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Comparison of Fractional Flow Reserve–Guided PCI and Coronary Bypass Surgery in 3-Vessel Disease
Study Overview
Objective: To determine whether fractional flow reserve (FFR)–guided percutaneous coronary intervention (PCI) is noninferior to coronary-artery bypass grafting (CABG) in patients with 3-vessel coronary artery disease (CAD).
Design: Investigator-initiated, multicenter, international, randomized, controlled trial conducted at 48 sites.
Setting and participants: A total of 1500 patients with angiographically identified 3-vessel CAD not involving the left main coronary artery were randomly assigned to receive FFR-guided PCI with zotarolimus-eluting stents or CABG in a 1:1 ratio. Randomization was stratified according to trial site and diabetes status.
Main outcome measures: The primary end point was major adverse cardiac or cerebrovascular event, defined as death from any cause, myocardial infarction (MI), stroke, or repeat revascularization. The secondary end point was defined as a composite of death, MI, or stroke.
Results: At 1 year, the incidence of the composite primary end point was 10.6% for patients with FFR-guided PCI and 6.9% for patients with CABG (hazard ratio [HR], 1.5; 95% CI, 1.1-2.2; P = .35 for noninferiority), which was not consistent with noninferiority of FFR-guided PCI compared to CABG. The secondary end point occurred in 7.3% of patients in the FFR-guided PCI group compared with 5.2% in the CABG group (HR, 1.4; 95% CI, 0.9-2.1). Individual findings for the outcomes comprising the primary end point for the FFR-guided PCI group vs the CABG group were as follows: death, 1.6% vs 0.9%; MI, 5.2% vs 3.5%; stroke, 0.9% vs 1.1%; and repeat revascularization, 5.9% vs 3.9%. The CABG group had more extended hospital stays and higher incidences of major bleeding, arrhythmia, acute kidney injury, and rehospitalization within 30 days than the FFR-guided PCI group.
Conclusion: FFR-guided PCI was not found to be noninferior to CABG with respect to the incidence of a composite of death, MI, stroke, or repeat revascularization at 1 year.
Commentary
Revascularization for multivessel CAD can be performed by CABG or PCI. Previous studies have shown superior outcomes in patients with multivessel CAD who were treated with CABG compared to PCI.1-3 The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial, which compared CABG to PCI in patients with multivessel disease or unprotected left main CAD, stratified the anatomic complexity based on SYNTAX score and found that patients with higher anatomic complexity with a high SYNTAX score derive larger benefit from CABG compared to PCI.4 Therefore, the current guidelines favor CABG over PCI in patients with severe 3-vessel disease, except for patients with a lower SYNTAX score (<22) without diabetes.5,6 However, except for a smaller size study,3 the previous trials that led to this recommendation used mostly first-generation drug-eluting stents and have not evaluated second-generation stents that have lower rates of in-stent restenosis and stent thrombosis. In addition, there have been significant improvements in PCI techniques since the study period, including the adoption of a radial approach and superior adjunct pharmacologic therapy. Furthermore, previous studies have not systematically investigated the use of FFR-guided PCI, which has been shown to be superior to angiography-guided PCI or medical treatment alone.7-9
In this context, Fearon and the FAME-3 trial investigators studied the use of FFR-guided PCI with second-generation zotarolimus drug-eluting stents compared to CABG in patients with 3-vessel CAD. They randomized patients with angiographically identified 3-vessel CAD in a 1:1 ratio to receive FFR-guided PCI or CABG at 48 sites internationally. Patients with left main CAD, recent ST-elevation MI, cardiogenic shock, and left-ventricular ejection fraction <30% were excluded. The study results (composite primary end point incidence of 10.6% for patients with FFR-guided PCI vs 6.9% in the CABG group [HR, 1.5; 95% CI, 1.1-2.2; P = 0.35 for noninferiority]) showed that FFR-guided PCI did not meet the noninferiority criterion.
Although the FAME-3 study is an important study, there are a few points to consider. First, 24% of the lesions had a FFR measured at >0.80. The benefit of FFR-guided PCI lies in the number of lesions that are safely deferred compared to angiography-guided PCI. The small number of deferred lesions could have limited the benefit of FFR guidance compared with angiography. Second, this study did not include all comers who had angiographic 3-vessel disease. Patients who had FFR assessment of moderate lesions at the time of diagnostic angiogram and were found to have FFR >0.80 or were deemed single- or 2-vessel disease were likely treated with PCI. Therefore, as the authors point out, the patients included in this study may have been skewed to a higher-risk population compared to previous studies.
Third, the study may not reflect contemporary interventional practice, as the use of intravascular ultrasound was very low (12%). Intravascular ultrasound–guided PCI has been associated with increased luminal gain and improved outcomes compared to angiography-guided PCI.10 Although 20% of the patients in each arm were found to have chronic total occlusions, the completeness of revascularization has not yet been reported. It is possible that the PCI arm had fewer complete revascularizations, which has been shown in previous observational studies to be associated with worse clinical outcomes.11,12
Although the current guidelines favor CABG over PCI in patients with multivessel disease, this recommendation is stratified by anatomic complexity.6 In fact, in the European guidelines, CABG and PCI are both class I recommendations for the treatment of 3-vessel disease with low SYNTAX score in patients without diabetes.5 Although the FAME-3 study failed to show noninferiority in the overall population, when stratified by the SYNTAX score, the major adverse cardiac event rate for the PCI group was numerically lower than that of the CABG group. The results from the FAME-3 study are overall in line with the previous studies and the current guidelines. Future studies are necessary to assess the outcomes of multivessel PCI compared to CABG using the most contemporary interventional practice and achieving complete revascularization in the PCI arm.
Applications for Clinical Practice
In patients with 3-vessel disease, FFR-guided PCI was not found to be noninferior to CABG; this finding is consistent with previous studies.
