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E L S E V I E R . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R T H E C C B Y - N C - N D L I C E N S E

( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / ) .

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THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Invasive FFR and Noninvasive CFRin the Evaluation of Ischemia
What Is the Future?
Nils P. Johnson, MD, MS,a K. Lance Gould, MD,a Marcelo F. Di Carli, MD,b Viviany R. Taqueti, MD, MPHb

ABSTRACT

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This review provides an integrative and forward-looking perspective on the gamut of coronary physiology for the

diagnosis and management of atherosclerosis. Because clinical events serve as the ultimate gold standard, the future of

all diagnostic tests, including invasive fractional flow reserve and noninvasive coronary flow reserve, depends on their

ability to improve patient outcomes. Given the prominent role of acute coronary syndromes and invasive procedures in

cardiology, we practically consider 2 broad categories of patients with coronary disease: acute and stable. For patients

with acute coronary disease, coronary physiology may potentially refine treatment of the culprit lesion. For both patients

with stable and acute nonculprit disease, reducing hard endpoints with revascularization potentially occurs at the

severe end of the focal physiological spectrum, an area under-represented in existing trials. Nonepicardial disease

and diffuse atherosclerosis remain underexplored aspects of coronary physiology for testing of novel treatments. (J Am

Coll Cardiol 2016;67:2772–88) © 2016 by the American College of Cardiology Foundation. Published by Elsevier. This is

an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

T his review provides an integrative andforward-looking perspective on the gamutof coronary physiology for the diagnosis

and management of atherosclerosis. It ranges fromacute coronary syndrome (ACS) as a “perfect storm”

(1,2) of pathophysiological progression (3), visualizedas a severe anatomic stenosis (4) benefitting fromrevascularization, to stable coronary artery disease(CAD) as a complex interplay of focal and diffuse pla-que burden (5). Although atherosclerotic severity andcomplexity have long been associated with symptomsand risk, a presumed revascularization benefit has

m the aWeatherhead PET Center For Preventing and Reversing Atherosc

ne, McGovern Medical School at UTHealth andMemorial Hermann Hospita

d Radiology, Noninvasive Cardiovascular Imaging Program, Heart and Vas

partment of Medicine, and the Division of Nuclear Medicine and Molecu

men’s Hospital, Harvard Medical School, Boston, Massachusetts. Dr.

atherhead PET Center for Preventing and Reversing Atherosclerosis; and h

m St. Jude Medical (for clinical trial NCT02184117) and Volcano/Philips Co

racoronary pressure and flow sensors. Dr. Gould has received internal f

nting and Reversing Atherosclerosis; and is the 510(k) applicant for CFR

ckages for cardiac positron emission tomography image processing and an

rli receives research grant support from Gilead Sciences. Dr. Taqueti is

estigator Training award from the Harvard Clinical and Translational Sci

nuscript received November 3, 2015; revised manuscript received March

not been confirmed using an anatomic assessment.Rather, we suggest that coronary physiology, withits mechanistic link between intracoronary hemody-namic stress and plaque failure (6), provides a naturalset of tools to quantify both focal and diffuse diseaseof a severity that may be associated with improvedhard outcomes, independent of symptom relief.Accordingly, this review on the future of clinical cor-onary physiology starts with interventions in ACS, theextreme and final common pathway associated withsevere anatomic stenosis, marked flow-pressure ab-normalities, and vasomotor dysfunction. From there,

lerosis, Division of Cardiology, Department of Med-

l, Houston, Texas; and the bDepartments of Medicine

cular Institute, Division of Cardiovascular Medicine,

lar Imaging, Department of Radiology, Brigham and

Johnson has received internal funding from the

as received significant institutional research support

rporation (for clinical trial NCT02328820), makers of

unding from the Weatherhead PET Center for Pre-

Quant (K113754) and HeartSee (K143664), software

alysis, including absolute flow quantification. Dr. Di

supported by a Harvard Catalyst Medical Research

ence Center.

