Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC K3HPHFfdmfX9tchdVMkgRPc S0066-782X2018001600542 S0066-782X2018005013109 10.5935/abc.20180170 Original Article Fractional Flow Reserve-Guided Strategy in Acute Coronary Syndrome. A Systematic Review and Meta-Analysis Martins José Luís 1 Afreixo Vera 2 Santos José 1 Gonçalves Lino 3 Baixo Vouga Hospital Center Department of Cardiology Aveiro Portugal Department of Cardiology, Baixo Vouga Hospital Center, Aveiro - Portugal University of Aveiro Department of Mathematics Aveiro Portugal CIDMA/IBIMED/Department of Mathematics, University of Aveiro, Aveiro - Portugal Coimbra Universitary Hospital Center Department of Cardiology Coimbra Portugal Department of Cardiology, Coimbra Universitary Hospital Center, Coimbra - Portugal Mailing Address: José Luis Martins, Av. Artur Ravara. Aveiro E-mail: zeluismartins@gmail.com

Author contributions

Conception and design of the research, Acquisition of data, Analysis and interpretation of the data and Writing of the manuscript: Martins JL; Statistical analysis: Martins JL, Afreixo V; Critical revision of the manuscript for intellectual content: Martins JL, Afreixo V, Santos J, Gonçalves L.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 21 09 2018 10 2018 111 4 542 550 27 03 2018 09 05 2018 09 05 2018 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited Abstract Background:

There are limited data on the prognosis of deferral of lesion treatment in patients with acute coronary syndrome (ACS) based on fractional flow reserve (FFR).

 Objectives:

To provide a systematic review of the current evidence on the prognosis of deferred lesions in ACS patients compared with deferred lesions in non-ACS patients, on the basis of FFR.

 Methods:

We searched Medline, EMBASE, and the Cochrane Library for studies published between January 2000 and September 2017 that compared prognosis of deferred revascularization of lesions on the basis of FFR in ACS patients compared with non-ACS patients. We conducted a pooled relative risk meta-analysis of four primary outcomes: mortality, cardiovascular (CV) mortality, myocardial infarction (MI) and target-vessel revascularization (TVR).

 Results:

We identified 7 studies that included a total of 5,107 patients. A pooled meta-analysis showed no significant difference in mortality (relative risk [RR] = 1.44; 95% CI, 0.9-2.4), CV mortality (RR = 1.29; 95% CI = 0.4-4.3) and TVR (RR = 1.46; 95% CI = 0.9-2.3) after deferral of revascularization based on FFR between ACS and non-ACS patients. Such deferral was associated with significant additional risk of MI (RR = 1.83; 95% CI = 1.4-2.4) in ACS patients.

 Conclusion:

The prognostic value of FFR in ACS setting is not as good as in stable patients. The results demonstrate an increased risk of MI but not of mortality, CV mortality, and TVR in ACS patients.

 Keywords: Acute Coronary Syndrome/physiopathology Percutaneous Coronary Intervention/methods Coronary Angiography/methods Fractional Flow Reserve Myocardial/physiology Microvessels Vascular Resistance Reproducibility of Results Introduction

Fractional flow reserve is a well-validated, effective technique to determine the functional significance of intermediate coronary lesions; FFR-guided percutaneous coronary intervention (PCI) improves clinical outcomes in patients with stable coronary disease.1-3 Although robust data supports FFR use in stable coronary disease, its use in acute coronary syndrome (ACS) is less well investigated because maximal hyperemia is required to accurately measure FFR. In patients with ACS, microvascular changes may prevent vasodilatation thus affecting the validity of FFR.1,4-6 These changes appear to be vessel-dependent (culprit vs. non-culprit) and related to the type of infarction - ST-elevation myocardial infarction (STEMI) vs. non-ST-elevation myocardial infarction (NSTEMI).7 FFR values in the culprit vessel are recognized to be higher when measured during acute episodes than when measured after the microcirculation has had some time to recover. Higher FFR values are assumed to be caused by reduced levels of hyperemia in the culprit vessel due to embolization of thrombus and plaque, ischemic microvascular dysfunction and myocardial stunning. Hence, efficacy of the use of FFR in culprit artery disease remains uncertain.8,9

Multivessel coronary disease (MVD), observed in approximately 30-50% of patients presenting with STEMI and in 30-59% with NSTEMI, is associated with a poor prognosis.10-12 Complete revascularization of hemodynamically significant vessels identified in the hemodynamic laboratory early after acute event appears attractive: this approach provides the patient with a well-defined, definitive therapeutic plan. However, several studies suggest that a FFR-guided revascularization strategy in ACS reduces the rate of coronary revascularization without compromising short-term safety.13-15 However, the results of this approach are inconsistent in several studies involving patients with non-ACS.13,14

Therefore, the aims of this study are to provide a systematic review of the current evidence of the deferral of PCI based on FFR in ACS patients and compare it with that supporting this decision in non-ACS patients.

 Methods Data sources and searches

We systematically searched MEDLINE, EMBASE, and the Cochrane Library for relevant articles published between January 2000 and September 2017. Previous qualitative and systematic reviews, if available, were searched for additional studies. The query terms “Flow Fractional Reserve” OR “Acute Coronary Syndrome” were used in the search. References of the studies identified by the search strategy were reviewed for potentially relevant articles not identified by the above search. No language restrictions were enforced.

 Study selection

The title/abstract of citations were first screened by 2 independent reviewers (JM and VA), and complete manuscripts were retrieved if considered potentially relevant. Additional studies were identified by reviewing the bibliographies of included studies and relevant reviews. Disagreements were resolved by consensus. The same reviewers independently appraised identified articles according to the following inclusion criteria: studies that compared clinical outcomes of lesions after PCI deferred based on FFR between ACS patients and non-ACS patients (Figure 1).

Flowchart of studies included in the meta-analysis.

Endpoints

The endpoints studied were: mortality, cardiovascular mortality, myocardial infarction (MI), and target vessel revascularization (TVR) during the follow-up period. TVR of the target vessel was defined as subsequent revascularization of the index vessel by either PCI or bypass grafting. In all trials, in the ACS group, distinction between culprit and non-culprit lesions was based on the operator's discretion, and hence subjective, similar to clinical practice.

 Statistical analysis

Continuous variables were expressed as means ± standard deviations or median (with interquartile range) values, and categorical variables were described as numbers and percentages. To calculate pooled effect estimates, we used the inverse variance assuming a fixed-effects model and the DerSimonian-Laird method assuming a random-effects model.16 Homogeneity among the studies was evaluated using Cochran's Q test and the I2 statistic (the values of 0.25, 0.50, and 0.75 indicated low, moderate, and high degrees of heterogeneity, respectively). Publication bias was evaluated using funnel plots. We performed a sensitivity analysis to evaluate the impact of each study on the results. MetaXL 2.0 (EpiGear International Pty Ltd, Wilston, Queensland, Australia) was used to calculate the pooled risk difference effect sizes (difference in occurrence risk between revascularization and conservative management groups).

 Results Study identification

The search strategy initially retrieved 129 citations. Of these, 96 articles were excluded after review of the title or abstract. After assessment or the studies for the selection criteria, we excluded an additional 26 studies. A total of 7 studies met criteria for the meta-analysis, involving 5,107 (3,540 non-ACS and 1,567 ACS) patients.

 Characteristics of included studies

Of the 7 studies included, 1 was a prospective study and 6 had an observational, retrospective in design (Table 1 and Table 2).

