Letter by Ballo et al Regarding Article, “Serial Biomarker Measurements in Ambulatory Patients With Chronic Heart Failure: The Importance of Change Over Time”
To the Editor:
We greatly appreciated the article by Miller et al.1 In contrast to several studies showing a major role of brain natriuretic peptide (BNP) as a predictor of adverse prognosis in heart failure,2,3 the study by Miller et al reported that elevated BNP at baseline was not significantly associated with outcome (primary end point: death/cardiac transplantation) in a cohort of 190 patients with New York Heart Association class III-IV heart failure who were followed up for 24 months, after adjustment for troponin T levels, New York Heart Association class, biventricular pacing, and history of myocardial infarction (hazard ratio 1.53, P=0.15). Notably, an association between elevated BNP and outcome was evident in univariate analysis and in unadjusted models that were based on simple interaction of troponin T and BNP values or in those accounting for temporal changes in BNP levels.
An unexpected finding in their study1 is that biventricular pacing was identified as a powerful predictor of the primary end point (hazard ratio 2.79, P=0.011). Although this may reflect a particularly advanced degree of heart failure in subjects who had previously undergone biventricular pacemaker implantation, a beneficial effect of cardiac resynchronization therapy could reasonably be expected to emerge in multivariate models after adjusting for markers of heart failure severity. Surprisingly, the association between biventricular pacing and the risk of death or transplantation was maintained and further strengthened in multivariate analysis (hazard ratio 3.42, P=0.003).
Considering the large amount of evidence supporting the beneficial independent prognostic impact of cardiac resynchronization in heart failure,4 the finding that biventricular pacing but not baseline BNP independently predicted adverse outcomes in the study by Miller et al1 is difficult to interpret. One possibility is that multivariate analysis results may have been affected by a collinearity problem. Collinearity results from over-adjustment due to strong associations between independent variables and is characterized by inappropriate signs and/or magnitudes of regression coefficient estimates. Biventricular pacing is known to yield considerable reduction in BNP levels and improvement in New York Heart Association class in most patients.5 Because of these close inverse associations, simultaneous insertion of these variables into multivariate models may significantly increase the risk of over-adjustment.
Under this hypothesis, the possibility that the independent prognostic role of baseline BNP levels in the study population may have been more evident than what was suggested by the model proposed by the authors should be taken into account. If so, the intriguing message of the study, ie, the usefulness of combined assessment of troponin T and BNP in heart failure patients both at baseline and over time, would be further strengthened.
Miller WL, Hartman KA, Burritt MF, Grill DE, Rodeheffer RJ, Burnett JC Jr, Jaffe AS. Serial biomarker measurements in ambulatory patients with chronic heart failure: the importance of change over time. Circulation. 2007; 116: 249–257.
Berger R, Huelsman M, Strecker K, Bojic A, Moser P, Stanek B, Pacher R. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation. 2002; 105: 2392–2397.
Tsutamoto T, Wada A, Maeda K, Hisanaga T, Maeda Y, Fukai D, Ohnishi M, Sugimoto Y, Kinoshita M. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation. 1997; 96: 509–516.
Rao RK, Kumar UN, Schafer J, Viloria E, De Lurgio D, Foster E. Reduced ventricular volumes and improved systolic function with cardiac resynchronization therapy: a randomized trial comparing simultaneous biventricular pacing, sequential biventricular pacing, and left ventricular pacing. Circulation. 2007; 115: 2136–2144.