- Email: [email protected]
Meta-Analysis of Head-to-Head Comparison of Intracoronary Versus Intravenous Adenosine for the Assessment of Fractional Flow Reserve
Meta-Analysis of Head-to-Head Comparison of Intracoronary Versus Intravenous Adenosine for the Assessment of Fractional Flow Reserve Stefano Rigattieri, MD, PhDa,*, Giuseppe Biondi Zoccai, MD, MStatb,c, Alessandro Sciahbasi, MD, PhDa, Cristian Di Russo, MD, PhDa, Maria Cera, MDa, Roberto Patrizi, MDa, Silvio Fedele, MDa, Andrea Berni, MDd,e, and Francesco Rocco Pugliese, MDf Intravenous (IV) infusion of adenosine represents the gold standard for measuring fractional flow reserve (FFR). However, IV adenosine is more expensive and timeconsuming compared with intracoronary (IC) boluses of adenosine. We conducted a meta-analysis of studies comparing IC with IV adenosine for FFR assessment in the same coronary lesions. We searched for studies comparing IC with IV adenosine and reporting absolute FFR values or rate of abnormal FFR for both routes. Prespecified subgroup analysis was performed to appraise studies using low-dose (<100 mg) or high-dose IC adenosine (‡100 mg). We retrieved 11 studies amounting to 587 patients and 621 lesions. Six studies evaluated low-dose IC boluses (15 to 80 mg) and 5 studies high-dose boluses (120 to 600 mg). Absolute FFR values were slightly, yet significantly lower with IV adenosine compared with IC adenosine (mean difference 0.02, 95% confidence interval [CI] 0.00 to 0.03, p [ 0.02). This difference, however, did not translate into a significant difference in the rate of abnormal FFR between IC and IV adenosine (hazard ratio 0.93, 95% CI 0.76 to 1.13, p [ 0.57); moreover, no statistically significant difference was observed between lowdose and high-dose IC adenosine subgroups. Adverse events were less frequent with IC adenosine compared with IV adenosine (risk ratio 0.17, 95% CI 0.07 to 0.43, p <0.001). In conclusion, IC administration of adenosine, although inducing a slightly lower amount of hyperemia compared with IV infusion of adenosine, yields a similar diagnostic accuracy in identifying hemodynamically significant coronary stenosis and is better tolerated by the patients. Ó 2017 Elsevier Inc. All rights reserved. (Am J Cardiol 2017;120:563e568) The fractional flow reserve (FFR), defined as the ratio of pressure distal to a coronary stenosis and aortic pressure during maximal hyperemia, represents the gold standard for the assessment of physiological significance of a coronary stenosis and was shown to be predictive of clinical outcomes.1 To be reliable, FFR measurement requires maximal vasodilatation of the coronary microcirculation, which should be preferably obtained by infusion of adenosine through a central vein.2 In the clinical practice, however, intracoronary (IC) administration of adenosine boluses is more popular3 because this route is less expensive (less amount of drug is needed), better tolerated by patients, and does not require the placement of a central venous catheter.
a Interventional Cardiology and fEmergency Department, Sandro Pertini Hospital, Azienda Sanitaria Locale Roma 2, Rome, Italy; bDepartment of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy; cDepartment of Angio-Cardio-Neurology, Istituto di Ricovero e Cura a Carattere Scientifico Neuromed, Pozzilli, Italy; and d Cardiology Department and eClinical and Molecular Medicine Department, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy. Manuscript received March 12, 2017; revised manuscript received and accepted May 4, 2017. See page 567 for disclosure information. *Corresponding author: Tel: þ(39) 06-41433870; fax: þ(39) 0641433481. E-mail address: [email protected] (S. Rigattieri).
0002-9149/17/$ - see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2017.05.024
Nevertheless, both the optimal dose of IC adenosine and its diagnostic performance compared with intravenous (IV) adenosine are still a matter of debate; therefore, we aimed to systematically review available studies comparing head-tohead, in the same patient, IC bolus of adenosine with IV adenosine infusion for FFR assessment. Methods This meta-analysis was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) recommendations.4 Major electronic databases were searched through February 2017 using the following terms: “adenosine,” “intracoronary,” “intravenous,” “fractional flow reserve,” and “hyperemia.” The “Similar articles” section of PubMed and references from selected papers were also checked. Studies comparing IC adenosine bolus with IV adenosine infusion in the same patients and reporting either absolute values of FFR or the rate of abnormal FFR according to conventional cutoffs (0.75 or 0.80 depending on the study) were included in the analysis. The following data were extracted: absolute FFR values (mean SD); rate of abnormal FFR; rate of adverse events, as defined by each study; and rate of complete atrioventricular (AV) block. For studies investigating different IC boluses of adenosine, only data relative to the highest dose were included in the analysis. Two authors (SR www.ajconline.org
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variation across studies that is because of heterogeneity, was also performed for every comparison. Heterogeneity is described as low, moderate, and high, based on I2 values of 25%, 50%, and 75%, respectively. A 2-sided p value was considered statistically significant. A random effect model was used for all analyses. All statistical calculations were performed using Review Manager Version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Results
Figure 1. Study flow diagram.