Characteristics of included studies
Author Year Follow up Study design Total FU Age (yrs) Men Non-ACS (n) ACS (n) STEMI (n) NSTEMI/UA (n) FFR value used to defer Median time between Clinical presentation and FFR measurement Multivessel disease Adenosine administration Exclusion criteria
Potvin JM et al 9 2006 11 ± 6 months Retrospective cohort 201 62 ± 10 131 61 124 11 113 ≥ 0.75 24 hours (range 2 to 144) NR intracoronary administration of adenosine (median dose 60 µg, range 30 to 300, for the left coronary artery and 30 µg, range 18 to 120, for the right coronary artery) and/or nitroprusside (median dose 250 µg, range 100 to 1,000, for the left and right coronary arteries). Intracoronary adenosine was used in 135 cases, intracoronary nitroprusside in 14 cases, and adenosine andnitroprusside in 52 cases Patients within 24 hours of acute STEMI were excluded
Fischer J et al 8 2006 12 months Retrospective cohort 111 ACS → 58 ± 14Non-ACS → 63 ± 10 72 76 35 11 24 ≥ 0.75 Recent(within 7 days) ST segment elevation MI treated with lytic Therapy ACS → 9Non-ACS → 9 intracoronary adenosine (30 µg bolus in the right coronary artery or 40-60 µg bolus in the left coronary artery NR
Sels et al 24 2011 2 years Prospective cohort 1005 ACS → 64.8 ± 10.7Non-ACS → 64.3 ± 10 744 677 328 0 328 ≥ 0.80 NR NR Intravenous adenosine, administered at a rate of 140 µg/kg/min through a central vein. Exclusion criteria were left main disease, previous CABG, and STEMI < 5 days before, because the use of FFR is not validated in recent STEMI. Patients admitted for UA and NSTEMI with positive troponin but total creatine kinase < 1,000 U/l could be included
Mehta et al 25 2015 3.4 ± 1.6 years Retrospective cohort 674 ACS → 63.8 ± 11.9Non-ACS → 65.3 ± 10.2 380 340 334 7 327 > 0.80 NR ACS → 221Non-ACS → 209 Predominant use of intracoronary adenosine with similar maximum doses for both groups (120 µg) NR
Hakeem A et al 34 2016 3,4 ± 1,6 anos Retrospective cohort 576 ACS → 66.6 ± 8Non-ACS → 64.7 ± 8.7 554 370 206 0 206 > 0.75 NR ACS → 135Non-ACS → 216 Intravenous (140 mg/kg/min) or intracoronary (at least 60 mg) adenosine. The median dose of intracoronary adenosine in our cohort was 130 mg NR
Van Belle et al 38 2017 1 year Retrospective cohort 958 ACS → 66 ± 11.2Non-ACS → 66.4 ± 10 693 721 237 - - > 0.75 e > 0.80 NR NR NR NR
Lee JM et al 37 2017 722 days Retrospective cohort 1596 ACS → 62.0 ± 11.1Non-ACS → 62.4 ± 9.4 1112 1295 301 0 301 > 0.80 NR NR Hyperemia was induced with an intracoronary bolus administration (80 µg in left coronary artery, 40 µg in right coronary artery), intracoronary (240 µg/min) or, iv continuous infusion (140 µg/Kg/min) of adenosine. NR

FU: Follow-up; yrs: years; ACS: acute coronary syndrome; STEMI: ST segment elevation myocardial infarction; NSTEMI: non- ST segment elevation myocardial infarction; UA: unstable angina; FFR: fractional flow reserve; PCI: Percutaneous coronary intervention; MI: Myocardial Infarction; TVR: target vessel revascularization; CABG: Coronary artery bypass grafting; NR: not reported.

 Clinical outcomes of ACS and non-ACS patients with deferred lesion treatment based on fractional flow reserve
Author Year Patients[FFR > cutoff] * Mortality CV Mortality Myocardial infarction Target lesion revascularization Target vessel revascularization
Potvin JM et al 9 2006 ACS → 124Non-ACS → 61 NR ACS → 0Non-ACS → 1 ACS → 2Non-ACS → 1 NR ACS → 11Non-ACS → 7
Fischer J. et al 8 2006 ACS → 35Non-ACS → 76 ACS → 3Non-ACS → 5 ACS → 2Non-ACS → 1 ACS → 1Non-ACS → 1 NR ACS → 6Non-ACS → 7
Sels et al 24 2011 NR** ACS → 12Non-ACS → 20 NR Non-ACS → 36Non-ACS → 44 NR ACS → 45Non-ACS → 72
Mehta et al 25 2015 ACS → 334Non-ACS → 340 NR ACS → 23 Non-ACS → 8 ACS → 47Non-ACS → 26 ACS → 78Non-ACS → 66 NR
Hakeem A et al 34 2016 ACS → 206Non-ACS → 370 NR ACS → 9Non-ACS → 30 ACS → 16Non-ACS → 11 ACS → 36Non-ACS → 29 ACS → 15 Non-ACS → 14
Van Belle et al 38 2017 ACS → 237Non-ACS → 721 ACS → 10Non-ACS → 17 NR ACS → 3Non-ACS → 7 NR NR***ACS → 9;***Non-ACS → 42]
Lee JM et al 37 2017 ACS → 301Non-ACS 1295 NR ACS → 3Non-ACS → 5 ACS → 2Non-ACS → 4 ACS → 8Non-ACS → 10

ACS: acute coronary syndrome; CV: cardiovascular; NR: not reported;

Cut-off values varied from 0.75 to 0.80 among the studies;

Sels et al.24 evaluated whether there is a difference in benefit of fractional flow reserve (FFR) guidance for percutaneous coronary intervention (PCI) in multivessel coronary disease in patients with acute coronary syndrome (ACS) vs. non-ACS without discriminating those patients with FFR > 0.80;

Target-vessel revascularization was not specified.

 Quantitative synthesis of outcomes

Mortality: We included 3 studies, a total of 2,074 patients, in the pooled analysis. The forest plot (Figure 2) describes the weighted meta-analysis for relative risk (RR) of mortality in ACS patients in comparison with non-ACS patients when revascularization decisions were based on FFR. Pooled analysis showed negligible heterogeneity among the studies (I2 = 0%; p = 0.78) and the ACS and non-ACS patients did not differ significantly; their pooled RR was 1.44 (95% CI = 0.89-2.35). Exclusion of any single study did not significantly alter the overall combined result.

Forest plots of the pooled risk ratio of the outcomes. (A) mortality, (B) cardiovascular mortality; (C) myocardial infarction; (D) target-vessel revascularization. Size of data markers reflects the relative weight of the study. CI indicates confidence interval.

Cardiovascular mortality: We included 5 studies, a total of 3,144 patients, in the pooled analysis. The forest plot (Figure 2) describes the weighted meta-analysis for mortality risk of basing revascularization decisions on FFR. Pooled analysis showed significant heterogeneity among the studies (I2 = 70%; p = 0.01) and the ACS and non-ACS patients did not differ significantly; their pooled RR was 1.29 (95% CI = 0.39-4.25). Exclusion of any single study did not significantly alter the overall combined result.

Myocardial Infarction: 7 studies were included, a total of 5,107 patients, in the pooled analysis. Deferring lesions based on FFR was associated with a significant additional risk of MI (RR = 1.83; 95% CI = 1.39-2.40) in ACS patients versus non-ACS patients. Figure 2 describes the weighted meta-analysis of MI. The pooled analysis showed negligible heterogeneity among the studies (I2 = 0%; p = 0.96).

Target-vessel revascularization: We included 5 studies, a total of 3,475 patients, in the pooled analysis. The forest plot (Figure 2) describes the weighted meta-analysis of TVR in patients when revascularization decisions were based on FFR. Pooled analysis showed negligible heterogeneity among the studies (I2 = 39%; p = 0.16). ACS and non-ACS patients did not differ significantly in RR of TVR; their pooled RR was 1.46 (95% CI = 0.93-2.29).

 Study Bias

Visual inspection of the funnel plots for the outcomes did not reveal any asymmetry among the studies. Further, the Begg rank correlation test was not statistically significant.

