BNP-guided therapy for chronic heart failure: anything more than just an attractive concept?

The measurement of plasma natriuretic peptides (NPs) is well established in the diagnostic work-up of patients with suspected heart failure (HF), and is known to be a powerful prognostic tool, but the evidence that serial measurement can help improve the outcome of patients with HF hasbeen elusive. Asyet, no international guideline supports such use. The theoretical appeal of such an approach is clear. Other chronic conditions are monitored, and treatment adjusted, according to biomarkers: thyroid disease and diabetes mellitus are obvious examples. The plasma concentration of NPs (including BNP and NT-proBNP) falls with better control of the HF syndrome: this is seen with the ‘decongestion’ produced by diuretics, but also with increased chronic dosing with angiotensin-converting enzyme (ACE) inhibitors, betablockers, and aldosterone-blockers. The attraction of having a simple, single numerical target to guide management is clear, particularly when underdosing of lifesaving medication for HF is a wellrecognized problem (Figure 1). Pilot and early studies were promising, suggesting benefit in terms of mortality and HF hospitalization, albeit in small numbers of patients and with short-term follow-up. Larger randomized trials have now been published, with the largest being TIME-CHF, with 500 patients with systolic HF followed for 18 months. This reported a 24% reduction in all-cause mortality and a 30% reduction in HF hospitalization, but neither of these effects reached statistical significance. Pre-specified subgroup analysis suggested that the benefit of an NP-guided strategy was confined to younger patients (aged , 75 years). Several aggregate data meta-analyses have been published, suggesting that an NP-guided treatment strategy might be associated with a 20–30% reduction in all-cause mortality, –11 but these have not persuaded guideline committees or reimbursement authorities. Troughton and colleagues are to be congratulated on performing an individual patient data (IPD) meta-analysis, including 9 of the 11 published randomized trials in this area, with 1081 patients randomized to BNP-guided therapy and 1070 to usual clinical care at the recruiting centres. The IPD allows a standardized approach to the clinical endpoints, and an explorationof potential effect modifiers across the studies. Two further studies have provided aggregate data. The vast majority of patients in the trials had reduced systolic function (only 9% had an ejection fraction .45%), 67% were male, and the average age was 72 years. Use of disease-modifying therapy was much better than in typical practice, with 90% on an ACE inhibitor or angiotensin receptor blocker (ARB) at baseline, 76% on a betablocker, and 29% on an aldosterone antagonist. About half of the studies followed patients for at least 12 months, and most had a single target BNP or NT-proBNP plasma concentration. The IPD meta-analysis suggests that there is consistent evidence of a reduction in all-cause mortality in the younger subgroup (those aged ,75 years) randomized to NP-guided therapy [hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.45–0.85, P 1⁄4 0.004], but no effect on all-cause mortality in those aged ≥75 years (HR 0.98, 95% CI 0.75–1.3, P 1⁄4 0.96). In addition, there appeared to be a consistent reduction in HF hospitalization across both age groups with an HR of 0.80 (95% CI 0.67–0.94, P 1⁄4 0.009). The effect on cardiovascular hospitalization was similar but only just reached statistical significance (HR 0.82, 95% CI 0.67–0.99, P 1⁄4 0.048), and there was no difference in total hospitalizations (HR 0.94, 95% CI 0.84–1.07, P 1⁄4 0.38). The meta-analysis raises many questions. How might using serial measurement of plasma NP concentration improve survival for younger patients with chronic HF, but not in older patients? Does providing the physician (and perhaps the patient) with a single numerical target merely improve physician and patient adherence to guideline-recommended therapy? And, ultimately, could other less costly strategies, such as education, decision support software, or pay for performance measures, have the same effect? Troughton and colleagues explore some of these issues. Although baseline therapy was better than found in usual practice, as is often the case in randomized trials, it improved further during the trials. Overall, the dosing of ACE inhibitors (or ARBs) improved