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Optimal treatment strategy for coronary artery stenoses with grey zone fractional flow reserve values. A systematic review and meta-analysis
CARREV-01602; No of Pages 6 Cardiovascular Revascularization Medicine xxx (xxxx) xxx
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Cardiovascular Revascularization Medicine
Optimal treatment strategy for coronary artery stenoses with grey zone fractional flow reserve values. A systematic review and meta-analysis☆ Constantinos Andreou a,⁎, Frederik M. Zimmermann b, Pim A.L. Tonino b, Christos Maniotis c, Michalis Koutouzis d, Leonidas E. Poulimenos e, Andreas S. Triantafyllis b,e a
Department of Cardiology, Limassol General Hospital, Limassol, Cyprus Heart Center, Catharina Hospital Eindhoven, Eindhoven, the Netherlands Cardiology Department, Hygeia Hospital, Athens, Greece d 2nd Department of Cardiology, Hellenic Red Cross Hospital, Athens, Greece e Department of Cardiology, Asklepeion General Hospital, Athens, Greece b c
a r t i c l e
i n f o
Article history: Received 7 April 2019 Received in revised form 14 May 2019 Accepted 17 May 2019 Available online xxxx Keywords: FFR Grey zone Revascularization Deferral
a b s t r a c t Objectives: We conducted a review and meta-analysis of published data to compare revascularization to deferral strategy for coronary lesions with grey zone fractional flow reserve (FFR). Background: Optimal treatment for coronary stenoses with FFR values between 0.75 and 0.80, the so-called grey zone, remains a matter of debate. Methods: We included all studies evaluating revascularization versus deferral for lesions with grey zone FFR. The primary outcome was study-defined major adverse cardiac events (MACE). Secondary outcomes were the composite of death or MI and target vessel revascularization (TVR). A total of 2362 patients were included, of whom 1181 underwent revascularization (revascularization group) and 1181 received medical treatment only (deferral group). Results: After a mean follow-up period of 2.4 years, no difference was found for the primary outcome of the studydefined MACE between the two groups [RR = 1.33 (0.73–2.44), p = 0.35]. In addition, there was no difference for the secondary outcomes of death or MI and TVR between the two groups [RR = 1.39 (0.56–3.47), p = 0.48 and RR = 1.49 (0.89–2.51), p = 0.13, respectively]. Conclusions: In this meta-analysis revascularization of coronary stenoses with grey zone FFR showed no advantage over a deferral strategy in terms of study-defined MACE. Case by case judgment should be implemented to guide treatment in this special subset of patients. © 2019 Elsevier Inc. All rights reserved.
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Introduction . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . 2.1. Literature search strategy . . . . . . . 2.2. Study eligibility criteria . . . . . . . . 2.3. Data extraction and quality assessment 2.4. Statistical analysis . . . . . . . . . . 2.5. End points. . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . 3.1. Trial selection . . . . . . . . . . . . 3.2. Outcomes . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . .
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Abbreviations: ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; FFR, fractional flow reserve; IVUS, intravascular ultrasound; MACE, major adverse cardiac events; MI, myocardial infarction; PCI, percutaneous coronary intervention; RCT, randomized controlled trials; RR, risk ratio; TVR, target vessel revascularization. ☆ Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ⁎ Corresponding author at: Limassol General Hospital, Nikeas Str, Kato Polemidia, P. O. Box 56060, Limassol, Cyprus. E-mail address: [email protected] (C. Andreou).
https://doi.org/10.1016/j.carrev.2019.05.018 1553-8389/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: C. Andreou, F.M. Zimmermann, P.A.L. Tonino, et al., Optimal treatment strategy for coronary artery stenoses with grey zone fractional flow reserve value..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.05.018
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C. Andreou et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
4.1. Limitations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Fractional flow reserve (FFR) represents the standard invasive method for functional evaluation of intermediate coronary artery lesions and serves as a guide for percutaneous revascularization [1–3]. FFR-guided percutaneous coronary intervention (PCI) has shown better clinical outcomes than standard angiography-guided PCI [1–7]. The DEFER trial [1,4] used an FFR b 0.75 threshold for revascularization, while the subsequent FAME family of studies along with other trials [2,3,8–11] moved to an FFR ≤ 0.80 in an effort to avoid undertreatment [12]. Revascularization for coronary stenoses with FFR values ≤0.80 is associated with improved clinical outcomes [8–10], whereas medical treatment is favored with FFR values ≥0.75 [1,4]. However, FFR values between 0.75 and 0.80, occurring in approximately 15% of measurements [13], represent the so-called grey zone FFR and optimal treatment of these lesions remains a matter of debate. A limited number of studies have examined revascularization versus deferral for lesions with grey zone FFR, with conflicting results [14–21]. Additionally, the recently introduced FFR risk continuum theory suggests that FFR potentially relates to subsequent outcomes in a graded fashion, with revascularization offering a greater absolute benefit for more severe FFR values. Going one step further, studies have underlined that there is a significant, independent and nonlinear association between the functional severity of coronary artery disease as expressed by FFR quartiles and the risk of MACE [22]. In particular, near normal (high) FFR values indicate a favorable prognosis, where the risk from revascularization procedures equals or even exceeds any potential benefit. Worse (low) FFR values increase the risk of events such that the absolute benefit from PCI or coronary artery bypass grafting (CABG) accrues in parallel [13]. In between these extremes, comes the area of the grey zone FFR where the differences in clinical outcomes are the smallest. Therefore, a large cohort is needed to detect small differences in this grey zone, hence the need to conduct a meta-analysis. This article aims to provide a systematic review of the currentliterature on optimal treatment for lesions with grey zone FFR and analyze available data on revascularization versus medical treatment alone (deferral strategy) for this subset of patients.