—Shubham Kanake, BS, Chirag Bavishi, MD, MPH, and Taishi Hirai, MD, University of Missouri, Columbia, MO
Disclosures: None.
1. Farkouh ME, Domanski M, Sleeper LA, et al; FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012;367(25):2375-2384. doi:10.1056/NEJMoa1211585
2. Serruys PW, Morice MC, Kappetein AP, et al; SYNTAX Investigators. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009;360(10):961-972. doi:10.1056/NEJMoa0804626
3. Park SJ, Ahn JM, Kim YH, et al; BEST Trial Investigators. Trial of everolimus-eluting stents or bypass surgery for coronary disease. N Engl J Med. 2015;372(13):1204-1212. doi:10.1056/NEJMoa1415447
4. Stone GW, Kappetein AP, Sabik JF, et al; EXCEL Trial Investigators. Five-year outcomes after PCI or CABG for left main coronary disease. N Engl J Med. 2019; 381(19):1820-1830. doi:10.1056/NEJMoa1909406
5. Neumann FJ, Sousa-Uva M, Ahlsson A, et al; ESC Scientific Document Group. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J. 2019;40(2):87-165. doi:10.1093/eurheartj/ehy394
6. Writing Committee Members, Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79(2):e21-e129. doi:10.1016/j.jacc.2021.09.006
7. Tonino PAL, De Bruyne B, Pijls NHJ, et al; FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213-224. doi:10.1056/NEJMoa0807611
8. De Bruyne B, Fearon WF, Pijls NHJ, et al; FAME 2 Trial Investigators. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med. 2014;371(13):1208-1217. doi:10.1056/NEJMoa1408758
9. Xaplanteris P, Fournier S, Pijls NHJ, et al; FAME 2 Investigators. Five-year outcomes with PCI guided by fractional flow reserve. N Engl J Med. 2018;379(3):250-259. doi:10.1056/NEJMoa1803538
10. Zhang J, Gao X, Kan J, et al. Intravascular ultrasound versus angiography-guided drug-eluting stent implantation: The ULTIMATE trial. J Am Coll Cardiol. 2018;72:3126-3137. doi:10.1016/j.jacc.2018.09.013
11. Garcia S, Sandoval Y, Roukoz H, et al. Outcomes after complete versus incomplete revascularization of patients with multivessel coronary artery disease: a meta-analysis of 89,883 patients enrolled in randomized clinical trials and observational studies. J Am Coll Cardiol. 2013;62:1421-1431. doi:10.1016/j.jacc.2013.05.033
12. Farooq V, Serruys PW, Garcia-Garcia HM et al. The negative impact of incomplete angiographic revascularization on clinical outcomes and its association with total occlusions: the SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) trial. J Am Coll Cardiol. 2013;61:282-294. doi: 10.1016/j.jacc.2012.10.017
Study Overview
Objective: To determine whether fractional flow reserve (FFR)–guided percutaneous coronary intervention (PCI) is noninferior to coronary-artery bypass grafting (CABG) in patients with 3-vessel coronary artery disease (CAD).
Design: Investigator-initiated, multicenter, international, randomized, controlled trial conducted at 48 sites.
Setting and participants: A total of 1500 patients with angiographically identified 3-vessel CAD not involving the left main coronary artery were randomly assigned to receive FFR-guided PCI with zotarolimus-eluting stents or CABG in a 1:1 ratio. Randomization was stratified according to trial site and diabetes status.
Main outcome measures: The primary end point was major adverse cardiac or cerebrovascular event, defined as death from any cause, myocardial infarction (MI), stroke, or repeat revascularization. The secondary end point was defined as a composite of death, MI, or stroke.
Results: At 1 year, the incidence of the composite primary end point was 10.6% for patients with FFR-guided PCI and 6.9% for patients with CABG (hazard ratio [HR], 1.5; 95% CI, 1.1-2.2; P = .35 for noninferiority), which was not consistent with noninferiority of FFR-guided PCI compared to CABG. The secondary end point occurred in 7.3% of patients in the FFR-guided PCI group compared with 5.2% in the CABG group (HR, 1.4; 95% CI, 0.9-2.1). Individual findings for the outcomes comprising the primary end point for the FFR-guided PCI group vs the CABG group were as follows: death, 1.6% vs 0.9%; MI, 5.2% vs 3.5%; stroke, 0.9% vs 1.1%; and repeat revascularization, 5.9% vs 3.9%. The CABG group had more extended hospital stays and higher incidences of major bleeding, arrhythmia, acute kidney injury, and rehospitalization within 30 days than the FFR-guided PCI group.
Conclusion: FFR-guided PCI was not found to be noninferior to CABG with respect to the incidence of a composite of death, MI, stroke, or repeat revascularization at 1 year.
Commentary
Revascularization for multivessel CAD can be performed by CABG or PCI. Previous studies have shown superior outcomes in patients with multivessel CAD who were treated with CABG compared to PCI.1-3 The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial, which compared CABG to PCI in patients with multivessel disease or unprotected left main CAD, stratified the anatomic complexity based on SYNTAX score and found that patients with higher anatomic complexity with a high SYNTAX score derive larger benefit from CABG compared to PCI.4 Therefore, the current guidelines favor CABG over PCI in patients with severe 3-vessel disease, except for patients with a lower SYNTAX score (<22) without diabetes.5,6 However, except for a smaller size study,3 the previous trials that led to this recommendation used mostly first-generation drug-eluting stents and have not evaluated second-generation stents that have lower rates of in-stent restenosis and stent thrombosis. In addition, there have been significant improvements in PCI techniques since the study period, including the adoption of a radial approach and superior adjunct pharmacologic therapy. Furthermore, previous studies have not systematically investigated the use of FFR-guided PCI, which has been shown to be superior to angiography-guided PCI or medical treatment alone.7-9
In this context, Fearon and the FAME-3 trial investigators studied the use of FFR-guided PCI with second-generation zotarolimus drug-eluting stents compared to CABG in patients with 3-vessel CAD. They randomized patients with angiographically identified 3-vessel CAD in a 1:1 ratio to receive FFR-guided PCI or CABG at 48 sites internationally. Patients with left main CAD, recent ST-elevation MI, cardiogenic shock, and left-ventricular ejection fraction <30% were excluded. The study results (composite primary end point incidence of 10.6% for patients with FFR-guided PCI vs 6.9% in the CABG group [HR, 1.5; 95% CI, 1.1-2.2; P = 0.35 for noninferiority]) showed that FFR-guided PCI did not meet the noninferiority criterion.
