Persons with advanced chronic kidney disease (CKD) have. Heart Failure

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1 Heart Failure Chronic Kidney Disease, Cardiovascular Risk, and Response to Angiotensin-Converting Enzyme Inhibition After Myocardial Infarction The Survival And Ventricular Enlargement (SAVE) Study Mariya P. Tokmakova, MD, PhD; Hicham Skali, MD, MSc; Satish Kenchaiah, MD, MSc; Eugene Braunwald, MD; Jean L. Rouleau, MD; Milton Packer, MD; Glenn M. Chertow, MD, MPH; Lemuel A. Moyé, MD, PhD; Marc A. Pfeffer, MD, PhD; Scott D. Solomon, MD Background Persons with end-stage renal disease and those with lesser degrees of chronic kidney disease (CKD) have an increased risk of death after myocardial infarction (MI) that is not fully explained by associated comorbidities. Future cardiovascular event rates and the relative response to therapy in persons with mild to moderate CKD are not well characterized. Methods and Results We calculated the estimated glomerular filtration rate (egfr) using the 4-variable Modification of Diet in Renal Disease method in 2183 Survival And Ventricular Enlargement (SAVE) trial subjects. SAVE randomized post-mi subjects (3 to 16 days after MI) with left ventricular ejection fraction 40% and serum creatinine 2.5 mg/dl to captopril or placebo. Cox proportional hazards models were used to evaluate the relative hazard rates for death and cardiovascular events associated with reduced egfr. Subjects with reduced egfr were older and had more extensive comorbidities. The multivariable adjusted risk ratio for total mortality associated with reduced egfr from 60 to 74, 45 to 59, and 45 ml min m 2 (compared with egfr 75 ml min m 2 ) was 1.11 (0.86 to 1.42), 1.24 (0.96 to 1.60) and 1.81 (1.32 to 2.48), respectively (P for trend 0.001). Similar adjusted trends were present for CV mortality (P 0.001), recurrent MI (P 0.017), and the combined CV mortality and morbidity outcome (P 0.002). The absolute benefit of captopril tended to be greater in subjects with CKD: 12.4 versus 5.5 CV events prevented per 100 subjects with (n 719) and without (n 1464) CKD, respectively. Conclusions CKD was associated with a heightened risk for all major CV events after MI, particularly among subjects with an estimated glomerular filtration rate 45 ml min m 2. Randomization to captopril resulted in a reduction of CV events irrespective of baseline kidney function. (Circulation. 2004;110: ) Key Words: kidney myocardial infarction mortality Persons with advanced chronic kidney disease (CKD) have an elevated risk for major cardiovascular (CV) morbidity and mortality above that anticipated from their other accompanying risk factors. 1 3 In the setting of an acute myocardial infarction (MI), a graded inverse association has been observed between mild to moderate CKD and survival, especially in the elderly and other high-risk patients. 4 8 The association between mild to moderate CKD and other cardiovascular outcomes is less well characterized, and little is known about the relative efficacy of standard therapies in post-mi patients with and without CKD. The Survival And Ventricular Enlargement (SAVE) trial randomized patients with acute MI and left ventricular dysfunction (left ventricular ejection fraction [LVEF] 40%) to receive the ACE inhibitor captopril or placebo and demonstrated that ACE inhibitor therapy was associated with reductions in the risk of death, the development of heart failure, and recurrent MI. 9 Patients with a baseline serum creatinine concentration 2.5 mg/dl were excluded from SAVE. Although most persons with advanced CKD would have been excluded by the serum creatinine criterion, the range of serum creatinine allowed for inclusion of study subjects with mild and moderate CKD (defined here as estimated glomerular filtration rate [egfr] 45 to 60 and 45 ml min m 2, respectively). We evaluated the association between egfr, calculated from baseline serum Received July 16, 2004; accepted September 14, From the Department of Cardiology, St. George Hospital, Medical University Plovdiv (M.P.T.), Plovdiv, Bulgaria; Division of Cardiology, Brigham and Women s Hospital (H.S., S.K., E.B., M.A.P., S.D.S.), Boston, Mass; Office of the Dean, University of Montreal (J.L.R.), Quebec, Canada; Center for Biostatistics and Clinical Science, University of Texas Southwestern Medical Center (M.P.), Dallas, Tex; Division of Nephrology, University of California (G.M.C.), San Francisco, Calif; and School of Public Health, University of Texas (L.A.M.), Houston, Tex. Reprint requests to Scott D. Solomon MD, Director, Noninvasive Cardiac Lab, Brigham and Women s Hospital, Harvard Medical School, 75 Francis St, Boston, MA. ssolomon@rics.bwh.harvard.edu 2004 American Heart Association, Inc. Circulation is available at DOI: /01.CIR BF 3667

2 3668 Circulation December 14, 2004 TABLE 1. Comparison of Baseline Characteristics of Patients by Groups of Baseline egfr (ml min m 2 )(n 2183) Group 1, 75 (n 799) creatinine with the Modification of Diet in Renal Disease equation, and post-mi outcomes and determined the relative effects of captopril in subjects with and without CKD. We hypothesized that egfr would be inversely correlated with mortality and recurrent cardiac events, and that subjects with CKD would derive similar or greater benefit from captopril therapy than subjects without CKD. Methods Patients The design of the SAVE trial has been described in detail elsewhere. 9 In brief, SAVE was a randomized trial of captopril versus placebo in 2231 patients with acute MI (3 to 16 days) and LVEF 40%. All-cause mortality, CV mortality, development of heart failure or recurrent fatal or nonfatal MI, and a combination outcome of CV mortality and morbidity were assessed during a follow-up period of 42 months. The SAVE trial was performed between 1988 and 1991 in the United States and Canada. Group 2, (n 665) Group 3, (n 516) Group 4, 45 (n 203) P Age, y * Age 65 y 149 (18.7) 192 (28.9) 216 (41.9) 129 (63.6) * Baseline creatinine, mg/dl * Baseline egfr * Female gender 116 (14.5) 101 (15.2) 106 (20.5) 58 (28.8) * BMI, kg/m LVEF, % LVEF 25% 113 (14.1) 120 (18.1) 118 (22.9) 45 (22.2) Killip class (35.5) 252 (37.9) 229 (44.4) 103 (50.7) Hypertension 272 (34.0) 255 (38.4) 250 (48.5) 134 (66.0) Diabetes 163 (20.4) 120 (18.1) 126 (24.4) 68 (33.5) Previous MI 228 (29.7) 234 (37.1) 214 (43.0) 98 (52.1) History of CHF 25 (3.1) 43 (6.5) 40 (7.8) 19 (9.4) Current smoking 415 (60.5) 255 (44.7) 179 (42.6) 58 (33.3) Ever smoked 641 (80.2) 526 (79.1) 388 (75.2) 159 (78.3) Alcohol use 384 (48.1) 276 (41.5) 210 (40.7) 65 (32.0) Diuretics within 72 hours of randomization 117 (15.7) 129 (20.2) 162 (33.1) 92 (48.2) Blockers 140 (18.6) 136 (21.4) 121 (24.6) 55 (28.7) Thrombolytics 291 (36.7) 208 (31.5) 171 (33.2) 43 (21.4) Catheterization between MI and randomization 180 (22.5) 169 (25.4) 143 (27.7) 60 (29.6) PTCA 31 (3.9) 17 (2.6) 23 (4.5) 9 (4.4) Assignment to captopril 394 (49.3) 340 (51.1) 268 (51.9) 91 (44.8) BMI indicates body mass index; CHF, congestive heart failure. Values are mean SD or n (%). *Not independent covariates. creatinine of 2.2 mg/dl would have an estimated GFR of 24.2 ml min m 2. This formula has been shown to agree closely with measurements of GFR utilizing iothalamate, which, like inulin, is filtered by the kidney and neither secreted nor absorbed. 4 We were able to assess baseline egfr with this formula in 2183 SAVE subjects with baseline serum creatinine. The 48 subjects without baseline egfr did not differ significantly from the rest of the SAVE population included in the analysis in demographic characteristics, comorbid conditions, treatment received, and major outcomes (data not shown). We categorized subjects a priori into 4 groups by 15-mL Baseline Kidney Function Potential subjects with a serum creatinine concentration 2.5 mg/dl (221 mol/l) were excluded from participation in SAVE. Because kidney function varies by factors other than the serum creatinine, we estimated the glomerular filtration rate (egfr) using the 4-variable Modification of Diet in Renal Disease equation [186 serum creatine age in years (if black) (if female)]. 10 For example, a 60-year-old white woman with a serum Figure 1. Relative risk of CV mortality/morbidity by groups of egfr. Referent group is egfr 75 ml min m 2.

