Limitations of Natriuretic Peptide Guided Heart Failure Therapy
The question arises as to why natriuretic peptide-guided therapy in chronic HF – at least for HFrEF – is not yet recommended in the European guidelines2 despite the uniformly positive meta-analyses.3–7 It needs to be mentioned that the American guidelines interpret the results on natriuretic peptide-guided therapy rather differently.41 Thus, these guidelines encourage the use of BNP or NT-proBNP to achieve optimal dosing of guideline-directed medical therapy in clinically euvolaemic patients (class IIa recommendation).41 However, these guidelines also state that the usefulness of serial measurements of BNP or NT-proBNP to reduce hospitalisation or mortality in patients with HF is less well-established (class IIb recommendation).41 These two statements are contradictory and not easy to interpret for implementation into clinical practice. They are an expression of controversial opinions on this topic, as reflected in the lack of recommendations in the European guidelines.
Potentially there are several reasons for this. First, treatment response in the individual trials was not uniform; natriuretic peptideguided therapy resulted in a significant improvement of the primary endpoint in some, but not all studies (Table 1). This is partly related to the fact that different endpoints were used. For example, in TIMECHF, all-cause hospitalisation-free survival was the primary endpoint, which was not reduced and TIME-CHF – the largest natriuretic peptide-guided therapy study so far – is therefore considered as a negative study. However, if HF hospitalisation-free survival had been chosen as primary endpoint, as is often the case in HF trials, TIMECHF would have been a positive trial (HR=0.68, P=0.01).20 Second, the evidence is mainly based on relatively small trials; the largest included 499 HFrEF patients, which was formally negative as outlined above.20 Additionally, follow-up time varied significantly and was relatively short in some of the trials (Table 1). Third, natriuretic peptide-guided therapy trials did not investigate single-drug interventions (i.e. drug A versus placebo or drug B), but rather complex changes in the treatment, often left to the discretion of the treating physicians. Moreover, recommendations to react on persistently elevated natriuretic peptide levels differed considerably between trials as did the target values of natriuretic peptide levels (Table 1). Therefore, it is difficult to determine which aspects of natriuretic peptide-guided therapy gave the greatest contribution to improved outcome. It is not even entirely certain which trials have to be included in the meta-analyses; still, the results did not differ between them although they did not include exactly the same studies. In Figure 1, it is also obvious that the positive effect of natriuretic peptide-guided therapy is not based on one or two trials. This fact is also supported by sensitivity analysis of one of the meta-analyses.4 Importantly, trials that achieved greater intensification of drugs that showed beneficial effects on outcome in large treatment trials (i.e. ACE-inhibitors, ARBs, MRAs, beta-blockers), but not primarily intensified diuretic therapy, tended to have more positive effects on outcome than trials where mainly diuretic therapy was intensified or therapy was simply maintained (Tables 1 and 2).
Fourth, an often-heard argument against natriuretic peptide-guided therapy is the fact that natriuretic peptide levels were simply used to further optimise guideline-recommended therapy. Thus, applying guidelines correctly may be sufficient, without knowing natriuretic peptide levels. The results of the NorthStar study support this view.33 However, in the majority of patients, in daily practice treatment is far from being in accordance to the guidelines. In particular, optimal doses as recommended are often not achieved,35 but optimal doses are important to improve outcome.42 As stated in an editorial to the IPD meta-analysis,43 “use of disease-modifying therapy was much better than in typical practice”. This referred to the baseline use of medication in the natriuretic peptide-guided trials. Therefore, despite being better than in “real-world” practice even at baseline, knowing natriuretic peptide levels resulted in more aggressive up-titration and optimisation of therapy in chronic HF, thereby achieving better outcome. Simply applying guidelines to optimise therapy is more wishful thinking than clinical reality and additional means may help to achieve this goal. Disease management programmes may be helpful in this although results are not heterogeneous given the large differences between the various programmes.44 Repeatedly measuring natriuretic peptide levels is a simple means to optimise medical therapy in chronic HF and trials available so far suggest that such an approach is beneficial, even when directly comparing with disease management intervention.21
Finally, it is claimed that cost-effectiveness has not yet been proven for this approach. There are cost-effectiveness analyses of two of the trials of 777 patients and both concluded that NT-proBNP-guided therapy is highly cost-effective or even dominant (i.e. cost-saving and more efficient) as compared with standard care.45,46 Importantly, the additional measurements of NT-proBNP contributed to only a small fraction of the total costs, which were more than outweighed by reduction in HF-related hospitalisations.45 However, given the heterogeneity between the trials, interventions and populations, it remains to be determined as to whether cost-effectiveness is present for natriuretic peptide-guided therapy in general.
Taken together, there are important arguments in favour of the use of BNP or NT-proBNP levels for optimising the therapy in chronic HFrEF, at least in patients with few co-morbidities. This notion is also supported by most of the meta-analyses and/or systematic reviews,3–7,47 other than those which concluded that the evidence is of low quality.8 Despite these positive signals, major uncertainty remains to be resolved before a natriuretic peptide-guided treatment approach can be recommended as standard. A sufficiently large trial is required to address the remaining questions and, as a result, the US National Heart Lung Blood Institute has funded the GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment (GUIDE-IT) study (NCT01685840, clinicaltrials.gov). GUIDE-IT is a prospective, multicentre, randomised trial of 1,100 patients with HFrEF at the time of discharge from an HF hospitalisation to either reduce NT-proBNP levels below 1,000 pg/ml or usual care.48 Enrolment began in January 2013 at more than 40 sites in the USA and Canada. In association with the data already reviewed above, GUIDE-IT should be adequately powered to provide more definitive answers about safety and efficacy of natriuretic peptide-guided therapy in chronic HF.