Although the FAME-3 study is an important study, there are a few points to consider. First, 24% of the lesions had a FFR measured at >0.80. The benefit of FFR-guided PCI lies in the number of lesions that are safely deferred compared to angiography-guided PCI. The small number of deferred lesions could have limited the benefit of FFR guidance compared with angiography. Second, this study did not include all comers who had angiographic 3-vessel disease. Patients who had FFR assessment of moderate lesions at the time of diagnostic angiogram and were found to have FFR >0.80 or were deemed single- or 2-vessel disease were likely treated with PCI. Therefore, as the authors point out, the patients included in this study may have been skewed to a higher-risk population compared to previous studies.
Third, the study may not reflect contemporary interventional practice, as the use of intravascular ultrasound was very low (12%). Intravascular ultrasound–guided PCI has been associated with increased luminal gain and improved outcomes compared to angiography-guided PCI.10 Although 20% of the patients in each arm were found to have chronic total occlusions, the completeness of revascularization has not yet been reported. It is possible that the PCI arm had fewer complete revascularizations, which has been shown in previous observational studies to be associated with worse clinical outcomes.11,12
Although the current guidelines favor CABG over PCI in patients with multivessel disease, this recommendation is stratified by anatomic complexity.6 In fact, in the European guidelines, CABG and PCI are both class I recommendations for the treatment of 3-vessel disease with low SYNTAX score in patients without diabetes.5 Although the FAME-3 study failed to show noninferiority in the overall population, when stratified by the SYNTAX score, the major adverse cardiac event rate for the PCI group was numerically lower than that of the CABG group. The results from the FAME-3 study are overall in line with the previous studies and the current guidelines. Future studies are necessary to assess the outcomes of multivessel PCI compared to CABG using the most contemporary interventional practice and achieving complete revascularization in the PCI arm.
Applications for Clinical Practice
In patients with 3-vessel disease, FFR-guided PCI was not found to be noninferior to CABG; this finding is consistent with previous studies.
—Shubham Kanake, BS, Chirag Bavishi, MD, MPH, and Taishi Hirai, MD, University of Missouri, Columbia, MO
Disclosures: None.
Study Overview
Objective: To determine whether fractional flow reserve (FFR)–guided percutaneous coronary intervention (PCI) is noninferior to coronary-artery bypass grafting (CABG) in patients with 3-vessel coronary artery disease (CAD).
Design: Investigator-initiated, multicenter, international, randomized, controlled trial conducted at 48 sites.
Setting and participants: A total of 1500 patients with angiographically identified 3-vessel CAD not involving the left main coronary artery were randomly assigned to receive FFR-guided PCI with zotarolimus-eluting stents or CABG in a 1:1 ratio. Randomization was stratified according to trial site and diabetes status.
Main outcome measures: The primary end point was major adverse cardiac or cerebrovascular event, defined as death from any cause, myocardial infarction (MI), stroke, or repeat revascularization. The secondary end point was defined as a composite of death, MI, or stroke.
Results: At 1 year, the incidence of the composite primary end point was 10.6% for patients with FFR-guided PCI and 6.9% for patients with CABG (hazard ratio [HR], 1.5; 95% CI, 1.1-2.2; P = .35 for noninferiority), which was not consistent with noninferiority of FFR-guided PCI compared to CABG. The secondary end point occurred in 7.3% of patients in the FFR-guided PCI group compared with 5.2% in the CABG group (HR, 1.4; 95% CI, 0.9-2.1). Individual findings for the outcomes comprising the primary end point for the FFR-guided PCI group vs the CABG group were as follows: death, 1.6% vs 0.9%; MI, 5.2% vs 3.5%; stroke, 0.9% vs 1.1%; and repeat revascularization, 5.9% vs 3.9%. The CABG group had more extended hospital stays and higher incidences of major bleeding, arrhythmia, acute kidney injury, and rehospitalization within 30 days than the FFR-guided PCI group.
Conclusion: FFR-guided PCI was not found to be noninferior to CABG with respect to the incidence of a composite of death, MI, stroke, or repeat revascularization at 1 year.
Commentary
Revascularization for multivessel CAD can be performed by CABG or PCI. Previous studies have shown superior outcomes in patients with multivessel CAD who were treated with CABG compared to PCI.1-3 The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial, which compared CABG to PCI in patients with multivessel disease or unprotected left main CAD, stratified the anatomic complexity based on SYNTAX score and found that patients with higher anatomic complexity with a high SYNTAX score derive larger benefit from CABG compared to PCI.4 Therefore, the current guidelines favor CABG over PCI in patients with severe 3-vessel disease, except for patients with a lower SYNTAX score (<22) without diabetes.5,6 However, except for a smaller size study,3 the previous trials that led to this recommendation used mostly first-generation drug-eluting stents and have not evaluated second-generation stents that have lower rates of in-stent restenosis and stent thrombosis. In addition, there have been significant improvements in PCI techniques since the study period, including the adoption of a radial approach and superior adjunct pharmacologic therapy. Furthermore, previous studies have not systematically investigated the use of FFR-guided PCI, which has been shown to be superior to angiography-guided PCI or medical treatment alone.7-9
In this context, Fearon and the FAME-3 trial investigators studied the use of FFR-guided PCI with second-generation zotarolimus drug-eluting stents compared to CABG in patients with 3-vessel CAD. They randomized patients with angiographically identified 3-vessel CAD in a 1:1 ratio to receive FFR-guided PCI or CABG at 48 sites internationally. Patients with left main CAD, recent ST-elevation MI, cardiogenic shock, and left-ventricular ejection fraction <30% were excluded. The study results (composite primary end point incidence of 10.6% for patients with FFR-guided PCI vs 6.9% in the CABG group [HR, 1.5; 95% CI, 1.1-2.2; P = 0.35 for noninferiority]) showed that FFR-guided PCI did not meet the noninferiority criterion.