and AS) extracted data in duplicate; differences were resolved by consensus. Mean differences were calculated with the inverse variance method for continuous variables, whereas risk ratios were calculated with the MantelHaenszel method for dichotomous variables. We performed prespecified subgroup analysis to appraise studies using standard, low-dose (<100 mg)5,6 or high-dose IC adenosine boluses (100 mg). The heterogeneity of the studies was analyzed using a chi-square test for which a p value <0.2 was considered potentially heterogeneous. An I2 test of heterogeneity, which describes the percentage of total
Of the 47 records initially screened, 11 studies met the inclusion criteria6e16 (Figure 1, Table 1). The included studies contained a total of 587 patients who underwent invasive evaluation for suspected coronary artery disease and 621 lesions. Common exclusion criteria were represented by acute coronary syndrome at presentation, previous myocardial infarction in the target vessel, diffuse stenosis or ostial lesions, AV conduction abnormalities and heart failure, or reduced left ventricular function. The target lesions were of intermediate angiographic severity in all studies and were most frequently located in the left anterior descending coronary artery (Table 1). FFR was measured according to standard technique with commercially available devices. A sequential, nonrandomized protocol of adenosine administration (IC boluses followed by IV infusion in each patient) was adopted by most studies, whereas a formal, randomized crossover design was only used in one study.15 In most studies, a 140 mg/kg/min IV adenosine infusion was used; as far as IC adenosine is concerned, 6 studies evaluated lowdose boluses (15 to 80 mg) and 5 studies evaluated highdose boluses (120 to 600 mg). IV adenosine was administered through a central venous access in 8 studies, whereas both central and peripheral venous access were used in 3 studies (Table 1). FFR values (mean SD) were available for 456 lesions in IC adenosine arm and 463 lesions in IV adenosine arm, this difference arising from the fact that, in 1 study, the 600 mg dose of IC adenosine could not be given to 7 patients due to complete AV block.10 Absolute FFR values were slightly, yet significantly lower with IV adenosine compared with IC adenosine (mean difference 0.02, 95% confidence interval [CI] 0.00 to 0.03, p ¼ 0.02); this result was mainly driven by studies investigating low IC adenosine doses, although no statistically significant difference was observed between low-dose and high-dose subgroups (p ¼ 0.26) (Figure 2). The rates of abnormal FFR were available for 477 lesions in IC adenosine arm and 484 lesions in IV adenosine arm (again, because of development of AV block at high IC adenosine doses in 7 patients in 1 study). The slight difference observed in absolute FFR values did not translate into a significant difference in the rate of abnormal FFR between IC and IV adenosine (hazard ratio 0.93, 95% CI 0.76 to 1.13, p ¼ 0.57); moreover, no significant difference was observed between lowdose and high-dose IC adenosine subgroups (Figure 3). Overall, both IC and IV routes were safe; most events were represented by angina-like chest pain, dyspnea, flushing, and nausea which usually disappeared after stopping drug administration. However, the IC route was associated with a significantly lower rate of adverse events compared with the
565
IV route (risk ratio 0.17, 95% CI 0.07 to 0.43, p <0.001). One patient developed atrial fibrillation and another one an episode of severe bronchospasm (both with IV adenosine infusion). Severe ventricular arrhythmias were not reported by any study. Differently, the incidence of transient AV block was higher with IC adenosine administration compared with IV infusion, although the difference was not statistically significant (hazard ratio 1.73, 95% CI 0.59 to 5.05, p ¼ 0.32). Notably, the incidence of AV block was nearly threefold higher with high IC boluses compared with IV infusion (11.6% vs 4.4%). Discussion
IC ¼ intracoronary; IV ¼ intravenous; LAD ¼ left anterior descending coronary artery; LCA ¼ left coronary artery; RCA ¼ right coronary artery.
IC equivalent to IV IC equivalent to IV IV better than IC IV better than IC IV better than IC IV better than IC IC equivalent to IV IC equivalent to IV IC equivalent to IV IC equivalent to IV IC equivalent to IV Jugular or femoral vein Femoral vein Brachial or femoral vein Femoral vein Femoral vein Femoral or brachial vein Femoral vein Right atrium Large systemic vein Femoral or brachial vein Femoral vein 2000 2003 2004 2005 2009 2012 2012 2013 2013 2014 2015 Jeremias De Bruyne Casella Koo Yoon Leone Seo López-Palop Sandhu Khashaba Schlundt
52 21 50 20 43 45 68 102 50 22 114
(60) (21) (50) (20) (44) (50) (68) (108) (56) (30) (114)
26 6 27 7 38 33 44 59 25 17 57
(43) (29) (54) (35) (86) (74) (65) (55) (45) (57) (50)
5624 5914 6512 6717 6310 5819 5711 538 6413 5819 6710
15-20 (RCA); 18-24 (LCA) 20, 40 60, 90, 120, 150 40 (RCA);80 (LCA) 36-60 (RCA); 48-80 (LCA) 60, 300, 600 40 (RCA); 80 (LCA) 60, 180, 300, 600 120 150 40 (RCA); 80 (LCA)
140 140-180 140 140 140 140 140 140-200 140-180 140 140
Main result N. of patients (lesions) Year First Author
Table 1 Characteristics of included studies
Target vessel LAD n (%)
Mean stenosis degree (%)
IC adenosine dose (mg)
IV adenosine dose (mg/Kg/min)
IV adenosine route
Coronary Artery Disease/Intracoronary Versus Intravenous Adenosine for FFR
This systematic review aimed to compare the performance of 2 different routes of administration of adenosine, IC and IV, for the invasive assessment of FFR in coronary stenosis in humans. Main results of the study can be summarized as follows: (1) IV adenosine yields slightly lower values of FFR compared with IC adenosine; (2) this difference does not translate into a clear advantage of IV adenosine, compared with IC adenosine, in detecting functionally significant coronary stenosis according to conventional FFR cutoffs; (3) serious adverse events are negligible with both routes, whereas transient discomfort, mainly represented by angina-like chest pain, nausea, and dyspnea, is more frequent with the IV route; and (4) complete AV block, although transient and not needing intervention, is more common with the IC route, especially when high (>100 mg) adenosine boluses are used. The use of FFR to identify hemodynamically relevant coronary lesion in stable patients when evidence of ischemia is not available has gained a class I, level A recommendation in the European Society of Cardiology Guidelines on Myocardial Revascularization.17 This was because of the results of several randomized trials, such as the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) trial,1 in which invasive assessment of FFR was performed through a coronary pressure wire while inducing maximal hyperemia with adenosine infusion into a central vein; accordingly, adenosine