 Discussion

This report provides a systematic review and a meta-analysis comparing the strategy in patients in whom lesion treatment was deferred based on FFR, and no revascularization was undertaken in ACS patients to that in non-ACS patients. FFR-guided revascularization in ACS patients appears to be as safe as in non-ACS patients.2,17-18 Briasoulis et al.,15 in a meta-analysis, evaluated FFR-guided management in NSTEMI patients, where a modest reduction in incidence of MI was noted, with no significant differences in incidence of major adverse cardiac events (MACE), death or all-cause mortality, and target-vessel revascularization between the FFR guided approach in comparison with coronary angiography-guided approach.15

Four important pathophysiological considerations need to be considered when comparing the FFR results in ACS patients to those of non-ACS patients:

Microvascular dysfunction: The timing of FFR measurement in the ACS patient is an important issue. As described above, immediately after MI, the initial, temporary microvascular injury caused by the inflammatory environment may artificially elevate the initial FFR measurements. Antithrombotic therapy, administered for 3 to 4 days to stabilize the plaque, may reduce microvascular dysfunction, and FFR may then reflect the true hemodynamic situation. This approach of waiting > 5 days to measure FFR in ACS patients was suggested by the European Society of Cardiology guidelines.19-21 However, most referral centers that study FFR in ACS perform early invasive evaluation of ACS patients, within 48 h of presentation, a practice that could lead to artificially higher FFR values.19,22-27,34,37,38

Plaque instability: At least two-thirds of lesions arising from vessels with < 50% stenosis are responsible for unstable syndromes involving plaque instability, assuming that these vessels previously had normal flow. A non-flow-limiting culprit lesion may be "anatomically significant" but "physiologically nonsignificant", and because FFR is not intended to evaluate plaque characteristics, care must be taken in the use of FFR in vessels with unstable characteristics but normal flow.28,29

Myocardial mass involved: The mass of viable myocardium being perfused by the artery in question is relevant pathophysiologically to the interpretation of FFR results in ACS patients. The FFR value is inversely proportional to the ejection fraction: hence, a lower ejection fraction, which implies a large area of infarction with less viable myocardium, could produce a higher FFR reading for the same degree of stenosis.14,30

Presentation type of ACS: Because ACS describe a range of myocardial ischemic states with distinct clinical and pathophysiological characteristics, the use of FFR should be differentiated by type of ACS. DANAMI3-PRIMULTI and COMPARE ACUTE were the only studies that evaluated the risk of events following FFR-guided PCI in patients with STEMI and MVD.31,32 Of these, only COMPARE ACUTE reported the rate of events at follow-up in patients whose PCI was deferred based on FFR; patients who did not undergo additional revascularization had a similar event rate to those who were revascularized based on positive (elevated) FFR. On the other hand, FAME, which included 328 patients with ACS out of a total of 1,005 patients with MVD, reported similar rates of mortality, MI, or revascularization in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients who had PCI deferred based on an FFR cutoff value > 0.80 compared to non-ACS patients.24 However, the FAME study did not define the exact time of FFR measurement nor the lesions assessed (culprit vs. non-culprit). Furthermore, the event rate in patients with deferred PCI based on FFR was not reported. In addition, the FAMOUS-NSTEMI trial compared a FFR-guided versus an angiography-only approach in NSTEMI and MVD patients; the rate of major adverse cardiac events (defined as cardiac mortality or hospitalization for MI or heart failure) was 7.5% in patients with deferred PCI based on FFR and 0% in those deferred PCI based on angiography.13

The aim of this analysis was not to evaluate FFR-guided decisions per-lesion level, but rather to focus on the relevance of FFR-guided decision per-patient level, considering that patients with ACS frequently have more than 1 lesion suitable for revascularization and the identification of the culprit lesion is not always straightforward. Undoubtedly, patients with MVD have worse outcomes than patients who present with single vessel disease. The natural history of patients who are revascularized in an acute setting is known to differ from those who are revascularized in a stable setting.33 For example, the probability of malignant dysrhythmias is significantly more common in acute patients and is an important cause of mortality.33

This systematic review and meta-analysis summarizes all published studies that assessed and compared clinical outcomes in which revascularization decisions were based on FFR in ACS versus non-ACS setting. Among the clinical endpoints evaluated, only the RR of MI was significantly higher in patients with ACS.

The higher risk of subsequent MI found in this study and by several authors is explained by the different pathophysiology of ACS versus stable coronary disease.34-36 Hakeem et al. compared the outcomes in NSTEMI patients who did not undergo PCI of any lesion on the basis of FFR to those in a similar group of non-ACS patients. After an average 3.4-years follow-up, using propensity score matching, the MI and TVR rates were higher in NSTEMI patients than in non-ACS patients (25% vs. 12%, respectively; p < 0.0001).34 Similar results were reported recently by Lee et al. in non-ACS patients.37

When MI injury (defined as any MI attributable to a deferred revascularization based on the index FFR) was specifically evaluated, deferring treatment of lesions based on FFR did not differ significantly in the RR of MI injury between ACS and non-ACS patients [RR 1.84 (95% CI = 0.82-4.11); (I2 = 0%; p = 0.98)] (Figure 3).

Forest plot of the pooled risk ratio for myocardial infarction injury. Size of data markers reflects the relative weight of the study. CI indicates confidence interval.

If on the one hand, Briasoulis et al.15 showed that a FFR-guided strategy in ACS seems to be associated with a better prognosis compared to an angiography strategy, the primary finding of our study was that deferring the treatment of lesions was associated with an increased risk of MI in ACS patients compared to non-ACS patients, represented by the RRs of the target-vessel revascularization or MI lesion.15 In addition, mortality and CV mortality did not differ between ACS and non-ACS patients.

Our results are consistent with the recently published study by Van Belle et al.,38,39 who compared the impact differing the management of intermediate lesions, based on FFR, on the prognosis of ACS vs. non-ACS patients from two important registries, R3F and POST-iT. They concluded that revascularization decisions based on FFR for differing treatment of lesions were safe in ACS patients.38-40

Some authors have questioned whether we should be less permissive and adopt a different cut-off value for FFR in unstable vessels. Hakeem et al.,34 recently determined that the best FFR cut-off value for predicting MI or TVR was > 0.80 in patients with stable coronary artery disease, supporting current practice. However, in NSTE-ACS patients, the best cutoff value was >0.84. However, some limitations suggested by some authors deserve consideration in interpreting their results. For example, it is unclear why mortality, the most important outcome, was not included in the composite endpoint in this study. In addition, medical therapy was not optimal for the patients, 14% of patients did not receive statin, and approximately two-thirds did not receive dual antiplatelet therapy. Moreover, several technical issues might explain the higher FFR cut-off values reported in these studies.34,41-43

Despite most of the studies included did not report clinical outcomes by type of lesions (culprit or non-culprit) lesions, available evidence suggests, as previously mentioned, that in patients with ACS, microvascular dysfunction may be less marked, and the ability to achieve maximal hyperemia is sufficient to maintain the diagnostic use of FFR, both in culprit and non-culprit vessels.44

Besides that, due to the great heterogeneity of inclusion criteria, follow-up period and the vessel assessed by FFR, results and conclusion of the current study should be the interpreted with caution.

Limitations

The conclusions drawn from this meta-analysis are subject to the limitations and differences of the original studies included in the analysis. First, our meta-analysis included both randomized clinical trials and (mostly) observational studies. The conclusions of this study may be somewhat limited due to biases inherent in the observational studies, including design, selection, and treatment bias. Another possible limitation is the potential publication bias because the results only included short-term mortality.

 Conclusion

The prognostic value of FFR in ACS setting is not as good as in stable patients. More homogeneous studies with larger populations of patients are necessary to reach definitive and robust conclusions. Careful definition and interpretation of the clinical results is important when analysis of FFR is not performed in patient-level but in vessel-level only.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any thesis or dissertation work.

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

 Acknowledgements

We thank the CIDMA - Center for Research and Development in Mathematics and Applications of the University of Aveiro for the statistical analysis, and the Portuguese Foundation for Science and Technology (FCT - Fundação para a Ciência e a Tecnologia) (project UID/MAT/04106/2013).