Although the FAME-3 study is an important study, there are a few points to consider. First, 24% of the lesions had a FFR measured at >0.80. The benefit of FFR-guided PCI lies in the number of lesions that are safely deferred compared to angiography-guided PCI. The small number of deferred lesions could have limited the benefit of FFR guidance compared with angiography. Second, this study did not include all comers who had angiographic 3-vessel disease. Patients who had FFR assessment of moderate lesions at the time of diagnostic angiogram and were found to have FFR >0.80 or were deemed single- or 2-vessel disease were likely treated with PCI. Therefore, as the authors point out, the patients included in this study may have been skewed to a higher-risk population compared to previous studies.
Third, the study may not reflect contemporary interventional practice, as the use of intravascular ultrasound was very low (12%). Intravascular ultrasound–guided PCI has been associated with increased luminal gain and improved outcomes compared to angiography-guided PCI.10 Although 20% of the patients in each arm were found to have chronic total occlusions, the completeness of revascularization has not yet been reported. It is possible that the PCI arm had fewer complete revascularizations, which has been shown in previous observational studies to be associated with worse clinical outcomes.11,12
Although the current guidelines favor CABG over PCI in patients with multivessel disease, this recommendation is stratified by anatomic complexity.6 In fact, in the European guidelines, CABG and PCI are both class I recommendations for the treatment of 3-vessel disease with low SYNTAX score in patients without diabetes.5 Although the FAME-3 study failed to show noninferiority in the overall population, when stratified by the SYNTAX score, the major adverse cardiac event rate for the PCI group was numerically lower than that of the CABG group. The results from the FAME-3 study are overall in line with the previous studies and the current guidelines. Future studies are necessary to assess the outcomes of multivessel PCI compared to CABG using the most contemporary interventional practice and achieving complete revascularization in the PCI arm.
Applications for Clinical Practice
In patients with 3-vessel disease, FFR-guided PCI was not found to be noninferior to CABG; this finding is consistent with previous studies.
—Shubham Kanake, BS, Chirag Bavishi, MD, MPH, and Taishi Hirai, MD, University of Missouri, Columbia, MO
Disclosures: None.
1. Farkouh ME, Domanski M, Sleeper LA, et al; FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012;367(25):2375-2384. doi:10.1056/NEJMoa1211585
2. Serruys PW, Morice MC, Kappetein AP, et al; SYNTAX Investigators. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009;360(10):961-972. doi:10.1056/NEJMoa0804626
3. Park SJ, Ahn JM, Kim YH, et al; BEST Trial Investigators. Trial of everolimus-eluting stents or bypass surgery for coronary disease. N Engl J Med. 2015;372(13):1204-1212. doi:10.1056/NEJMoa1415447
4. Stone GW, Kappetein AP, Sabik JF, et al; EXCEL Trial Investigators. Five-year outcomes after PCI or CABG for left main coronary disease. N Engl J Med. 2019; 381(19):1820-1830. doi:10.1056/NEJMoa1909406
5. Neumann FJ, Sousa-Uva M, Ahlsson A, et al; ESC Scientific Document Group. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J. 2019;40(2):87-165. doi:10.1093/eurheartj/ehy394
6. Writing Committee Members, Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79(2):e21-e129. doi:10.1016/j.jacc.2021.09.006
7. Tonino PAL, De Bruyne B, Pijls NHJ, et al; FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213-224. doi:10.1056/NEJMoa0807611
8. De Bruyne B, Fearon WF, Pijls NHJ, et al; FAME 2 Trial Investigators. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med. 2014;371(13):1208-1217. doi:10.1056/NEJMoa1408758
9. Xaplanteris P, Fournier S, Pijls NHJ, et al; FAME 2 Investigators. Five-year outcomes with PCI guided by fractional flow reserve. N Engl J Med. 2018;379(3):250-259. doi:10.1056/NEJMoa1803538
10. Zhang J, Gao X, Kan J, et al. Intravascular ultrasound versus angiography-guided drug-eluting stent implantation: The ULTIMATE trial. J Am Coll Cardiol. 2018;72:3126-3137. doi:10.1016/j.jacc.2018.09.013
11. Garcia S, Sandoval Y, Roukoz H, et al. Outcomes after complete versus incomplete revascularization of patients with multivessel coronary artery disease: a meta-analysis of 89,883 patients enrolled in randomized clinical trials and observational studies. J Am Coll Cardiol. 2013;62:1421-1431. doi:10.1016/j.jacc.2013.05.033
12. Farooq V, Serruys PW, Garcia-Garcia HM et al. The negative impact of incomplete angiographic revascularization on clinical outcomes and its association with total occlusions: the SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) trial. J Am Coll Cardiol. 2013;61:282-294. doi: 10.1016/j.jacc.2012.10.017
1. Farkouh ME, Domanski M, Sleeper LA, et al; FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012;367(25):2375-2384. doi:10.1056/NEJMoa1211585
2. Serruys PW, Morice MC, Kappetein AP, et al; SYNTAX Investigators. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009;360(10):961-972. doi:10.1056/NEJMoa0804626
3. Park SJ, Ahn JM, Kim YH, et al; BEST Trial Investigators. Trial of everolimus-eluting stents or bypass surgery for coronary disease. N Engl J Med. 2015;372(13):1204-1212. doi:10.1056/NEJMoa1415447
4. Stone GW, Kappetein AP, Sabik JF, et al; EXCEL Trial Investigators. Five-year outcomes after PCI or CABG for left main coronary disease. N Engl J Med. 2019; 381(19):1820-1830. doi:10.1056/NEJMoa1909406
5. Neumann FJ, Sousa-Uva M, Ahlsson A, et al; ESC Scientific Document Group. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J. 2019;40(2):87-165. doi:10.1093/eurheartj/ehy394
6. Writing Committee Members, Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79(2):e21-e129. doi:10.1016/j.jacc.2021.09.006
7. Tonino PAL, De Bruyne B, Pijls NHJ, et al; FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213-224. doi:10.1056/NEJMoa0807611