infusion at a rate of 140 mg/kg/min, usually in the femoral vein, has become the gold standard for the assessment of FFR. Nevertheless, IC administration of adenosine boluses is much more popular in the clinical practice compared with IV infusion because the latter is more expensive, time-consuming, and associated with more systemic adverse effects such as chest pain, dyspnea, flushing, and nausea. In contrast, the administration of IC adenosine boluses has several drawbacks, mainly represented by a shorter effect, making this route not suitable for assessment of tandem lesions and diffuse coronary artery disease,18 the absence of evidence-based data coming from large randomized studies, and, most importantly, uncertainty regarding the optimal dose needed to achieve maximal hyperemia. As far as the last point is concerned, conflicting results were reported in the literature. De Luca et al,19 indeed, showed a dose-response relation between IC adenosine dose up to 720 mg and FFR values. Differently, Adjedj et al20 showed that boluses as high as 100 mg in the right coronary artery and 200 mg in the left were sufficient to induce maximal hyperemia and Rother et al21 observed
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Figure 2. Meta-analysis of FFR. The forest plot graphs the weighted mean differences in absolute Pd/Pa values during maximal hyperemia between IC and intravenous adenosine administration. Low IC dose identifies the subgroup of studies using IC bolus doses <100 mg; high IC dose identifies the subgroup of studies using IC bolus doses 100 mg.
Figure 3. Meta-analysis of the rates of abnormal FFR according to conventional cutoffs as reported by each study. The forest plot graphs the risk ratios of abnormal FFR between IC and intravenous adenosine administration. Low IC dose identifies the subgroup of studies using IC bolus doses <100 mg; high IC dose identifies the subgroup of studies using IC bolus doses 100 mg.
strong correlation between FFR determined with standarddose adenosine (40 to 80 mg) and high-dose adenosine (200 to 400 mg). Similarly, heterogeneous results were observed in the studies included in the present meta-analysis and comparing head-to-head different IC adenosine boluses with IV adenosine infusion (Table 1). As an example, in the Nitroprussiato versus Adenosina nelle Stenosi Coronariche Intermedie (NASCI) study,11 only high (600 mg) IC adenosine doses were found to yield FFR values similar to IV adenosine, whereas in the study by Schlundt et al16 low IC adenosine doses (40 mg for the right and 80 mg for the left coronary artery) yielded identical FFR results as IV adenosine; similar results were observed by Lim et al,22 who
reported an excellent correlation between low IC adenosine doses (40 to 80 mg) and IV infusion of the drug. In this meta-analysis, we observed a slight, although significant, difference of 0.02 FFR units in favor of IV adenosine, which however did not translate in a significant difference in the rate of abnormal FFR according to conventional cutoffs. Interestingly, this difference is approximately equal to the standard deviation of the test/retest repeatability of FFR as shown in a recent work,23 suggesting that the difference itself is not clinically significant. This is furthermore confirmed by the results of the FFR-based DEFERal versus performance of coronary angioplasty (DEFER) trial, which employed IC adenosine in 42% of cases; indeed, FFR values
Coronary Artery Disease/Intracoronary Versus Intravenous Adenosine for FFR
obtained with IC adenosine, albeit larger, were still within 0.02 U of IV adenosine and these small differences in FFR were neither clinically nor statistically significant in the trial.24 We also performed a sensitivity analysis to appraise studies using low-dose (<100 mg) and high-dose (100 mg) IC adenosine boluses and we observed that mean difference was 0.00 in high-dose subgroup and 0.02 in low-dose subgroup. This finding, although statistically not significant, suggests that lower adenosine doses might still be associated with suboptimal hyperemia. On the contrary, higher doses were found to be associated with a higher rate of AV block which, albeit being transitory, causes artifacts in pressure tracings and might cloud the accuracy of the measurement given the short-lasting effect of IC adenosine. Therefore, IC adenosine doses in the range between 100 and 200 mg, as previously suggested,20 might represent the best compromise between diagnostic accuracy and safety. This meta-analysis presents several limitations: first, it was a study-level, not a patient-level meta-analysis and, among the included studies, only one had a formal crossover design in which each patient received the 2 treatments (IC and IV adenosine) in a random order16; in the other studies, IC adenosine boluses were followed by IV infusion in nonrandomized sequence. Second, patients enrolled in the studies represent a very selected population characterized by focal coronary artery disease, intermediate severity coronary lesions, no history of previous myocardial infarction, mostly stable ischemic heart disease, and good left ventricular function; therefore the results of the single studies and of the meta-analysis itself may not apply to more complex, realworld patients. In conclusion, this meta-analysis shows that the IC administration of adenosine has similar diagnostic accuracy as the IV infusion with the advantage of being associated to less systemic adverse events; the main drawback of IC route is represented by the occurrence of transient AV block, particularly at high doses. Disclosures The authors have no conflicts of interest to disclose. 1. Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van’ t Veer M, Klauss V, Manoharan G, Engstrom T, Oldroyd KG, Ver Lee PN, MacCarthy PA, Fearon WF. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213e224. 2. Vranckx P, Cutlip DE, McFadden EP, Kern MJ, Mehran R, Muller O. Coronary pressure-derived fractional flow reserve measurements: recommendations for standardization, recording, and reporting as a core laboratory technique. Proposals for integration in clinical trials. Circ Cardiovasc Interv 2012;5:312e317. 3. Van Belle E, Rioufol G, Pouillot C, Cuisset T, Bougrini K, Teiger E, Champagne S, Belle L, Barreau D, Hanssen M, Besnard C, Dauphin R, Dallongeville J, El Hahi Y, Sideris G, Bretelle C, Lhoest N, Barnay P, Leborgne L, Dupouy P. Outcome impact of coronary revascularization strategy reclassification with fractional flow reserve at time of diagnostic angiography: insights from a large French multicenter fractional flow reserve registry. Circulation 2014;129:173e185. 4. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg 2010;8:336e341. 5. Murtagh B, Higano S, Lennon R, Mathew V, Holmes DR Jr, Lerman A. Role of incremental doses of intracoronary adenosine for fractional flow reserve assessment. Am Heart J 2003;146:99e105.