3 Tokmakova et al Chronic Kidney Disease, CV Risk, and ACE Inhibition 3669 TABLE 2. Association Between Baseline egfr and Outcomes Outcomes by Groups of egfr, ml min m 2 Total mortality Unadjusted Hazard Ratio (95% CI) min m 2 increments in egfr ( 75, 60 to 74, 45 to 59, and 45) using a modification of the classification scheme recently proposed by the National Kidney Foundation s Kidney Disease Outcomes Quality Initiative. 11 We evaluated the associations of baseline kidney function with the risk of death due to all causes, CV death, recurrent MI, heart failure (need for open-label ACE inhibition and/or hospitalization for management of heart failure), and the combined risk of CV mortality and morbidity. Statistical Analysis To assess differences in baseline characteristics among the egfr categories, we used 1-way ANOVA and the Kruskal-Wallis test (where appropriate) for continuous variables and the 2 test for categorical variables. Survival (time to event) analyses were conducted with the Cox proportional hazards model. Multivariable analyses included the effects of age, gender, diabetes, hypertension, Killip class, previous MI, body mass index (in kg/m 2 ), and captopril assignment. Because age, gender, and race were incorporated in the egfr estimate, the inclusion of these variables in multivariable models estimates the residual effects of age, gender, and race on outcomes. We analyzed egfr as a continuous variable using tests of trend. In companion analyses, we dichotomized egfr above or below 60 ml min m 2. We defined CKD by an egfr 60 Hazard Ratio (95% CI) Adjusted for Residual Age and Gender Hazard Ratio (95% CI) With Multivariable Adjustment Group 2 ( ); n ( ) 1.13 ( ) 1.11 ( ) Group 3 ( ); n ( ) 1.44 ( ) 1.24 ( ) Group 4 ( 45.0); n ( ) 2.08 ( ) 1.81 ( ) P for trend CV mortality Group 2 ( ); n ( ) 1.26 ( ) 1.19 ( ) Group 3 ( ); n ( ) 1.50 ( ) 1.19 ( ) Group 4 ( 45.0); n ( ) 2.43 ( ) 1.96 ( ) P for trend Recurrent MI Group 2 ( ); n ( ) 1.04 ( ) 1.08 ( ) Group 3 ( ); n ( ) 1.57 ( ) 1.42 ( ) Group 4 ( 45.0); n ( ) 1.71 ( ) 1.48 ( ) P for trend Heart failure Group 2 ( ); n ( ) 0.99 ( ) 0.95 ( ) Group 3 ( ); n ( ) 1.44 ( ) 1.21 ( ) Group 4 ( 45.0); n ( ) 1.70 ( ) 1.28 ( ) P for trend CV mortality/morbidity Group 2 ( ); n ( ) 1.11 ( ) 1.09 ( ) Group 3 ( ); n ( ) 1.41 ( ) 1.22 ( ) Group 4 ( 45.0); n ( ) 1.83 ( ) 1.48 ( ) P for trend Group 1 ( 75.0 ml min m 2 ;n 799) is the referent group. Other significant variables in adjusted model: age, diabetes mellitus, LVEF (as a 5% decrease), Killip class 2 at baseline, hypertension, history of prior MI, and treatment with captopril. Although gender was not a statistically significant predictor, it was included in the adjusted model. Because age and gender are incorporated within the GFR estimate, inclusion of these variables in predictive models would tend to reduce the significance of the egfr term. ml min m 2. We tested the potential interaction between CKD and randomization to captopril or placebo to determine the relative benefit of captopril in subjects with and without CKD. Finally, we calculated the number needed to treat to prevent 1 death or CV event among subjects with and without CKD. Statistical analyses were performed with STATA software, version 7 (Stata Corp). Results Baseline Characteristics The mean egfr from the 2183 SAVE subjects was ml min m 2. Baseline demographic characteristics of study subjects across the 4 egfr groups are shown in Table 1. As expected, subjects with lower egfr were older, were more likely to be women, and had higher serum creatinine concentrations. Subjects with lower egfr also had more comorbidity, as assessed by a higher incidence of hypertension, diabetes, prior MI, and history of heart failure. The SAVE-qualifying MI was associated with a higher Killip class and a greater proportion of subjects with

