BNP-guided therapy
Efficiency of BNP-guided therapy on cardiomyopathies is not yet elucidated. However, BNP levels reflect therapeutic effect in patients with HF. Aggressive treatment with diuretics and vasodilators such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-II receptor antagonists reduce BNP level rapidly in conjunction with reduced intra-ventricular filling pressures. On the other hand, the effects of beta blockers on BNP concentrations are complex. Because adrenergic stimulation inhibits release of natriuretic peptides, beta blocking may initially increase BNP concentrations. By contrast, long-term use of beta blocker reduces BNP concentrations with the improvement in cardiac dysfunction. Thus, BNP measurement would help physicians to make clinical decisions to titrate pharmacological treatments.
BNP-guided therapy improves a treatment outcome in patients with HF. Two provocative pilot studies have prospectively assessed the utility of BNP to guide selection and intensity of pharmacotherapy. In one study, 69 symptomatic patients (NYHA class II to IV) with impaired systolic function defined as LVEF of <40% were randomly allocated to receive either standardised clinical assessment consist of symptoms and physical findings-guided therapy or N-terminal BNP-guided therapy (< 200 pmol/L) (33). During the follow up of at least 6 months, fewer patients had combined cardiovascular events (death, hospital admission, or heart failure decompensation) in the N-terminal BNP group than in the clinical group, which was associated with higher doses of ACEIs and diuretics. In a second multicenter randomised trial: The STARS-BNP Multicenter Study, 220 patients with symptomatic (NYHA class II to III) systolic HF defined as LVEF of <45% were randomized to medical treatments on either the basis of clinical findings from the physical examination and usual paraclinical and biological parameters or the basis of a decreasing BNP plasma levels of <100 pg/ml (34). After a mean follow-up of 15 months, significantly fewer patients had HF-related death in the BNP group than in the clinical group, which was in part associated with an increase in ACEIs and beta-blocker dosages.
Fig. 2. Changes in B-type natriuretic peptide (BNP) levels and echocardiographic findings during a clinically compensated status in patients with dilated cardiomyopathy.
Changes in BNP level at 3-month intervals after hospital discharge for decompensated heart failure (A) and in echocardiographic variables between discharge and 6 months (B). BNP levels were decreased during 6 months in event-free patients but not in readmitted patients, which was accompanied by the reduction of cardiac dimensions. Solid or open circles indicate BNP levels, echocardiographic dimensions (left ventricular end-diastolic dimension [LVDd]; left atrial diastolic dimension [LADd]), and left ventricular ejection fraction (LVEF) in event-free patients or patients readmitted for decompensated heart failure, respectively. Values are mean ± standard error of the mean. p values comparing changes in BNP and echocardiographic variables between readmitted patients and event-free patients are for repeated measures multivariate analysis of variance over 6 months.
On the other hand, it remained uncertain whether BNP guide is available for asymptomatic patients or not. We reported that in 83 outpatients with asymptomatic (NYHA class I to II) systolic HF defined as LVEF of <40%, BNP cutoff point of about 200 pg/ml at 6 months after the discharge for decompensated HF can identify patients at the high risk of readmission and sudden death (13) (Figure 3). Interestingly, Beta blocker use and its dosage were significantly lower in high risk patients [>200 vs. <200 pg/ml: 60 vs. 100%, P=0.001; 8 ± 5 vs. 16 ± 5 mg/day (carvedilol), P=0.0003; 64 ± 22 vs. 107 ± 40 mg/day (metoprolol), P=0.036; respectively]. The cutoff point might determine the requirement of initiation or titration of beta blockers. Even in asymptomatic HF setting, BNP-guided therapy may be also helpful.
The limitations on BNP-guided therapy
We have to consider the limitations on BNP-guided therapy, also. Recent multicenter trial (the randomized Trial of Intensified vs. Standard Medical Therapy in Elderly Patients with Congestive Heart Failure: TIME-CHF) could not identify the advantage of BNP-guided therapy over symptom-guided therapy in 499 elderly patients aged more than 60 years with symptomatic (NYHA class II or greater) systolic HF (LVEF of <45%) and prior hospitalization for decompensated HF (35). They were randomized to N-terminal BNP-guided HF therapy (levels of less than two times the upper limit of normal) and symptom-guided HF therapy (NYHA class of less than II). However, the improvements of outcomes including mortality, hospitalization, and quality of life were similar in both groups. Especially in patients aged more than 75 years, BNP-guided HF therapy did not improve outcome. In general, dosages of drugs such as ACEIs and beta-blockers are increased more in patients receiving BNP-guided therapy. Although persistence in intensifying medical therapy seems to be indispensable for better outcome in young and middle aged patients, it may be harmful to push dosages to the limits in elderly patients aged more than 75 years. Additionally, BNP-guided therapy may be disadvantageous in patients with low output syndrome resulting from severe systolic and diastolic dysfunctions. Because such cases require more ventricular load as a compensatory mechanism for congestive HF, rapid titration of ACEIs, beta blockers, and diuretics on the basis of BNP-guided HF therapy may lead to further deterioration of HF. Furthermore, edtablished cardiomyopathy with irreversible LV dilatation often shows persistently high level of BNP despite aggressive treatment for HF. A unified level of BNP-guided therapy would be unavailable for such cases. These emphasize the need of setting up individual BNP target level in accordance with cardiac conditions.