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6. De Bruyne B, Pijls NH, Barbato E, Bartunek J, Bech JW, Wijns W, Heyndrickx GR. Intracoronary and intravenous adenosine 5’-triphosphate, adenosine, papaverine, and contrast medium to assess fractional flow reserve in humans. Circulation 2003;107:1877e1883. 7. Jeremias A, Whitbourn RJ, Filardo SD, Fitzgerald PJ, Cohen DJ, Tuzcu EM, Anderson WD, Abizaid AA, Mintz GS, Yeung AC, Kern MJ, Yock PG. Adequacy of intracoronary versus intravenous adenosine-induced maximal coronary hyperemia for fractional flow reserve measurements. Am Heart J 2000;140:651e657. 8. Casella G, Leibig M, Schiele TM, Schrepf R, Seelig V, Stempfle HU, Erdin P, Rieber J, Konig A, Siebert U, Klauss V. Are high doses of intracoronary adenosine an alternative to standard intravenous adenosine for the assessment of fractional flow reserve? Am Heart J 2004;148:590e595. 9. Koo BK, Kim CH, Na SH, Youn TJ, Chae IH, Choi DJ, Kim HS, Lee MM, Oh BH, Park YB, Choi YS, Tahk SJ. Intracoronary continuous adenosine infusion. Circ J 2005;69:908e912. 10. Yoon MH, Tahk SJ, Yang HM, Park JS, Zheng M, Lim HS, Choi BJ, Choi SY, Choi UJ, Hwang JW, Kang SJ, Hwang GS, Shin JH. Comparison of the intracoronary continuous infusion method using a microcatheter and the intravenous continuous adenosine infusion method for inducing maximal hyperemia for fractional flow reserve measurement. Am Heart J 2009;157:1050e1056. 11. Leone AM, Porto I, De Caterina AR, Basile E, Aurelio A, Gardi A, Russo D, Laezza D, Niccoli G, Burzotta F, Trani C, Mazzari MA, Mongiardo R, Rebuzzi AG, Crea F. Maximal hyperemia in the assessment of fractional flow reserve: intracoronary adenosine versus intracoronary sodium nitroprusside versus intravenous adenosine: the NASCI (Nitroprussiato versus Adenosina nelle Stenosi Coronariche Intermedie) study. JACC Cardiovasc Interv 2012;5:402e408. 12. Seo MK, Koo BK, Kim JH, Shin DH, Yang HM, Park KW, Lee HY, Kang HJ, Kim HS, Oh BH, Park YB. Comparison of hyperemic efficacy between central and peripheral venous adenosine infusion for fractional flow reserve measurement. Circ Cardiovasc Interv 2012;5:401e405. 13. Lopez-Palop R, Carrillo P, Frutos A, Cordero A, Agudo P, Mashlab S, Bertomeu-Martinez V. Comparison of effectiveness of high-dose intracoronary adenosine versus intravenous administration on the assessment of fractional flow reserve in patients with coronary heart disease. Am J Cardiol 2013;111:1277e1283. 14. Sandhu PS, Kaul U, Gupta RK, Ghose T. Fractional flow reserve: intracoronary versus intravenous adenosine induced maximal coronary hyperemia. Indian Heart J 2013;65:147e151. 15. Khashaba A, Mortada A, Omran A. Intracoronary versus intravenous adenosine-induced maximal coronary hyperemia for fractional flow reserve measurements. Clin Med Insights Cardiol 2014;8:17e21. 16. Schlundt C, Bietau C, Klinghammer L, Wiedemann R, Rittger H, Ludwig J, Achenbach S. Comparison of intracoronary versus intravenous administration of adenosine for measurement of coronary fractional flow reserve. Circ Cardiovasc Interv 2015;8. http://dx.doi.org/ 10.1161/CIRCINTERVENTIONS.114.001781. 17. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C, Head SJ, Juni P, Kappetein AP, Kastrati A, Knuuti J, Landmesser U, Laufer G, Neumann FJ, Richter DJ, Schauerte P, Sousa Uva M, Stefanini GG, Taggart DP, Torracca L, Valgimigli M, Wijns W, Witkowski A. 2014 ESC/EACTS Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541e2619. 18. Johnson NP, Jeremias A, Zimmermann FM, Adjedj J, Witt N, Hennigan B, Koo BK, Maehara A, Matsumura M, Barbato E, Esposito G, Trimarco B, Rioufol G, Park SJ, Yang HM, Baptista SB, Chrysant GS, Leone AM, Berry C, De Bruyne B, Gould KL, Kirkeeide RL, Oldroyd KG, Pijls NH, Fearon WF. Continuum of vasodilator stress from rest to contrast medium to adenosine hyperemia for fractional flow reserve assessment. JACC Cardiovasc Interv 2016;9:757e767. 19. De Luca G, Venegoni L, Iorio S, Giuliani L, Marino P. Effects of increasing doses of intracoronary adenosine on the assessment of fractional flow reserve. JACC Cardiovasc Interv 2011;4: 1079e1084.