8. De Bruyne B, Fearon WF, Pijls NHJ, et al; FAME 2 Trial Investigators. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med. 2014;371(13):1208-1217. doi:10.1056/NEJMoa1408758
9. Xaplanteris P, Fournier S, Pijls NHJ, et al; FAME 2 Investigators. Five-year outcomes with PCI guided by fractional flow reserve. N Engl J Med. 2018;379(3):250-259. doi:10.1056/NEJMoa1803538
10. Zhang J, Gao X, Kan J, et al. Intravascular ultrasound versus angiography-guided drug-eluting stent implantation: The ULTIMATE trial. J Am Coll Cardiol. 2018;72:3126-3137. doi:10.1016/j.jacc.2018.09.013
11. Garcia S, Sandoval Y, Roukoz H, et al. Outcomes after complete versus incomplete revascularization of patients with multivessel coronary artery disease: a meta-analysis of 89,883 patients enrolled in randomized clinical trials and observational studies. J Am Coll Cardiol. 2013;62:1421-1431. doi:10.1016/j.jacc.2013.05.033
12. Farooq V, Serruys PW, Garcia-Garcia HM et al. The negative impact of incomplete angiographic revascularization on clinical outcomes and its association with total occlusions: the SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) trial. J Am Coll Cardiol. 2013;61:282-294. doi: 10.1016/j.jacc.2012.10.017
FFR-Guided or Angiography-Guided Nonculprit Lesion PCI in Patients With STEMI Without Cardiogenic Shock
Study Overview
Objective. To determine whether fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) of nonculprit lesion in patients with ST-segment elevation myocardial infarction (STEMI) is superior to angiography-guided PCI.
Design. Multicenter randomized control trial blinded to outcome, conducted in 41 sites in France.
Setting and participants. A total of 1163 patients with STEMI and multivessel coronary disease, who had undergone successful PCI to the culprit lesion were randomized to either FFR-guided PCI or angiography-guided PCI for nonculprit lesions. Randomization was stratified according to the trial site and timing of the procedure (immediate or staged).
Main outcome measures. The primary outcome was a composite of death from any cause, nonfatal myocardial infarction (MI) or unplanned hospitalization leading to urgent revascularization at 1 year.
Main results. At 1 year, the primary outcome occurred in 32 of 586 patients (5.5%) in the FFR-guided group and in 24 of 577 (4.2%) in the angiography-guided group (hazard ratio [HR], 1.32; 95% CI, 0.78-2.23; P = .31). The rate of death (1.5% vs 1.7%), nonfatal MI (3.1% vs 1.7%), and unplanned hospitalization leading to urgent revascularization (3.1% vs 1.7%) were also similar between FFR-guided and angiography-guided groups.
Conclusion. Among patients with STEMI and multivessel disease who had undergone successful PCI of the culprit vessel, an FFR-guided strategy for complete revascularization was not superior to angiography-guided strategy for reducing death, MI, or urgent revascularization at 1 year.
Commentary
Patients presenting with STEMI often have multivessel disease.1 Recently, multiple studies have reported the benefit of nonculprit vessel revascularization in patients presenting with hemodynamically stable STEMI compared to culprit-only strategy including the most recent COMPLETE trial which showed reduction in death and MI.2-6 However, the previous studies have variable design in evaluating the nonculprit vessel, some utilized FFR guidance, while others used angiography guidance. Whether FFR-guided PCI of nonculprit vessel can improve outcome in patients presenting STEMI remains unknown.
In the FLOWER-MI study, Puymirat et al investigated the use of FFR compared to angiography-guided nonculprit vessel PCI. A total of 1163 patients presenting with STEMI and multivessel disease who had undergone successful PCI to the culprit vessel, were randomized to either FFR guidance or angiography guidance among 41 centers in France. The authors found that after 1 year, there was no difference in composite endpoint of death, nonfatal MI or unplanned hospitalization leading to urgent revascularization in the FFR-guided group compared to angiography-guided group (5.5% vs 4.2%, HR, 1.32; 95% CI, 0.678-2.23; P = .31). There was also no difference in individual components of primary outcomes or secondary outcomes such as rate of stent thrombosis, any revascularization, or hospitalization.
There are a few interesting points to consider in this study. Ever since the Fractional Flow Reserve vs Angiography for Multivessel Evaluation (FAME) trial reported the lower incidence of major adverse events in routine FFR measurement during PCI compared to angiography-guided PCI, physiological assessment has become the gold standard for treatment of stable ischemic heart disease.7 However, the results of the current FLOWER-MI trial were not consistent with the FAME trial and there are few possible reasons to consider.
First, the use of FFR in the setting of STEMI is less validated compared to stable ischemic heart disease.8 Microvascular dysfunction during the acute phase can affect the FFR reading and the lesion severity can be underestimated.8 Second, the rate of composite endpoint was much lower in this study compared to FAME despite using the same composite endpoint of death, nonfatal MI, and unplanned hospitalization leading to urgent revascularization. At 1 year, the incidence of primary outcome was 13.5% in the FFR-guided group compared to 18.6% in the angiography-guided group in the FAME study compared to 5.5% and 4.2% in the FLOWER-MI study, despite having a sicker population presenting with STEMI. This is likely due to improvement in the PCI techniques such as radial approach, imaging guidance, and advancement in medical therapy such as use of more potent antiplatelet therapy. With lower incidence of primary outcome, larger number of patients are needed to detect the difference in the composite outcome. Finally, the operators’ visual assessment may have been calibrated to the physiologic assessment as the operators are routinely using FFR assessment which may have diminished the benefit of FFR guidance seen in the early FAME study.
