Transcatheter Aortic Valve Replacement Influence on Coronary Hemodynamics: A Quantitative Meta-Analysis and Proposed Decision-Making Algorithm

Abstract: Background. As transcatheter aortic valve replacement (TAVR) expands to younger and lower-risk severe aortic stenosis patients, appropriate coronary artery disease treatment is key to reducing long-term adverse cardiovascular outcomes. Recently, studies have been exploring the role of coronary-physiology guided revascularization strategies. Our aim was to investigate whether TAVR influences coronary physiology measurements using quantitative meta-analytic methods. Methods. We performed a Medline and Embase search for studies evaluating coronary physiology indices before and after TAVR. Double independent screening and extractions of baseline, procedural, angiographic, and echocardiographic data were performed. Risk of bias was assessed using the ACROBAT-NRSI tool. Pooled mean difference estimates of coronary hemodynamic indices before and after TAVR were derived using random-effects models with the inverse variance method (RevMan, Review Manager, version 5.3.5; Nordic Cochrane Centre). Results. Five studies evaluating 250 coronary vessels in 169 severe aortic stenosis patients were quantitatively synthesized. Coronary flow reserve did not change immediately after TAVR in non-diseased vessels (n = 3; mean difference, 0.11; 95% confidence interval [CI], -0.10-0.32; P=.29; I²=0%; P=.68). Importantly, fractional flow reserve also did not vary significantly following TAVR in both non-diseased (n = 3; mean difference, -0.01; 95% CI, -0.04-0.03; P=.75; I²=41; P=.19) and diseased coronaries (n = 3; mean difference, -0.01; 95% CI, -0.03-0.01; P=.49; I²=0%; P=.46). Similarly, instantaneous wave-free ratio remained stable following TAVR (n = 2; mean difference, 0.00; 95% CI, -0.02-0.02; P>.99; I²=0; P>.99. Conclusions. Pooled coronary physiology measurements before and after TAVR are similar, but data on variation within individual lesions are limited.

Key words: coronary flow reserve, TAVR

Coronary artery disease (CAD) co-exists in 50%-75% of severe aortic stenosis (AS) patients undergoing transcatheter aortic valve replacement (TAVR). With the expansion of TAVR to younger and lower surgical risk AS patients, appropriately treating CAD is key to improving long-term cardiovascular outcomes. Contemporary studies are exploring the feasibility of coronary physiology in patients with severe AS and the potential for its incorporation into clinical decision-making algorithms.^1-5 The aim of this study was to perform a meta-analysis of available studies exploring the influence of TAVR on coronary physiology and propose an algorithm on how to use physiology according to existing evidence. 

Methods

Search strategy. We conducted a search of Medline and Embase from conception to February 2019 using the following terms: (TAVR or transcatheter aortic valve replacement or TAVI or transcatheter aortic valve implantation) and (coronary hemodynamics or FFR or fractional flow reserve or IFR or instantaneous wave-free ratio or IMR or intramyocardial resistance or CFR or coronary flow reserve).

Study selection. The abstracts and titles identified were screened by two independent investigators (RAK and SR) to include studies published in English and evaluating hemodynamic indices of diseased or non-diseased coronaries before and after TAVR. Abstracts and unpublished studies were excluded.

Data collection and analysis. Full reports of relevant studies were retrieved, and data were extracted on study design, participant and lesion characteristics, echocardiographic measurements, and coronary hemodynamic indices by two independent investigators (RAK and SR). Pooled mean difference of coronary hemodynamic indices before and after TAVR was determined using RevMan (Review Manager, version 5.3.5; Nordic Cochrane Centre) to perform random-effects meta-analysis using the inverse-variance method. Confidence intervals (CIs) were transformed to standard deviation using RevMan. The Cochrane Q statistic was used to assess interstudy consistency. Two-sided P-values of <.05 were considered significant.

Quality and risk of bias assessment. The Cochrane risk of bias assessment tool for non-randomized studies of interventions (ACROBAT-NRSI) was employed to assess the risk of bias of the included studies.⁶

Results

Study population. A total of five studies^1-5 including 169 patients with severe AS met the inclusion criteria for the quantitative meta-analysis (Figure 1 and Table 1); among these, two assessed coronary physiology in diseased vessels,^1,3 two assessed non-diseased vessels,^2,5 and one assessed both diseased and non-diseased vessels.⁴ Mean patient age was 81 years, 44% were men, 35% had diabetes mellitus, and 62% had dyslipidemia. Mean aortic valve area (AVA) and mean pressure gradient improved following TAVR from 0.71 cm² to 1.79 cm² and 45 mm Hg to 9 mm Hg, respectively. 

Quality assessment. Risk of bias assessment according to ACROBAT-NRSI indicated that one study was at low risk of bias, two studies were at moderate risk of bias, and two studies were at serious risk of bias (Table 2).