0 0 0
studies reporting major adverse cardiac events (MACE), all-cause death, cardiac death, myocardial infarction (MI), target vessel revascularization (TVR) in in patients with FFR values between 0.75 and 0.80 undergoing revascularization (PCI or CABG) or not (deferral). 2.3. Data extraction and quality assessment Two reviewers (C.A. and A.T.) independently extracted data from each eligible study and potential disagreements were resolved by consensus. We documented study characteristics (year of publication, study design, length of follow-up, number of participants), patient and procedure characteristics (age, gender, history of diabetes, history of hypertension, dyslipidemia, body mass index (BMI), smoking, previous PCI, previous stroke, chronic kidney disease, ejection fraction, clinical setting, number of lesions and type of lesion with revascularization or deferral, FFR values and mean FFR). Quality assessment for each study was independently performed by two authors (C.A. and C.M.) using the Newcastle-Ottawa Scale [23]. A meta-analysis was performed, including published literature detailing the number of MACE, TVR and MI between groups. 2.4. Statistical analysis We present data on categorical variables as frequencies and percentages, whereas continuous variables are presented as means and standard deviations (SD) or medians and interquartile ranges (IQR). We used Der-Simonian and Laird random-effect models to synthesize individual study effects of revascularization or deferral lesions. Risk ratio (RR) was the summary metric of choice for the meta-analyses of binary outcomes. Presence of statistical heterogeneity was assessed using the Q statistic based on the chi-squared test (with p b 0.10 considered significant) and I2 was used to quantify the proportion of variance due to between-study heterogeneity. Heterogeneity was defined as I2 values N 25% and I2 values N75% indicate very large heterogeneity. The presence of publication bias was assessed by visual inspection of funnel plots. Statistical analysis was performed by the Rev Man ver. 5.3 software package.
2. Methods 2.1. Literature search strategy We systematically searched the Cochrane library, EMBASE, Scopus, and MEDLINE databases from inception up to May 2018, using the search terms “grey/grey zone FFR” OR “borderline fractional flow reserve”, OR “FFR, intermediate”, OR “moderate coronary lesions and stenoses” to identify all relevant observational studies and randomized control trials (RCTs). All items resulting from these searches were reviewed at the title and abstract level and potentially eligible articles were reviewed in full text to assess eligibility. In addition, reference lists of the retrieved eligible articles as well as review articles on the topic were searched for potentially relevant publications not previously identified by database search. The retrieved studies were examined to eliminate overlapping data (Fig. 1). 2.2. Study eligibility criteria Our literature search was limited to studies conducted in humans and published in peer-review journals in English. We included all
2.5. End points The primary outcome was ‘study-defined MACE’, which followed the definition of MACE in the respective trials (Table 1). Secondary outcomes were the composite of death or MI and TVR. 3. Results 3.1. Trial selection The search of the literature identified 1677 studies (Fig. 1). After exclusion of duplicates, non-relevant studies, case reports, and reviews by controlling study titles and abstracts, 10 studies were retrieved for further full-text evaluation. After screening of the articles and application of the aforementioned criteria, 6 observational studies were included in this meta-analysis [14–19] comprising a total of 2362 patients, of whom 1181 underwent revascularization (PCI or CABG) and 1181 received medical treatment only (deferral group). Study and patient characteristics are summarized in Table 1 and Table 2, respectively.
Please cite this article as: C. Andreou, F.M. Zimmermann, P.A.L. Tonino, et al., Optimal treatment strategy for coronary artery stenoses with grey zone fractional flow reserve value..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.05.018
C. Andreou et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
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Fig. 1. Flow chart of studies selected for the systematic review and meta-analysis. Caption: The search of the literature identified 1677 studies. After exclusion of duplicates, non-relevant studies, case reports, and reviews by controlling study titles and abstracts, 10 studies were retrieved for further full-text evaluation. After screening of the aforementioned criteria, 6 observational studies were included in this meta-analysis with a total of 2362 patients.
Table 1 Characteristics of the studies included in the systematic review and meta-analysis. Author
Type of study
Year
FFR
Number of patients
Kang et al. [14]
Prospective registry
2018
0.75–0.80
1334
Adjedj et al. [15]
Retrospective
2016
0.76–0.80
453
Lindstaedt et al. [19]
Retrospective
2009
0.75–0.80
97
Agarwal et al. [16]
Retrospective
2017
0.75–0.80
238
Courtis et al. [17]
Prospective non randomized
2008
0.75–0.80
107
Li et al. [18]
Prospective non randomized
2013
0.75–0.80
133
MACE definition A composite of death from any cause, target vessel MI and target vessel revascularization A composite of overall death or MI, overall death, cardiovascular death, MI, and target vessel revascularization A composite of cardiac death, MI or any coronary revascularization procedure A composite of death, MI not related to intervention, and target-vessel revascularization A composite of cardiac death, MI, and revascularization A composite of cardiac death, nonfatal MI, target vessel revascularization
FU (years) 2,9 5
2 2,5 1,1 1
The columns refer to the study author, the type of the study, the year of the publication and the population number included in each study. The MACE definition and the FFR values used in each study are also demonstrated. FFR = fractional flow reserve; FU = Follow up; MACE = major adverse cardiac events; MI = myocardial infarction.
Please cite this article as: C. Andreou, F.M. Zimmermann, P.A.L. Tonino, et al., Optimal treatment strategy for coronary artery stenoses with grey zone fractional flow reserve value..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.05.018
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C. Andreou et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
Table 2 Baseline characteristics of the patients participating in the included studies Author Do-Yoon Kang et al. Deferred PCI or CABG Julien Adjedj et al. Deferred PCI or CABG Michael Lindstaedt et al. Deferred PCI or CABG Shiv Kumar Agarwal et al. Deferred PCI Javier Courtis et al. Deferred PCI or CABG Lin Li et al. Deferred PCI
Male (%)
Mean age
DM (%)
HTN (%)
Smoking (%)
Dyslipidemia (%)
ACS (%)
Previous PCI
535 (78) 478 (73)
64.2±9.8 63.8±9.9
220 (32) 203 (31)
441 (64) 418 (64)
164 (24) 130 (20)
388 (56) 363 (56)
125 (18) 163 (25)
153 (22) 102 (15)
184 (69) 137 (73)
64±11 64±10
64 (24) 49 (26)
145 (55) 100 (53)
87 (33) 71 (38)
152 (57) 114 (60)
70 (26) 46 (25)
40 (83) 37 (79)
64.9±9.6 64.3±10.8
10 (21) 15 (30)
31 (65) 32 (65)
12 (25) 7 (14)
46 (96) 48 (98)
0 0
46 (96) 186 (98)
65.6±8.5 63.9±8.6
24 (50) 84 (44)
47 (98) 179 (94)
27 (56) 52 (27)
45 (94) 176 (93)
12 (25) 66 (35)
35 (80) 51 (81)
62±10 62±10
12 (27) 18 (29)
22 (50) 37 (58)
12 (27) 17 (27)
30 (68) 49 (78)
20 (45) 32 (51)
35 (38) 23 (57)
63 (68) 30 (75)
42 (45) 17 (42)
34 (36) 27 (67)
49 (53) 24 (60)
30 (62) 28 (57)
20 (45) 21 (33)
Values are mean ± SD or %. ACS = acute coronary syndrome; CABG = coronary artery bypass grafting; DM = Diabetes Mellitus; HTN = Hypertension; PCI = percutaneous coronary intervention.