7, 2016, accepted March 15, 2016.

http://creativecommons.org/licenses/by-nc-nd/4.0/

https://www.clinicaltrials.gov/ct2/show/NCT02184117?term=NCT02184117%26rank=1

https://www.clinicaltrials.gov/ct2/show/NCT02328820?term=NCT02328820%26rank=1

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AB BR E V I A T I O N S

AND ACRONYM S

ACS = acute coronary

syndrome

CABG = coronary artery bypass

graft

CAD = coronary artery disease

CFR = coronary flow reserve

FFR = fractional flow reserve

HMR = hyperemic

microvascular resistance

IMR = index of microcirculatory

resistance

MI = myocardial infarction

PCI = percutaneous coronary

intervention

PET = positron emission

tomography

J A C C V O L . 6 7 , N O . 2 3 , 2 0 1 6 Johnson et al.J U N E 1 4 , 2 0 1 6 : 2 7 7 2 – 8 8 Future of FFR and CFR

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we extrapolate from pre-ACS coronary physiology,leading to testable hypotheses for personalized inter-ventions. The Central Illustration provides a visualsummary of the paper.

THE GOLD STANDARD

Clinical outcomes serve as the ultimate gold standardfor diagnostic tests. Unlike a therapy that directlyaffects patients, a useful diagnostic test must influ-ence management decisions that in turn alter out-comes. As evidence of this trend, several recentreports highlight the surprisingly small effect of mostnoninvasive cardiac stress testing on clinical care(7–9). The ongoing ISCHEMIA (International Study ofComparative Health Effectiveness with Medical andInvasive Approaches) trial asks if abnormal stress testresults can change hard endpoints of death andmyocardial infarction (MI) using revascularization(10). Thus, the future of all diagnostic tests dependson their ability to improve patient outcomes.

Within the broad community of diagnostic tests,measurements like fractional flow reserve (FFR) andcoronary flow reserve (CFR) belong to the category ofclinical coronary physiology. Invasively, we candirectly measure intracoronary pressure and flow(and indirectly speak of resistance), whereas non-invasively, we can image myocardial perfusion (ineither relative or absolute units). Although a deepfoundation of basic physics, molecular and geneticmechanisms, and fundamental animal and humanphysiology underlie these tools, our goal as physi-cians remains pragmatic: how can we help the patientbefore us?

Consequently, we reframe this review as a discus-sion of an important tool to improve the end goal ofpatient well-being. To remain practical, we consider2 broad categories of patients with CAD: acute andstable. For decision-making and ethical, informeddiscussion with patients, we distinguish among 3easily understood outcomes: death, MI, and angina.Although themost common therapeutic decisionmadeusing coronary physiology remains revascularization,we also consider customized medical therapy distinctfrom treating general risk factors, as detailed later.

PATIENTS WITH ACUTE CORONARY DISEASE

Existing studies of patients with acute coronarydisease provide 3 profound, but often overlookedinsights for assessing physiologically-guided inter-ventions. First, simultaneous “perfect storms”causing an MI in 2 or more distinct coronary arteriesin the same patient are rare. Second, the majority ofACS arises from a very severe lesion that evolved

rapidly via sequential, asymptomatic plaqueruptures that healed with progressive steno-sis (3,4,11). Third, the long-term risk afterrevascularized ACS typically returns to thebackground level of patients with known, butstable CAD. These 3 insights together suggestthat nonculprit stenosis in patients with acutecoronary disease likely reflects the samebackground of disease known to exist in pa-tients with stable coronary disease, incontrast to the culprit lesion, whose revas-cularization without physiological assess-ment has already been shown to reduce deathand MI (12). As such, the concepts derived forstable CAD likely apply to the nonculprit le-sions noted at the time of acute presentation,thereby linking the 2 scenarios. Therefore,this connection and commonality necessi-
tates our initially reviewing acute manifestations.
Acute presentations account for approximately70% to 80% of the contemporary total numberof patients undergoing coronary revascularization(13,14), an inversion of the balance from 25 years ago(14). Due to improved clinical outcomes demon-strated in randomized trials, most patients with acutecoronary disease proceed directly to invasive angiog-raphy and revascularization of culprit lesions withoutphysiological assessment. However, as detailed next,2 key questions have emerged recently and needfuture answers. First, can physiology refine treatmentin the culprit vessel in some patients? Second, ifintervention on nonculprit stenosis fails to reducedeath and MI, howmuch do patients value a reductionin future revascularization procedures? Definitiveanswers will require trials in large populations withrational selection criteria and hard endpoints.ROUTINE INVASIVE ANGIOGRAPHY WITHOUT

