Intravenous Adenosine Infusion is Safe and Well Tolerated During Coronary Fractional Flow Reserve Assessment in Elderly Patients With Severe Aortic Stenosis

Abstract: Background. This study assessed the safety of intravenous adenosine infusion during fractional flow reserve (FFR) evaluation of intermediate coronary lesions in severe aortic stenosis (AS). In severe AS, the extent of underlying coronary artery disease (CAD) can be an important determinant for deciding between surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). Hemodynamic assessment of coronary lesion severity using FFR may reduce the extent of revascularization needed and make TAVR more feasible in higher-risk patients (compared with coronary artery bypass surgery with SAVR). Methods and Results. We retrospectively analyzed the demographic, clinical, and hemodynamic parameters of 72 patients with severe AS who underwent FFR procedure with intravenous adenosine infusion for hemodynamic assessment of intermediate coronary artery lesions. Severe AS patients were elderly, predominantly male, and had a high prevalence of peripheral arterial disease, prior myocardial infarction, left ventricular hypertrophy, and chronic kidney disease. Mean aortic valve area in these patients was 0.71 ± 0.24 cm². No patient with severe AS required discontinuation of the adenosine and all patients tolerated the infusion well. We observed a statistically significant reduction in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) during adenosine infusion compared with the baseline values. However, no clinically significant adverse events occurred. Conclusion. In elderly patients with severe AS, adenosine infusion is safe and well tolerated during FFR evaluation of intermediate coronary lesions. There was a significantly greater drop in SBP, DBP, MAP, and HR with adenosine infusion as compared with baseline values. This, however, was not associated with clinically significant adverse events.

J INVASIVE CARDIOL 2016;28(9):357-361. 2016 June 15 (Epub ahead of print)

Key words: fractional flow reserve, safety, intravenous adenosine, severe aortic stenosis

The prevalence of underlying coronary artery disease (CAD) in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) is noted to be high (48%-75%).¹ However, there is no consensus in regard to the management of CAD in patients undergoing TAVR.² The majority of published studies have excluded patients with CAD, or have not reported the extent of non-revascularized CAD.^1,3

The risk of complications from TAVR may be higher in those with significant obstructive CAD, especially as the procedure often requires rapid ventricular pacing and valvuloplasty that may cause transient hypotension.⁴ While intuitively beneficial, revascularization with percutaneous coronary intervention (PCI) prior to TAVR is not without risks and may be associated with adverse outcomes.^5,6 Thus, an accurate assessment of the hemodynamic significance of intermediate coronary lesions with fractional flow reserve (FFR) assessment in these patients may select lesions that will benefit from PCI. This will likely decrease the extent of coronary revascularization needed and may even make TAVR a more feasible option in some patients who would otherwise be considered for open surgical aortic valve replacement (SAVR) with concurrent CABG.^7,8 The FFR procedure requires the creation of a maximal hyperemic state, which is performed by administration of intravenous adenosine, a potent coronary artery vasodilator.⁸ However, although short lasting, adenosine may cause significant hemodynamic changes, including systemic hypotension, cardiac rhythm abnormalities, and high-degree atrioventricular block.⁹ In terms of age, recent literature suggests that the incidence of adverse symptoms is similar with adenosine infusion in patients above or below 65 years of age (in the setting of non-invasive pharmacologic stress tests).¹⁰ However, exaggerated hemodynamic response in elderly patients with severe AS remains a concern for adenosine use in an invasive assessment of CAD. 

Contemporary literature assessing the safety of intravenous adenosine administration in patients with severe AS is sparse and limited to non-invasive testing modalities.^9,11 To our knowledge, besides a small case series,¹² there are no published studies that have assessed the use and safety of intravenous adenosine administration during FFR assessment in elderly patients with severe AS. The aim of this study was to assess the hemodynamic effects and safety of intravenous adenosine during FFR evaluation of coronary lesions in patients with severe AS who are potential TAVR candidates. 