3.2. Outcomes After a mean follow-up period of 2.4 years, no difference was demonstrated for the primary outcome of ‘study-defined MACE’ between revascularization (revascularization group) and medical therapy alone strategy (deferral group) [Fig. 2, RR = 1.33 (0.73–2.44), p = 0.35]. Regarding the secondary outcomes of the composite death or MI and TVR, both therapeutic strategies exhibited equal safety and efficacy [Fig. 3, RR = 1.39 (0.56–3.47), p = 0.48, Fig. 4, RR = 1.49 (0.89–2.51), p = 0.13].
4. Discussion This systematic review and meta-analysis of observational trials comparing revascularization versus deferral for lesions with grey zone FFR, highlights that revascularization of lesions with grey zone FFR did not reduce the primary endpoint of ‘study-defined MACE’ when compared to medical treatment alone. In addition, the secondary endpoints of the composite of death or MI and TVR did not differ significantly between the two groups. According to the FFR risk continuum theory, FFR is potentially related to subsequent outcomes in a graded fashion, with revascularization offering a greater absolute benefit for more severe FFR values and vice versa [13] In the DEFER study, focusing on patients with an FFR N 0.75, performance of PCI did not improve the rate of MACE. However, a higher rate of myocardial infarction was observed in the PCI arm after 15 years of follow up, On the contrary, in patients with an FFR b 0.80 performance of PCI improved MACE versus medical therapy [3,11,24], including a 28% relative risk reduction of the composite
outcome of cardiac death or myocardial infarction in a recent patientlevel meta-analysis [25]. However, limited studies specifically evaluated the best treatment strategy for intermediate stenoses in the narrow grey zone FFR values that is between 0.75 and 0.80. The recent IRIS-FFR prospective registry [14], the largest cohort to date studying patients with grey zone FFR lesions, included 1334 de novo coronary lesions from 1334 patients with grey zone FFR. Half of these lesions were revascularized (PCI or CABG), in a non-randomized fashion, without any report of the baseline symptoms which could potentially interfere with clinical decision making for any of the two strategies. The risk of the composite of MACE (death, target vessel MI and TVR) was similar between the two therapeutic options. Revascularization occurred more frequently in multivessel disease, complex lesions and acute coronary syndromes (ACS). During a median follow-up of 2.9 years, overall mortality and spontaneous MI did not differ between the deferred and performed revascularization groups. MI was significantly higher in the performed group mainly driven due to an increase in periprocedural MI while TVR was significantly higher in the deferred group. Related to all observational studies, why some lesions were revascularized and why other lesions were deferred remains unanswered. Additionally, a limited number of smaller observational studies have examined revascularization versus deferral for lesions with grey zone FFR. Adjedj et al. [15] included 1459 patients with single-segment disease and an FFR value within the grey zone or within the 2 neighboring FFR strata (0.70–0.75 and 0.81–0.85). In the grey zone, MACE rate (death, MI and any revascularization) up to 5 years was similar between deferral and revascularization (PCI or CABG), whereas a strong trend towards a higher rate of death or MI and overall death was observed in the deferral group. Agarwal et al. [16] reported reduced risk of MACE
Fig. 2. Forrest plot of summarized studies for the primary endpoint of study-defined MACE. Caption: After a mean follow-up period of 2.4 years, no difference was demonstrated for the primary outcome of ‘study-defined MACE’ between revascularization (revascularization group) and medical therapy alone strategy (deferral group) [in this figure, RR = 1.33 (CI 0.73– 2.44), p = 0.35]. CI = confidence intervals, MACE = major adverse cardiac events, p = p value, RR = risk ratio.
Please cite this article as: C. Andreou, F.M. Zimmermann, P.A.L. Tonino, et al., Optimal treatment strategy for coronary artery stenoses with grey zone fractional flow reserve value..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.05.018
C. Andreou et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
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Fig. 3. Forrest plot of summarized studies for the composite of death or MI. Caption: Secondary outcomes of the composite death or MI, both therapeutic strategies exhibited equal efficacy [in this figure, RR = 1.39 (CI 0.56–3.47), p = 0.48]. CI = confidence intervals, MI = myocardial infarction, p = p value, RR = risk ratio.