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Outcomes of coronary stenoses deferred revascularization for borderline versus nonborderline fractional flow reserve values. Am J Cardiol 2014;113(11):1788-93. Depta JP Patel JS Novak E Masrani SK Raymer D Facey G Outcomes of coronary stenoses deferred revascularization for borderline versus nonborderline fractional flow reserve values Am J Cardiol 2014 113 11 1788 1793 20 Layland J, Oldroyd KG, Curzen N, Sood A, Balachandran K, Das R, et al; FAMOUS-NSTEMI investigators. Fractional flow reserve vs. angiography in guiding management to optimize outcomes in non-ST-segment elevation myocardial infarction: the British Heart Foundation FAMOUS-NSTEMI randomized trial. Eur Heart J. 2015;36(2):100-11. Layland J Oldroyd KG Curzen N Sood A Balachandran K Das R FAMOUS-NSTEMI investigators Fractional flow reserve vs. angiography in guiding management to optimize outcomes in non-ST-segment elevation myocardial infarction: the British Heart Foundation FAMOUS-NSTEMI randomized trial Eur Heart J 2015 36 2 100 111 21 Kolh P, Windecker S. ESC/EACTS myocardial revascularization guidelines 2014. Eur Heart J. 2014;35(46):3235-6. Kolh P Windecker S ESC/EACTS myocardial revascularization guidelines 2014 Eur Heart J 2014 35 46 3235 3236 22 Niccoli G, Indolfi C, Davies JE. Evaluation of intermediate coronary stenoses in acute coronary syndromes using pressure guidewire. Open Heart. 2017;4(2):e000431. Niccoli G Indolfi C Davies JE Evaluation of intermediate coronary stenoses in acute coronary syndromes using pressure guidewire Open Heart 2017 4 2 e000431 23 Lopez-Palop R, Carrillo P, Torres F, Lozano I, Frutos A, Avanzas P, et al. Results of fractional flow reserve measurement to evaluate nonculprit coronary artery stenoses in patients with acute coronary syndrome. Rev Esp Cardiol (Engl Ed). 2012;65(2):164-70. Lopez-Palop R Carrillo P Torres F Lozano I Frutos A Avanzas P Results of fractional flow reserve measurement to evaluate nonculprit coronary artery stenoses in patients with acute coronary syndrome Rev Esp Cardiol (Engl Ed) 2012 65 2 164 170 24 Sels JW, Tonino PA, Siebert U, Fearon WF, Van't Veer M, De Bruyne B, et al. Fractional flow reserve in unstable angina and non-ST-segment elevation myocardial infarction experience from the FAME (Fractional flow reserve versus angiography for Multivessel evaluation) study. JACC Cardiovasc Interv. 2011;4(11):1183-9. Sels JW Tonino PA Siebert U Fearon WF Van't Veer M De Bruyne B Fractional flow reserve in unstable angina and non-ST-segment elevation myocardial infarction experience from the FAME (Fractional flow reserve versus angiography for Multivessel evaluation) study JACC Cardiovasc Interv 2011 4 11 1183 1189 25 Masrani Mehta S, Depta JP, Novak E, Patel JS, Patel Y, Raymer D, et al. Association of lower fractional flow reserve values with higher risk of adverse cardiac events for lesions deferred revascularization among patients with acute coronary syndrome. J Am Heart Assoc. 2015;4(8):e002172. Masrani Mehta S Depta JP Novak E Patel JS Patel Y Raymer D Association of lower fractional flow reserve values with higher risk of adverse cardiac events for lesions deferred revascularization among patients with acute coronary syndrome J Am Heart Assoc 2015 4 8 e002172 26 Picchi A, AntonioMaria Leone AM, Zilio F, Enrico Cerrato E, D'Ascenzo F, Fineschi M, et al. Outcome of coronary lesions with deferred revascularization due to negative fractional flow reserve in subjects with acute coronary syndrome. Int J Cardiol. 2017 Mar 1;230:335-8. Picchi A AntonioMaria Leone AM Zilio F Enrico Cerrato E D'Ascenzo F Fineschi M Outcome of coronary lesions with deferred revascularization due to negative fractional flow reserve in subjects with acute coronary syndrome Int J Cardiol 01 03 2017 230 335 338 27 Leesar MA, Abdul-Baki T, Akkus NI, Sharma A, Kannan T, Bolli R. Use of fractional flow reserve versus stress perfusion scintigraphy after unstable angina. Effect on duration of hospitalization, cost, procedural characteristics, and clinical outcome. J Am Coll Cardiol. 2003;41(7):1115-21. Leesar MA Abdul-Baki T Akkus NI Sharma A Kannan T Bolli R Use of fractional flow reserve versus stress perfusion scintigraphy after unstable angina. Effect on duration of hospitalization, cost, procedural characteristics, and clinical outcome J Am Coll Cardiol 2003 41 7 1115 1121 28 Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med. 2007;356(8):830-40. Camici PG Crea F Coronary microvascular dysfunction N Engl J Med 2007 356 8 830 840 29 Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation. 2005;111(3):363-8. Lerman A Zeiher AM Endothelial function: cardiac events Circulation 2005 111 3 363 368 30 De Bruyne B, Pijls NH, Bartunek J, Kulecki K, Bech JW, De Winter H, et al. Fractional flow reserve in patients with prior myocardial infarction. Circulation. 2001;104(2):157-62. De Bruyne B Pijls NH Bartunek J Kulecki K Bech JW De Winter H Fractional flow reserve in patients with prior myocardial infarction. Circulation 2001 104 2 157 162 31 Engstrøm T, Kelbæk H, Helqvist S, Høfsten DE, Kløvgaard L, Holmvang L, et al; DANAMI-3-PRIMULTI Investigators. Complete revascularization versus treatment of the culprit lesion only in patients with STsegment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial. Lancet. 2015;386(9994):665-71. Engstrøm T Kelbæk H Helqvist S Høfsten DE Kløvgaard L Holmvang L DANAMI-3-PRIMULTI Investigators Complete revascularization versus treatment of the culprit lesion only in patients with STsegment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial Lancet 2015 386 9994 665 671 32 Smits PC, Abdel-Wahab M, Neumann FJ, Boxma-de Klerk BM, Lunde K, Schotborgh CE, et al; Compare-acute investigators. fractional flow reserve-guided multivessel angioplasty in myocardial infarction. N Engl J Med. 2017;376(13):1234-44. Smits PC Abdel-Wahab M Neumann FJ Boxma-de Klerk BM Lunde K Schotborgh CE Compare-acute investigators fractional flow reserve-guided multivessel angioplasty in myocardial infarction N Engl J Med 2017 376 13 1234 1244 33 Alcock RF, Yong AS, Ng AC, Chow V, Cheruvu C, Aliprandi-Costa B, et al. Acute coronary syndrome and stable coronary artery disease: are they so different? Long-term outcomes in a contemporary PCI cohort. Int J Cardiol. 2013;167(4):1343-6. Alcock RF Yong AS Ng AC Chow V Cheruvu C Aliprandi-Costa B Acute coronary syndrome and stable coronary artery disease: are they so different? Long-term outcomes in a contemporary PCI cohort Int J Cardiol 2013 167 4 1343 1346 34 Hakeem A, Edupuganti MM, Almomani A, Pothineni NV, Payne J, Abualsuod AM, et al. Long-term prognosis of deferred acute coronary syndrome lesions based on nonischemic fractional flow reserve. Am Coll Cardiol. 2016;68(11):1181-91. Hakeem A Edupuganti MM Almomani A Pothineni NV Payne J Abualsuod AM Long-term prognosis of deferred acute coronary syndrome lesions based on nonischemic fractional flow reserve Am Coll Cardiol 2016 68 11 1181 1191 35 Morrow DA. Cardiovascular risk prediction in patients with stable and unstable coronary heart disease. Circulation. 2010;121(24):2681-91. Morrow DA Cardiovascular risk prediction in patients with stable and unstable coronary heart disease Circulation 2010 121 24 2681 2691 36 Mahaffey KW, Wojdyla DM, Pieper KS, Tricoci P, Alexander JH, Lincoff AM, et al. Comparison of clinical trial outcome patterns in patients following acute coronary syndromes and in patients with chronic stable atherosclerosis. Clin Cardiol. 2014;37(6):337-42. Mahaffey KW Wojdyla DM Pieper KS Tricoci P Alexander JH Lincoff AM Comparison of clinical trial outcome patterns in patients following acute coronary syndromes and in patients with chronic stable atherosclerosis Clin Cardiol 2014 37 6 337 342 37 Lee JM, Choi KH, Koo BK, Shin ES, Nam CW, Doh JH, et al. Prognosis of deferred non-culprit lesions according to fractional flow reserve in patients with acute coronary syndrome. Eurointervention. 2017;13(9):e1112-9. Lee JM Choi KH Koo BK Shin ES Nam CW Doh JH Prognosis of deferred non-culprit lesions according to fractional flow reserve in patients with acute coronary syndrome Eurointervention 2017 13 9 e1112 e1119 38 Van Belle E, Baptista SB, Raposo L, Henderson J, Rioufol G, Santos L, et al; PRIME-FFR Study Group. Impact of Routine Fractional Flow Reserve on Management Decision and 1-Year Clinical Outcome of Patients With Acute Coronary Syndromes: PRIME-FFR (Insights From the POST-IT [Portuguese Study on the Evaluation of FFR-Guided Treatment of Coronary Disease] and R3F [French FFR Registry] Integrated Multicenter Registries - Implementation of FFR [Fractional Flow Reserve] in Routine Practice). Circ Cardiovasc Interv. 2017; 10(6). pii: e004296 Van Belle E Baptista SB Raposo L Henderson J Rioufol G Santos L PRIME-FFR Study Group Impact of Routine Fractional Flow Reserve on Management Decision and 1-Year Clinical Outcome of Patients With Acute Coronary Syndromes: PRIME-FFR (Insights From the POST-IT [Portuguese Study on the Evaluation of FFR-Guided Treatment of Coronary Disease] and R3F [French FFR Registry] Integrated Multicenter Registries - Implementation of FFR [Fractional Flow Reserve] in Routine Practice) Circ Cardiovasc Interv 2017 10 6 e004296 39 Van Belle E, Rioufol G, Pouillot C, Cuisset T, Bougrini K, Teiger E, et al; Investigators of the Registre Français de la FFR-R3F. 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(2):173-85. Van Belle E Rioufol G Pouillot C Cuisset T Bougrini K Teiger E Investigators of the Registre Français de la FFR-R3F 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 2 173 185 40 Baptista SB, Raposo L, Santos L, Ramos R, Calé R, Jorge E, et al. Impact of routine fractional flow reserve evaluation during coronary angiography on management strategy and clinical outcome: one-year results of the prospective POST-IT multicenter registry. Circ Cardiovasc Interv. 2016;9(7). pii: e003288. Baptista SB Raposo L Santos L Ramos R Calé R Jorge E Impact of routine fractional flow reserve evaluation during coronary angiography on management strategy and clinical outcome: one-year results of the prospective POST-IT multicenter registry Circ Cardiovasc Interv 2016 9 7 e003288 41 Fearon WF, De Bruyne B, Pijls NHJ. Fractional flow reserve in acute coronary syndromes. J Am Coll Cardiol. 2016;68(11):1192-4. Fearon WF De Bruyne B Pijls NHJ Fractional flow reserve in acute coronary syndromes J Am Coll Cardiol 2016 68 11 1192 1194 42 Rodés-Cabau J, Gutiérrez M, Courtis J, Larose E, Déry JP, Côté M, et al. Importance of diffuse atherosclerosis in the functional evaluation of coronary stenosis in the proximal-mid segment of a coronary artery by myocardial fractional flow reserve measurements. Am J Cardiol 2011;108(4):483-90. Rodés-Cabau J Gutiérrez M Courtis J Larose E Déry JP Côté M Importance of diffuse atherosclerosis in the functional evaluation of coronary stenosis in the proximal-mid segment of a coronary artery by myocardial fractional flow reserve measurements Am J Cardiol 2011 108 4 483 490 43 Adjedj J, Toth GG, Johnson NP, Pellicano M, Ferrara A, Floré V, et al. Intracoronary adenosine: dose-response relationship with hyperemia. JACC Cardiovasc Interv. 2015;8(11):1422-30. Adjedj J Toth GG Johnson NP Pellicano M Ferrara A Floré V Intracoronary adenosine: dose-response relationship with hyperemia JACC Cardiovasc Interv 2015 8 11 1422 1430 44 Esen AM, Acar G, Esen O, Emiroglu Y, Akcakoyun M, Pala S, et al. The prognostic value of combined fractional flow reserve and TIMI frame count measurements in patients with stable angina pectoris and acute coronary syndrome. J Interv Cardiol. 2010;23(5):421-8. Esen AM Acar G Esen O Emiroglu Y Akcakoyun M Pala S The prognostic value of combined fractional flow reserve and TIMI frame count measurements in patients with stable angina pectoris and acute coronary syndrome J Interv Cardiol 2010 23 5 421 428 Artigo Original Estratégia Guiada por Reserva de Fluxo Fracionada na Síndrome Coronária Aguda: Revisão Sistemática Metanálise Martins José Luís 1 Afreixo Vera 2 Santos José 1 Gonçalves Lino 3 Department of Cardiology, Baixo Vouga Hospital Center, Aveiro - Portugal CIDMA/IBIMED/Department of Mathematics, University of Aveiro, Aveiro - Portugal Department of Cardiology, Coimbra Universitary Hospital Center, Coimbra - Portugal Correspondência: José Luis Martins, Av. Artur Ravara. Aveiro E-mail: zeluismartins@gmail.com