PHYSIOLOGICAL ASSESSMENT. The definition ofacute MI includes “imaging evidence of new loss ofviable myocardium” (15), thereby acknowledgingthe need for noninvasive perfusion imaging to clarifythe diagnosis in some cases. However, relying onnoninvasive testing or symptoms to guide invasiveangiography in patients with acute coronary diseasewith non-ST-segment elevation myocardial infarction(NSTEMI), a “selective invasive” strategy, has provedinferior to immediate angiography, a “routine inva-sive” strategy (12). Specifically, routine comparedwith selective angiography reduced cardiovasculardeath (from 8.1% to 6.8%; hazard ratio [HR]: 0.83;95% confidence interval [CI]: 0.68 to 1.01; p ¼ 0.068)and MI (from 12.9% to 10.0%; HR: 0.77; 95% CI: 0.65to 0.90; p ¼ 0.001) over 5 years (12). The relativereduction in events remained constant across the

CENTRAL ILLUSTRATION The Future of Coronary Physiology

• Coronary physiology may support deferring percutaneous coronary intervention (PCI) in NSTEMI patients and augmenting PCIin STEMI patients

• Not yet ready forclinical practice

• Need randomized controlled trial (RCT)

• Diffuse disease carries an equal risk to focal lesions

• Global CFR quantifies the burden of diffuse CAD (CFR<1.5 hasthe highest risk)

• Future RCT in diffuse disease must compare coronary artery bypass grafting versus medical therapy

• Can produce refractory angina despite FFR>0.8

• Because many therapies can be tried empirically without much cost or side-effects, this subset needs an RCT of expensive or morerisky treatments showing a marked improvement

• Coronary physiology quantifies risk of future events and magnitude of revascularization benefit, thereby personalizing risk/benefit decisions

• Future RCT of revascularization for focal, severe lesions has best chance of identifying a benefit for hard outcomes of death and myocardial infarction

• Angina with FFR≤0.8 responds betterto revascularization than medication

Culprit lesion(s)

Angiogram AngiogramPET imageFFR tracing PET image

Non-culprit lesion(s)

Patient with acute coronary artery disease (CAD) Patient with stable CAD

FocalCAD

DiffuseCAD

MicrovascularCAD

Johnson, N.P. et al. J Am Coll Cardiol. 2016;67(23):2772–88.

A visual summary and outline of this review begins by considering 2 general types of patients: acute (left) and stable (right). For patients with acute coronary disease,

coronary physiology can be directed at either the culprit or nonculprit stenosis. For patients with stable coronary disease, coronary physiology can identify patterns

of focal, diffuse, and microvascular disease. Each category lists key questions (thin box) with an image and summary of major messages. Images reprinted

with permission from Johnson et al. (85,98,99) and Gould et al. (100). CAD ¼ coronary artery disease; CFR ¼ coronary flow reserve; FFR ¼ fractional flow reserve;

NSTEMI ¼ non–ST-segment myocardial infarction; PCI ¼ percutaneous coronary intervention; PET ¼ positron emission tomography; RCT ¼ randomized controlled trial;

STEMI ¼ ST-segment elevation myocardial infarction.

Johnson et al. J A C C V O L . 6 7 , N O . 2 3 , 2 0 1 6

Future of FFR and CFR J U N E 1 4 , 2 0 1 6 : 2 7 7 2 – 8 8

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spectrum of absolute risk. Thus, the largest benefitsfrom a routine invasive strategy accrued to thehighest-risk patients—a theme that will re-emergelater for stable populations as well. For ST-segmentelevation myocardial infarction (STEMI) patients un-dergo rapid cardiac catheterization and mechanicalreperfusion when geographically available, or intra-venous lytic treatment and transfer for angiographywithin 24 h if invasive management exists onlydistantly (16,17).

WHAT IS THE ACUTE CULPRIT LESION: A ROLE FOR

CORONARY PHYSIOLOGY? In the majority of ACS, asingle culprit lesion can be identified using a com-bination of angiographic appearance, regional leftventricular dysfunction, and localizing electrocar-diographic changes. Some patients have no obviousculprit, whereas rare patients have 2 simultaneousculprits.