(composite of death, MI and TVR) among 238 patients with grey zone FFR undergoing revascularization (PCI) when compared with medical therapy alone during a mean follow-up period of 30 ± 17 months. Courtis et al. [17] evaluated 107 patients with at least one moderate coronary lesion and grey zone FFR for a mean follow-up of 13 ± 7 months. Deferral of revascularization (PCI or CABG) was associated with a higher rate of MACE (coronary revascularization) and prevalence of angina at follow-up, especially in patients with previous MI in the territory evaluated by FFR. Li et al. [18] applied imaging with intravascular ultrasound (IVUS) in 88 patients with grey zone FFR. During 1-year follow-up the incidence of MACE (cardiac death, nonfatal MI, TVR, including PCI or coronary artery bypass grafting, and unstable angina) was lower in the IVUS group compared to patients who were treated only with drugs without IVUS measurement. Thus, the authors suggested that patients with the same FFR values may need different therapeutic strategy based on IVUS parameters. MACE rate did not differ between the IVUSrevascularization (PCI) and IVUS-defer groups. Finally, Lindstaedt et al. [19] identified 97 patients with borderline FFR. During mean followup of 24 ± 16 months, event-free survival in the deferral group was significantly better regarding overall MACE (cardiac death, MI, coronary revascularization) compared to the revascularization group (PCI or CABG), as well as MACE related to the FFR-evaluated vessel. Therefore, it becomes evident that the conclusions regarding MACEs in the studies being included in our analysis are controversial. The two largest trials revealed equality between revascularization and conservative treatment [14,15], whereas three studies [16–18] favored revascularization. Only one study [19] suggested the superiority of medical treatment regarding MACE. Although there was some heterogeneity in MACE definitions (Table 1), our analysis and synthesis of the aforementioned studies revealed that there were no differences noted in terms of ‘study-defined MACE’, all-cause death or MI and TVR between the revascularization and deferral strategies for lesions with grey zone FFR. Additionally, TVR was numerically higher in the deferral group but not statistical significant. Accordingly, studies have shown that deferral of revascularization in patients with grey zone FFR resulted in higher risk of TVR than those with FFR N 0.80 [21]. Not only lower values of FFR (b0.80), but also the presence of diabetes are strong determinants of early and delayed events in deferred lesions [26]. In addition, Niida et al. [27] demonstrated that worsening of physiological indices after PCI was not uncommon in territories showing greyzone FFR and suggested that physiological assessment combining FFR and index of microcirculatory resistance (IMR) can help identify
patients who may benefit by PCI, particularly those in the grey zone. Recently, investigators of the RCT GZ-FFR trial favored PCI over medical treatment alone among patients with stable coronary artery disease with FFR between 0.75 and 0.82 regarding angina frequency and quality of life. In addition, the combination of PCI and optimal medical treatment was associated with 50% greater reduction in ischemia on stress magnetic resonance imaging [28]. The results on MACEs from this RCT are awaited with great interest. In patients with grey zone FFR values other factors could play an additional role, i.e. non-invasive stress imaging, focal versus a diffuse gradient, patient preference, extent of viability, bleeding tendency, comorbidities [12]. Therefore, we believe that although the dichotomous cut-off value of 0,80 provides a practical guidance on a cohort level, lesions with FFR values within the grey zone should be evaluated on an individual basis. 4.1. Limitations Our study has several limitations. Firstly, all studies included in this meta-analysis were observational with its inherent limitations. Secondly, there were small differences in the definition of MACEs among the studies included. To overcome this heterogeneity we used the ‘study-defined MACE’, which followed the original definition of MACE in the respective trials, as has been used in several other studies (29). Additionally, in four out of the six (4/6) studies included in our analysis, revascularization was performed either by means of PCI or CABG, a detail which may have affected MACE. Moreover, we performed an aggregate data (AD) rather than an individual patient data (IPD) metaanalysis due to inability to fully access raw data from all six studies included. Even though IPD meta-analysis is more accurate, precluding some studies due to access limitations would cause selection bias and weaken the meta-analysis. Language bias may also be present because research published only in English was included in our meta-analysis. 5. Conclusions In this systematic review and meta-analysis, revascularization of coronary stenoses with grey zone FFR did not lower the primary endpoint of study-defined MACE compared to a deferral strategy. Case by case judgment should be implemented to guide treatment. Further research with RCTs and longer follow up periods will clarify the best therapeutic option in this subset of patients.
Fig. 4. Forrest plot of summarized studies for TVR. Caption: Secondary outcomes of TVR, both therapeutic strategies exhibited equal efficacy [in this figure, RR = 1.49 (CI 0.89–2.51), p = 0.13]. CI = confidence intervals, p = p value, RR = risk ratio, TVR = target vessel revascularization.
Please cite this article as: C. Andreou, F.M. Zimmermann, P.A.L. Tonino, et al., Optimal treatment strategy for coronary artery stenoses with grey zone fractional flow reserve value..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.05.018
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Declaration of Competing Interest None. References [1] Pijls NH, van Schaardenburgh P, Manoharan G, Boersma E, Bech JW, van't Veer M, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol 2007;49(21): 2105–11. [2] Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van' t Veer M, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360(3):213–24. [3] De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA, Piroth Z, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367(11):991–1001. [4] Zimmermann FM, Ferrara A, Johnson NP, van Nunen LX, Escaned J, Albertsson P, et al. Deferral vs. performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15-year follow-up of the DEFER trial. Eur Heart J 2015;36(45):3182–8. [5] Pijls NH, De Bruyne B, Peels K, Van Der Voort PH, Bonnier HJ, Bartunek JKJJ, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996;334(26):1703–8. [6] Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, et al. 2011 ACCF/ AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions J Am Coll Cardiol 2011;58(24):e44–122. [7] Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, et al. 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(37):2541–619. [8] van Nunen LX, Zimmermann FM, Tonino PA, Barbato E, Baumbach A, Engstrom T, et al. Fractional flow reserve versus angiography for guidance of PCI in patients with multivessel coronary artery disease (FAME): 5-year follow-up of a randomised controlled trial. Lancet 2015;386(10006):1853–60. [9] Fearon WF, Nishi T, De Bruyne B, Boothroyd DB, Barbato E, Tonino P, et al. Clinical outcomes and cost-effectiveness of fractional flow reserve-guided percutaneous coronary intervention in patients with stable coronary artery disease: three-year follow-up of the FAME 2 trial (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation). Circulation 2018;137(5):480–7. [10] Zimmermann FM, De Bruyne B, Pijls NH, Desai M, Oldroyd KG, Park SJ, et al. Rationale and design of the Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) 3 Trial: a comparison of fractional flow reserve-guided percutaneous coronary intervention and coronary artery bypass graft surgery in patients with multivessel coronary artery disease. Am Heart J 2015;170(4):619–26 e2. [11] Smits PC, Abdel-Wahab M, Neumann FJ, Boxma-de Klerk BM, Lunde K, Schotborgh CE, et al. Fractional flow reserve-guided multivessel angioplasty in myocardial infarction. N Engl J Med 2017;376(13):1234–44. [12] Johnson NP, Zimmermann FM. Yellow traffic lights and grey zone fractional flow reserve values: stop or go? Eur Heart J 2018;39(18):1620–2.