Contribuição dos autores

Concepção e desenho da pesquisa, Obtenção de dados, Análise e interpretação dos dados e Redação do manuscrito: Martins JL; Análise estatística: Martins JL, Afreixo V; Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Martins JL, Afreixo V, Santos J, Gonçalves L.

Potencial conflito de interesses

Declaro não haver conflito de interesses pertinentes.

 Resumo Fundamento:

Existem dados limitados sobre o prognóstico do adiamento do tratamento das lesões em pacientes com síndrome coronária com base na reserva de fluxo fracionada (FFR).

 Objetivos:

Realizar uma revisão sistemática da evidência atual sobre o prognóstico do adiamento do tratamento de lesões em pacientes com SCA com base na FFR, comparando-o com o prognóstico em pacientes sem SCA.

 Métodos:

Pesquisamos as bases de dados do Medline, EMBASE, e Cochrane Library por estudos publicados entre janeiro de 2000 e setembro de 2017 que compararam o prognóstico do adiamento da revascularização das lesões com base na FFR em pacientes com SCA em comparação a pacientes sem SCA. Conduzimos uma metanálise do risco relativo de quatro desfechos primários: mortalidade, mortalidade cardiovascular, infarto do miocárdio (IM) e revascularização do vaso-alvo (TVR).

 Resultados:

Identificamos sete estudos que incluíram um total de 5107 pacientes. A metanálise mostrou que não houve diferença quanto à mortalidade [risco relativo (RR) = 1,44; IC95%, 0,9-2,4), mortalidade cardiovascular (RR = 1,29; IC95% = 0,4-4,3) e TVR (RR = 1,46; IC95% = 0,9-2,3) após adiamento da revascularização com base na FFR entre pacientes com SCA e pacientes sem SCA. Tal adiamento foi associado com risco adicional de IM (RR = 1,83; IC95% = 1,4-2,4) em pacientes com SCA.

 Conclusão:

O valor prognóstico da FFR na SCA não é tão bom como em pacientes estáveis. Os resultados mostram um risco aumentado de IM, mas não de mortalidade, mortalidade cardiovascular, e TVR em pacientes com SCA.