Methods

Patient selection. This study was approved by the institutional review board at the University of Kansas Medical Center. This is a single-center, retrospective study. Using electronic medical records, we identified all patients who had a confirmed diagnosis of severe AS and underwent FFR assessment as a part of work-up for TAVR from September 30, 2012 to September 30, 2014. Intermediate lesions were defined as >50% stenosis of native coronary artery or bypass graft vessel with a reference diameter >2.5 mm by visual estimation. There were 72 such patients with severe AS and all were included in this study. Detailed manual chart review was then performed on these subjects to collect the demographic, echocardiographic, clinical, angiographic, and intraprocedural hemodynamic information. Severity of AS was confirmed with use of Doppler echocardiography and/or direct invasive measurements. Severe AS was diagnosed if the patient met at least two of the following criteria: aortic valve area <1 cm²; mean gradient across the aortic valve >40 mm Hg; and/or a peak velocity across the aortic valve >4 m/s. 

Exclusion criteria. Those with urgent and emergent procedures were excluded. Patients who underwent FFR using intracoronary infusion of adenosine were excluded. 

Fractional flow reserve assessment. Patients having intermediate coronary stenosis by visual estimation on coronary angiography underwent the FFR procedure at the discretion of the treating cardiologist. FFR was performed using either the PressureWire Aeris or the PressureWire Certus FFR Measurement system (St. Jude Medical, Inc) The procedures were performed as per the manufacturer’s instructions for use and per our institutional protocol. In brief, the FFR pressure wire was introduced into 6 Fr or 7 Fr guide, and pressure equalization was performed with the sensor being placed just distally to the tip of the guide, or in case of ostial lesions, equalization was performed in the ascending aorta. Subsequently, the wire was advanced across the coronary lesion of interest and positioned distal to it and baseline value was established. In cases of ostial lesions, the guide was disengaged from the coronary artery after distal wire passage. Maximum hyperemia was achieved with intravenous adenosine and the ratio of the mean distal to the average aortic pressure was used to determine the FFR. Per standard guidelines, an FFR value of <0.80 was considered hemodynamically significant.

Adenosine infusion protocol. Antianginal medications were maintained at their usual dosages, except for oral dipyridamole, which was withheld for 48 hours prior to procedure. Xanthine derivatives and caffeine-containing products were discontinued 48 and 24 hours prior to testing, respectively. Peripheral intravenous adenosine was administrated at a dose of 140 µg/kg/min for up to 4 minutes. The infusion was terminated earlier than this time frame if a value that denoted hemodynamic significance (<0.80) was attained or if hemodynamic alterations resulting in adverse symptoms were noted. Invasive hemodynamic parameters and 12-lead electrocardiograms (ECGs) were recorded at baseline and continuously thereafter for the duration of adenosine administration and at least 5 minutes after adenosine was stopped. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), and occurrence of any arrhythmias or heart blocks of any degree were recorded. 

Intraprocedural clinical and hemodynamic data points. Cardiac catheterization procedural reports (hemodynamic monitoring reports by Mac-Lab data [GE Healthcare, Inc] and nursing notes) were manually reviewed in detail by the study investigators. Baseline values and lowest values during adenosine infusion for SBP, DBP, MAP, and HR were recorded. Any rhythm abnormalities were noted and all medications used during the procedure to counteract the hemodynamic events were recorded. Any infusion stopped early secondary to hemodynamic changes or otherwise was also recorded. 

Statistical methods. Continuous variables are reported as means ± standard deviations and categorical variables as percentages. Comparisons of continuous variables were performed using the Student’s t-test and categorical variables with Chi-square test. A P-value of <.05 was considered statistically significant. All analyses were performed using STATA (Version 12.1, StataCorp).

Results

Baseline clinical characteristics. Baseline characteristics of the 72 patients with severe AS are presented in Table 1. Subjects with AS were elderly, predominantly men, and had a high prevalence of hypertension, prior myocardial infarction, chronic kidney disease, peripheral arterial disease, and left ventricular hypertrophy. A high prevalence of underlying CAD was noted with prior PCI or CABG performed in 67.6% and 29.6% of patients, respectively. The mean aortic valve area estimated by continuity equation on echocardiography was 0.71 ± 0.24 cm².