Another interesting finding from this study was that although the study protocol encouraged the operators to perform the nonculprit PCI in the same setting, only 4% had nonculprit PCI in the same setting and 96% of the patients underwent a staged PCI. The advantage of performing the nonculprit PCI on the same setting is to have 1 fewer procedure for the patient. On the other hand, the disadvantage of this approach includes prolongation of the index procedure, theoretically higher risk of complication during the acute phase and vasospasm leading to overestimation of the lesion severity. A recent analysis from the COMPLETE study did not show any difference when comparing staged PCI during the index hospitalization vs after discharge.9 The optimal timing of the staged PCI needs to be investigated in future studies.
A limitation of this study is the lower than expected incidence of clinical events decreasing the statistical power of the study. However, there was no signal that FFR-guided PCI is better compared to the angiography-guided group. In fact, the curve started to diverge at 6 months favoring the angiography-guided group. In addition, there was no core-lab analysis for completeness of revascularization.
Applications for Clinical Practice
In patients presenting with hemodynamically stable STEMI for undergoing nonculprit vessel PCI, both FFR-guided or angiography-guided strategies can be considered.
Financial disclosures: None.
1. Park DW, Clare RM, Schulte PJ, et al. Extent, location, and clinical significance of non-infarct-related coronary artery disease among patients with ST-elevation myocardial infarction. JAMA. 2014;312(19):2019-27. doi:10.1001/jama.2014.15095
2. Wald DS, Morris JK, Wald NJ, et al. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med. 2013;369(12):1115-23. doi:10.1056/NEJMoa1305520
3. Gershlick AH, Khan JN, Kelly DJ, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial. J Am Coll Cardiol. 2015;65(10):963-72. doi:10.1016/j.jacc.2014.12.038
4. Engstrøm T, Kelbæk H, Helqvist S, et al. Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial. Lancet. 2015;386(9994):665-71. doi:10.1016/s0140-6736(15)60648-1
5. Smits PC, Abdel-Wahab M, Neumann FJ, , et al. Fractional Flow Reserve-Guided Multivessel Angioplasty in Myocardial Infarction. N Engl J Med. 2017;376(13):1234-44. doi:10.1056/NEJMoa1701067
6. Mehta SR, Wood DA, Storey RF, et al. Complete Revascularization with Multivessel PCI for Myocardial Infarction. N Engl J Med. 2019;381(15):1411-21. doi:10.1056/NEJMoa1907775
7. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213-24. doi:10.1056/NEJMoa0807611
8. Thim T, van der Hoeven NW, Musto C, et al. Evaluation and Management of Nonculprit Lesions in STEMI. JACC Cardiovasc Interv. 2020;13(10):1145-54. doi:10.1016/j.jcin.2020.02.030
9. Wood DA, Cairns JA, Wang J, et al. Timing of Staged Nonculprit Artery Revascularization in Patients With ST-Segment Elevation Myocardial Infarction: COMPLETE Trial. J Am Coll Cardiol. 2019;74(22):2713-23. doi:10.1016/j.jacc.2019/09.051
Study Overview
Objective. To determine whether fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) of nonculprit lesion in patients with ST-segment elevation myocardial infarction (STEMI) is superior to angiography-guided PCI.
Design. Multicenter randomized control trial blinded to outcome, conducted in 41 sites in France.
Setting and participants. A total of 1163 patients with STEMI and multivessel coronary disease, who had undergone successful PCI to the culprit lesion were randomized to either FFR-guided PCI or angiography-guided PCI for nonculprit lesions. Randomization was stratified according to the trial site and timing of the procedure (immediate or staged).
Main outcome measures. The primary outcome was a composite of death from any cause, nonfatal myocardial infarction (MI) or unplanned hospitalization leading to urgent revascularization at 1 year.
Main results. At 1 year, the primary outcome occurred in 32 of 586 patients (5.5%) in the FFR-guided group and in 24 of 577 (4.2%) in the angiography-guided group (hazard ratio [HR], 1.32; 95% CI, 0.78-2.23; P = .31). The rate of death (1.5% vs 1.7%), nonfatal MI (3.1% vs 1.7%), and unplanned hospitalization leading to urgent revascularization (3.1% vs 1.7%) were also similar between FFR-guided and angiography-guided groups.
Conclusion. Among patients with STEMI and multivessel disease who had undergone successful PCI of the culprit vessel, an FFR-guided strategy for complete revascularization was not superior to angiography-guided strategy for reducing death, MI, or urgent revascularization at 1 year.
Commentary
Patients presenting with STEMI often have multivessel disease.1 Recently, multiple studies have reported the benefit of nonculprit vessel revascularization in patients presenting with hemodynamically stable STEMI compared to culprit-only strategy including the most recent COMPLETE trial which showed reduction in death and MI.2-6 However, the previous studies have variable design in evaluating the nonculprit vessel, some utilized FFR guidance, while others used angiography guidance. Whether FFR-guided PCI of nonculprit vessel can improve outcome in patients presenting STEMI remains unknown.
In the FLOWER-MI study, Puymirat et al investigated the use of FFR compared to angiography-guided nonculprit vessel PCI. A total of 1163 patients presenting with STEMI and multivessel disease who had undergone successful PCI to the culprit vessel, were randomized to either FFR guidance or angiography guidance among 41 centers in France. The authors found that after 1 year, there was no difference in composite endpoint of death, nonfatal MI or unplanned hospitalization leading to urgent revascularization in the FFR-guided group compared to angiography-guided group (5.5% vs 4.2%, HR, 1.32; 95% CI, 0.678-2.23; P = .31). There was also no difference in individual components of primary outcomes or secondary outcomes such as rate of stent thrombosis, any revascularization, or hospitalization.