 Palavras-chave: Síndrome Coronariana Aguda/fisiopatologia Intervenção Coronária Percutânea/métodos Angiografia Coronária/métodos Reserva Fracionada de Fluxo Miocárdio/fisiologia Microvasos Resistência Vascular Reprodutibilidade dos Testes Introdução

A reserva de fluxo fracionada (do inglês “fractional flow reserve, FFR”) é um método bem validado e eficaz para determinar a relevância funcional de lesões coronarianas intermediárias; a intervenção coronária percutânea (ICP) guiada pela FFR melhora os desfechos clínicos de pacientes com doença coronária estável.1-3 Apesar dos dados consistentes a favor do uso da FFR na doença coronária estável, seu uso na síndrome coronariana aguda (SCA) não é tão bem investigado, uma vez que uma medida precisa da FFR requer uma hiperemia máxima. Em pacientes com SCA, alterações microvasculares podem prevenir a vasodilatação, afetando a validade da FFR.1,4-6 Tais alterações parecem ser dependentes do vaso (culpado ou não culpado) e relacionadas ao tipo de infarto - infarto com supradesnivelamento do segmento IAMCSST vs. infarto sem supradesnivelamento do segmento IAMSSST.7 Os valores de FFR no vaso culpado são reconhecidamente mais elevados quando medidos durante episódios agudos que os medidos depois que a microcirculação teve algum tempo para se recuperar. Supõe-se que valores mais altos de FFR sejam causados por níveis reduzidos de hiperemia no vaso culpado devido à embolização do trombo ou placa, disfunção microvascular isquêmica e miocárdio atordoado. Assim, a eficácia do uso da FFR em doença da artéria culpada ainda é incerta.8,9

A doença coronária de múltiplos vasos, observada em aproximadamente 30-50% dos pacientes com IAMCSST e 30-59% dos pacientes com IAMSSST, está associada a um prognóstico ruim.10-12 A revascularização de vasos considerados importantes do ponto de vista hemodinâmico, identificados no laboratório de hemodinâmica logo após o evento agudo, parece atrativo - essa abordagem fornece um plano terapêutico definitivo, bem estabelecido ao paciente. No entanto, vários estudos sugerem que uma estratégia de revascularização guiada por FFR reduz a taxa de revascularização coronária sem comprometer a segurança em curto prazo.13-15 Contudo, os resultados dessa abordagem são inconsistentes em muitos estudos com pacientes sem SCA.13,14

Portanto, os objetivos deste estudo é realizar uma revisão sistemática das evidências atuais sobre o adiamento da ICP com base na FFR em pacientes com SCA e as comparar com evidências dessa decisão em pacientes sem SCA.

 Métodos Fontes e busca dos dados

Fizemos uma busca sistemática nas bases de dados MEDLINE, EMBASE e Cochrane Library de artigos relevantes publicados entre janeiro de 2000 e setembro de 2017. Também foram pesquisadas revisões sistemáticas qualitativas disponíveis, para a busca de estudos adicionais. Os termos “Flow Fractional Reserve” OR “Acute Coronary Syndrome” foram usados na busca. Além disso, as referências dos estudos identificados nessa estratégia de busca também foram revisadas quanto a artigos potencialmente relevantes não identificados na busca. Não houve restrição de idioma.

 Seleção dos estudos

Primeiramente, o título e o resumo das citações foram rastreados por dois revisores independentes (JM e VA), que então selecionaram artigos completos. Outros estudos foram identificados revisando-se a bibliografia dos estudos incluídos e revisões relevantes. Discordâncias foram resolvidas por consenso. Os mesmos revisores avaliaram os artigos de forma independente, seguindo os seguintes critérios de inclusão: estudos que compararam os desfechos clínicos de lesões após adiamento da ICP com base na FFR entre pacientes com SCA e pacientes sem SCA (Figura 1).

Fluxograma dos estudos incluídos na metanálise.

Desfechos

Os desfechos estudados foram: mortalidade, mortalidade cardiovascular, infarto do miocárdio (IM), e revascularização do vaso alvo (TVR, do inglês target vessel revascularization) durante o período de acompanhamento. TVR foi definida como revascularização subsequente do vaso, por ICP ou cirúrgica. Em todos os estudos, no grupo SCA, a distinção entre lesões culpadas e não culpadas foi feita pelo cirurgião, sendo, portanto, subjetiva, tal como ocorre na prática clínica.

 Análise estatística

As variáveis contínuas foram expressas em média ± desvio padrão ou mediana (intervalo interquartil), e as variáveis categóricas expressas em números e porcentagens. Para calcular o efeito conjunto, utilizamos o inverso da variância assumindo um modelo de efeitos mistos e o método de DerSimonian e Laird assumindo um modelo de efeitos aleatórios.16 A homogeneidade entre os estudos foi avaliada pelo teste Q de Cochran e estatística I2 (os valores 0,25, 0,50, e 0,75 indicaram graus baixo, moderado e alto de heterogeneidade, respectivamente). O viés de publicação foi avaliado pelo gráfico de funil. Realizamos uma análise de sensibilidade para avaliar o impacto de cada estudo sobre os resultados. O MetaXL 2,0 (EpiGear International Pty Ltd, Wilston, Queensland, Austrália) foi usado para calcular o tamanho do efeito sobre a diferença do risco (diferença no risco de ocorrência entre o grupo tratado por revascularização e o grupo que recebeu tratamento conservador).

 Resultados Identificação do estudo

Inicialmente, a estratégia de busca identificou 129 citações. Dessas, 96 artigos foram excluídos após revisão do título e do resumo. Após avaliação dos estudos quanto aos critérios de seleção, excluímos outros 26 artigos. Um total de 7 estudos atingiram os critérios para a metanálise, incluindo 5107 pacientes (3540 sem SCA e 1567 com SCA).

 Características dos estudos incluídos

Dos 7 estudos incluídos, 1 estudo foi prospectivo, e 6 eram observacionais, com delineamento retrospectivo (Tabelas 1 e 2).

Características dos estudos incluídos
Autor Ano Acompanhamento Delineamento do estudo Acompanhamento Total Idade (anos) Homens Sem SCA (n) SCA (n) IAMSST (n) IAMSSST/AI (n) Valor de FFR usado para adiamento do tratamento Tempo mediano entre apresentação clínica e medida de FFR Doença de múltiplos vasos Administração de adenosina Critérios de exclusão
Potvin JM et al 9 2006 11 ± 6 meses Coorte retrospectivo 201 62 ± 10 131 61 124 11 113 ≥ 0,75 24 horas (2 - 144 horas) NR Administração intracoronária de adenosina - dose mediana 60ug (30-300 µg) para a artéria coronária esquerda, e 30 µg (18‑120 µg) para artéria coronária direita e/ou nitroprussiato - dose mediana 250 µg (100-1000 µg) para as artérias coronárias esquerda e direita. A adenosina intracoronária foi usada em 135 casos, nitroprussiato intracoronário em 14 casos, e adenosina mais nitroprusisiato em 52 casos. Foram excluídos pacientes com 24 horas de IAMST
Fischer J et al 8 2006 12 meses Coorte retrospectivo 111 SCA → 58 ± 14Sem SCA → 63 ± 10 72 76 35 11 24 ≥ 0,75 Recente(dentro de 7 dias) IM com elevação do segmento ST tratado com terapia lítica SCA → 9Sem SCA → 9 Adenosina intracoronária (30 µg em bolus na artéria coronária direita ou 40-60 ug em bolus na artéria coronária esquerda NR
Sels et al 24 2011 2 anos Coorte prospectivo 1005 SCA → 64,8 ± 10,7Sem SCA → 64,3 ± 10 744 677 328 0 328 ≥ 0,80 NR NR Adenosina endovenosa administrada a uma taxa de 140 µg/kg/min por uma veia central Critérios de exclusão foram doença na artéria esquerda principal, bypass coronário prévio, e IAMSTE < 5 dias antes da FFR não foi validado em IAMSTE recente. Pacientes admitidos por AI e IAMSSSTE com troponina positiva e creatinina quinase < 1000 U/l poderiam ser incluídos
Mehta et al 25 2015 4,5 ± 2,1 anos Coorte retrospectivo 674 SCA → 63,8 ± 11,9Sem SCA → 65,3 ± 10,2 380 340 334 7 327 > 0,80 NR SCA → 221Sem SCA → 209 Uso predominante de adenosina intracoronária com doses máximas similares para ambos os grupos (120 µg) NR
Hakeem A et al 34 2016 3,4 ± 1,6 anos Coorte retrospectivo 576 SCA → 66,6 ± 8Sem SCA → 64,7 ± 8,7 554 370 206 0 206 > 0,75 NR SCA → 135Sem SCA → 216 Adenosina ntravenosa (140 mg/kg/min) ou intracoronária (> 60 mg), A dose mediana de adenosina intracoronária em nossa coorte foi 130 mg NR
Van Belle et al 38 2017 1 ano Coorte retrospectivo 958 SCA → 66 ± 11,2Sem SCA → 66,4 ± 10 693 721 237 - - > 0,75 e > 0,80 NR NR NR NR
Lee JM et al 37 2017 722 dias Coorte retrospectivo 1596 SCA → 62,0 ± 11,1Sem SCA → 62,4 ± 9,4 1112 1295 301 0 301 > 0,80 NR NR Hiperemia foi induzida com administração intracoronária em bolus (80 µg na artéria coronária esquerda, 40 µg na artéroa coronária direita), intracoronária (240 µg/min) ou infusão endovenosa contínua (140 µg/Kg/min) de adenosina NR

SCA: síndrome coronária aguda; IAMSST: infarto do miocárdio com supradesnivelamento do segmento ST; IAMSSST: infarto do miocárdio sem supradesnivelamento do segmento ST; AI: angina instável; FFR: reserva de fluxo fracionada; ICP: intervenção coronária percutânea; IM: infarto do miocárdio; TVR: revascularização do vaso alvo; NR: não relatado.

