Intravenous Adenosine-Based Fractional Flow Reserve in Pre-TAVR Assessment of Severe AS: Finally Some Clarity?

Aortic stenosis (AS) is a major cause of morbidity and mortality, and the prevalence of severe AS is approximately 3.4% in elderly patients.¹ Concomitant coronary artery disease (CAD) occurs in approximately 50% of AS patients² and is associated with increased mortality after surgical or transcatheter aortic valve replacement (TAVR).^3,4 In addition, the presence of severe obstructive CAD may modify the treatment strategy for patients with an indication for concurrent coronary revascularization at the time of definitive therapy of AS.

While prior studies have demonstrated the feasibility of performing percutaneous coronary interventions (PCI) concurrently with TAVR, the optimal management of TAVR-eligible AS patients with coexisting CAD is unclear. From a clinical standpoint, it is relevant to identify which coronary lesions are hemodynamically significant in order to risk-stratify patients and guide clinical management. Compared with an angiography-alone guided approach, fractional flow reserve (FFR) has been demonstrated to be a useful tool to guide revascularization in patients with intermediate coronary stenoses, with improved clinical outcomes despite decreased resource utilization.⁵ There are, however, limited data on the use of FFR among AS patients,⁶ with no definitive data examining the safety and efficacy of an FFR-guided approach in this population.

In this issue of the Journal of Invasive Cardiology, Stanojevic et al report an important analysis of the safety of intravenous (IV) adenosine use during FFR assessment of coronary artery lesions in patients with severe AS.⁷ In this single-center retrospective study, 72 patients with severe AS received IV adenosine (140 µg/kg/min for up to 4 minutes) during FFR evaluations of intermediate coronary lesions (defined as >50% stenosis of a native coronary artery or bypass graft vessel). Notably, significant reductions in heart rate, systolic blood pressure, diastolic blood pressure, and mean arterial pressure were noted during the IV adenosine infusions compared with baseline. However, there were no significant adverse events and no adenosine infusions had to be stopped for hemodynamic reasons. Of the 82 identified lesions, 45% were found to be hemodynamically significant, and the authors went on to treat these lesions prior to TAVR as part of an FFR-guided approach, which had excellent patient- and lesion-specific outcomes.

This study echoes findings from prior studies demonstrating the general safety of IV adenosine administration during non-invasive stress testing of AS patients. However, the treating clinician should be aware of the potential for hemodynamic perturbations during the infusion. Hussain et al evaluated the use of IV adenosine for nuclear stress testing in severe AS patients and found greater hemodynamically significant decreases in systolic blood pressure in patients with severe AS compared with controls (-17.9 ± 20.1 mm Hg vs -2.6 ± 24.9 mm Hg; P=.03).⁸ In this analysis, 45% of patients with severe AS had a decrease in systolic blood pressure >20 mm Hg compared with only 24% of controls, but no serious adverse events occurred among patients with severe AS. Therefore, while these studies offer encouraging data regarding the safety of IV adenosine, this medication must be used with caution in this often tenuous patient population – especially in patients who are borderline hypotensive at baseline. A significant proportion of severe AS patients will have serious decreases in blood pressure and the benefit-to-risk ratio of performing FFR with IV adenosine must be considered carefully on a case-by-case basis.

Additionally, there are several limitations that may impact the generalizability of the present study to the overall AS population. This was a retrospective study and the use of FFR and IV adenosine, as opposed to intracoronary adenosine, was at the operator’s discretion. Thus, these patients likely had certain clinical characteristics (for example, preexisting hypertension) that made IV adenosine use appear safer in this cohort than a non-selected patient population with severe AS. Only approximately one-third of AS patients suffer from hypertension;⁹ thus, caution is required prior to applying the results of this study more broadly. The lack of a control group is also somewhat limiting when assessing the relative hemodynamic impact of IV adenosine in the AS population compared with non-AS patients. Whether simple measurement of Pd/Pa, or even consideration of instantaneous wave-free ratio could have obviated the need for intravenous adenosine in this population is not currently known, but both approaches are potentially attractive when considering the potential risks of IV adenosine. Finally, the overall accuracy of FFR measurement for the assessment of hemodynamically significant stenoses in the AS population is something that could be debated, particularly among patients with lower blood pressures at baseline, given that the equation to extrapolate coronary flow from pressure-based measurements assumes that mean arterial pressure is much greater than left ventricular end-diastolic pressure when FFR is being calculated.

Nonetheless, the present study provides encouraging data supporting the use of IV adenosine for FFR evaluation of coronary lesions in selected AS patients. This area will be increasingly important as TAVR has evolved from a therapy reserved for high surgical risk candidates to a therapy for lower-risk and intermediate-risk AS patients, in whom the contribution of coexisting CAD burden to overall quality of life and even survival may become more relevant to clinical triage and decision making. The safe and accurate identification of hemodynamically significant lesions in this lower-risk population may strongly influence not only which lesions to revascularize, but also the revascularization strategy itself (eg, AVR with coronary artery bypass grafting vs TAVR with PCI). As such, the data presented in the present study enhance our current understanding of how to evaluate CAD in this burgeoning patient population.

References

1.    Osnabrugge RL, Mylotte D, Head SJ, et al. Aortic stenosis in the elderly: disease prevalence and number of candidates for transcatheter aortic valve replacement: a meta-analysis and modeling study. J Am Coll Cardiol. 2013;62:1002-1012.

2.    Silaruks S, Clark D, Thinkhamrop B, Sia B, Buxton B, Tonkin A. Angina pectoris and coronary artery disease in severe isolated valvular aortic stenosis. Heart Lung Circ. 2001;10:14-23.

3.    Dewey TM, Brown DL, Herbert MA, et al. Effect of concomitant coronary artery disease on procedural and late outcomes of transcatheter aortic valve implantation. Ann Thorac Surg. 2010;89:758-767; discussion 767.

4.    Nowicki ER, Birkmeyer NJ, Weintraub RW, et al. Multivariable prediction of in-hospital mortality associated with aortic and mitral valve surgery in Northern New England. Ann Thorac Surg. 2004;77:1966-1977.

5.    Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360:213-224.

6.    Di Gioia G, Pellicano M, Toth GG, et al. Fractional flow reserve-guided revascularization in patients with aortic stenosis. Am J Cardiol. 2016;117:1511-1515.

7.    Stanojevic D, Gunasekaran P, Tadros P, et al. Intravenous adenosine infusion is safe and well tolerated during coronary fractional flow reserve assessment in elderly patients with severe aortic stenosis. J Invasive Cardiol 2016;28:357-361.

8.    Hussain N, Chaudhry W, Ahlberg AW, et al. An assessment of the safety, hemodynamic response, and diagnostic accuracy of commonly used vasodilator stressors in patients with severe aortic stenosis. J Nuclear Cardiol. 2016 Mar 15 (Epub ahead of print).

9.    Antonini-Canterin F, Huang G, Cervesato E, et al. Symptomatic aortic stenosis: does systemic hypertension play an additional role? Hypertension. 2003;41:1268-1272.

From the Columbia University Medical Center/New York-Presbyterian Hospital, New York, New York. 

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kirtane reports funds to his institution from Medtronic, Boston Scientific, Vascular Dynamics, St. Jude Medical, Abiomed, Abbott Vascular, and Eli Lilly. Dr Ng reports no conflicts of interest regarding the content herein.

Address for correspondence: Ajay Kirtane, MD, SM, Associate Professor of Medicine, Columbia University Medical Center, 161 Fort Washington Ave, 6th Floor, New York, NY 10032. Email: akirtane@columbia.edu