[13] Johnson NP, Toth GG, Lai D, Zhu H, Acar G, Agostoni P, et al. Prognostic value of fractional flow reserve. linking physiologic severity to clinical outcomes J Am Coll Cardiol 2014;64(16):1641–54. [14] Kang DY, Ahn JM, Lee CH, Lee PH, Park DW, Kang SJ, et al. Deferred vs. performed revascularization for coronary stenosis with grey-zone fractional flow reserve values: data from the IRIS-FFR registry. Eur Heart J 2018;39 (18):1610–9. [15] Adjedj J, De Bruyne B, Flore V, Di Gioia G, Ferrara A, Pellicano M, et al. Significance of intermediate values of fractional flow reserve in patients with coronary artery disease. Circulation 2016;133(5):502–8. [16] Agarwal SK, Kasula S, Edupuganti MM, Raina S, Shailesh F, Almomani A, et al. Clinical decision-making for the hemodynamic “gray zone” (FFR 0.75-0.80) and long-term outcomes. J Invasive Cardiol 2017;29(11):371–6. [17] Courtis J, Rodes-Cabau J, Larose E, Dery JP, Nguyen CM, Proulx G, et al. Comparison of medical treatment and coronary revascularization in patients with moderate coronary lesions and borderline fractional flow reserve measurements. Catheter Cardiovasc Interv 2008;71(4):541–8. [18] Li L, Li B, Xie H, Zhai CJ, Liu QW, Zhang HZ, et al. Long-term outcome of intravascular ultrasound application in patients with moderate coronary lesions and grey-zone fractional flow reserve. Coron Artery Dis 2016;27(3):221–6. [19] Lindstaedt M, Halilcavusogullari Y, Yazar A, Holland-Letz T, Bojara W, Mugge A, et al. Clinical outcome following conservative vs revascularization therapy in patients with stable coronary artery disease and borderline fractional flow reserve measurements. Clin Cardiol 2010;33(2):77–83. [20] Yamashita J, Tanaka N, Shindo N, Ogawa M, Kimura Y, Sakoda K, et al. Seven-year clinical outcomes of patients with moderate coronary artery stenosis after deferral of revascularization based on gray-zone fractional flow reserve. Cardiovasc Interv Ther 2015;30(3):209–15. [21] Shiono Y, Kubo T, Tanaka A, Ino Y, Yamaguchi T, Tanimoto T, et al. Long-term outcome after deferral of revascularization in patients with intermediate coronary stenosis and gray-zone fractional flow reserve. Circ J 2015;79(1):91–5. [22] Barbato E, Toth GG, Johnson NP, Pijls NH, Fearon WF, Tonino PA, et al. A prospective natural history study of coronary atherosclerosis using fractional flow reserve. J Am Coll Cardiol 2016;68(21):2247–55. [23] Lo CK, Mertz D, Loeb M. Newcastle-Ottawa Scale: comparing reviewers' to authors' assessments. BMC Med Res Methodol 2014;14:45. [24] Engstrom T, Kelbaek H, Helqvist S, Hofsten DE, Klovgaard L, Holmvang L, et al. Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3PRIMULTI): an open-label, randomised controlled trial. Lancet 2015;386(9994): 665–71. [25] Zimmermann FM, Omerovic E, Fournier S, Kelbæk H, Johnson NP, Rothenbühler M, et al. Fractional flow reserve-guided percutaneous coronary intervention vs. medical therapy for patients with stable coronary lesions: meta-analysis of individual patient data. Eur Heart J 2019 Jan 7;40(2):180–6. https://doi.org/10. 1093/eurheartj/ehy812. [26] Doh JH, et al. Long-term patient-related and lesion-related outcomes after realworld fractional flow reserve use. J Invasive Cardiol 2015;27(9):410–5. [27] Niida T, Murai T, Yonetsu T, Kanaji Y, Usui E, Matsuda J, et al. Coronary physiological assessment combining fractional flow reserve and index of microcirculatory resistance in patients undergoing elective percutaneous coronary intervention with grey zone fractional flow reserve. Catheter Cardiovasc Interv 2018;92(6):1077–87. [28] Hennigan B. GZ-FFR: a randomised controlled trial of PCI vs. optimal medical therapy in patients with stable angina and Grey-Zone Fractional Flow Reserve values. EuroPCR; 24/05/2018; Paris; 2018.
Please cite this article as: C. Andreou, F.M. Zimmermann, P.A.L. Tonino, et al., Optimal treatment strategy for coronary artery stenoses with grey zone fractional flow reserve value..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.05.018
Contents lists available at ScienceDirect
Cardiovascular Revascularization Medicine
Optimal treatment strategy for coronary artery stenoses with grey zone fractional flow reserve values. A systematic review and meta-analysis☆ Constantinos Andreou a,⁎, Frederik M. Zimmermann b, Pim A.L. Tonino b, Christos Maniotis c, Michalis Koutouzis d, Leonidas E. Poulimenos e, Andreas S. Triantafyllis b,e a
Department of Cardiology, Limassol General Hospital, Limassol, Cyprus Heart Center, Catharina Hospital Eindhoven, Eindhoven, the Netherlands Cardiology Department, Hygeia Hospital, Athens, Greece d 2nd Department of Cardiology, Hellenic Red Cross Hospital, Athens, Greece e Department of Cardiology, Asklepeion General Hospital, Athens, Greece b c
a r t i c l e
i n f o
Article history: Received 7 April 2019 Received in revised form 14 May 2019 Accepted 17 May 2019 Available online xxxx Keywords: FFR Grey zone Revascularization Deferral
a b s t r a c t Objectives: We conducted a review and meta-analysis of published data to compare revascularization to deferral strategy for coronary lesions with grey zone fractional flow reserve (FFR). Background: Optimal treatment for coronary stenoses with FFR values between 0.75 and 0.80, the so-called grey zone, remains a matter of debate. Methods: We included all studies evaluating revascularization versus deferral for lesions with grey zone FFR. The primary outcome was study-defined major adverse cardiac events (MACE). Secondary outcomes were the composite of death or MI and target vessel revascularization (TVR). A total of 2362 patients were included, of whom 1181 underwent revascularization (revascularization group) and 1181 received medical treatment only (deferral group). Results: After a mean follow-up period of 2.4 years, no difference was found for the primary outcome of the studydefined MACE between the two groups [RR = 1.33 (0.73–2.44), p = 0.35]. In addition, there was no difference for the secondary outcomes of death or MI and TVR between the two groups [RR = 1.39 (0.56–3.47), p = 0.48 and RR = 1.49 (0.89–2.51), p = 0.13, respectively]. Conclusions: In this meta-analysis revascularization of coronary stenoses with grey zone FFR showed no advantage over a deferral strategy in terms of study-defined MACE. Case by case judgment should be implemented to guide treatment in this special subset of patients. © 2019 Elsevier Inc. All rights reserved.
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Introduction . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . 2.1. Literature search strategy . . . . . . . 2.2. Study eligibility criteria . . . . . . . . 2.3. Data extraction and quality assessment 2.4. Statistical analysis . . . . . . . . . . 2.5. End points. . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . 3.1. Trial selection . . . . . . . . . . . . 3.2. Outcomes . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . .
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Abbreviations: ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; FFR, fractional flow reserve; IVUS, intravascular ultrasound; MACE, major adverse cardiac events; MI, myocardial infarction; PCI, percutaneous coronary intervention; RCT, randomized controlled trials; RR, risk ratio; TVR, target vessel revascularization. ☆ Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ⁎ Corresponding author at: Limassol General Hospital, Nikeas Str, Kato Polemidia, P. O. Box 56060, Limassol, Cyprus. E-mail address: [email protected] (C. Andreou).
https://doi.org/10.1016/j.carrev.2019.05.018 1553-8389/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: C. Andreou, F.M. Zimmermann, P.A.L. Tonino, et al., Optimal treatment strategy for coronary artery stenoses with grey zone fractional flow reserve value..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.05.018
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4.1. Limitations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Fractional flow reserve (FFR) represents the standard invasive method for functional evaluation of intermediate coronary artery lesions and serves as a guide for percutaneous revascularization [1–3]. FFR-guided percutaneous coronary intervention (PCI) has shown better clinical outcomes than standard angiography-guided PCI [1–7]. The DEFER trial [1,4] used an FFR b 0.75 threshold for revascularization, while the subsequent FAME family of studies along with other trials [2,3,8–11] moved to an FFR ≤ 0.80 in an effort to avoid undertreatment [12]. Revascularization for coronary stenoses with FFR values ≤0.80 is associated with improved clinical outcomes [8–10], whereas medical treatment is favored with FFR values ≥0.75 [1,4]. However, FFR values between 0.75 and 0.80, occurring in approximately 15% of measurements [13], represent the so-called grey zone FFR and optimal treatment of these lesions remains a matter of debate. A limited number of studies have examined revascularization versus deferral for lesions with grey zone FFR, with conflicting results [14–21]. Additionally, the recently introduced FFR risk continuum theory suggests that FFR potentially relates to subsequent outcomes in a graded fashion, with revascularization offering a greater absolute benefit for more severe FFR values. Going one step further, studies have underlined that there is a significant, independent and nonlinear association between the functional severity of coronary artery disease as expressed by FFR quartiles and the risk of MACE [22]. In particular, near normal (high) FFR values indicate a favorable prognosis, where the risk from revascularization procedures equals or even exceeds any potential benefit. Worse (low) FFR values increase the risk of events such that the absolute benefit from PCI or coronary artery bypass grafting (CABG) accrues in parallel [13]. In between these extremes, comes the area of the grey zone FFR where the differences in clinical outcomes are the smallest. Therefore, a large cohort is needed to detect small differences in this grey zone, hence the need to conduct a meta-analysis. This article aims to provide a systematic review of the currentliterature on optimal treatment for lesions with grey zone FFR and analyze available data on revascularization versus medical treatment alone (deferral strategy) for this subset of patients.
0 0 0
studies reporting major adverse cardiac events (MACE), all-cause death, cardiac death, myocardial infarction (MI), target vessel revascularization (TVR) in in patients with FFR values between 0.75 and 0.80 undergoing revascularization (PCI or CABG) or not (deferral). 2.3. Data extraction and quality assessment Two reviewers (C.A. and A.T.) independently extracted data from each eligible study and potential disagreements were resolved by consensus. We documented study characteristics (year of publication, study design, length of follow-up, number of participants), patient and procedure characteristics (age, gender, history of diabetes, history of hypertension, dyslipidemia, body mass index (BMI), smoking, previous PCI, previous stroke, chronic kidney disease, ejection fraction, clinical setting, number of lesions and type of lesion with revascularization or deferral, FFR values and mean FFR). Quality assessment for each study was independently performed by two authors (C.A. and C.M.) using the Newcastle-Ottawa Scale [23]. A meta-analysis was performed, including published literature detailing the number of MACE, TVR and MI between groups. 2.4. Statistical analysis We present data on categorical variables as frequencies and percentages, whereas continuous variables are presented as means and standard deviations (SD) or medians and interquartile ranges (IQR). We used Der-Simonian and Laird random-effect models to synthesize individual study effects of revascularization or deferral lesions. Risk ratio (RR) was the summary metric of choice for the meta-analyses of binary outcomes. Presence of statistical heterogeneity was assessed using the Q statistic based on the chi-squared test (with p b 0.10 considered significant) and I2 was used to quantify the proportion of variance due to between-study heterogeneity. Heterogeneity was defined as I2 values N 25% and I2 values N75% indicate very large heterogeneity. The presence of publication bias was assessed by visual inspection of funnel plots. Statistical analysis was performed by the Rev Man ver. 5.3 software package.
2. Methods 2.1. Literature search strategy We systematically searched the Cochrane library, EMBASE, Scopus, and MEDLINE databases from inception up to May 2018, using the search terms “grey/grey zone FFR” OR “borderline fractional flow reserve”, OR “FFR, intermediate”, OR “moderate coronary lesions and stenoses” to identify all relevant observational studies and randomized control trials (RCTs). All items resulting from these searches were reviewed at the title and abstract level and potentially eligible articles were reviewed in full text to assess eligibility. In addition, reference lists of the retrieved eligible articles as well as review articles on the topic were searched for potentially relevant publications not previously identified by database search. The retrieved studies were examined to eliminate overlapping data (Fig. 1). 2.2. Study eligibility criteria Our literature search was limited to studies conducted in humans and published in peer-review journals in English. We included all
2.5. End points The primary outcome was ‘study-defined MACE’, which followed the definition of MACE in the respective trials (Table 1). Secondary outcomes were the composite of death or MI and TVR. 3. Results 3.1. Trial selection The search of the literature identified 1677 studies (Fig. 1). After exclusion of duplicates, non-relevant studies, case reports, and reviews by controlling study titles and abstracts, 10 studies were retrieved for further full-text evaluation. After screening of the articles and application of the aforementioned criteria, 6 observational studies were included in this meta-analysis [14–19] comprising a total of 2362 patients, of whom 1181 underwent revascularization (PCI or CABG) and 1181 received medical treatment only (deferral group). Study and patient characteristics are summarized in Table 1 and Table 2, respectively.
Please cite this article as: C. Andreou, F.M. Zimmermann, P.A.L. Tonino, et al., Optimal treatment strategy for coronary artery stenoses with grey zone fractional flow reserve value..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.05.018
C. Andreou et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
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Fig. 1. Flow chart of studies selected for the systematic review and meta-analysis. Caption: The search of the literature identified 1677 studies. After exclusion of duplicates, non-relevant studies, case reports, and reviews by controlling study titles and abstracts, 10 studies were retrieved for further full-text evaluation. After screening of the aforementioned criteria, 6 observational studies were included in this meta-analysis with a total of 2362 patients.
