In this issue: Cardiac Markers. The World is Changing – Are We Ready? Can natriuretic peptides be used to guide therapy? Antoni Bayes-Genis1,2, Josep Lupón1,2, Allan S. Jaffe3 1 Heart Failure Clinic, Cardiology Service, Hospital Universitari Germans Trias i Pujol, Badalona (Barcelona), Spain 2 Department of Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain 3 Department of Medicine, Mayo Clinic and Foundation, Rochester, MN, USA ARTICLE INFO ABSTRACT Corresponding author: Over the last 15 years, the hypothesis that intensified Antoni Bayes-Genis, M.D., PhD treatment directed at reducing natriuretic peptide Chief of the Cardiology Service Department of Medicine, UAB (NP) concentrations may improve the outcomes of Hospital Universitari Germans Trias i Pujol patients with heart failure (HF) has been scrutinized Carretera del Canyet s/n 08916 in several prospective clinical trials, with conflicting Badalona, Spain Phone: +34 934978915 results. Collectively, however, the data suggest that Fax: +34 934978939 NP concentrations may be useful in guiding HF man- E-mail: abayesgenis@gmail.com agement and improving HF-related morbidity and Key words: mortality. In this review, we summarize the existing natriuretic peptides, guided-therapy, data investigating the use of NPs as targets for outpa- BNP, NT-proBNP tient HF therapy. We focus on the information gath- ered in randomized clinical trials and comprehensive meta-analyses, and also on the recommendations of international guidelines (primarily guidelines from the European Society of Cardiology and the American College of Cardiology/American Heart Association). Although the results for this approach are promis- ing overall, additional well-designed prospective randomized controlled trials (e.g., the GUIDE-IT trial) are necessary to confirm or refute the utility of NP- guided outpatient HF management. Page 208 eJIFCC2016Vol27No3pp208-216 Antoni Bayes-Genis, Josep Lupón, Allan S. Jaffe Can natriuretic peptides be used to guide therapy? CAN NATRIURETIC PEPTIDES for using cardiac peptides in the management VALUES BE USED TO GUIDE of HF patients may be considered. HEART FAILURE THERAPY? The first approach consists of targeting phar- Clinicians have been asking this question for 15 macologic therapy to prespecified NP concen- years now, and the answer is still unclear. Richard trations to optimize the effects of drugs. This Troughton and Mark Richards published a semi- approach has received much interest and has nal paper in The Lancet in 2000, in which they been tested in several prospective random- launched the hypothesis of guiding heart failure ized trials that yielded conflicting results. Some (HF) treatment with objective measurement of studies demonstrated mortality or morbidity natriuretic peptides (NPs). This prospective pi- benefits from NP-guided therapy: Troughton, lot study was conducted in Christchurch, New STARS-BNP, Berger, PROTECT (1,3-5); others re- Zealand and included 69 patients with a history ported benefits only in younger patients: TIME- of decompensated HF and systolic dysfunction. CHF, BATTLESCARRED (6,7); or only in responder The participants were randomized to manage- patients: UPSTEP (8); and other studies showed ment by a standardized clinical algorithm or to no advantages for NP-guided compared to clini- clinical management with NP-guided drug upti- cally guided therapy: Beck-da-Silva, SIGNAL-HF, tration (1). The goal in the NP-guided arm was PRIMA, Anguita, STARBRITE (9-13). to drive plasma concentrations of NTproBNP The second strategy, reported in the recent to <200 pmol/L (approximately 1700 pg/mL). NorthStar trial (2), assessed whether high‑risk During 9 months of follow-up, patients who but stable chronic HF patients, identified as received NP-guided treatment had signifi- those with NTproBNP levels >1000 pg/mL, would cantly fewer deaths or hospitalizations for HF. benefit from prolonged specialized HF clinical as- This study recruited relatively young patients sistance (pre‑PARADIGM clinical treatment) com- with reduced left ventricular ejection fraction pared to referral back to general practitioners. (LVEF); however, due to patient enrollment in The results demonstrated no differences in the the late 1990s, very few of the patients were composite score for mortality and hospitalization on beta