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Background: The relationship between the extent and severity of stress-induced ischemia and the extent and severity of anatomic coronary artery disease (CAD) in patients with obstructive CAD is multifactorial and includes the intensity of stress achieved, type of testing used, presence and extent of prior infarction, collateral blood flow, plaque characteristics, microvascular disease, coronary vasomotor tone, and genetic factors. Among chronic coronary disease participants with site-determined moderate or severe ischemia, we investigated associations between ischemia severity on stress testing and the extent of CAD on coronary computed tomography angiography., Methods: Clinically indicated stress testing included nuclear imaging, echocardiography, cardiac magnetic resonance imaging, or nonimaging exercise tolerance test. Among those with preserved renal function who underwent coronary computed tomography angiography, we examined relationships between ischemia and CAD by coronary computed tomography angiography, overall, and by stress test modality, regardless of subsequent randomization. Core laboratories categorized ischemia as severe, moderate, mild, or none, while the extent and severity of anatomic CAD were categorized based on the modified Duke prognostic index., Results: Among 3601 participants with interpretable stress tests and coronary computed tomography angiography, ischemia severity was weakly associated with CAD extent/severity (r=0.27), with modest variability in strength of association by modality: nuclear (n=1532; r=0.40), echocardiography (n=827; r=0.15), cardiac magnetic resonance imaging (n=108; r=0.31), and exercise tolerance test (n=1134; r=0.18). The extent of infarction on nuclear imaging and echocardiography was weakly associated with CAD extent/severity., Conclusions: Overall, ischemia severity on stress testing showed weak to moderate associations with the anatomic extent of CAD in this cohort with moderate or severe ischemia on local interpretation and controlled symptoms., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522., Competing Interests: Dr Reynolds reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study, and consulting fees from HeartFlow; she receives support from Abbott Vascular (donation of optical coherence tomography catheters for an unrelated research study) and Biotelemetry, Inc (donation of telemetry monitors for an unrelated research study). Dr Berman receives software royalties from Cedars-Sinai Medical Center, outside the submitted work. Dr Chaitman reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study and personal fees from Merck, Novo Nordisk, Sanofi, Lilly, Johnson and Johnson, Daiichi Sankyo, Tricida, Relypsa, Imbria, and Xylocor, outside the submitted work. Dr Kwong reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Min reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study; other from Cleerly, Inc, grants; and other from GE Healthcare and Arineta, outside the submitted work. Dr Leipsic is a consultant and has stock options in HeartFlow and Circle CVI and received research grant from GE Healthcare, outside the submitted work. Dr Mancini reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study; grants and personal fees from Amgen, grants and personal fees from Sanofi, Boehringer Ingelheim, AstraZeneca, Bayer, Janssen, Novo Nordisk, and HLS Therapeutics; and grants from Novartis, outside the submitted work. Dr Budoff reports grant support from General Electric, outside the submitted work. Dr Hague reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Senior reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study and speaker fees from Bracco, Lantheus Medical Imaging Boston USA, and Philips Healthcare, outside the submitted work. Dr Bhargava reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study. Dr Celutkiene reported personal fees from Boehringer Ingelheim, AstraZeneca, Bayer, and Novartis. Dr Bainey received unrestricted research grant support from the Heart and Stroke Foundation of Canada, AstraZeneca, and Bayer; speaker honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb-Pfizer Alliance, and Boehringer Ingelheim-Eli Lilly Alliance; consultancy and advisory board memberships in AstraZeneca, Abbott Vascular, Bayer, Bristol-Myers Squibb-Pfizer Alliance, and Boehringer Ingelheim-Eli Lilly Alliance; and proctorship honoraria from Abbott Vascular. Dr Doerr reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Ong reports speaker honoraria from Abbott Medical, Phillips, Bayer Healthcare, Pfizer, and Medtronic and research funding from the Berthold Leibinger Foundation, Ditzingen, Germany. Dr Steg reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study and research grants from Amarin, Bayer, Sanofi, and Servier; he serves as a member of the Steering Committee, Clinical Events Committee, or Data and Safety Monitoring Board for clinical trials conducted in Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Idorsia, Myokardia, Novartis, Pfizer, Sanofi, and Servier; consulting or speaker’s fees from Amgen, Novo Nordisk, and Regeneron. Dr Chow holds the Saul and Edna Goldfarb Chair in Cardiac Imaging Research; receives research support from TD Bank, CV Diagnostix and AusculSciences, and Siemens Healthineers; and has equity interest in General Electric. Dr Phillips has served as a consultant for Novo Nordisk. Dr Mark reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study, and grants from HeartFlow and Merck, outside the submitted work. Dr Spertus reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study; personal fees from Bayer, Novartis, AstraZeneca, Amgen, Janssen, and United Healthcare; grants from the American College of Cardiology; and personal fees from Blue Cross Blue Shield of Kansas City, outside the submitted work; in addition, Dr Spertus has a patent Copyright to Seattle Angina Questionnaire with royalties paid and Equity in Health Outcomes Sciences. Dr O’Brien reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Boden reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study; grants from Abbvie, Amarin, and