 Desfechos clínicos de pacientes com SCA e pacientes sem SCA com tratamento adiado com base na reserva de fluxo fracionada (FFR)
Autor Ano Pacientes[FFR > ponto de corte] * Mortalidade Mortalidade cardiovascular Infarto do miocárdio Revascularização da lesão alvo Revascularização do vaso alvo
Potvin JM et al, 9 2006 SCA → 124Sem SCA → 61 NR SCA → 0 Sem SCA → 1 SCA → 2 Sem SCA → 1 NR SCA → 11 Sem SCA → 7
Fischer J, et al, 8 2006 SCA → 35Sem SCA → 76 SCA → 3Sem SCA → 5 SCA → 2 Sem SCA → 1 SCA → 1Sem SCA → 1 NR SCA → 6Sem SCA → 7
Sels et al, 24 2011 NR ** SCA → 12Sem SCA → 20 NR Sem SCA → 36Sem SCA → 44 NR SCA → 45Sem SCA → 72
Mehta et al, 25 2015 SCA → 334Sem SCA → 340 NR SCA → 23 Sem SCA → 8 SCA → 47Sem SCA → 26 SCA → 78Sem SCA → 66 NR
Hakeem A et al, 34 2016 SCA → 206Sem SCA → 370 NR SCA → 9Sem SCA → 30 SCA → 16Sem SCA → 11 ACS → 36 Sem SCA → 29 SCA → 15 Sem SCA → 14
Van Belle et al, 38 2017 SCA → 237Sem SCA → 721 SCA → 10Sem SCA → 17 NR SCA → 3Sem SCA → 7 NR NR ***SCA → 9;***Sem SCA → 42
Lee JM et al, 2017 SCA → 301Sem SCA → 1295 NR SCA → 3Sem SCA → 5 SCA → 2Sem SCA → 4 SCA → 8Sem SCA → 10

SCA: síndrome coronária aguda; NR: não relatado.

Os pontos de corte variaram entre 0,75 e 0,80 entre os estudos;

Sels et al. avaliaram se há uma diferença no efeito benéfico do uso da reserva de fluxo fracionada (FFR) na orientação da intervenção coronária percutânea (ICP) na doença coronária de múltiplos vasos em pacientes com síndrome coronária aguda vs. pacientes sem SCA, sem discriminar pacientes com FFR > 0,80;

Revascularização do vaso alvo (TVR) não foi especificada.

 Síntese quantitativa dos desfechos

Mortalidade: Incluímos 3 estudos, um total de 2074 pacientes na análise. O gráfico de floresta (Figura 2) descreve a metanálise ponderada para o risco relativo da mortalidade em pacientes com SCA em comparação a pacientes sem SCA, quando as decisões relativas à revascularização foram feitas com base na FFR. A análise mostrou heterogeneidade mínima entre os estudos (I2 = 0%; p = 0,78), e não houve diferença significativa entre os pacientes com SCA e sem SCA; o valor do RR total foi 1,44 (IC95% = 0,89-2,35). A exclusão de qualquer estudo não alterou de maneira significativa esses resultados.

Gráficos de floresta do risco relativo dos desfechos. (A) mortalidade, (B) mortalidade cardiovascular; (C) infarto do miocárdio; (D) revascularização do vaso alvo. O tamanho dos marcadores dos dados reflete o peso relativo do estudo. IC: intervalo de confiança.

Mortalidade cardiovascular: incluímos na análise 5 estudos, um total de 3144 pacientes. O gráfico de floresta (Figura 2) descreve a metanálise ponderada do risco de mortalidade da realização de revascularização com base na FFR. Houve heterogeneidade significativa entre os estudos (I2 = 70%; p = 0.01) e não foi observada diferença significativa entre pacientes com SCA e pacientes sem SCA; o RR total foi de 1,29 (IC95% = 0,39-4.25). A exclusão de qualquer dos estudos não alterou de maneira significativa o resultado conjunto.

Infarto do miocárdio: foram incluídos sete estudos, com um total de 5107 pacientes em análise conjunta. Lesões diferidas com base na FFR associou-se com um risco adicional significativo de IM (RR = 1,83; IC95% = 1,39-2,40) em pacientes com SCA em comparação a pacientes sem SCA. A Figura 2 descreve metanálise ponderada para IM. A análise combinada mostrou pouca heterogeneidade entre os estudos (I2 = 0%; p = 0,96).

Revascularização do vaso alvo: Incluímos na análise 5 estudos, um total de 3475 pacientes. O gráfico de floresta (Figura 2) descreve a metanálise ponderada da TVR em pacientes quando as decisões de revascularização foram tomadas com base na FFR. A análise dos estudos mostrou pouca heterogeneidade entre eles (I2 = 39%; p = 0,16). Não foi observada diferença entre pacientes com SCA e sem SCA quanto ao RR de TVR; o RR total foi 1,46 (IC95% = 0,93 - 2,29).

 Viés do estudo

A análise visual dos gráficos de funil dos desfechos não revelou assimetria entre os estudos. O teste de Begg não foi estatisticamente significativo.

 Discussão

O estudo apresenta revisão sistemática e metanálise comparando a estratégia de diferir lesões e portanto sem revascularização com base no FFR em doentes com ACS e sem ACS. A revascularização guiada por FFR em pacientes com SCA parece ser tão segura como em pacientes sem SCA.2,17,18 Briasoulis et al.,15 em uma metanálise, avaliaram a abordagem guiada por FFR em pacientes com IAMSSST, em que se observou uma pequena redução na incidência de IM, sem diferenças significativas na incidência de eventos cardíacos adversos importantes (MACE), óbito ou mortalidade por todas as causas, e revascularização do vaso alvo entre a abordagem guiada por FFR em comparação à abordagem guiada por angiografia.15

Disfunção microvascular: O momento da medida da FFR em pacientes com SCA é uma questão importante. Como descrito acima, imediatamente após IM, a lesão inicial e temporária causada pelo meio inflamatório pode aumentar artificialmente as medidas iniciais de FFR. A terapia antitrombótica, administrada por 3-4 dias para estabilizar a placa, pode reduzir a disfunção microvascular, e a FFR pode, assim, refletir a situação hemodinâmica real. Essa abordagem, em que se espera mais que 5 dias para medir a FFR em pacientes com SCA, foi sugerida pela Sociedade Europeia de Cardiologia.19-21 Contudo, a maioria dos centros de referência em que se investiga a FFR em pacientes com SCA realizam avaliação invasiva em pacientes com SCA precocemente, dentro de 48 horas, prática que poderia elevar os valores da FFR artificialmente.19,22-27,34,37,38

Instabilidade da placa: Pelo menos dois terços das lesões originadas dos vasos com estenose < 50% são responsáveis por síndromes instáveis envolvendo instabilidade da placa, assumindo-se que esses vasos apresentavam um fluxo prévio normal. Uma lesão não culpada, que não compromete o fluxo, pode ser “anatomicamente significativa”, mas “fisiologicamente não significativa”, e uma vez que a FFR não objetiva avaliar as características da placa, deve-se ter cuidado no uso da FFR em vasos com características de instabilidade, mas fluxo normal.28,29