There are a few interesting points to consider in this study. Ever since the Fractional Flow Reserve vs Angiography for Multivessel Evaluation (FAME) trial reported the lower incidence of major adverse events in routine FFR measurement during PCI compared to angiography-guided PCI, physiological assessment has become the gold standard for treatment of stable ischemic heart disease.7 However, the results of the current FLOWER-MI trial were not consistent with the FAME trial and there are few possible reasons to consider.
First, the use of FFR in the setting of STEMI is less validated compared to stable ischemic heart disease.8 Microvascular dysfunction during the acute phase can affect the FFR reading and the lesion severity can be underestimated.8 Second, the rate of composite endpoint was much lower in this study compared to FAME despite using the same composite endpoint of death, nonfatal MI, and unplanned hospitalization leading to urgent revascularization. At 1 year, the incidence of primary outcome was 13.5% in the FFR-guided group compared to 18.6% in the angiography-guided group in the FAME study compared to 5.5% and 4.2% in the FLOWER-MI study, despite having a sicker population presenting with STEMI. This is likely due to improvement in the PCI techniques such as radial approach, imaging guidance, and advancement in medical therapy such as use of more potent antiplatelet therapy. With lower incidence of primary outcome, larger number of patients are needed to detect the difference in the composite outcome. Finally, the operators’ visual assessment may have been calibrated to the physiologic assessment as the operators are routinely using FFR assessment which may have diminished the benefit of FFR guidance seen in the early FAME study.
Another interesting finding from this study was that although the study protocol encouraged the operators to perform the nonculprit PCI in the same setting, only 4% had nonculprit PCI in the same setting and 96% of the patients underwent a staged PCI. The advantage of performing the nonculprit PCI on the same setting is to have 1 fewer procedure for the patient. On the other hand, the disadvantage of this approach includes prolongation of the index procedure, theoretically higher risk of complication during the acute phase and vasospasm leading to overestimation of the lesion severity. A recent analysis from the COMPLETE study did not show any difference when comparing staged PCI during the index hospitalization vs after discharge.9 The optimal timing of the staged PCI needs to be investigated in future studies.
A limitation of this study is the lower than expected incidence of clinical events decreasing the statistical power of the study. However, there was no signal that FFR-guided PCI is better compared to the angiography-guided group. In fact, the curve started to diverge at 6 months favoring the angiography-guided group. In addition, there was no core-lab analysis for completeness of revascularization.
Applications for Clinical Practice
In patients presenting with hemodynamically stable STEMI for undergoing nonculprit vessel PCI, both FFR-guided or angiography-guided strategies can be considered.
Financial disclosures: None.
Study Overview
Objective. To determine whether fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) of nonculprit lesion in patients with ST-segment elevation myocardial infarction (STEMI) is superior to angiography-guided PCI.
Design. Multicenter randomized control trial blinded to outcome, conducted in 41 sites in France.
Setting and participants. A total of 1163 patients with STEMI and multivessel coronary disease, who had undergone successful PCI to the culprit lesion were randomized to either FFR-guided PCI or angiography-guided PCI for nonculprit lesions. Randomization was stratified according to the trial site and timing of the procedure (immediate or staged).
Main outcome measures. The primary outcome was a composite of death from any cause, nonfatal myocardial infarction (MI) or unplanned hospitalization leading to urgent revascularization at 1 year.
Main results. At 1 year, the primary outcome occurred in 32 of 586 patients (5.5%) in the FFR-guided group and in 24 of 577 (4.2%) in the angiography-guided group (hazard ratio [HR], 1.32; 95% CI, 0.78-2.23; P = .31). The rate of death (1.5% vs 1.7%), nonfatal MI (3.1% vs 1.7%), and unplanned hospitalization leading to urgent revascularization (3.1% vs 1.7%) were also similar between FFR-guided and angiography-guided groups.
Conclusion. Among patients with STEMI and multivessel disease who had undergone successful PCI of the culprit vessel, an FFR-guided strategy for complete revascularization was not superior to angiography-guided strategy for reducing death, MI, or urgent revascularization at 1 year.
Commentary
Patients presenting with STEMI often have multivessel disease.1 Recently, multiple studies have reported the benefit of nonculprit vessel revascularization in patients presenting with hemodynamically stable STEMI compared to culprit-only strategy including the most recent COMPLETE trial which showed reduction in death and MI.2-6 However, the previous studies have variable design in evaluating the nonculprit vessel, some utilized FFR guidance, while others used angiography guidance. Whether FFR-guided PCI of nonculprit vessel can improve outcome in patients presenting STEMI remains unknown.
In the FLOWER-MI study, Puymirat et al investigated the use of FFR compared to angiography-guided nonculprit vessel PCI. A total of 1163 patients presenting with STEMI and multivessel disease who had undergone successful PCI to the culprit vessel, were randomized to either FFR guidance or angiography guidance among 41 centers in France. The authors found that after 1 year, there was no difference in composite endpoint of death, nonfatal MI or unplanned hospitalization leading to urgent revascularization in the FFR-guided group compared to angiography-guided group (5.5% vs 4.2%, HR, 1.32; 95% CI, 0.678-2.23; P = .31). There was also no difference in individual components of primary outcomes or secondary outcomes such as rate of stent thrombosis, any revascularization, or hospitalization.
There are a few interesting points to consider in this study. Ever since the Fractional Flow Reserve vs Angiography for Multivessel Evaluation (FAME) trial reported the lower incidence of major adverse events in routine FFR measurement during PCI compared to angiography-guided PCI, physiological assessment has become the gold standard for treatment of stable ischemic heart disease.7 However, the results of the current FLOWER-MI trial were not consistent with the FAME trial and there are few possible reasons to consider.