Individual target threshold of BNP
To set up individual target threshold of BNP for the risk reduction that were associated with cardiac dilatation and identify its prognostic utility, clinically stable 113 patients with systolic HF after decompensated HF represented by non-ischemic dilated cardiomyopathy were examined. Among these patients, 32 patients reached end-point composed of readmission for decompensated HF or death. Various variables were related to its combined event, including atrial fibrillation, low LVEF below the best cutoff value of 34%, cardiac dilatation (CD) indicated by left ventricular end-diastolic dimension*LAD/wall thickness/body surface area above the best cutoff value of 115 /m2, high levels of BNP above the best cutoff value of 195 pg/ml. Furthermore, we found a significant positive correlation between BNP level and CD specific for event-free patients. The rage between 95% confidence interval on this specific linear regression line were closely associated with an incidence rate of readmission or death, also (Figure 4A, B). Thus, we defined this rage as individual target threshold of BNP.
Fig. 3. Kaplan-Meier Analyses (Nishii M, et al. J Am Coll Cardiol. 2008;51:2329-2335) Kaplan-Meier curves showing the incidence rate of readmission for decompensated heart failure or sudden death (A) or of readmission alone (B) according to 6-month post-discharge B-type natriuretic peptide (BNP) ranges in outpatients with dilated cardiomyopathy. The risk of a combined event increased in a stepwise fashion across increasing ranges of 6-month post-discharge BNP, namely at <190 pg/ml, 190 to 380 pg/ml, and >380 pg/ml (Fig. 2A). Further, Kaplan-Meier curves for incidence of readmission alone (Fig. 2B) showed the same pattern. B-type natriuretic peptide ranges were <190 (the best cutoff level for predicting readmission or sudden death), 190 to 380, and >380 (its 2-fold level) pg/ml. p < 0.0001 (the log-rank test) versus a BNP range of <190 pg/ml.
Next, we examined its prognostic advantage over other variables. When adjusted to high-risk patients with advanced dilated cardiomyopathy, namely symptomatic non-ischemic systolic HF (LVEF below 34%) complicated by severe cardiac dilatation (CD above 115 /m2), this individual target threshold alone was associated with the incidence rate (Figure 5). Based on Laplace Law (pressure x radius/2 wall thickness), this threshold may reflect individual optimal wall stretch for clinical stabilization. The left atrium (LA) acts as a reservoir during LV overload (36), and elevated LV filling pressure results in LA overload as well as LV diastolic dysfunction (37). Thus, LA dimension reflects intra-ventricular pressure, in part. A combined assessment of BNP level and echocardiographic dimensions may facilitate individual disease management. Among overall patients, those with BNP levels over or under its target threshold required titration or withdrawal, respectively of pharmocological therapy including diuretics or vosadilators to keep a balance between ventricular load and cardiac function. Additionally, cases refractory to such pharmacological optimization may be considered application of mechanical circulatory assist device implantation or subsequent surgical intervention including heart transplantation.
Fig. 4. Prognostic utility of individual target threshold of B-type natriuretic peptide (BNP) on readmission for decompensated heart failure or sudden death in patients with non-ischemic dilated cardiomyopathy A: Individual target threshold of BNP. Event-free patients had a significantly positive correlation between BNP level and cardiac dilatation (CD) (r=0.88; P<0.0001), but event patients did not (r=0.26; P=0.421). BNP levels in event patients tended to be out of the range between dotted lines: 95% confidence interval (CI) on solid line: the linear regression line specific for event-free patients (BNP= -144.64 + 3.16 X CD), namely individual target threshold of BNP. B: Kaplan-Meier curves showing the incidence rate of event according to individual target threshold of BNP. Out of this threshold was closely associated with an increase in event risk (the log-rank test: P<0.0001).
Open circles or triangles indicate even-free or event patients, respectively. CD was defined as left ventricular end-diastolic dimensionxleft atrial diastolic dimension/wall thickness/body surface area.
Fig. 5. Prognostic predictors on readmission for decompensated heart failure or death in patients with advanced dilated cardiomyopathy, namely symptomatic systolic heart failure (left ventricular ejection fraction below the best cutoff value of 34%) complicated by severe cardiac dilatation (CD) above the best cutoff value of 115 / m2.
A: Kaplan-Meier curves showing the incidence rate of event according to levels of BNP above or below the best cutoff value of 340 pg/ml or atrial fibrillation. These variables had no significant association with an increase in event risk (the log-rank test; BNP levels: P=0.2689; atrial fibrillation: P=0.4450). B: Individual target threshold of BNP. Event-free patients had a significantly positive correlation between BNP level and CD (r=0.91; P<0.0001), independently of event patients (r=0.10; P=0.71). BNP levels in event patients tended to be out of individual target threshold of BNP between dotted lines: 95% confidence interval (CI) on solid line: the linear regression line specific for event-free patients C: Kaplan-Meier curves showing the incidence rate of event according to individual target threshold of BNP. Out of individual target threshold of BNP was significantly associated with an increase in event incidence (the log-rank test: P<0.0001). Open circles or triangles indicate even-free or event patients. CD was defined as left ventricular end-diastolic dimension X left atrial diastolic dimension/wall thickness/body surface area.
The number of patients in our study is, however, relatively small, and our population was limited to only patients with non-ischemic dilated cardiomyopathy. Additional prospective multi-center studies including cases with ischemic heart disease would confirm our observation and extend it to various settings of systolic HF.
Conclusion
BNP measurement has facilitated the diagnosis of HF and decision of pharmacotherapy and improved outcome during the hospitalization and after the discharge for decompensated HF in cardiomyopathies, although BNP cutoff points for risk assessment are different on time course after decompensated HF and cardiac dysfunctions. On the other hand, availability of this BNP measurement was less especially in patients with advanced dilated cardiomyopathy as well as in elderly patients. However, individual target threshold of BNP for risk reduction related to cardiac dilatation exerted a strong prognostic power even in such advanced cases. This target threshold-guided therapy would facilitate individual disease management and thus contribute to further improvement of treatment outcome.