Results of FFR assessment. Lesion-specific angiographic data and results of FFR testing are detailed in Table 2. Positive FFR assessments were noted in 45% of the 82 lesions in the severe AS group and the mean FFR value in these lesions was 0.76 ± 0.03. Absolute values of FFR assessment at baseline and at the time of cessation of infusion in patients with both positive and negative test outcomes are depicted in Figure 1.

Intraprocedural hemodynamic changes. Changes in hemodynamic parameters and incidence of clinically relevant adverse events in the study group during intravenous adenosine infusion are detailed in Tables 3A and 3B. During adenosine infusion, there was a statistically significant drop in SBP, DBP, MAP, and HR when compared with baseline values. One patient had a very transient complete heart block during adenosine infusion. This resolved spontaneously with continued infusion. Reductions in SBP, DBP, MAP, and HR during infusion were not associated with clinically significant symptoms of hypoperfusion. No infusion had to be stopped early for hemodynamic reasons. 

Long-term outcomes following PCI in severe aortic stenosis guided by FFR assessment. All lesions that demonstrated a positive FFR assessment (n = 37; 45%) underwent PCI and subsequent TAVR. Among all 72 patients (both FFR positive and FFR negative) who underwent TAVR, only 4 presented with acute coronary syndrome and underwent subsequent coronary angiography over a mean follow-up period of 19 ± 14 months after TAVR. All stents placed after FFR-guided PCI prior to TAVR were patent. Only 1 of these 4 patients underwent repeat PCI in a vessel different from the one subjected to FFR-guided PCI prior to TAVR. Within the same follow-up period, all-cause mortality rate was 22% (16 patients) and cardiac death (resulting from acute coronary syndrome, congestive heart failure, or a witnessed cardiac arrest) was reported in 7 patients (9.7%) following TAVR. The cause of death was unknown (out-of-hospital deaths as ascertained by social security death index) in 8 patients (11.1%). Among the 8 patients who died due to unknown cause, 5 patients had a negative FFR assessment preceding TAVR and among the 7 patients with a cardiac cause of death, 4 patients had a prior negative FFR assessment.

Discussion

The main finding of this study is that invasive hemodynamic assessment of coronary lesions using intravenous adenosine is safe and well tolerated in elderly patients with severe AS. There is limited information on how to manage concomitant CAD in those with severe AS undergoing TAVR. Most patients with unrevascularized CAD were excluded from the randomized TAVR trials.^1,3 Few studies have directly reported the impact of CAD on outcomes of patients with TAVR and they are significantly limited by their small sample size and retrospective design; it is therefore difficult to draw firm conclusions.^5,13-15 

There is evidence that during TAVR, any need for mechanical hemodynamic support due to severe sustained hypotension or hemodynamic collapse is an independent predictor of early as well as late mortality.⁴ The reason for less revascularization of severe CAD in the TAVR population might relate to safety concerns of performing PCI in patients with severe AS, given worse postprocedural outcomes in this population.² Patients with severe AS, high Society of Thoracic Surgeons (STS) score ≥10%, and ejection fraction ≤30% who underwent PCI had an overall higher 30-day post-PCI mortality rate of 4.3% when compared with a propensity-matched control group.⁶ The risk of adverse clinical outcomes following TAVR may be higher in those with unrevascularized CAD despite the lack of robust data to prove this hypothesis. Precise identification of hemodynamically significant lesions could lead to less extensive coronary revascularization (or less complex procedures) and enhance the feasibility of TAVR (with PCI) as opposed to SAVR (with CABG). 

An expanding body of evidence pertaining to FFR assessment of hemodynamic significance of coronary lesions suggests a reduction in the extent of revascularization, enhancement of overall cost efficacy and better long-term outcomes.^7,8,16 There are limited data regarding use of FFR in patients with severe AS.¹² Until the advent of TAVR, there was no compelling indication for routinely performing FFR because even intermediate lesions received a bypass along with SAVR. Another reason is safety concerns about using intravenous adenosine in this clinical setting in the elderly population. 