Coronary physiology. A total of 250 coronary vessels were studied, with 201 classified as diseased (mean diameter stenosis 46% as assessed by quantitative coronary angiography). Physiological assessments were performed using commercially available pressure guidewires,³ combined pressure and Doppler sensor guidewires,^1,5 or combined pressure/thermodilution guidewires.⁴ 

Coronary flow reserve (n = 3; mean difference, 0.11; 95% CI, -0.10-0.32; P=.29; I²=0%; P=.68) (Figure 2A) and fractional flow reserve (n = 2; mean difference, -0.01; 95% CI, -0.04-0.03; P=.75, I²=41; P=.19) (Figure 2B) in non-diseased vessels did not significantly change following TAVR. Fractional flow reserve (n = 3; mean difference, -0.01; 95% CI, -0.03-0.01; P=.49, I²=0%; P=.46) (Figure 2C) and instantaneous wave-free ratio (n = 2; mean difference, 0.00; 95% CI, -0.02-0.02; P>.99, I²=0; P>.99) (Figure 2D) in stenosed vessels did not significantly change following TAVR with comparable precision.

Discussion

This meta-analysis demonstrates that overall there are only minor variations in coronary physiology measurements before and immediately after TAVR. However, previous studies show that individual lesions may cross the treatment threshold after TAVR — especially lesions with borderline physiology readings determined by resting indices. ³ 

Recently published work suggests that coronary physiology is well correlated with myocardial perfusion imaging and can be considered a valuable tool in assessing the ischemic risk of intermediate coronary lesions.^7,8 Nonetheless, a lower cut-off for instantaneous wave-free ratio was proposed to reduce the number of false positive results (0.82 vs the conventional value of 0.89). This may be explained by the increase of resting coronary flow generated by the increased left ventricular mass and work⁸; although dedicated studies exploring the differences between instantaneous wave-free ratio and fractional flow reserve in AS are needed.

In the absence of outcome-driven data, we are proposing a simple, physiology-based revascularization algorithm in patients undergoing TAVR (Figure 2E). This algorithm enables the functional characterization of a given coronary obstruction, with percutaneous coronary intervention recommended in lesions with definitive ischemic potential (fractional flow reserve <0.75 or instantaneous wave-free ratio <0.82). Given the not insignificant risk of percutaneous coronary intervention in severe AS patients,^9,10 revascularization of physiologically borderline lesions (fractional flow reserve of 0.75-0.85 and instantaneous wave-free ratio of 0.82-0.92) warrants a carefully individualized clinical appraisal that factors in ischemic, bleeding, and procedural risks. 

Ultimately, the impact of physiology-guided revascularization in severe AS patients on clinically relevant endpoints is under investigation in two randomized studies: the Nordic Aortic Valve Intervention (NOTION 3) study (NCT03058627) and the Functional Assessment In TAVI (FAITAVI) trial (NCT03360591). 

Study limitations. Our study has several limitations. First, there is a small number of included studies, which are also non-randomized. Furthermore, the unavailability of lesion-level data precludes robust adjustments for clinical and anatomical variables or a sensitivity analysis for individual lesion discordance following TAVR. Finally, the algorithm we are proposing is based on a synthesis of available literature on coronary physiology assessment of ischemic risk and not on clinical endpoint data.

Conclusion

This meta-analysis demonstrates the stability of overall coronary physiology measurements before and after TAVR. Limited data are available on individual lesion variation after TAVR. Physiology may be a useful tool to assess bystander CAD in TAVR candidates using ischemic thresholds recently validated with myocardial scintigraphy. Higher-level evidence is warranted to inform physiology-guided revascularization in TAVR patients.

References

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From ¹Oxford Heart Centre, Oxford University Hospitals, NHS Trust, Oxford, United Kingdom; ²the Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom; and ³the Department of Medicine, Division of Cardiology, University of Verona, Verona, Italy.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Banning reports grant support (institutional funding for a fellow) and speaker fees from Boston Scientific;  personal fees from Abbott, Medtronic, and Philips; partially funded by the NHS NIHR Biomedical Research Centre, Oxford. Dr Kharbanda reports personal fees from Boston Scientific; partially funded by the NHS NIHR Biomedical Research Centre, Oxford. Dr Ribichini reports grant support from Philips Volcano. Dr Kotronias’s post is funded by the National Institute for Health Research. Dr Scarsini reports an EAPCI Education and Training grant. The remaining authors report no conflicts of interest regarding the content herein. 

Manuscript submitted July 22, 2019, provisional acceptance given August 1, 2019, final version accepted August 12, 2019.

Address for correspondence: Professor Adrian P. Banning, Oxford Heart Centre, John Radcliffe Hospital, Headley Way, OX3 7BA, Oxford, United Kingdom. Email: Adrian.Banning@ouh.nhs.uk