4 3670 Circulation December 14, 2004 LVEF 25% in the lower egfr groups. Subjects with lower egfr were also more likely to receive diuretics and -blockers and less likely to receive thrombolytic therapy. There were no significant differences in the frequency of post-mi cardiac catheterization and PTCA across the egfr groups. egfr, Categories of CKD, and Study Outcomes egfr was significantly associated with a higher risk for all CV events (linear tests for trend, P for all outcomes). Even mild reductions in egfr (60 to 74 ml min m 2, relative to 75 ml min m 2 ) were associated with a significantly increased risk for total mortality, CV mortality, and the combined CV mortality and morbidity outcome (Figure 1). Table 2 shows unadjusted, age- and gender-adjusted, and multivariable-adjusted hazard ratios for each outcome by egfr group. The relationship between egfr and outcomes was attenuated after adjustment for the residual effects of age and gender. After additional adjustment for diabetes, LVEF, Killip class 2, hypertension, history of prior MI, and treatment with the study drug captopril, egfr remained a significant determinant of total mortality (P ), CV mortality (P ), recurrent MI (P 0.017), and the combined CV mortality and morbidity outcome (P 0.002). Lower egfr was associated with a nonsignificant trend (P 0.07) toward a higher risk of developing heart failure after multivariable adjustment. The relative risks of death and CV death increased markedly with reduced egfr. Subjects with an egfr 45 ml min m 2 experienced an 81% increase in the risk of death and a 96% increase in the risk of CV death compared with subjects whose egfr was 75 ml min m 2 (despite adjustment for many of the key determinants of CKD, ie, age, diabetes, and hypertension). The rate of CV events declined steadily with increasing egfr until egfr reached 60 ml min m 2 and then remained relatively constant (Figures 2 and 3). Table 3 shows the relative risks associated with egfr above or below 60 ml min m 2 and each of the comorbid conditions for each of the outcome measures. Effects of Captopril in Subjects With and Without CKD We determined whether captopril was equally efficacious in subjects with and without CKD. As shown in Table 4, the Figure 2. Annualized CV mortality/morbidity per decile of egfr. relative risk reduction due to captopril was nominally higher in subjects with CKD (31% versus 20%). Nevertheless, the interaction between study drug and CKD was not statistically significant (P 0.29). As a consequence of the higher event rate in subjects with CKD, the absolute benefit of captopril was greater in this group (12.4 versus 5.5 CV events prevented per 100 subjects with and without CKD, respectively). The number needed to treat to prevent 1 CV death, MI, or development of heart failure during the trial duration was 9 for patients with CKD and 19 for those without CKD. Mean doses of active therapy were lower at 6 and 12 months, and overall discontinuation of either active study medication or placebo was more common in patients in the lowest egfr groups, although of all reasons for stopping study medication, only the need for open-label ACE inhibitor secondary to refractory heart failure increased with decreasing egfr group (P for trend 0.02 for both active and placebo groups). Despite these trends, the absolute benefit of captopril therapy was still greater in the lowest egfr groups. Discussion In these analyses of the SAVE cohort, we confirmed that among nonelderly and elderly post-mi subjects, CKD was Figure 3. Kaplan-Meier curves for CV mortality/morbidity stratified by egfr above and below 60 ml min m 2 and by treatment assignment.