blockers or mineralocorticoid receptor for cardiac causes, suggesting that baseline NP antagonists (MRAs). This initial study has pro- had limited value in the selection of out‑of‑hos- vided the nucleus for a multitude of prospec- pital management strategy in HF patients. tive studies launched in the forthcoming years. The problems with these trials are multiple Nevertheless, as of 2015, the results from the but in many ways understandable as clinicians clinical trials published to date are in most cas- struggle to find the right metrics to use to guide es conflicting, in part due to disparities in their therapy. Although some trials have had targets design. Thus, the multiple meta-analyses that for titration of the natriuretic peptides, in many have been performed to clarify the situation instances, these goals have not been achieved have been less definitive. in a majority of the patients. If only 30% of the cohort reaches the goal suggested, one might WHAT DO THE CLINICAL TRIALS SAY? ask “has the hypothesis really been tested?” In Because NPs are reflective of hemodynamic addition, should the goals of therapy be a fixed state and disease severity in HF, their role in level of natriuretic peptide regardless of the therapeutic guidance has been investigated in starting point or should it be some percentage several clinical trials. Three potential strategies change in the baseline value or is there a need Page 209 eJIFCC2016Vol27No3pp208-216 Antoni Bayes-Genis, Josep Lupón, Allan S. Jaffe Can natriuretic peptides be used to guide therapy? for both types of criteria. This is of particular im- candidate to switch to LCZ696 in order to im- portance because of the marked biological vari- prove symptoms, reduce mortality (both sud- ation of natriuretic peptides (14). In some stud- den and pump failure death), and reduce HF- ies, very large changes are necessary to be sure hospitalizations (Figure 1). This is not strictly that the changes observed are due to treatment NP guided therapy, as it was firstly hypoth- and not conjoint biological and clinical variabil- esized by Troughton and Richards, but rather ity (15). Finally, the types of patients included using NPs to prescribe a new treatment option may make a huge difference. Those with heart which has shown a dramatic beneficial effect failure with preserved ejection fractions (HFPEF) compared with conventional treatment. This tend to have different natriuretic peptide levels new strategy is supported by the data from than those with heart failure with reduced ejec- the PARADIGM Trial, the first trial in incorpo- tion fractions (HFREF). Those with valvular heart rating an objective measure of severity using disease may or may not be similar to either of NPs into the inclusion criteria (17). those groups. A third strategy may emerge with availability WHAT DO THE META-ANALYSES SAY? of LCZ696 in the market (post-PARADIGM clini- To overcome the uncertainty produced by the cal treatment). Although the mechanisms in- conflicting results of single studies of the first volved are complex, it appears that BNP levels strategy described above, three meta-analyses are increased by LCZ696. On the other hand, investigated the utility of NP-guided therapy in NTproBNP values are reduced although we do patients with chronic HF (18-20). These meta- not know if they are reduced commensurate analyses comprised data from six, eight, or 12 with the levels that would be necessary to randomized clinical trials. make outcomes with agents that do not include Neprilysin inhibition. Thus, it could be that In the meta-analysis by Felker et al. (18), only NTproBNP will become the preferred peptide six studies were collected, which reported on biomarker for therapy guidance (16). 