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20. Adjedj J, Toth GG, Johnson NP, Pellicano M, Ferrara A, Flore V, Di Gioia G, Barbato E, Muller O, De Bruyne B. Intracoronary adenosine: dose-response relationship with hyperemia. JACC Cardiovasc Interv 2015;8:1422e1430. 21. Rother J, Achenbach S, Trobs M, Blachutzik F, Nef H, Marwan M, Schlundt C. Comparison of standard- and high-dose intracoronary adenosine for the measurement of coronary fractional flow reserve (FFR). Clin Res Cardiol 2016;105: 1003e1010. 22. Lim WH, Koo BK, Nam CW, Doh JH, Park JJ, Yang HM, Park KW, Kim HS, Takashima H, Waseda K, Amano T, Kato D, Kurita A, Oi M, Toyofuku M, van Nunen L, Pijls NH. Variability of fractional flow reserve according to the methods of
hyperemia induction. Catheter Cardiovasc Interv 2015;85: 970e976. 23. Berry C, van ’t Veer M, Witt N, Kala P, Bocek O, Pyxaras SA, McClure JD, Fearon WF, Barbato E, Tonino PA, De Bruyne B, Pijls NH, Oldroyd KG. VERIFY (VERification of Instantaneous Wave-Free Ratio and Fractional Flow Reserve for the Assessment of Coronary Artery Stenosis Severity in EverydaY Practice): a multicenter study in consecutive patients. J Am Coll Cardiol 2013;61:1421e1427. 24. Bech GJ, De Bruyne B, Pijls NH, de Muinck ED, Hoorntje JC, Escaned J, Stella PR, Boersma E, Bartunek J, Koolen JJ, Wijns W. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: a randomized trial. Circulation 2001;103:2928e2934.
a Interventional Cardiology and fEmergency Department, Sandro Pertini Hospital, Azienda Sanitaria Locale Roma 2, Rome, Italy; bDepartment of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy; cDepartment of Angio-Cardio-Neurology, Istituto di Ricovero e Cura a Carattere Scientifico Neuromed, Pozzilli, Italy; and d Cardiology Department and eClinical and Molecular Medicine Department, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy. Manuscript received March 12, 2017; revised manuscript received and accepted May 4, 2017. See page 567 for disclosure information. *Corresponding author: Tel: þ(39) 06-41433870; fax: þ(39) 0641433481. E-mail address: [email protected] (S. Rigattieri).
0002-9149/17/$ - see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2017.05.024
Nevertheless, both the optimal dose of IC adenosine and its diagnostic performance compared with intravenous (IV) adenosine are still a matter of debate; therefore, we aimed to systematically review available studies comparing head-tohead, in the same patient, IC bolus of adenosine with IV adenosine infusion for FFR assessment. Methods This meta-analysis was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) recommendations.4 Major electronic databases were searched through February 2017 using the following terms: “adenosine,” “intracoronary,” “intravenous,” “fractional flow reserve,” and “hyperemia.” The “Similar articles” section of PubMed and references from selected papers were also checked. Studies comparing IC adenosine bolus with IV adenosine infusion in the same patients and reporting either absolute values of FFR or the rate of abnormal FFR according to conventional cutoffs (0.75 or 0.80 depending on the study) were included in the analysis. The following data were extracted: absolute FFR values (mean SD); rate of abnormal FFR; rate of adverse events, as defined by each study; and rate of complete atrioventricular (AV) block. For studies investigating different IC boluses of adenosine, only data relative to the highest dose were included in the analysis. Two authors (SR www.ajconline.org
564
The American Journal of Cardiology (www.ajconline.org)
variation across studies that is because of heterogeneity, was also performed for every comparison. Heterogeneity is described as low, moderate, and high, based on I2 values of 25%, 50%, and 75%, respectively. A 2-sided p value was considered statistically significant. A random effect model was used for all analyses. All statistical calculations were performed using Review Manager Version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Results
Figure 1. Study flow diagram.