5 Tokmakova et al Chronic Kidney Disease, CV Risk, and ACE Inhibition 3671 TABLE 3. Association of Reduced Baseline Renal Function With Outcomes in Cox Proportional Hazards Models Total Mortality Recurrent MI Heart Failure CV Mortality/Morbidity Unadjusted HR (95% CI); P value egfr 60 ml min m ( ); ( ); ( ); ( ); Adjusted HR (95% CI); P value GFR 60 ml min m ( ); ( ); ( ); ( ); Age (per year) 1.03 ( ); ( ); ( ); ( ); Male gender 1.21 ( ); ( ); ( ); ( ); Diabetes 1.31 ( ); ( ); ( ); ( ); Hypertension 1.25 ( ); ( ); ( ); ( ); Prior MI 1.51 ( ); ( ); ( ); ( ); Killip class ( ); ( ); ( ); ( ); LVEF (per 10-point increase) 1.89 ( ); ( ); ( ); ( ); Captopril therapy 0.79 ( ); ( ); ( ); ( ); HR indicates hazard ratio. GFR 60 ml min m 2 is the referent group. associated with an increased risk for total and CV mortality. Indeed, subjects with an egfr 60 ml min m 2 experienced an increased incidence in all outcomes including recurrent MI and heart failure, even after adjustment for important cofounders such as age, gender, diabetes, hypertension, prior MI, LVEF, and Killip class. We further explored the relative effects of treatment by CKD status and found a similar relative (and higher absolute) benefit of captopril in subjects with CKD. Prior studies have demonstrated that CKD is an independent risk factor for CV disease and mortality. 12 For example, using data from the Atherosclerosis Risk In Communities Study, Manjunath et al 12 showed that patients with an egfr 15 to 59 ml min m 2 experienced a 38% increase in the risk of major CV events relative to patients with normal egfr ( 90 ml min m 2 ). Patients with end-stage renal disease have a multifold increased mortality after an acute MI. 3,13 Wright et al 6 compared postdischarge death rates in post-mi patients with varying levels of CKD and found an increase in risk even among patients with mild CKD. Mortality rates during the 6-year follow-up of post-mi subjects from the Trandolapril Cardiac Evaluation (TRACE) study were increased in subjects with reduced kidney function, although only subjects with calculated creatinine clearance below 40 ml/min experienced an independent and clinically important increase in risk. 4 Shlipak et al 5 examined elderly post-mi patients (age 65 years) from the Cooperative Cardiovascular Project and established an elevated adjusted relative risk for death in persons with mild to moderate CKD, defined as serum creatinine concentrations of 1.5 to 2.4 mg/dl (1.7-fold) and 2.5 to 3.9 mg/dl (2.4-fold), respectively. A number of etiologic factors have been proposed to account for the increased CV risk in patients with CKD. Elevated blood pressure, dyslipidemia, microalbuminuria, increased plasma homocysteine, and anemia are likely to contribute to the overall risk of CV events, such as MI or stroke. 14 In addition, CKD is likely to contribute to the risk of heart failure in patients with ventricular dysfunction due to increased fluid retention and increased diuretic resistance. Additionally, a decrease in myocardial perfusion relatively acutely after infarction may reduce egfr and may portend subsequent increased risk. Other studies have examined the effects of treatment with ACE inhibitors on other CV outcomes in patients with CKD. The Captopril and Thrombolysis Study reported that the incidence of heart failure among survivors of first MI was significantly reduced by captopril and that the effect was most pronounced in patients with worse kidney function at baseline. 5,15 The findings of the present study are also consistent with data from the Health Outcomes Prevention Evaluation (HOPE) study, in which ramipril significantly TABLE 4. Subgroup Analysis of the Efficacy of Captopril by egfr Events/Patients, n/n (%) Variable Placebo Captopril Risk Reduction Power Test for Interaction Total mortality egfr /730 (19.5) 127/734 (17.3) 13 ( 11 to 31) P 0.30 egfr /360 (35.3) 96/359 (26.7) 28 (6 45) CV mortality/morbidity egfr /730 (34.0) 209/734 (28.5) 20 (4 33) P 0.29 egfr /360 (51.7) 141/359 (39.3) 31 (14 45) 0.773

