Cardiovascular Risk Stratification in Older Patients: Title and subTitle BreakRole of Brain Natriuretic Peptide, C-Reactive Protein, and Urinary Albumin Levels

Cardiovascular risk prediction by noninvasive laboratory testing in the general population is becoming increasingly recognized as an important health care issue. During the last decade, a variety of novel potentially powerful prognostic biomarkers emerged, which may yield prognostic information even in individuals without evidence of prevalent disease. Among the panel of promising parameters, the role of natriuretic peptides and inflammatory markers has been extensively studied in various populations and clinical settings. Natriuretic peptides have been shown to predict outcome of patients with heart failure, coronary artery, and valvular heart disease.^{1 - 4} However, unlike studies examining C-reactive protein (CRP),^{5 - 7} investigations of natriuretic peptides in predicting future cardiovascular events have not been conducted in population-based samples, and comparative analyses including a variety of prognostic biomarkers are scarce.^{5 ,8}

In this issue of JAMA, Kistorp and colleagues⁹ assessed the ability of N-amino terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP) to predict mortality and first major cardiovascular events in a population-based sample of older individuals, and compared the predictive ability of NT-proBNP with CRP and the urinary albumin/creatinine ratio. The authors enrolled 626 participants aged 50 to 89 years without prevalent heart or renal failure from a representative sample of 1088 inhabitants of Copenhagen, Denmark. Patients were followed up for mortality and hospitalization due to a first major cardiovascular event, including myocardial infarction, unstable angina, heart failure, stroke, and transient ischemic attack. Analyses of cardiovascular events were restricted to 537 of 626 participants without prevalent cardiovascular disease, and occurrence of de novo heart failure was analyzed in 598 patients with normal left ventricular systolic function (left ventricular ejection fraction ≥50%) at baseline.

During the 5-year observation period, 15% of 626 participants died, 12% of 537 patients without cardiovascular disease at baseline had a cardiovascular event, and 3% of 598 patients with normal left ventricular systolic function developed heart failure. A significant association between increased baseline levels of NT-proBNP (>80th percentile) and mortality was observed, independent of traditional cardiovascular risk factors, comorbid conditions, and echocardiographic left ventricular systolic dysfunction. NT-proBNP also was significantly associated with cardiovascular events and the occurrence of heart failure. CRP levels and urinary albumin/creatinine ratio above the 80th percentile predicted death with a substantially lower predictive value compared with NT-proBNP. With respect to cardiovascular events, CRP showed no significant association and the urinary albumin/creatinine ratio was less powerful than NT-proBNP. Neither CRP nor the urinary albumin/creatinine ratio was significantly associated with de novo heart failure during follow-up.

The authors concluded that NT-proBNP outperformed both CRP and the urinary albumin/creatinine ratio with respect to all outcomes in this population-based sample of older nonhospitalized individuals. Importantly, these associations were independent of traditional cardiovascular risk factors and left ventricular systolic dysfunction, suggesting that determination of NT-proBNP yields prognostic information beyond these factors and may be clinically useful in a broad range of older individuals. CRP as a prognostic factor in the older population may be clinically less important; in contrast, the urinary albumin/creatinine ratio seems a potential candidate for future investigations.

Pathophysiologically, the prognostic biomarkers NT-proBNP, CRP, and urinary albumin/creatinine ratio reflect3 mechanisms of cardiovascular disease, which can be summarized as cardiac dysfunction, vascular inflammation, and renal dysfunction due to microvascular disease.

Cardiac Dysfunction Measured by NT-proBNP. Brain natriuretic peptide (BNP) is synthesized as a prohormone in ventricular cardiocytes as a response to increased cardiac wall stress and pressure overload and is cleaved into the active BNP and inactive NT-proBNP, the latter being a more stable cardiac marker. Both levels of BNP and NT-proBNP associate with left ventricular dilatation, remodeling, and dysfunction¹⁰ and were initially recognized mainly as markers of chronic heart failure.¹¹ More recently, BNP and NT-proBNP emerged as sensitive prognostic parameters in patients with myocardial ischemia.^{1 - 2} Even transient myocardial ischemia results in an immediate increase of BNP and NT-proBNP, with the magnitude of the increase proportional to the severity of ischemia.¹² In this context, a substudy of Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease (FRISC II) trial indicated a survival benefit from early revascularization of patients with increased NT-proBNP and high levels of interleukin 6.¹³ The Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy–Thrombolysis in Myocardial Infarction 18 (TACTICS-TIMI-18) trial,¹⁴ in contrast, suggested that revascularization did not benefit patients with increased BNP levels.