and AS) extracted data in duplicate; differences were resolved by consensus. Mean differences were calculated with the inverse variance method for continuous variables, whereas risk ratios were calculated with the MantelHaenszel method for dichotomous variables. We performed prespecified subgroup analysis to appraise studies using standard, low-dose (<100 mg)5,6 or high-dose IC adenosine boluses (100 mg). The heterogeneity of the studies was analyzed using a chi-square test for which a p value <0.2 was considered potentially heterogeneous. An I2 test of heterogeneity, which describes the percentage of total
Of the 47 records initially screened, 11 studies met the inclusion criteria6e16 (Figure 1, Table 1). The included studies contained a total of 587 patients who underwent invasive evaluation for suspected coronary artery disease and 621 lesions. Common exclusion criteria were represented by acute coronary syndrome at presentation, previous myocardial infarction in the target vessel, diffuse stenosis or ostial lesions, AV conduction abnormalities and heart failure, or reduced left ventricular function. The target lesions were of intermediate angiographic severity in all studies and were most frequently located in the left anterior descending coronary artery (Table 1). FFR was measured according to standard technique with commercially available devices. A sequential, nonrandomized protocol of adenosine administration (IC boluses followed by IV infusion in each patient) was adopted by most studies, whereas a formal, randomized crossover design was only used in one study.15 In most studies, a 140 mg/kg/min IV adenosine infusion was used; as far as IC adenosine is concerned, 6 studies evaluated lowdose boluses (15 to 80 mg) and 5 studies evaluated highdose boluses (120 to 600 mg). IV adenosine was administered through a central venous access in 8 studies, whereas both central and peripheral venous access were used in 3 studies (Table 1). FFR values (mean SD) were available for 456 lesions in IC adenosine arm and 463 lesions in IV adenosine arm, this difference arising from the fact that, in 1 study, the 600 mg dose of IC adenosine could not be given to 7 patients due to complete AV block.10 Absolute FFR values were slightly, yet significantly lower with IV adenosine compared with IC adenosine (mean difference 0.02, 95% confidence interval [CI] 0.00 to 0.03, p ¼ 0.02); this result was mainly driven by studies investigating low IC adenosine doses, although no statistically significant difference was observed between low-dose and high-dose subgroups (p ¼ 0.26) (Figure 2). The rates of abnormal FFR were available for 477 lesions in IC adenosine arm and 484 lesions in IV adenosine arm (again, because of development of AV block at high IC adenosine doses in 7 patients in 1 study). The slight difference observed in absolute FFR values did not translate into a significant difference in the rate of abnormal FFR between IC and IV adenosine (hazard ratio 0.93, 95% CI 0.76 to 1.13, p ¼ 0.57); moreover, no significant difference was observed between lowdose and high-dose IC adenosine subgroups (Figure 3). Overall, both IC and IV routes were safe; most events were represented by angina-like chest pain, dyspnea, flushing, and nausea which usually disappeared after stopping drug administration. However, the IC route was associated with a significantly lower rate of adverse events compared with the
565
IV route (risk ratio 0.17, 95% CI 0.07 to 0.43, p <0.001). One patient developed atrial fibrillation and another one an episode of severe bronchospasm (both with IV adenosine infusion). Severe ventricular arrhythmias were not reported by any study. Differently, the incidence of transient AV block was higher with IC adenosine administration compared with IV infusion, although the difference was not statistically significant (hazard ratio 1.73, 95% CI 0.59 to 5.05, p ¼ 0.32). Notably, the incidence of AV block was nearly threefold higher with high IC boluses compared with IV infusion (11.6% vs 4.4%). Discussion
IC ¼ intracoronary; IV ¼ intravenous; LAD ¼ left anterior descending coronary artery; LCA ¼ left coronary artery; RCA ¼ right coronary artery.
IC equivalent to IV IC equivalent to IV IV better than IC IV better than IC IV better than IC IV better than IC IC equivalent to IV IC equivalent to IV IC equivalent to IV IC equivalent to IV IC equivalent to IV Jugular or femoral vein Femoral vein Brachial or femoral vein Femoral vein Femoral vein Femoral or brachial vein Femoral vein Right atrium Large systemic vein Femoral or brachial vein Femoral vein 2000 2003 2004 2005 2009 2012 2012 2013 2013 2014 2015 Jeremias De Bruyne Casella Koo Yoon Leone Seo López-Palop Sandhu Khashaba Schlundt
52 21 50 20 43 45 68 102 50 22 114
(60) (21) (50) (20) (44) (50) (68) (108) (56) (30) (114)
26 6 27 7 38 33 44 59 25 17 57
(43) (29) (54) (35) (86) (74) (65) (55) (45) (57) (50)
5624 5914 6512 6717 6310 5819 5711 538 6413 5819 6710
15-20 (RCA); 18-24 (LCA) 20, 40 60, 90, 120, 150 40 (RCA);80 (LCA) 36-60 (RCA); 48-80 (LCA) 60, 300, 600 40 (RCA); 80 (LCA) 60, 180, 300, 600 120 150 40 (RCA); 80 (LCA)
140 140-180 140 140 140 140 140 140-200 140-180 140 140
Main result N. of patients (lesions) Year First Author
Table 1 Characteristics of included studies
Target vessel LAD n (%)
Mean stenosis degree (%)
IC adenosine dose (mg)
IV adenosine dose (mg/Kg/min)
IV adenosine route
Coronary Artery Disease/Intracoronary Versus Intravenous Adenosine for FFR
This systematic review aimed to compare the performance of 2 different routes of administration of adenosine, IC and IV, for the invasive assessment of FFR in coronary stenosis in humans. Main results of the study can be summarized as follows: (1) IV adenosine yields slightly lower values of FFR compared with IC adenosine; (2) this difference does not translate into a clear advantage of IV adenosine, compared with IC adenosine, in detecting functionally significant coronary stenosis according to conventional FFR cutoffs; (3) serious adverse events are negligible with both routes, whereas transient discomfort, mainly represented by angina-like chest pain, nausea, and dyspnea, is more frequent with the IV route; and (4) complete AV block, although transient and not needing intervention, is more common with the IC route, especially when high (>100 mg) adenosine boluses are used. The use of FFR to identify hemodynamically relevant coronary lesion in stable patients when evidence of ischemia is not available has gained a class I, level A recommendation in the European Society of Cardiology Guidelines on Myocardial Revascularization.17 This was because of the results of several randomized trials, such as the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) trial,1 in which invasive assessment of FFR was performed through a coronary pressure wire while inducing maximal hyperemia with adenosine infusion into a central vein; accordingly, adenosine infusion at a rate of 140 mg/kg/min, usually in the femoral vein, has become the gold standard for the assessment of FFR. Nevertheless, IC administration of adenosine boluses is much more popular in the clinical practice compared with IV infusion because the latter is more expensive, time-consuming, and associated with more systemic adverse effects such as chest pain, dyspnea, flushing, and nausea. In contrast, the administration of IC adenosine boluses has several drawbacks, mainly represented by a shorter effect, making this route not suitable for assessment of tandem lesions and diffuse coronary artery disease,18 the absence of evidence-based data coming from large randomized studies, and, most importantly, uncertainty regarding the optimal dose needed to achieve maximal hyperemia. As far as the last point is concerned, conflicting results were reported in the literature. De Luca et al,19 indeed, showed a dose-response relation between IC adenosine dose up to 720 mg and FFR values. Differently, Adjedj et al20 showed that boluses as high as 100 mg in the right coronary artery and 200 mg in the left were sufficient to induce maximal hyperemia and Rother et al21 observed
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Figure 2. Meta-analysis of FFR. The forest plot graphs the weighted mean differences in absolute Pd/Pa values during maximal hyperemia between IC and intravenous adenosine administration. Low IC dose identifies the subgroup of studies using IC bolus doses <100 mg; high IC dose identifies the subgroup of studies using IC bolus doses 100 mg.