6 3672 Circulation December 14, 2004 reduced the CV risk associated with CKD. In the HOPE study, in which participants with heart failure or impaired LVEF were excluded, the risk reduction was at least as great for subjects with CKD as in those without. For CV mortality, all-cause mortality, and heart failure related hospitalization, the risk reduction was greater for subjects with reduced kidney function. 8 Wright et al 6 reported a reduced risk of in-hospital death if patients were treated (nonrandomized) with ACE inhibitors; however, the authors indicated that the use of ACE inhibitors during index hospitalization was lower in patients with CKD. Data from the Cooperative Cardiovascular Project, which included older patients with MI, showed that ACE inhibitors were used more frequently in patients with CKD than in patients with no renal insufficiency and were associated with enhanced survival. In the same cohort, 1-year survival was higher for those treated with ACE inhibitors, and the benefit of ACE inhibitors was greater in patients with elevated serum creatinine and among those with the highest mortality risk (with severely reduced left ventricular function). 16,17 Patients with CKD are often undertreated with CV preventive measures and drugs, and both increased risk and less aggressive care have correlated with the degree of renal dysfunction. 5,6,18 Because SAVE was randomized (balancing unmeasured confounders and selection bias), these data confirm the important protective effect that captopril provides to CKD patients with acute MI. The number needed to treat was low overall and was quite low among persons with CKD. Some limitations of the present study should be noted. Kidney function was estimated and not measured. The SAVE trial was conducted between 1988 and 1991, and the treatment of post-mi patients has changed in the interim. Although these data allow us to comment on the relationship between ACE inhibitor benefit and renal dysfunction, we cannot exclude the possibility that current differences in care might influence this relationship. The difference between egfr and true GFR may have led to misclassification of some subjects, although misclassification would be likely to bias the association between CKD and outcomes toward the null. In other words, the use of egfr rather than measured GFR probably underestimated the strength of the link between GFR and CV outcomes. We elected to use a modification of the published National Kidney Foundation Kidney Disease Outcomes Quality Initiative classification scheme, in which persons with egfr 30 to 59 ml min m 2 are considered stage 3 and persons with egfr 15 to 29 ml min m 2 are considered stage 4. We did so in part because the number of SAVE subjects with egfr 30 ml min m 2 was extremely small, and also because we anticipated that there would be measurable differences in risk among persons with egfr 45 to 59 and 30 to 45 ml min m 2. Differences were indeed observed between the 2 stage 3 subgroups. Because there were so few subjects with egfr 30 ml min m 2,we cannot evaluate the relative efficacy of captopril in persons with very low egfr. In addition, egfr may systematically underestimate true GFR in the GFR range of the majority of SAVE subjects ( 30 ml min m 2 ). 19 Moreover, because SAVE included subjects with reduced left ventricular function, we are unable to generalize these results to patients with MI and preserved left ventricular function or to patients with reduced left ventricular function who are not post-mi patients. We also cannot exclude the possibility that anemia may have contributed to the increased risk in the low-egfr groups, because hemoglobin was not measured in this cohort, and we do not have proteinuria data on these patients. Finally, although we adjusted for numerous variables collected within SAVE, we could not adjust for all potential sources of confounding. It is unlikely that residual confounding could fully explain the increases in relative risks that were observed in the present study. Conclusions In a comprehensive analysis of the SAVE trial, mild to moderate CKD was associated with a heightened risk for all major CV events. An egfr of 60 ml min m 2 may be considered as a threshold value below which the relative risk of CV events increases more rapidly and in a nonlinear fashion. The benefit of captopril observed among all study subjects was evident in subjects with CKD (with a nominally larger relative risk reduction). Absent major contraindications (eg, refractory hyperkalemia), these data suggest that ACE inhibitors should be routinely administered to patients with CKD after myocardial infarction. References 1. McCullough PA, Sandberg KR, Borzak S. Cardiovascular outcomes and renal disease. Ann Intern Med. 2002;136: Dries DL, Exner DV, Domanski MJ, Greenberg B, Stevenson LW. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol. 2000;35: Beattie JN, Soman SS, Sandberg KR, Yee J, Borzak S, Garg M, McCullough PA. Determinants of mortality after myocardial infarction in patients with advanced renal dysfunction. Am J Kidney Dis. 2001;37: Sorensen CR, Brendorp B, Rask-Madsen C, Kober L, Kjoller E, Torp- Pedersen C. The prognostic importance of creatinine clearance after acute myocardial infarction. Eur Heart J. 2002;23: Shlipak MG, Heidenreich PA, Noguchi H, Chertow GM, Browner WS, McClellan MB. 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