1,627 patients. Although a significant benefit for all-cause mortality in patients assigned to In addition, given its markedly improved ef- NP-guided therapy was reported, the analysis ficacy, it may be that natriuretic peptides el- was limited by the inclusion of three still unpub- evations will help to identify those who may lished studies, which prevented detailed collec- benefit from Neprilysin inhibition. An analogy tion of patient population characteristics. between acute coronary syndrome (ACS) and chronic HF relative to the use of biomarkers The meta-analysis by Porapakkham et al. (19) and their impact on therapy is clear. In ACS, included 1,726 patients in eight studies. In this the presence of chest pain, ST segment ups analysis, the favorable effect on all-cause mor- and downs in the ECG and cardiac troponin tality in patients assigned to NP-guided therapy rise and fall is indicative of a high-risk patient was mostly driven by the TIME-CHF trial (6) in that requires urgent-preferred catheterization the sensitivity analysis section of the meta- to open the culprit artery in order to relief analysis. The statistical significance of the effect symptoms and improve prognosis. In chronic was lost when the TIME-CHF trial, but not any HF, the presence of dyspnea, a reduced ejec- other trial included in the meta-analysis, was tion fraction in the echocardiogram and a removed from the analysis. Notably, no differ- very high level of circulating natriuretic pep- ence was observed for all-cause or HF-related tides may identify a high-risk patient who is a hospitalization. Page 210 eJIFCC2016Vol27No3pp208-216 Antoni Bayes-Genis, Josep Lupón, Allan S. Jaffe Can natriuretic peptides be used to guide therapy? Figure 1 Scheme of the analogy between ACS and chronic HF (with the advent of LCZ696), and the value of biomarkers to guide decisions* ACS CHRONIC HF Chest pain Dyspnea ST ups and downs LVEF <35% Rise-fall troponin High NTproBNP Cath Lab to open culprit artery Switch to LCZ696 HOSPITAL AMBULATORY SETTING SETTING * Created by Carolina Gálvez-Montón Page 211 eJIFCC2016Vol27No3pp208-216 Antoni Bayes-Genis, Josep Lupón, Allan S. Jaffe Can natriuretic peptides be used to guide therapy? The most recent and largest meta-analysis by of caution is necessary here, since no single trial Savarese et al. (20) included 2,686 patients includ- has been designed specifically to compare head- ed in 12 studies (Figures 2,3). This meta-analysis to-head BNP- vs. NTproBNP-guided therapy. for the first time reports a benefit for HF-related Meta-analysis data did not find a significant hospitalization; moreover, the mortality benefit benefit for elderly patients when, elderly sub- observed was more consistent and not influenced in the sensitivity analysis by any single study or groups from three trials were analyzed: TIME- by any potential confounders. This meta-analysis CHF, BATTLESCARRED, and UPSTEP Trials (6-8). It was the only one to investigate separately the ef- is conceivable that the more frequent presence fects of BNP- and NTproBNP-guided therapy, sug- of comorbidities may prevent or even promote gesting that NTproBNP- but not BNP-guided ther- potentially harmful up titration of HF drugs in el- apy was significantly associated with improved derly patients; however, this speculation requires survival as well reduced hospitalization. A word further confirmation. Figure 2 Odds ratios of all-cause mortality* * Taken from (20). Page 212 eJIFCC2016Vol27No3pp208-216 Antoni Bayes-Genis, Josep Lupón, Allan S. Jaffe Can natriuretic peptides be used to guide therapy? Figure 3 Odds ratios of heart failure–related hospitalization* * Taken from (20). WHAT DO THE GUIDELINES SAY? NP-guided treatment (intensifying treatment in order to lower peptide levels) have given The dense and comprehensive guidelines on HF conflicting results. It is uncertain whether from both the European Society of Cardiology outcome is better using this approach than (ESC) (65 pages) (21) and the American College by simply optimizing treatment (combina- of Cardiology/American Heart Association (ACC/ tions and doses of drugs, devices) according AHA) (92 pages)(22) devote just a few lines to to guidelines” (21). No indications on Class the issue of NP-guided therapy. of Recommendation or Level of Evidence are The ESC guidelines for the diagnosis and treat- provided in the ESC guidelines. ment of HF published in 2012 state that “High The 2013 ACC/AHA guidelines for the manage- NP concentrations are associated with a poor ment of HF state that NP-guided HF therapy prognosis, and a fall in peptide levels corre- can be useful in achieving optimal dosing of lates with a better prognosis. However, sev- guideline-directed medical treatment in select eral randomized clinical trials that evaluated clinically euvolemic patients who are followed Page 213 eJIFCC2016Vol27No3pp208-216 Antoni Bayes-Genis, Josep Lupón, Allan