Figure 3. Meta-analysis of the rates of abnormal FFR according to conventional cutoffs as reported by each study. The forest plot graphs the risk ratios of abnormal FFR between IC and intravenous adenosine administration. Low IC dose identifies the subgroup of studies using IC bolus doses <100 mg; high IC dose identifies the subgroup of studies using IC bolus doses 100 mg.
strong correlation between FFR determined with standarddose adenosine (40 to 80 mg) and high-dose adenosine (200 to 400 mg). Similarly, heterogeneous results were observed in the studies included in the present meta-analysis and comparing head-to-head different IC adenosine boluses with IV adenosine infusion (Table 1). As an example, in the Nitroprussiato versus Adenosina nelle Stenosi Coronariche Intermedie (NASCI) study,11 only high (600 mg) IC adenosine doses were found to yield FFR values similar to IV adenosine, whereas in the study by Schlundt et al16 low IC adenosine doses (40 mg for the right and 80 mg for the left coronary artery) yielded identical FFR results as IV adenosine; similar results were observed by Lim et al,22 who
reported an excellent correlation between low IC adenosine doses (40 to 80 mg) and IV infusion of the drug. In this meta-analysis, we observed a slight, although significant, difference of 0.02 FFR units in favor of IV adenosine, which however did not translate in a significant difference in the rate of abnormal FFR according to conventional cutoffs. Interestingly, this difference is approximately equal to the standard deviation of the test/retest repeatability of FFR as shown in a recent work,23 suggesting that the difference itself is not clinically significant. This is furthermore confirmed by the results of the FFR-based DEFERal versus performance of coronary angioplasty (DEFER) trial, which employed IC adenosine in 42% of cases; indeed, FFR values
Coronary Artery Disease/Intracoronary Versus Intravenous Adenosine for FFR
obtained with IC adenosine, albeit larger, were still within 0.02 U of IV adenosine and these small differences in FFR were neither clinically nor statistically significant in the trial.24 We also performed a sensitivity analysis to appraise studies using low-dose (<100 mg) and high-dose (100 mg) IC adenosine boluses and we observed that mean difference was 0.00 in high-dose subgroup and 0.02 in low-dose subgroup. This finding, although statistically not significant, suggests that lower adenosine doses might still be associated with suboptimal hyperemia. On the contrary, higher doses were found to be associated with a higher rate of AV block which, albeit being transitory, causes artifacts in pressure tracings and might cloud the accuracy of the measurement given the short-lasting effect of IC adenosine. Therefore, IC adenosine doses in the range between 100 and 200 mg, as previously suggested,20 might represent the best compromise between diagnostic accuracy and safety. This meta-analysis presents several limitations: first, it was a study-level, not a patient-level meta-analysis and, among the included studies, only one had a formal crossover design in which each patient received the 2 treatments (IC and IV adenosine) in a random order16; in the other studies, IC adenosine boluses were followed by IV infusion in nonrandomized sequence. Second, patients enrolled in the studies represent a very selected population characterized by focal coronary artery disease, intermediate severity coronary lesions, no history of previous myocardial infarction, mostly stable ischemic heart disease, and good left ventricular function; therefore the results of the single studies and of the meta-analysis itself may not apply to more complex, realworld patients. In conclusion, this meta-analysis shows that the IC administration of adenosine has similar diagnostic accuracy as the IV infusion with the advantage of being associated to less systemic adverse events; the main drawback of IC route is represented by the occurrence of transient AV block, particularly at high doses. Disclosures The authors have no conflicts of interest to disclose. 1. Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van’ t Veer M, Klauss V, Manoharan G, Engstrom T, Oldroyd KG, Ver Lee PN, MacCarthy PA, Fearon WF. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213e224. 2. Vranckx P, Cutlip DE, McFadden EP, Kern MJ, Mehran R, Muller O. Coronary pressure-derived fractional flow reserve measurements: recommendations for standardization, recording, and reporting as a core laboratory technique. Proposals for integration in clinical trials. Circ Cardiovasc Interv 2012;5:312e317. 3. Van Belle E, Rioufol G, Pouillot C, Cuisset T, Bougrini K, Teiger E, Champagne S, Belle L, Barreau D, Hanssen M, Besnard C, Dauphin R, Dallongeville J, El Hahi Y, Sideris G, Bretelle C, Lhoest N, Barnay P, Leborgne L, Dupouy P. Outcome impact of coronary revascularization strategy reclassification with fractional flow reserve at time of diagnostic angiography: insights from a large French multicenter fractional flow reserve registry. Circulation 2014;129:173e185. 4. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg 2010;8:336e341. 5. Murtagh B, Higano S, Lennon R, Mathew V, Holmes DR Jr, Lerman A. Role of incremental doses of intracoronary adenosine for fractional flow reserve assessment. Am Heart J 2003;146:99e105.