Table 1 Characteristics of the studies included in the systematic review and meta-analysis. Author
Type of study
Year
FFR
Number of patients
Kang et al. [14]
Prospective registry
2018
0.75–0.80
1334
Adjedj et al. [15]
Retrospective
2016
0.76–0.80
453
Lindstaedt et al. [19]
Retrospective
2009
0.75–0.80
97
Agarwal et al. [16]
Retrospective
2017
0.75–0.80
238
Courtis et al. [17]
Prospective non randomized
2008
0.75–0.80
107
Li et al. [18]
Prospective non randomized
2013
0.75–0.80
133
MACE definition A composite of death from any cause, target vessel MI and target vessel revascularization A composite of overall death or MI, overall death, cardiovascular death, MI, and target vessel revascularization A composite of cardiac death, MI or any coronary revascularization procedure A composite of death, MI not related to intervention, and target-vessel revascularization A composite of cardiac death, MI, and revascularization A composite of cardiac death, nonfatal MI, target vessel revascularization
FU (years) 2,9 5
2 2,5 1,1 1
The columns refer to the study author, the type of the study, the year of the publication and the population number included in each study. The MACE definition and the FFR values used in each study are also demonstrated. FFR = fractional flow reserve; FU = Follow up; MACE = major adverse cardiac events; MI = myocardial infarction.
Please cite this article as: C. Andreou, F.M. Zimmermann, P.A.L. Tonino, et al., Optimal treatment strategy for coronary artery stenoses with grey zone fractional flow reserve value..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.05.018
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Table 2 Baseline characteristics of the patients participating in the included studies Author Do-Yoon Kang et al. Deferred PCI or CABG Julien Adjedj et al. Deferred PCI or CABG Michael Lindstaedt et al. Deferred PCI or CABG Shiv Kumar Agarwal et al. Deferred PCI Javier Courtis et al. Deferred PCI or CABG Lin Li et al. Deferred PCI
Male (%)
Mean age
DM (%)
HTN (%)
Smoking (%)
Dyslipidemia (%)
ACS (%)
Previous PCI
535 (78) 478 (73)
64.2±9.8 63.8±9.9
220 (32) 203 (31)
441 (64) 418 (64)
164 (24) 130 (20)
388 (56) 363 (56)
125 (18) 163 (25)
153 (22) 102 (15)
184 (69) 137 (73)
64±11 64±10
64 (24) 49 (26)
145 (55) 100 (53)
87 (33) 71 (38)
152 (57) 114 (60)
70 (26) 46 (25)
40 (83) 37 (79)
64.9±9.6 64.3±10.8
10 (21) 15 (30)
31 (65) 32 (65)
12 (25) 7 (14)
46 (96) 48 (98)
0 0
46 (96) 186 (98)
65.6±8.5 63.9±8.6
24 (50) 84 (44)
47 (98) 179 (94)
27 (56) 52 (27)
45 (94) 176 (93)
12 (25) 66 (35)
35 (80) 51 (81)
62±10 62±10
12 (27) 18 (29)
22 (50) 37 (58)
12 (27) 17 (27)
30 (68) 49 (78)
20 (45) 32 (51)
35 (38) 23 (57)
63 (68) 30 (75)
42 (45) 17 (42)
34 (36) 27 (67)
49 (53) 24 (60)
30 (62) 28 (57)
20 (45) 21 (33)
Values are mean ± SD or %. ACS = acute coronary syndrome; CABG = coronary artery bypass grafting; DM = Diabetes Mellitus; HTN = Hypertension; PCI = percutaneous coronary intervention.
3.2. Outcomes After a mean follow-up period of 2.4 years, no difference was demonstrated for the primary outcome of ‘study-defined MACE’ between revascularization (revascularization group) and medical therapy alone strategy (deferral group) [Fig. 2, RR = 1.33 (0.73–2.44), p = 0.35]. Regarding the secondary outcomes of the composite death or MI and TVR, both therapeutic strategies exhibited equal safety and efficacy [Fig. 3, RR = 1.39 (0.56–3.47), p = 0.48, Fig. 4, RR = 1.49 (0.89–2.51), p = 0.13].
4. Discussion This systematic review and meta-analysis of observational trials comparing revascularization versus deferral for lesions with grey zone FFR, highlights that revascularization of lesions with grey zone FFR did not reduce the primary endpoint of ‘study-defined MACE’ when compared to medical treatment alone. In addition, the secondary endpoints of the composite of death or MI and TVR did not differ significantly between the two groups. According to the FFR risk continuum theory, FFR is potentially related to subsequent outcomes in a graded fashion, with revascularization offering a greater absolute benefit for more severe FFR values and vice versa [13] In the DEFER study, focusing on patients with an FFR N 0.75, performance of PCI did not improve the rate of MACE. However, a higher rate of myocardial infarction was observed in the PCI arm after 15 years of follow up, On the contrary, in patients with an FFR b 0.80 performance of PCI improved MACE versus medical therapy [3,11,24], including a 28% relative risk reduction of the composite
outcome of cardiac death or myocardial infarction in a recent patientlevel meta-analysis [25]. However, limited studies specifically evaluated the best treatment strategy for intermediate stenoses in the narrow grey zone FFR values that is between 0.75 and 0.80. The recent IRIS-FFR prospective registry [14], the largest cohort to date studying patients with grey zone FFR lesions, included 1334 de novo coronary lesions from 1334 patients with grey zone FFR. Half of these lesions were revascularized (PCI or CABG), in a non-randomized fashion, without any report of the baseline symptoms which could potentially interfere with clinical decision making for any of the two strategies. The risk of the composite of MACE (death, target vessel MI and TVR) was similar between the two therapeutic options. Revascularization occurred more frequently in multivessel disease, complex lesions and acute coronary syndromes (ACS). During a median follow-up of 2.9 years, overall mortality and spontaneous MI did not differ between the deferred and performed revascularization groups. MI was significantly higher in the performed group mainly driven due to an increase in periprocedural MI while TVR was significantly higher in the deferred group. Related to all observational studies, why some lesions were revascularized and why other lesions were deferred remains unanswered. Additionally, a limited number of smaller observational studies have examined revascularization versus deferral for lesions with grey zone FFR. Adjedj et al. [15] included 1459 patients with single-segment disease and an FFR value within the grey zone or within the 2 neighboring FFR strata (0.70–0.75 and 0.81–0.85). In the grey zone, MACE rate (death, MI and any revascularization) up to 5 years was similar between deferral and revascularization (PCI or CABG), whereas a strong trend towards a higher rate of death or MI and overall death was observed in the deferral group. Agarwal et al. [16] reported reduced risk of MACE
Fig. 2. Forrest plot of summarized studies for the primary endpoint of study-defined MACE. Caption: After a mean follow-up period of 2.4 years, no difference was demonstrated for the primary outcome of ‘study-defined MACE’ between revascularization (revascularization group) and medical therapy alone strategy (deferral group) [in this figure, RR = 1.33 (CI 0.73– 2.44), p = 0.35]. CI = confidence intervals, MACE = major adverse cardiac events, p = p value, RR = risk ratio.