S. Jaffe Can natriuretic peptides be used to guide therapy? in a well-structured HF disease management in Heart Failure) study is designed to definitively program with a Class of Recommendation IIa assess the effects of an NP-guided strategy in high- and a Level of Evidence B (22). This statement risk patients with systolic HF on clinically relevant is followed by the explanatory text: “NP levels endpoints of mortality, hospitalization, quality improve with treatment of chronic HF, with of life, and medical resource use. GUIDE-IT is a lowering of levels over time in general, corre- prospective, randomized, controlled, unblinded, lating with improved clinical outcomes. Thus, multicenter clinical trial designed to randomize NP “guided” therapy has been studied against approximately 1,100 high-risk subjects with sys- standard care without NP measurement to de- tolic HF (LVEF ≤ 40%) to either usual care (op- termine whether guided therapy renders supe- timized guideline-recommended therapy) or a rior achievement of guideline-directed medical strategy of adjusting therapy with the goal of treatment in patients with HF. However, ran- achieving and maintaining a target NT-proBNP domized clinical trials have yielded inconsistent level of <1,000 pg/ml (23). The estimated study results. The positive and negative NP-guided completion date is December 2017. therapy trials differ primarily in their study In addition to revisiting the strategy in the event populations, with successful trials enrolling of new effective drugs, such as the groundbreak- younger patients and only those with HFrEF. ing LCZ696 (17), which has been approved for In addition, a lower NP goal and/or a sub- use in the United States, further studies should stantial reduction in NPs during treatment are examine the potential utility of other markers, consistently present in the positive “guided” such as ST2, either alone or in combination therapy trials. Although most trials examining with NPs (24). ST2 manifests much less variabil- the strategy of biomarker “guided” HF man- ity than do natriuretic peptides which may be agement were small and underpowered, two ideal for following changes with treatment (25). comprehensive meta-analyses concluded that However, the targets that need to be achieved NP‑guided therapy reduces all-cause mortality are still unclear. in patients with chronic HF compared with usu- al clinical care, especially in patients <75 years Despite the uncertainties, the consistently strong of age. This survival benefit may be attributed and independent relationship of NPs with prog- to increased achievement of guideline-directed nosis should encourage physicians to measure medical treatment. In some cases, NP levels NPs early after diagnosis and periodically there- may not be easily modifiable. If the NP value after for risk stratification. This will allow appro- does not fall after aggressive HF care, risk for priate surveillance and fully informed counsel- death or hospitalization for HF is significant” ling of both patients and their families. (22). In sum, both guidelines solicit additional information. CONCLUSIONS In spite of the fact that the trials conducted to WHAT IS THE FUTURE? date have had different designs and pursued Where to next for the biomarker-guided man- different NP targets in varied populations of agement of HF? There is no doubt that further patients with HF, the use of NPs to guide phar- trials are required to provide conclusive evi- macologic therapy in patients with chronic HF dence. Such a confirmation study is currently un- seems to be associated with a reductions in mor- der way: the GUIDE-IT (Guiding Evidence Based tality and HF-related hospitalization, especially Therapy Using Biomarker Intensified Treatment in younger patients (<75 years) with reduced Page 214 eJIFCC2016Vol27No3pp208-216 Antoni Bayes-Genis, Josep Lupón, Allan S. Jaffe Can natriuretic peptides be used to guide therapy? LVEF. There remains a need for definitive trials clinical assessment for beta-blocker titration in patients with heart failure. Congest Heart Fail 2005;11:248–53. with sufficient power to confirm the efficacy of this strategy (e.g., GUIDE-IT), yet the existing evi- 10. Persson H, Erntell H, Eriksson B, Johansson G, Swed- berg K, et al. 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