Discussion
The main findings of this study are that (1) Nt-proBNP ratio is strongly associated with all-cause mortality both in patients who underwent AVR, those with initial MT, and particularly in patients with combined non-severe AV lesions; (2) Nt-proBNP ratio provided significant incremental prognostic value beyond the traditional risk factors and clinical risk score to predict 1-year, 2-year and 5-year mortality; (3) Patients with Nt-proBNP ratio ≥3 are at high risk of early postoperative and long-term mortality. These findings suggest that Nt-proBNP ratio should be included as an additive clinical tool to enhance risk stratification in MAVD patients and that AVR in these patients may be reasonable before reaching a Nt-proBNP ratio ≥3.
MAVD patients’ integrative evaluation
Management of patients with MAVD (ie, combined AS and AR) remains challenging in terms of intervention timing and risk stratification.3 16 17 Recent studies showed poor postoperative outcomes with high occurrence of adverse events despite normal preoperative LV function.6 7 Current management of MAVD patients is mainly driven by the guideline’s recommendations of the predominant valve disease but remains controversial, especially in the presence of both moderate AS and AR.18 In addition to the severity of the valve impairment, the assessment of the valvular-related global repercussion is essential to accomplish with objective markers, such as natriuretic peptides. The concomitant presence of volume and pressure overload brings challenges in the assessment of cardiac remodelling, ventricular function, and thus identification of the optimal timing for intervention,19 as numerous MAVD patients develop symptoms and/or LV dysfunction before reaching intervention cut-offs for either isolated AR or AS.6 20 The presence of a concentric remodelling or hypertrophy with a relative wall thickness over 0.42, an elevated LV filing pressure, and a decreased global longitudinal strain have been associated with poorer prognosis, but needs to be further validated in prospective studies.21
Usefulness of the Nt-proBNP ratio in MAVD for risk stratification
BNP or Nt-proBNP were thoroughly validated in various isolated valvular heart diseases, either symptomatic or asymptomatic.12 14 22 23 Recently, Onishi et al demonstrated in a small MAVD population (ie, 81 patients) that BNP levels are independently associated with the endpoint of all-cause mortality, heart-failure hospitalisation and AVR.24 Nevertheless, as BNP or Nt-proBNP level increase with age and in women, and their elevation is lower in valvular heart diseases than heart failure, the use of the clinical activation ratio (ie, over the maximal expected value for age, sex and assay) has the advantage to take into account interpatient variability.25 In this study, median absolute Nt-proBNP value and its ratio were higher than what is observed in isolated AS or isolated AR, reflecting the presence of both volume and pressure overload.
In this study, continuous and dichotomised Nt-proBNP ratio independently and incrementally predicted survival. Increase in Nt-proBNP ratio demonstrated a dose–response relationship with an increase mortality in Nt-proBNP ratio ≥3 group superior than in Nt-proBNP ratio between 1 and 3 group. Moreover, patients with NT-proBNP≥3 have a substantial excess in mortality in all subsets. In the subset of patients who underwent AVR within 3 months, patients with preoperative Nt-proBNP ratio ≥3 had higher 30-day postoperative (4%) and long-term (43% at 4 years; ~2.5-fold increase) mortality. These patients may have irreversible preoperative subclinical LV dysfunction with myocardial fibrosis, which limits the potential improvement postoperatively. These results suggest that AVR in MAVD patients may be reasonable before reaching a Nt-proBNP ratio ≥3, even in combined non-severe lesions. Indeed, the latter had a ~1.9-fold increase in mortality with a strong trend after multivariable analysis when Nt-proBNP ratio was ≥3.
Finally, no sex-specific interaction in association between Nt-proBNP ratio and overall mortality has been found in this study. However, there is a clinical importance to normalise the absolute value for age, sex and each specific assay (ie, calculating the patient-specific Nt-proBNP ratio), as the absolute values increase with age and female sex.25
Clinical implications
Altogether, the data presented in the study demonstrate that a single Nt-proBNP ratio measurement in MAVD patients has considerable standalone and incremental value in determining prognosis, irrespectively of treatment strategy or AV lesions severity. Thus, Nt-proBNP ratio should be integrated in the clinical decision-making process of these patients. Nt-proBNP is a sensitive and powerful marker of myocardial stretch and early subclinical dysfunction both in isolated AR and AS,26 which amplify its importance in MAVD patients’ management. According to our results, AVR may be reasonable in patients with at least moderate AS or AR before Nt-proBNP ratio reach 3, especially if the concomitant lesion is also moderate. However, the benefits of early surgery based on Nt-proBNP ratio threshold of three in MAVD patients’ needs to be addressed in prospective studies.27
Our data undoubtedly shows that Nt-proBNP ratio could largely enhance risk stratification in MAVD patients, especially in patients with combined non-severe AS and AR. As a matter of fact, natriuretic peptides reflect mainly severity of heart failure and not severity of valvular diseases and can be influence by other factors such as presence of other valvular diseases and atrial fibrillation, per se.28 Nevertheless, AVR decision in these patients should be based not only on severity of valvular disease but on overall cardiac remodelling, including assessment of Nt-proBNP ratio, valve lesion and general patient’s health. In the era of cardiac damage staging classification, the conceptualisation of a scheme for MAVD patients which includes Nt-proBNP ratio comprised between 1 and 3 could further contribute to comprehensive risk stratification.29
Study limitations and strengths
Although the clinical, echocardiographic and outcome data were prospectively collected, the present analysis is of retrospective nature, and is thus subject to inherent limitations related to such design. However, this study includes a ‘real-life’ population, in which the patients were monitored in the context of heart valve clinics. Therapeutic decisions were left to the discretion of the patient’s treating physician, which referred patients according to its overall clinical presentation based of symptoms, signs and balance of risk/benefit of AVR. Our group who initially remained on MT is relatively small, and thus results have limited statistical power. The exact reasons for which these patients were treated medically are lacking. Nevertheless, more than 30% of patients in this subset died in early follow-up, and continuous Nt-proBNP ratio and ≥3 presented a strong trend towards being associated with all-cause mortality. One potential criticism could be that this cohort does not include high prevalence of severe AR. However, management of MAVD patients is mainly challenging in patients with non-severe AR/AS, and we demonstrated that Nt-proBNP was also independently associated with mortality in this subset. Reference Nt-proBNP values can differ between laboratories, but as they were dosed according to the Canadian reference laboratories guidelines, values remain highly accurate. We did not assess changes in Nt-proBNP ratio before and after AVR nor serial values in MT patients to test the potential additional prognostic value in risk assessment, but further studies should investigate these points.