Taking together these previous studies and the current data provided by Kistorp et al,⁹ the reason for the strong association between NT-proBNP and adverse outcome in these older patients can only partially be explained. First, it seems that the level of NT-proBNP is a global indicator of several comorbidities like age, hypertension, diabetes mellitus, and cardiac and renal dysfunction.¹⁵ Nevertheless, the authors statistically accounted for these interactions, suggesting an additive prognostic information of NT-proBNP beyond these risk factors. Second, an increase of NT-proBNP likely reflects preexisting subclinical ventricular dysfunction, which also may explain the higher levels of NT-proBNP in older individuals.¹⁵ And third, increased levels of NT-proBNP in patients with normal or slightly depressed left ventricular systolic function seem to indicate diastolic dysfunction,¹⁶ which contributes to adverse outcome.

Vascular Inflammation Measured by CRP. Substantial advances in basic and clinical studies have illuminated the role of inflammation and the underlying cellular and molecular mechanisms that contribute to atherogenesis.¹⁷ Accumulating epidemiological data from several large-scale cohort studies indicate that an increase of CRP levels heralds cardiovascular events.^{5 - 7} CRP was described not merely as a marker of cardiovascular risk, but also has been implicated in promoting endothelial cell activation, adhesion molecule expression, and resultant dysfunction.¹⁸ Based on a growing body of evidence, CRP is considered to be a promising cardiovascular risk predictor, and therefore was included as a reference parameter in the study by Kistorp et al.⁹ However, Danesh et al¹⁹ reported that CRP was only a moderate predictor of coronary artery disease in comparison with the established risk factors like total cholesterol or smoking. Similarly, the findings by Kistorp et al⁹ indicate that CRP did not substantially add to the prognostic information of traditional risk factors in an older population. These differences from previous findings likely arise from inclusion of different target populations. Age may be a relevant confounding factor, as the predictive value of CRP decreases with increasing age.⁶ The extent of preexisting atherosclerosis may also play a role, as CRP was described as a potent risk predictor in elderly patients with advanced atherosclerosis.²⁰

Renal Microvascular Disease Measured by Urinary Albumin/Creatinine Ratio. Investigating urinary albumin/creatinine excretion as a prognostic marker in the study by Kistorp et al⁹ reflects the authors’ attempt to include a third approach of biochemical risk stratification in an older population. Urinary albumin/creatinine excretion is an established marker of cardiovascular risk, indicative of renal dysfunction mainly due to microvascular disease.²¹ Although arising from pathophysiologically different mechanisms, NT-proBNP and the urinary albumin/creatinine ratio were significantly associated, which might be explained in part by an increased sensitivity to volume overload in patients with subclinical renal dysfunction. However, when analyzed simultaneously, both parameters remained significant predictors of outcome.

Addressing the potential clinical usefulness of these parameters and considering future application for risk cardiovascular stratification in older populations, 5 major issues arise. First, a clinically useful parameter should add to the prognostic information of established risk factors. In the study by Kistorp et al⁹ and supported by former findings, NT-proBNP and the urinary albumin/creatinine ratio both had an additive value beyond traditional risk factors, whereas the predictive value of CRP was attenuated, as previously recognized, in elderly patients.⁶ Alternatively to a common approach of single marker measurements, a multibiomarker approach has been applied in recent investigations. In this context, the predictive value of NT-proBNP has been demonstrated to be independent of CRP levels,^{22 - 23} but combining NT-proBNP and CRP was suggested to increase their predictive power.⁸

Second, cutoff values from population-based samples must be evaluated and validated with respect to sensitivity and specificity. Depending on the cutoff level of NT-proBNP, a sensitivity of almost 100% has been described for detecting heart failure in the community²⁴ ; however, with a rather low specificity (70%), NT-proBNP is mainly useful as a “rule-out” or exclusion test. In contrast, Kistorp et al⁹ chose a “rule-in approach” aiming to compare the prognostic impact of the biomarkers for predicting future events. Unfortunately, specificity of cutoff values and corresponding positive predictive values cannot be calculated from this study and warrant further investigations.

Third, a clinically useful parameter has to yield information about the benefit of specific treatment regimens. Increased NT-proBNP potentially identifies patients who will benefit from revascularization in states of acute myocardial ischemia,^{13 - 14 ,22} while comparative data suggest a substantially lower value of CRP in this context.²² Current data on this issue remain conflicting and are restricted to treatment of acute myocardial ischemia.

Fourth, a clinically useful parameter has to be reliable and rapidly obtainable—both can be achieved for NT-proBNP and CRP but to a lesser extent for the urinary albumin/creatinine ratio. And fifth, a clinically useful parameter has to be cost-effective, which may hold true for NT-proBNP in certain risk populations.²⁵

In conclusion, the study by Kistorp et al⁹ adds to the current knowledge of the usefulness of NT-proBNP as a prognostic biomarker in older patients without prevalent cardiovascular disease. NT-proBNP seems to be a powerful predictor for mortality and the occurrence of first cardiovascular adverse events in individuals older than 50 years, and appears more efficient than CRP and urinary albumin/creatinine ratio. Nevertheless, several issues remain to be addressed before NT-proBNP can be applied for routine screening purposes, including the issues of optimal cutoff values and whether specific treatment benefits patients with increased NT-proBNP levels.