoplea prospective study. Am J Med 2000;109:1-8.[Web of Science][Medline] 4. Pfeffer MA, Braunwald E, Moye LA, et al. The SAVE Investigators Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival And Ventricular Enlargement trial N Engl J Med 1992;327:669-677.[Abstract] 5. Laffeyette RA, Perrone RD, Levey AS. Laboratory evaluation of renal functionIn: Schrier RW, Gottschalk CW, editors. Diseases of the Kidney. Boston, MA: Little Brown; 1996. pp. 339. 6. National Kidney Foundation Kidney Disease Outcome Quality Initiative Advisory Board K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative Am J Kidney Dis 2002;39:S1-S266.[CrossRef][Web of Science][Medline] 7. Tong PC, Lee KF, So WY, et al. White blood cell count is associated with macro- and microvascular complications in Chinese patients with type 2 diabetes Diabetes Care 2004;27:216-222.[Abstract/Free Full Text] 8. Barzilay JI, Peterson D, Cushman M, et al. The relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertensionthe cardiovascular health study. Am J Kidney Dis 2004;44:25-34.[CrossRef][Web of Science][Medline] 9. Berton G, Cordiano R, Palmieri R, Cucchini F, De Toni R, Palatini P. Microalbuminuria during acute myocardial infarction; a strong predictor for 1-year mortality Eur Heart J 2001;22:1466-1475.[Abstract/Free Full Text] 10. Tokmakova MP, Skali H, Kenchaiah S, et al. Chronic kidney disease, cardiovascular risk, and response to angiotensin-converting enzyme inhibition after myocardial infarctionthe Survival And Ventricular Enlargement (SAVE) study. Circulation 2004;110:3667-3673.[Abstract/Free Full Text]
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