To the best of our knowledge, our study is the largest to evaluate the association of PVR objectively assessed by videodensitometry with survival after TAVI and the first to specifically address the prognostic relevance of intermediate VD-AR suggestive of mild PVR. Our main findings are as follows: (1) VD-AR > 17% is a significant, independent predictor of long-term mortality, with an approximately 50% increase in 3-year mortality compared to VD-AR < 6%, indicating trivial or no PVR. (2) Compared to VD-AR < 6%, VD-AR in the mid-range of 6–17% was not significantly associated with survival in either crude or adjusted analyses.
Grades of PVR assessed by conventional visual evaluation of aortic root angiograms or by transthoracic echocardiography were also predictive of 3-year mortality. However, grades of PVR assessed by conventional angiography or echocardiography matched the strata of VD-AR in only about half of the cohort. Compared with VD-AR, conventional grading was more likely to result in a lower category of PVR than in a higher category. Comparison of the associations of mortality with the PVR grades obtained from different methods suggests that, with current definitions, the range of PVR covered by the conventional grade “mild” includes PVRs that are prognostically irrelevant as well as those with an impact on survival. Conversely, the conventional grade of “moderate” appears to refer only to those PVRs within the range of prognostically relevant PVRs that carry a very high (echocardiography) or even extreme risk (angiography). Apart from different thresholds, the subjective nature of conventional grading with a potential bias towards lower grades, as well as the notorious inter-observer variability, would have contributed to the discrepancy between VD-AR and conventional grading of PVR [
10,
14,
20].
In addition to conventional angiography and echocardiography, haemodynamic assessment, such as aortic regurgitation index (ARI) [
22], may be considered in relation to VD-AR. However, in our TAVI cohort neither ARI nor ARI ratio was predictive of mortality [
18] and the same was true for the current subset (data not shown).
Comparison with previous studies
The present study validates previous findings on the prognostic relevance of VD-AR > 17%. [
4,
23,
24]. Previously, 228 patients from the Brazilian TAVI Registry (Interaction of de novo) were assessed for PVR by videodensitometry and followed for up to 3 years with a median of 521 days. Of these, 73 (32%) patients had a VD-AR > 17%. The estimated 3-year mortality was 45.5% in patients with VD-AR > 17% compared to 37.7% (log rank
P = 0.036), corresponding to an adjusted HR of 1.73 (95% CI 1.05–2.86;
P = 0.032). However, 3-year survival estimates were imprecise due to the small number of patients with follow-up beyond 18 months. With nearly complete 3-year follow-up and three times the number of patients, the current study provides more robust data. It validates the previous findings with similar survival rates and similar HRs for patients with a VD-AR > 17%. As an important new aspect, the present study addresses the role of VD-AR in the mid-range, which is considered to correspond to mild PVR by conventional angiographic or echocardiographic assessment. It refutes an association of intermediate VD-AR with increased mortality and thus strengthens the cut-off of VD > 17% as an identifier of prognostically relevant PVR.
Limitations
Although VD-AR, conventional angiography and echocardiography reliably identified subgroups at increased risk as shown by the Cox models, the C-statistics demonstrated that the identification of individual patients who will die was poor with each of these measures of PVR. The benefit of VD-AR over the other measures of PVR was not in improving individual prediction, but in more distinctly defining the risk group based on PVR.
The retrospective, observational design is a limitation of this study. Although we fitted Cox models to adjust for baseline and procedural characteristics, we cannot exclude unknown confounders. Moreover, angiograms in this retrospective cohort were not optimised for the assessment of VD-AR. Thus, VD-AR was available in only one-third of the original cohort, whereas a recent study with prospective optimisation of angiograms for videodensitometry reported readability in 95% [
15]. Nevertheless, patients with VD-AR readout may be considered largely representative of the entire cohort as we found no major differences in baseline characteristics or survival between those with and without VD-AR measurement.
To obtain complete information on the vital status we had to rely on public records that do not provide information on the cause of death. Therefore, we could not distinguish between cardiac and non-cardiac causes of death. The unknown admixture of non-cardiac deaths confounds the relationship between PVR and mortality. It is, however, reasonable to assume that the prognostic impact of PVR is at least as strong as that observed in this study.
Apart from mortality, VD-AR > 17% may be associated with repeat hospitalisation for heart failure, as suggested by a previous study of 51 patients [
24]. However, in the present study, complete data on repeat hospitalisation were not available for 3-year follow-up. Therefore, the current analysis did not address this issue.
Moreover, off-line core lab calculation of VD-AR compared with intraprocedural qualitative operator assessment may have penalised conventional grading. However, there is no alternative to operator judgement when it comes to clinical decision making for additional interventions to improve THV sealing. Alternatively, an online version of videodensitometry is available. A previous study found high agreement between online and the core laboratory calculation of VD-AR [
17].
Our study was not designed to compare different THVs. THVs were selected according to the clinical conditions. The observed associations between THV types and mortality, therefore, need to be interpreted cautiously. They cannot be considered specific to each THV, but rather to the subset of patients for whom that THV was chosen.
Implications for clinical practice
Currently, most TAVIs are performed without general anaesthesia. In this setting, the image quality of transthoracic echocardiography is often poor due to suboptimal patient positioning and transoesophageal echocardiography is too stressful for the patient. Therefore, in TAVI without general anaesthesia, operators must rely on angiography when deciding on the need for additional measures to reduce PVR.
Although both conventional and videodensitometric grading of PVR provide relevant prognostic information, videodensitometry offers several advantages for clinical practice. As established by previous studies, VD-AR is an operator independent, highly reproducible, objective measure of PVR [
2,
17,
24] and, therefore, provides the best basis not only for unbiased clinical decision making, but also for further scientific evaluation. More importantly, the present study suggests that VD-AR improves intraprocedural identification of PVR requiring correction. With conventional angiographic assessment, even PVR graded as “mild” would require further intervention, because the whole stratum carries an increased risk of death. With VD-AR, however, some of these “mild” PVRs fall in the intermediate range of VD-AR without prognostic relevance, thus obviating the need for additional intervention, as shown by the current data. Hence, application of the threshold of VD-AR > 17% may avoid potentially harmful extension of the procedure and limit additional measures to reduce PVR to those patients who may benefit. Given the limitations of a retrospective observational study, this concept needs to be confirmed by further research. In this respect, the present study breaks the ground for a randomised trial comparing the outcomes of TAVI guided by videodensitometry for assessment of PVR with those of TAVI guided by conventional angiography.