Amgen; and personal fees from Amgen, Cleveland Clinic Clinical Coordinating Center, and Janssen, outside the submitted work. Dr Bangalore reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study; grants and personal fees from Abbott Vascular; and personal fees from Biotronik, Pfizer, Amgen, and Reata, outside the submitted work. Dr Stone reports grants and personal fees from the National Heart, Lung, and Blood Institute during the conduct of the study; speaker honoraria from Medtronic, Pulnovo, Infraredx, Abiomed, Amgen, and Boehringer Ingelheim; is a consultant to Abbott, Daiichi Sankyo, Ablative Solutions, CorFlow, Apollo Therapeutics, Cardiomech, Gore, Robocath, Miracor, Vectorious, Abiomed, Valfix, TherOx, HeartFlow, Neovasc, Ancora, Elucid Bio, Occlutech, Impulse Dynamics, Adona Medical, Millennia Biopharma, Oxitope, Cardiac Success, and HighLife; and equity/options in Ancora, Cagent, Applied Therapeutics, Biostar Family of Funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter. Institutional disclosures: Dr Stone’s employer, Mount Sinai Hospital; Dr Stone receives research grants from Abbott, Abiomed, Bioventrix, Cardiovascular Systems, Inc, Phillips, Biosense Webster, Shockwave, Vascular Dynamics, Pulnovo, and V-wave. Family disclosure: Dr Stone’s daughter is an employee at IQVIA. Dr Maron reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Hochman was the PI for the ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) for which, in addition to support by the National Heart, Lung, and Blood Institute grant, devices and medications were provided by Abbott Vascular; Medtronic, Inc.; Abbott Laboratories (formerly St. Jude Medical, Inc); Royal Philips NV (formerly Volcano Corporation); Arbor Pharmaceuticals, LLC; AstraZeneca Pharmaceuticals, LP; Merck Sharp & Dohme Corporation; and Omron Healthcare, Inc; and financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. She is a PI for ISCHEMIA-EXTEND (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches Extended Follow-Up). The other authors report no conflicts.

Clinical benefit of invasive functionally guided revascularization has been mostly investigated and proven for percutaneous coronary intervention. It has never been prospectively evaluated whether a systematic fractional flow reserve (FFR) assessment is also beneficial in guiding coronary artery bypass graft surgery (CABG). The objective of the GRAft patency after FFR-guided versus angiography-guIded CABG (GRAFFITI) trial was to compare an FFR-guided revascularization strategy to the traditional angiography-guided revascularization strategy for patients undergoing CABG. Patients were enrolled with significantly diseased left anterior descending or left main stem and at least one major coronary artery with angiographically intermediate stenosis (30-90% diameter stenosis) that was assessed by FFR. Thereafter, while the FFR values were kept concealed, cardiac surgeons decided their intended procedural strategy based on the coronary angiography alone. At this point, patients underwent 1:1 randomization to either an FFR-guided or an angiography-guided CABG strategy. In case the patient was randomized to angiography-guided arm, cardiac surgeons kept their intended procedural strategy, i.e., CABG was guided solely on the basis of the coronary angiography. In case the patient was randomized to the FFR-guided arm, FFR values were disclosed to the surgeons who revised the surgical protocol according to the functional significance of each coronary stenosis. The primary endpoint of the trial was the rate of graft occlusion at 12 months, assessed by coronary computed tomography or coronary angiography. The secondary endpoints were (1) length of postoperative hospital stay; (2) changes in surgical strategy depending upon FFR results (in FFR-guided group only); and (3) rate of major adverse cardiac and cerebrovascular events, i.e., composite of death, myocardial infarction, stroke, and any revascularization during the follow-up period. This study is the first prospective randomized trial investigating potential clinical benefits, associated with FFR-guided surgical revascularization., Trial Registration: NCT01810224.

Background: Penetration of fractional flow reserve (FFR) in clinical practice varies extensively, and the applicability of results from randomized trials is understudied. We describe the extent to which the information gained from routine FFR affects patient management strategy and clinical outcome., Methods and Results: Nonselected patients undergoing coronary angiography, in which at least 1 lesion was interrogated by FFR, were prospectively enrolled in a multicenter registry. FFR-driven change in management strategy (medical therapy, revascularization, or additional stress imaging) was assessed per-lesion and per-patient, and the agreement between final and initial strategies was recorded. Cardiovascular death, myocardial infarction, or unplanned revascularization (MACE) at 1 year was recorded. A total of 1293 lesions were evaluated in 918 patients (mean FFR, 0.81±0.1). Management plan changed in 406 patients (44.2%) and 584 lesions (45.2%). One-year MACE was 6.9%; patients in whom all lesions were deferred had a lower MACE rate (5.3%) than those with at least 1 lesion revascularized (7.3%) or left untreated despite FFR≤0.80 (13.6%; log-rank P=0.014). At the lesion level, deferral of those with an FFR≤0.80 was associated with a 3.1-fold increase in the hazard of cardiovascular death/myocardial infarction/target lesion revascularization (P=0.012). Independent predictors of target lesion revascularization in the deferred lesions were proximal location of the lesion, B2/C type and FFR., Conclusions: Routine FFR assessment of coronary lesions safely changes management strategy in almost half of the cases. Also, it accurately identifies patients and lesions with a low likelihood of events, in which revascularization can be safely deferred, as opposed to those at high risk when ischemic lesions are left untreated, thus confirming results from randomized trials., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01835808., (© 2016 American Heart Association, Inc.)