Massa miocárdica envolvida: a massa do miocárdio viável perfundido pela artéria em questão é importante em termos fisiopatológicos para a interpretação dos resultados da FFR em pacientes com SCA. O valor da FFR é inversamente proporcional à fração de ejeção: assim, uma fração de ejeção mais baixa, que implica uma ampla área infartada e menor área de miocárdio viável, poderia resultar em uma maior leitura de FFR para o mesmo grau de estenose.14,30

Apresentação da SCA: Pelo fato de ACS descreverem uma gama de status de isquemia do miocárdio com características clínicas e fisiopatológicas distintas, o uso da FFR deveria ser diferenciado pelo tipo de ACS. Os estudos DANAMI3-PRIMULTI e COMPARE ACUTE foram os únicos a avaliarem o risco de eventos subsequentes à IPC guiada por FFR em pacientes com IAMSTE e doença de múltiplos vasos.31,32 Desses, somente o COMPARE ACUTE relatou a taxa de eventos em pacientes em que a ICP foi adiada com base na FFR; pacientes não submetidos à revascularização adicional tiveram uma taxa de evento similar àqueles que foram revascularizados com base em uma FFR positiva (elevada). Por outro lado, o estudo FAME, incluindo 328 pacientes com SCA de um total de 1005 pacientes com doença de múltiplos vasos, relatou taxas similares de mortalidade, IM e revascularização em pacientes com SCA sem elevação do segmento ST.24 Contudo, o estudo FAME não definiu o momento exato da medida da FFR ou as lesões avaliadas (culpadas vs. não culpadas). Além disso, a taxa de eventos em pacientes com ICP adiada com base na FFR não foi relatada. Ainda, o estudo FAMOUS-NSTEMI comparou uma abordagem guiada por FFR e outra em que se realizou somente angiografia em pacientes com IAMSSST e doença de múltiplos vasos. A taxa dos principais eventos adversos cardíacos, definidos como mortalidade cardíaca ou internação por IM ou insuficiência cardíaca, foi 7,5% em pacientes com ICP adiada com base na FFR e 0% naqueles com ICP adiada com base na angiografia.13

O objetivo desta análise não foi avaliar decisões guiadas por FFR por lesão, e sim focar na importância dessas decisões por pacientes, considerando que pacientes com SCA frequentemente apresentam mais de uma lesão adequada para revascularização e que a identificação de lesões culpadas não é sempre direta. Sem dúvida, pacientes com doença de múltiplos vasos apresentam piores desfechos que pacientes com doença coronariana em um único vaso. Sabe-se que a história natural de pacientes revascularizados em condição aguda é diferente daquela de pacientes revascularizados em condição estável.33 Por exemplo, a probabilidade de disritmias malignas é significativamente mais comum em pacientes agudos, e é importante causa de mortalidade.33

Esta revisão sistemática e metanálise resume todos os estudos publicados que avaliaram e compararam desfechos clínicos em que as decisões de revascularização foram baseadas na FFR em SCA versus síndrome coronariana não aguda. Entre os desfechos avaliados, somente o RR do IM foi significativamente maior em pacientes com SCA.

O risco mais elevado de IM subsequente encontrado neste estudo e por vários autores é explicado pela diferente fisiopatologia da SCA em comparação à doença coronariana estável.34-36 Hakeem et al. compararam os desfechos em pacientes com IAMSSST não submetidos à ICP com base na FFR àqueles em um grupo similar sem SCA. Após uma média de acompanhamento de 3,4 anos, utilizando-se pareamento por escore de propensão, as taxas de IM e de TVR foram mais altas em pacientes com IAMSSST que em pacientes sem SCA (25% vs. 12%, respectivamente; p < 0,0001).34 Resultados semelhantes foram recentemente relatados por Lee et al. em pacientes sem SCA.37

Quando uma lesão decorrente de IM (definida como qualquer IM atribuído ao adiamento da revascularização das lesões com base na FFR) foi especificamente avaliada, o adiamento do tratamento das lesões com base na FFR não foi significativamente diferente no RR da lesão pós-infarto entre pacientes com SCA e sem SCA [RR 1,84 (IC95% = 0,82-4,11); (I2 = 0%; p = 0,98)] (Figura 3).

Gráfico de floresta do risco relativo da lesão do infarto do miocárdio. O tamanho dos marcadores dos dados reflete o peso relativo do estudo. IC: intervalo de confiança.

Se por um lado, Briasoulis et al.,15 mostraram que a estratégia guiada por FFR na SCA parece estar associada a um melhor prognóstico em comparação à estratégia em que se usou apenas angiografia, o principal achado de nosso estudo foi o fato de que o adiamento do tratamento de lesões em pacientes com SCA associou-se a um risco aumentado de IM em comparação a pacientes sem SCA, representado pelos RRs da revascularização do vaso alvo ou lesão pós infarto.15 Além disso, mortalidade e mortalidade cardiovascular não foram diferentes entre pacientes com SCA e pacientes sem SCA.

Nossos resultados estão de acordo com os publicados recentemente por Van Belle et al.,38,39 que compararam o impacto de se adiar o tratamento de lesões intermediárias com base na FFR sobre o prognóstico de pacientes com SCA vs. pacientes sem SCA de dois importantes registros (R3F e POST-iT). Os autores concluíram que as decisões sobre revascularização tomadas com base na FFR em relação ao adiamento do tratamento das lesões foram seguras em pacientes com SCA.38-40

Alguns autores têm questionado se devemos ser menos permissivos e adotarmos um ponto de corte diferente para FFR em vasos instáveis. Recentemente, Hakeem et al.,34 determinaram que o melhor ponto de corte para predizer IM ou TVR é > 0,80 em pacientes com doença arterial coronariana estável, corroborando a prática atual. Contudo, em pacientes com SCA sem supradesnivelamento do segmento ST, o melhor ponto de corte foi > 0,84. No entanto, algumas limitações sugeridas por alguns autores devem ser consideradas. Por exemplo, não está claro por que mortalidade, o principal desfecho, não foi incluído no desfecho composto nesse estudo. Além disso, a terapia medicamentosa não foi ótima para os pacientes, 14% dos pacientes não receberam estatina, e aproximadamente dois terços não recebeu terapia antiplaquetária dupla. Ainda, várias questões técnicas podem explicar o maior ponto de corte de FFR observado por esses autores.34,41-43

Apesar de a maioria dos estudos não demonstrarem desfechos clínicos por tipo de lesão (culpada ou não culpada), a evidência atual sugere que, em pacientes com ACS, a disfunção microvascular pode ser menos evidente, e a capacidade de se atingir máxima hiperemia seja suficiente para se manter o uso diagnóstico da FFR, tanto em vasos culpados como em vasos não culpados.44

Além disso, dada a alta heterogeneidade dos critérios de inclusão, do período de acompanhamento e do vaso avaliado pela FFR, os resultados e a conclusão do presente estudo devem ser interpretados com cuidado.

Limitações

As conclusões tiradas desta metanálise estão sujeitas às limitações e diferenças dos estudos originais incluídos. Primeiramente, nossa metanálise incluiu tanto ensaios clínicos randomizados como estudos observacionais, a maioria sendo estudos observacionais. As conclusões deste estudo podem estar limitadas por vieses inerentes a estudos observacionais, tais como viés no delineamento, seleção e tratamento. Outra limitação em potencial é o possível viés de publicação pelo fato de os resultados terem incluído somente mortalidade em curto prazo.

 Conclusão

O valor prognóstico da FFR na SCA não é tão bom como em pacientes estáveis. Estudos mais homogêneos, incluindo populações maiores de pacientes, são necessários para se alcançar conclusões definitivas e robustas. Definição e interpretação cuidadosas dos resultados clínicos são importantes quando a análise da FFR é realizada somente no vaso, e não no paciente como um todo.

Fontes de financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação

Aprovação ética e consentimento informado

Este artigo não contém estudos com humanos ou animais realizados por nenhum dos autores.

 Agradecimentos

Agradecemos o CIDMA (Centro de Investigação e Desenvolvimento em Matemática e Aplicações) da Universidade de Aveiro pela análise estatística, e a FCT (Fundação para a Ciência e a Tecnologia) de Portugal (projeto UID/MAT/04106/2013).