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6. De Bruyne B, Pijls NH, Barbato E, Bartunek J, Bech JW, Wijns W, Heyndrickx GR. Intracoronary and intravenous adenosine 5’-triphosphate, adenosine, papaverine, and contrast medium to assess fractional flow reserve in humans. Circulation 2003;107:1877e1883. 7. Jeremias A, Whitbourn RJ, Filardo SD, Fitzgerald PJ, Cohen DJ, Tuzcu EM, Anderson WD, Abizaid AA, Mintz GS, Yeung AC, Kern MJ, Yock PG. Adequacy of intracoronary versus intravenous adenosine-induced maximal coronary hyperemia for fractional flow reserve measurements. Am Heart J 2000;140:651e657. 8. Casella G, Leibig M, Schiele TM, Schrepf R, Seelig V, Stempfle HU, Erdin P, Rieber J, Konig A, Siebert U, Klauss V. Are high doses of intracoronary adenosine an alternative to standard intravenous adenosine for the assessment of fractional flow reserve? Am Heart J 2004;148:590e595. 9. Koo BK, Kim CH, Na SH, Youn TJ, Chae IH, Choi DJ, Kim HS, Lee MM, Oh BH, Park YB, Choi YS, Tahk SJ. Intracoronary continuous adenosine infusion. Circ J 2005;69:908e912. 10. Yoon MH, Tahk SJ, Yang HM, Park JS, Zheng M, Lim HS, Choi BJ, Choi SY, Choi UJ, Hwang JW, Kang SJ, Hwang GS, Shin JH. Comparison of the intracoronary continuous infusion method using a microcatheter and the intravenous continuous adenosine infusion method for inducing maximal hyperemia for fractional flow reserve measurement. Am Heart J 2009;157:1050e1056. 11. Leone AM, Porto I, De Caterina AR, Basile E, Aurelio A, Gardi A, Russo D, Laezza D, Niccoli G, Burzotta F, Trani C, Mazzari MA, Mongiardo R, Rebuzzi AG, Crea F. Maximal hyperemia in the assessment of fractional flow reserve: intracoronary adenosine versus intracoronary sodium nitroprusside versus intravenous adenosine: the NASCI (Nitroprussiato versus Adenosina nelle Stenosi Coronariche Intermedie) study. JACC Cardiovasc Interv 2012;5:402e408. 12. Seo MK, Koo BK, Kim JH, Shin DH, Yang HM, Park KW, Lee HY, Kang HJ, Kim HS, Oh BH, Park YB. Comparison of hyperemic efficacy between central and peripheral venous adenosine infusion for fractional flow reserve measurement. Circ Cardiovasc Interv 2012;5:401e405. 13. Lopez-Palop R, Carrillo P, Frutos A, Cordero A, Agudo P, Mashlab S, Bertomeu-Martinez V. Comparison of effectiveness of high-dose intracoronary adenosine versus intravenous administration on the assessment of fractional flow reserve in patients with coronary heart disease. Am J Cardiol 2013;111:1277e1283. 14. Sandhu PS, Kaul U, Gupta RK, Ghose T. Fractional flow reserve: intracoronary versus intravenous adenosine induced maximal coronary hyperemia. Indian Heart J 2013;65:147e151. 15. Khashaba A, Mortada A, Omran A. Intracoronary versus intravenous adenosine-induced maximal coronary hyperemia for fractional flow reserve measurements. Clin Med Insights Cardiol 2014;8:17e21. 16. Schlundt C, Bietau C, Klinghammer L, Wiedemann R, Rittger H, Ludwig J, Achenbach S. Comparison of intracoronary versus intravenous administration of adenosine for measurement of coronary fractional flow reserve. Circ Cardiovasc Interv 2015;8. http://dx.doi.org/ 10.1161/CIRCINTERVENTIONS.114.001781. 17. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C, Head SJ, Juni P, Kappetein AP, Kastrati A, Knuuti J, Landmesser U, Laufer G, Neumann FJ, Richter DJ, Schauerte P, Sousa Uva M, Stefanini GG, Taggart DP, Torracca L, Valgimigli M, Wijns W, Witkowski A. 2014 ESC/EACTS Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541e2619. 18. Johnson NP, Jeremias A, Zimmermann FM, Adjedj J, Witt N, Hennigan B, Koo BK, Maehara A, Matsumura M, Barbato E, Esposito G, Trimarco B, Rioufol G, Park SJ, Yang HM, Baptista SB, Chrysant GS, Leone AM, Berry C, De Bruyne B, Gould KL, Kirkeeide RL, Oldroyd KG, Pijls NH, Fearon WF. Continuum of vasodilator stress from rest to contrast medium to adenosine hyperemia for fractional flow reserve assessment. JACC Cardiovasc Interv 2016;9:757e767. 19. De Luca G, Venegoni L, Iorio S, Giuliani L, Marino P. Effects of increasing doses of intracoronary adenosine on the assessment of fractional flow reserve. JACC Cardiovasc Interv 2011;4: 1079e1084.
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