Is tricuspid regurgitation a prognostic interventional target or is it just an indicator of worst prognosis in heart failure patients?

This editorial refers to ‘Tricuspid regurgitation is associated with increased mortality independent of pulmonary pressures and right heart failure: a systematic review and meta-analysis'†, by N. Wang et al., on page 476. In the current issue of the European Heart Journal, Wang et al. report an interesting meta-analysis conducted on 70 studies, showing that moderate and severe tricuspid regurgitation (TR) is associated with increased cardiac and all-cause mortality, independently from pulmonary artery pressure, left ventricular (LV), and right ventricular (RV) function.1 Although there is a huge heterogeneity among the studies and patients included in the meta-analysis (isolated and not isolated TR, patients after left-side valve surgery or intervention, patients after heart transplant, patients receiving tricuspid surgery, patients after pacemaker, patients with different aetiologies of pulmonary hypertension and/or cardiomyopathy, etc.) and both primary and functional TR are included (mostly functional), the findings observed by the authors confirm on a really large scale (>32 500 patients!!!) a clinical observation which is already well consolidated: the presence of relevant TR is ‘per se’ associated with excess mortality in different clinical settings.2–7 Not only is severe TR associated with higher risk of morbidity and mortality, but there is an increasing risk of mortality associated with the progression of the severity of TR, showing that even moderate TR is associated with worst outcomes compared with mild TR.3 , 6 Another important point that emerges from the study of Wang et al. is that precise quantification of TR severity is often an issue (partially due to the dynamicity of TR which is highly dependent on the loading condition of the patient). Although it has been demonstrated that quantitative assessment of TR [particularly effective regurgitant orifice (ERO) measurement] is a powerful independent predictor of outcome, superior to standard qualitative assessment,5 quantitative assessment of TR severity has been performed only in one of the studies included in the meta-analysis, suggesting a huge lack of standardization in the tricuspid field. While primary TR is a really rare condition in western countries, the clinical and economic burden of functional TR (FTR) is extremely relevant.2 Whether any tricuspid valve intervention on top of medical therapy is associated with an adjunctive prognostic benefit has never been demonstrated, and it is still the subject of debate. From a pathophysiological standpoint, correction of TR is beneficial for the patient. Independently from the aetiological ‘trigger’ (primary or secondary pulmonary hypertension with RV dilatation, chronic atrial fibrillation with right atrial and tricuspid annulus enlargement, etc.), the onset of TR generates a process which is self-maintaining and maladaptive on two ‘parallel’ levels (Figure 1). (i) On an anatomical level, severe TR promotes RV enlargement, which generates more tricuspid annular dilatation and valve tethering, which results in more TR. (ii) On a functional/hormonal level, TR causes fluid retention and visceral congestion, with reduction of renal function and chronic neuro-hormonal activation. Summary of the pathophysiology of tricuspid regurgitation, which underlines the progression of the disease. Tricupsid regurgitation is a pathogenetic moment in the onset and progression of the disease and therefore should be treated. While medical therapy can intervene mainly on the functional/hormonal level, the anatomical level can be corrected only by a structural intervention. Only the synergy of medical therapy and intervention on both levels can be associated with a real improvement of the natural history of the disease. Surgical correction of TR has for many years been the only available intervention. While there is a universal consensus that concomitant severe TR should be fixed at the time of left-side valve surgery (Class I level C), much less evidence is available in the context of isolated FTR, where the surgical correction of FTR should be considered only in the presence of symptoms or progressive RV dilatation or dysfunction (Class IIa level C).8 In this context, an improvement of survival has never been shown, as a consequence of the lack of properly designed trials. There are two main reasons why this evidence has never been provided. (i) Surgical mortality for isolated TR is extremely high, being stable at ∼8–9% despite the improvements in peri-operative care over the last decade.9 The consequence is that cardiologists are reluctant to refer these patients for surgery unless they are really symptomatic (usually too late), and surgeons are therefore often reluctant to operate on them. (ii) Patients with severe FTR remain asymptomatic for many years, due to the high efficacy of medical therapy; therefore, they are reluctant to undergo any surgical treatment, which carries such a high mortality rate, until they become highly symptomatic (usually concomitant with development of RV dysfunction). Taking these two biases into consideration, it is easy to understand why it has not been feasible to design a randomized trial to demonstrate whether tricuspid surgery has a prognostic effect. The recent introduction of transcatheter tricuspid valve intervention (TTVI) gives us the unique opportunity to have a less invasive and safer option to address TR,10 which can be used as a comparator as an adjunct to medical therapy over medical therapy alone, in order to investigate any prognostic effect of TR reduction. The International TriValve registry showed the high safety profile of TTVI even in very high-risk patients.10 The high safety is fundamental in considering a tricuspid intervention in the early stage of the disease, when the patient is still asymptomatic or oligosymptomatic, before the onset of severe RV failure, when the value of TR correction could be questionable. As a matter of fact, early timing is essential with any kind of intervention, if a prognostic effect on survival is what is aimed for. The recent COAPT and MITRA-FR trials clearly showed that the prognostic benefit of MitraClip is observed in heart failure patients only if the intervention is not performed too late in the course of the disease, and in synergy with optimal medical therapy.12 , 13 Similarly, also in isolated FTR, an early indication and should be carried out. On the other hand, before designing a proper trial, a better efficacy profile of TTVI would be required. The effectiveness of the current TTVI technologies in reducing TR is still suboptimal, with many patients remaining with residual TR that is still relevant after the procedure.11 Although a clinical improvement has been observed even with modest TR reduction (most probably due to an increase in left stroke volume),14 better devices and better patient selection are advocated for the near future, since more TR reduction seems to be associated with improved outcomes.15 Last, but not least, the design of a ‘Tricuspid COAPT-like’ trial poses a number of specific challenges, which have to be addressed. (i) Definition of the outcomes: how to define procedural, technical, and patient success in the tricuspid field. What are the most appropriate primary and secondary endpoints [all-cause mortality, re-hospitalization, TR reduction, functional or symptomatic improvement (is 6MWT enough?), quality of life changes (how to measure it?), pro-BNP changes, composite endpoint]? (ii) How to quantify TR severity, eventually adding a definition for ‘more than severe TR’, as proposed by Hahn et al.16 (iii) How to quantify TR reduction. (iv) What is the optimal trial design and which are the best comparator groups? In this regard, the need for a standardization of the definition through a dedicated multidisciplinary Tricuspid-VARC (TVARC) will soon become compelling. To conclude, the presence of significant TR is independently associated with increased morbidity and mortality, and consequently increased costs for the health system. Since TR represents a central pathophysiological element in the self-maintenance of the maladaptive process, which is responsible for the progressive worsening of the disease acting on two levels (anatomical and functional), only the synergy of interventional and medical treatments acting on both levels could aim for a prognostic effect on survival. In this regard, the timing of intervention is crucial, before the progression to irreversible RV failure. These observations have to be sustained by solid evidence that has to be provided by properly designed trials in the near future. Conflict of interest: none declared.