Please cite this article as: C. Andreou, F.M. Zimmermann, P.A.L. Tonino, et al., Optimal treatment strategy for coronary artery stenoses with grey zone fractional flow reserve value..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.05.018
C. Andreou et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
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Fig. 3. Forrest plot of summarized studies for the composite of death or MI. Caption: Secondary outcomes of the composite death or MI, both therapeutic strategies exhibited equal efficacy [in this figure, RR = 1.39 (CI 0.56–3.47), p = 0.48]. CI = confidence intervals, MI = myocardial infarction, p = p value, RR = risk ratio.
(composite of death, MI and TVR) among 238 patients with grey zone FFR undergoing revascularization (PCI) when compared with medical therapy alone during a mean follow-up period of 30 ± 17 months. Courtis et al. [17] evaluated 107 patients with at least one moderate coronary lesion and grey zone FFR for a mean follow-up of 13 ± 7 months. Deferral of revascularization (PCI or CABG) was associated with a higher rate of MACE (coronary revascularization) and prevalence of angina at follow-up, especially in patients with previous MI in the territory evaluated by FFR. Li et al. [18] applied imaging with intravascular ultrasound (IVUS) in 88 patients with grey zone FFR. During 1-year follow-up the incidence of MACE (cardiac death, nonfatal MI, TVR, including PCI or coronary artery bypass grafting, and unstable angina) was lower in the IVUS group compared to patients who were treated only with drugs without IVUS measurement. Thus, the authors suggested that patients with the same FFR values may need different therapeutic strategy based on IVUS parameters. MACE rate did not differ between the IVUSrevascularization (PCI) and IVUS-defer groups. Finally, Lindstaedt et al. [19] identified 97 patients with borderline FFR. During mean followup of 24 ± 16 months, event-free survival in the deferral group was significantly better regarding overall MACE (cardiac death, MI, coronary revascularization) compared to the revascularization group (PCI or CABG), as well as MACE related to the FFR-evaluated vessel. Therefore, it becomes evident that the conclusions regarding MACEs in the studies being included in our analysis are controversial. The two largest trials revealed equality between revascularization and conservative treatment [14,15], whereas three studies [16–18] favored revascularization. Only one study [19] suggested the superiority of medical treatment regarding MACE. Although there was some heterogeneity in MACE definitions (Table 1), our analysis and synthesis of the aforementioned studies revealed that there were no differences noted in terms of ‘study-defined MACE’, all-cause death or MI and TVR between the revascularization and deferral strategies for lesions with grey zone FFR. Additionally, TVR was numerically higher in the deferral group but not statistical significant. Accordingly, studies have shown that deferral of revascularization in patients with grey zone FFR resulted in higher risk of TVR than those with FFR N 0.80 [21]. Not only lower values of FFR (b0.80), but also the presence of diabetes are strong determinants of early and delayed events in deferred lesions [26]. In addition, Niida et al. [27] demonstrated that worsening of physiological indices after PCI was not uncommon in territories showing greyzone FFR and suggested that physiological assessment combining FFR and index of microcirculatory resistance (IMR) can help identify
patients who may benefit by PCI, particularly those in the grey zone. Recently, investigators of the RCT GZ-FFR trial favored PCI over medical treatment alone among patients with stable coronary artery disease with FFR between 0.75 and 0.82 regarding angina frequency and quality of life. In addition, the combination of PCI and optimal medical treatment was associated with 50% greater reduction in ischemia on stress magnetic resonance imaging [28]. The results on MACEs from this RCT are awaited with great interest. In patients with grey zone FFR values other factors could play an additional role, i.e. non-invasive stress imaging, focal versus a diffuse gradient, patient preference, extent of viability, bleeding tendency, comorbidities [12]. Therefore, we believe that although the dichotomous cut-off value of 0,80 provides a practical guidance on a cohort level, lesions with FFR values within the grey zone should be evaluated on an individual basis. 4.1. Limitations Our study has several limitations. Firstly, all studies included in this meta-analysis were observational with its inherent limitations. Secondly, there were small differences in the definition of MACEs among the studies included. To overcome this heterogeneity we used the ‘study-defined MACE’, which followed the original definition of MACE in the respective trials, as has been used in several other studies (29). Additionally, in four out of the six (4/6) studies included in our analysis, revascularization was performed either by means of PCI or CABG, a detail which may have affected MACE. Moreover, we performed an aggregate data (AD) rather than an individual patient data (IPD) metaanalysis due to inability to fully access raw data from all six studies included. Even though IPD meta-analysis is more accurate, precluding some studies due to access limitations would cause selection bias and weaken the meta-analysis. Language bias may also be present because research published only in English was included in our meta-analysis. 5. Conclusions In this systematic review and meta-analysis, revascularization of coronary stenoses with grey zone FFR did not lower the primary endpoint of study-defined MACE compared to a deferral strategy. Case by case judgment should be implemented to guide treatment. Further research with RCTs and longer follow up periods will clarify the best therapeutic option in this subset of patients.
Fig. 4. Forrest plot of summarized studies for TVR. Caption: Secondary outcomes of TVR, both therapeutic strategies exhibited equal efficacy [in this figure, RR = 1.49 (CI 0.89–2.51), p = 0.13]. CI = confidence intervals, p = p value, RR = risk ratio, TVR = target vessel revascularization.
Please cite this article as: C. Andreou, F.M. Zimmermann, P.A.L. Tonino, et al., Optimal treatment strategy for coronary artery stenoses with grey zone fractional flow reserve value..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.05.018
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Please cite this article as: C. Andreou, F.M. Zimmermann, P.A.L. Tonino, et al., Optimal treatment strategy for coronary artery stenoses with grey zone fractional flow reserve value..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.05.018