First, the use of FFR in the setting of STEMI is less validated compared to stable ischemic heart disease.8 Microvascular dysfunction during the acute phase can affect the FFR reading and the lesion severity can be underestimated.8 Second, the rate of composite endpoint was much lower in this study compared to FAME despite using the same composite endpoint of death, nonfatal MI, and unplanned hospitalization leading to urgent revascularization. At 1 year, the incidence of primary outcome was 13.5% in the FFR-guided group compared to 18.6% in the angiography-guided group in the FAME study compared to 5.5% and 4.2% in the FLOWER-MI study, despite having a sicker population presenting with STEMI. This is likely due to improvement in the PCI techniques such as radial approach, imaging guidance, and advancement in medical therapy such as use of more potent antiplatelet therapy. With lower incidence of primary outcome, larger number of patients are needed to detect the difference in the composite outcome. Finally, the operators’ visual assessment may have been calibrated to the physiologic assessment as the operators are routinely using FFR assessment which may have diminished the benefit of FFR guidance seen in the early FAME study.
Another interesting finding from this study was that although the study protocol encouraged the operators to perform the nonculprit PCI in the same setting, only 4% had nonculprit PCI in the same setting and 96% of the patients underwent a staged PCI. The advantage of performing the nonculprit PCI on the same setting is to have 1 fewer procedure for the patient. On the other hand, the disadvantage of this approach includes prolongation of the index procedure, theoretically higher risk of complication during the acute phase and vasospasm leading to overestimation of the lesion severity. A recent analysis from the COMPLETE study did not show any difference when comparing staged PCI during the index hospitalization vs after discharge.9 The optimal timing of the staged PCI needs to be investigated in future studies.
A limitation of this study is the lower than expected incidence of clinical events decreasing the statistical power of the study. However, there was no signal that FFR-guided PCI is better compared to the angiography-guided group. In fact, the curve started to diverge at 6 months favoring the angiography-guided group. In addition, there was no core-lab analysis for completeness of revascularization.
Applications for Clinical Practice
In patients presenting with hemodynamically stable STEMI for undergoing nonculprit vessel PCI, both FFR-guided or angiography-guided strategies can be considered.
Financial disclosures: None.
1. Park DW, Clare RM, Schulte PJ, et al. Extent, location, and clinical significance of non-infarct-related coronary artery disease among patients with ST-elevation myocardial infarction. JAMA. 2014;312(19):2019-27. doi:10.1001/jama.2014.15095
2. Wald DS, Morris JK, Wald NJ, et al. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med. 2013;369(12):1115-23. doi:10.1056/NEJMoa1305520
3. Gershlick AH, Khan JN, Kelly DJ, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial. J Am Coll Cardiol. 2015;65(10):963-72. doi:10.1016/j.jacc.2014.12.038
4. Engstrøm T, Kelbæk H, Helqvist S, et al. Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial. Lancet. 2015;386(9994):665-71. doi:10.1016/s0140-6736(15)60648-1
5. Smits PC, Abdel-Wahab M, Neumann FJ, , et al. Fractional Flow Reserve-Guided Multivessel Angioplasty in Myocardial Infarction. N Engl J Med. 2017;376(13):1234-44. doi:10.1056/NEJMoa1701067
6. Mehta SR, Wood DA, Storey RF, et al. Complete Revascularization with Multivessel PCI for Myocardial Infarction. N Engl J Med. 2019;381(15):1411-21. doi:10.1056/NEJMoa1907775
7. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213-24. doi:10.1056/NEJMoa0807611
8. Thim T, van der Hoeven NW, Musto C, et al. Evaluation and Management of Nonculprit Lesions in STEMI. JACC Cardiovasc Interv. 2020;13(10):1145-54. doi:10.1016/j.jcin.2020.02.030
9. Wood DA, Cairns JA, Wang J, et al. Timing of Staged Nonculprit Artery Revascularization in Patients With ST-Segment Elevation Myocardial Infarction: COMPLETE Trial. J Am Coll Cardiol. 2019;74(22):2713-23. doi:10.1016/j.jacc.2019/09.051
1. Park DW, Clare RM, Schulte PJ, et al. Extent, location, and clinical significance of non-infarct-related coronary artery disease among patients with ST-elevation myocardial infarction. JAMA. 2014;312(19):2019-27. doi:10.1001/jama.2014.15095
2. Wald DS, Morris JK, Wald NJ, et al. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med. 2013;369(12):1115-23. doi:10.1056/NEJMoa1305520
3. Gershlick AH, Khan JN, Kelly DJ, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial. J Am Coll Cardiol. 2015;65(10):963-72. doi:10.1016/j.jacc.2014.12.038
4. Engstrøm T, Kelbæk H, Helqvist S, et al. Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial. Lancet. 2015;386(9994):665-71. doi:10.1016/s0140-6736(15)60648-1
5. Smits PC, Abdel-Wahab M, Neumann FJ, , et al. Fractional Flow Reserve-Guided Multivessel Angioplasty in Myocardial Infarction. N Engl J Med. 2017;376(13):1234-44. doi:10.1056/NEJMoa1701067
6. Mehta SR, Wood DA, Storey RF, et al. Complete Revascularization with Multivessel PCI for Myocardial Infarction. N Engl J Med. 2019;381(15):1411-21. doi:10.1056/NEJMoa1907775
7. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213-24. doi:10.1056/NEJMoa0807611
8. Thim T, van der Hoeven NW, Musto C, et al. Evaluation and Management of Nonculprit Lesions in STEMI. JACC Cardiovasc Interv. 2020;13(10):1145-54. doi:10.1016/j.jcin.2020.02.030
9. Wood DA, Cairns JA, Wang J, et al. Timing of Staged Nonculprit Artery Revascularization in Patients With ST-Segment Elevation Myocardial Infarction: COMPLETE Trial. J Am Coll Cardiol. 2019;74(22):2713-23. doi:10.1016/j.jacc.2019/09.051