Influence of Renal Function on Cardiovascular Outcomes: A VALIANT Substudy

Linda Brookes, MSc

Disclosures

December 30, 2003

Editorial Collaboration

Medscape &

Presenter: Nagash Anavekar, MD, Brigham and Women's Hospital (Boston, Massachusetts)

Further support for the frequently voiced concerns of nephrologists has come from an analysis of 3-year outcomes in the Valsartan in Acute Myocardial Infarction trial (VALIANT),[1] which reported that baseline renal impairment is common and should be considered a potent, independent, and easily identifiable risk factor for cardiovascular complications post acute myocardial infarction (MI). This analysis further showed that none of the renin-angiotensin system-blocking therapies given in VALIANT altered the significant influence of baseline renal impairment on cardiovascular outcomes in these patients.

VALIANT enrolled 14,703 patients who presented with acute MI within 12 hours to 10 days.[2] All patients were considered at high risk because they had either clinical or radiologic signs of congestive heart failure and/or left ventricular (LV) dysfunction. Patients with baseline serum creatinine ≥ 2.5 mg/dL were excluded from the trial. Treatment, after randomization in a 1:1:1 ratio, consisted of valsartan (target dose 160 mg twice daily), captopril (target dose 50 mg 3 times daily), or combination (valsartan 80 mg twice daily + captopril 50 mg 3 times daily).

All patients were categorized by glomerular filtration rate (eGFR) estimated by using the 4-component Modification of Diet in Renal Disease equation:

eGFR = 186 × plasma Cr-1.154 × age in years -0.203 × 1.210 (if black) × 0.742 (if female)

(Note: Cr = creatinine.)

Incorporating National Kidney Foundation guidelines, the patients were divided into 4 eGFR categories:

  1. < 45 mL/min/1.73 m2

  2. 45.0-59.9 mL/min/1.73 m2

  3. 60.0-74.9 mL/min/1.73 m2

  4. > 75 mL/min/1.73 m2

Mean eGFR was 70 mL/min/1.73 m2. Despite the serum creatinine exclusion criterion, 4862 (> 30%) of the VALIANT patients met renal function criteria for chronic kidney disease. Individuals in the lower tier of renal function had a significantly higher proportion of coronary risk factors and percentage of clinically determined LV dysfunction. Despite this, these patients were less likely to be receiving cardiovascular pharmacotherapies. Stratification of the patients by eGFR group showed a significantly high risk of death over time associated with worsening renal impairment.

Cardiovascular events, expressed either as a composite endpoint over the 3-year follow-up period or as individually adjudicated events, showed a progressive increase in the proportion of patients experiencing events with worsening eGFR. This trend was highly significant in the worst eGFR group. These effects were persistent over time, particularly in those with eGFR < 45 mL/min/1.73 m2.

Each incremental lowering of eGFR by 10 units below 81 mL/min/1.73 m2 was independently associated with a hazard ratio (HR) of 1.099 (95% CI = 1.08-1.12) for risk of death and nonfatal cardiovascular complications.

Using the highest eGFR as a reference group, unadjusted HRs revealed a marked increase in death and composite cardiovascular events with worsening renal impairment. After adjustment for 70 factors, including hypertension, diabetes, dyslipidemia, and variables known to influence cardiovascular events such as time to treatment, infarct location, measures of systolic function, and hemodynamic parameters, baseline eGFR was found to be a significant and independent predictor for cardiovascular outcomes (Table 1). The increased risk varied from 10% in those with mild renal impairment to 49% in those in the worst eGFR category. This occurred despite all patients receiving some form of renin angiotensin system blockade.

Table 1. Events by eGFR
eGFR (mL/min/1.73 m2)
< 45 45.0-59.9 60.0-74.9 ≥ 75
Death (%) 45.5 28.9 20.5 14.1
Adjusted HR (95% CI) 1.70 (1.50-1.93) 1.38 (1.24-1.54) 1.14 (1.02-1.27) reference
Composite outcome* (%) 59.9 44.1 34.3 26.5
Adjusted HR (95% CI) 1.49 (1.35-1.65) 1.26 (1.16-1.37) 1.10 (1.02-1.19) reference
*Composite includes cardiovascular death, reinfarction, heart failure, resuscitated sudden death, and stroke.

Plotted as a continuous variable, the significantly independent association between baseline eGFR showed a curvilinear relationship in which lower values of renal function, particularly those < 60 mL/min (same criterion for defining chronic kidney disease), markedly predicted increased risk for adverse events.

Differences in mean serum creatinine between the groups were 0.2-0.4 mg/dL (Table 2).

Table 2. Serum Creatinine at Baseline
eGFR (mL/min/1.73 m2)
< 45 45.0-59.9 60.0-74.9 ≥ 75
Creatinine (mg/dL) 1.7 ± 0.4 1.3 ± 0.2 1.1 ± 0.1 0.9 ± 0.1

These small changes translated into much larger differences in renal function as measured by eGFR. This highlighted one of the limitations of serum creatinine as a descriptor of renal function, according to Dr. Anavekar. These measures, which would ordinarily be considered insignificant, actually have profound negative prognostic implications among this post-MI population, he pointed out.

References
  1. Anavekar A, McMurray JJ, Velazquez EJ, et al. Influence of renal function on one-year cardiovascular outcomes in the VALIANT trial. Circulation. 2003;106(17 suppl):IV-485.

  2. Pfeffer MA, McMurray JJV, Velazquez EJ, et al, for the Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893-1906.

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