Stahli et al performed FFR assessment in 5 patients who were being considered for TAVR and reported that FFR with intravenous adenosine was feasible and could be performed safely.¹² Apart from this report, existing literature assessing the safety of adenosine administration in patients with severe AS is sparse and limited mostly to non-invasive testing modalities.^9,11,17,18 Samuels et al tested the safety and diagnostic accuracy of stress myocardial perfusion imaging using intravenous adenosine (6 minute infusion at 140 µg/kg/min) in 35 patients with moderate to severe AS and compared it with 100 age-matched controls without AS.⁹ They demonstrated that patients with AS tolerated the infusion well, which is similar to our results, but there were no differences in the two groups in terms of decrease in BP or HR (net change in SBP 18% vs 14% and HR 21% vs 19% in AS patients vs controls, respectively). In our study, the net decrements in SBP, DBP, MAP, and HR were sharper during adenosine infusion in severe AS patients in comparison with their baseline values (32%, 25%, 29%, and 25%, respectively). These discrepant results could be explained by the higher magnitude of AS severity in our study in comparison with the results presented by Samuels et al (mean aortic valve area, 0.71 ± 0.24 cm² vs 0.84 ± 0.16 cm²). Additionally, the smaller sample size of severe AS patients in the other study (33 vs 72) could further explain the disparities in results. Furthermore, FFR assessment is done under conscious sedation while thallium is done in a fully awake state, and this may have had a differential effect on hemodynamics with adenosine infusion. Patsilinakos et al also published a report on 75 patients with severe AS undergoing thallium stress imaging using intravenous adenosine. The study did not have a control group, but reported that the infusion was safe and well tolerated, which is concordant with our results.¹¹

Our results show that despite the fact that the AS group was elderly and had a high prevalence of underlying comorbidities, they tolerated the procedure well without clinically relevant periprocedural adverse events. The significant drop in SBP, DBP, MAP, and HR observed did not correlate with clinical events, symptoms, or need for test interruption. Our results also indicate FFR positivity in 45% of lesions in patients with severe AS – similar to the reported rate in those without AS in the DEFER trial (44%), which utilized a more stringent FFR cut-off value of <0.75.⁸ Of note, 86% of severe AS patients in our study had underlying left ventricular hypertrophy (LVH). Previously published literature raises concerns over LVH adversely affecting FFR values.¹³ However, Chhatriwala et al have demonstrated that LVH does not limit the utility of FFR for hemodynamic assessment of lesion severity.¹³ Moreover, all-cause mortality over a follow-up period of 19 ± 14 months from our study with FFR-guided pre-TAVR PCI is 22%, which is consistent with the randomized TAVR trials (14%-30%).^1,3

The study demonstrates that intravenous adenosine is safe and well tolerated in patients with severe AS. This tool should be readily utilized for assessment of intermediate lesions in the TAVR population given its potential to alter procedural strategy and decrease the need for coronary revascularization.^7,8,19,20 This has significant clinical implications including more patients becoming candidates for TAVR and needing less extensive revascularization.

Study limitations. This is a single-center, retrospective study with a relatively small number of patients. However, the study population does reflect a real-life TAVR population. There are concerns as to whether the reduction in hemodynamic parameters could be explained by underlying AS or by older age per se. We were unable to obtain age-matched controls in our database that were as elderly as the cases (severe AS undergoing TAVR work-up) during the time period studied. Safety of intracoronary adenosine infusion or use of adenosine for FFR estimation in the post-TAVR population cannot be extrapolated from this study. 

Conclusion

In elderly patients with severe AS, intravenous adenosine infusion is safe and well tolerated during FFR evaluation of intermediate coronary lesions. There was a significantly greater drop in SBP, DBP, MAP, and HR during adenosine infusion in severe AS patients and this was not associated with any clinically relevant adverse clinical events.

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From the ¹Division of Cardiovascular Diseases, University of Kansas Medical Center, Kansas City, Kansas; ²Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas; and ³the University of Kansas School of Medicine, Kansas City, Kansas.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein. 

Manuscript submitted January 4, 2016, provisional acceptance given February 11, 2016, final version accepted April 19, 2016.

Address for correspondence: Kamal Gupta, MD, Professor, Division of Cardiovascular Diseases, University of Kansas Medical Center, Mail Stop 3006, 3901 Rainbow Boulevard, Kansas City, KS 66160. Email: kgupta@kumc.edu