For patients with no obvious culprit, a wide dif-ferential diagnosis exists, including both non-coronary (e.g., pulmonary embolism or myocarditis)and coronary (e.g., spasm or dissection) etiologies.Depending on the clinical context, invasive physi-ology provides objective quantification of stenosisseverity as a potential cause of the acute presentationbecause the majority of older individuals with riskfactors have some degree of atherosclerosis (18). Forexample, a high FFR value may direct the clinicianto search for an alternative diagnosis, such aspulmonary embolism (19). Alternatively, advancedphysiological assessment may uncover a host ofabnormalities (20), although establishing causal linkswith the presentation and proven courses of treat-ment remains difficult.

CULPRIT LESION PHYSIOLOGY TO GUIDE TREATMENT.

For patients with 1 or more culprit lesions, invasive


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coronary physiology may support deferring or,inversely, may augment revascularization. A recentlycompleted feasibility study, FAMOUS-NSTEMI(Fractional Flow Reserve vs. Angiography inGuiding Management to Optimize Outcomes inNon-ST-Elevation Myocardial Infarction), examinedthe hypothesis that using FFR to deferrevascularization for NSTEMI lesions of at least 30%diameter stenosis with normal TIMI (ThrombolysisIn Myocardial Infarction) flow may provide benefit(21). Although the study included both culprit andnonculprit lesions, there were late spontaneousmajor adverse cardiac events in 4 of 10 patients whochanged from percutaneous coronary intervention(PCI) to medical therapy in culprit arteries by FFR>0.8, which calls into question the long-term safetyof mixing both types of lesions.

After treatment of an acute culprit lesion, coronaryphysiology measurements have been associated withlong-term prognosis (22,23). Because acute lesionsinjure downstream myocardium, measures of micro-vasculature resistance (related directly to coronarypressure, but inversely to flow) may provide insightsbeyond FFR, which focuses on epicardial stenosis.After STEMI, serial invasive measurements in theculprit artery showed decreasing microvascularresistance and increasing CFR over the subsequent6 months (24), reflecting some myocardial recoveryafter an acute event.

Depending on the specific intracoronary sensor,either of 2 resistance indexes can be measured:hyperemic microvascular resistance (HMR) usingDoppler flow velocity (25) or the index of microcircu-latory resistance (IMR) using bolus thermodilution(26). Both HMR (27) and IMR (28) measured in theculprit vessel after primary PCI for STEMI show a sig-nificant, inverse association with subsequent prog-nosis. Thus, one may ask if this outcome spectrum canbe modified by treatment to reduce myocardial resis-tance, or if high resistance is simply a risk markerassociated with confounders, such as infarct size andejection fraction. Ongoing intervention trials evalu-ating the efficacy of intracoronary glycoprotein IIb/IIIainhibitors (29), aspiration thrombectomy (29–31), nic-orandil (32), and oral antiplatelet agents (33) are usingIMR as a primary or secondary endpoint in patientswith acute coronary disease. However, no randomizedtrial has validated IMR or HMR as a therapeutic guidefor meaningful clinical endpoints of death or MI.

We conclude that although coronary physiology ofthe acute culprit lesion may provide ancillary infor-mation of potential interest, it should not be useduntil supported by future, definitive, outcomes-basedrandomized trials.

CORONARY PHYSIOLOGY OF NONCULPRIT LESIONS.

Depending on the population and precise definitionof angiographic severity, a nonculprit, or “bystander”or “incidental,” lesion is found in approximately50% of patients presenting acutely (17). Currently,no consensus exists regarding proper treatment.European guidelines state that “the best strategy forSTEMI patients with multivessel disease, who un-derwent primary PCI of the infarct-related artery inthe acute phase with remaining multivessel disease,is still not well established” (16). American guidelinesnote the “great variability in the evaluation andmanagement of nonculprit coronary artery diseasein stable patients without [heart failure] or shock,both at the time of primary PCI and later during thehospital course” (17).

Three recent randomized trials of managingnonculprit stenosis in ACS have been completed,with several others ongoing. Heterogeneity andsubjectivity of anatomic definitions for multivesseldisease led to trials that incorporated invasivecoronary physiology. As examples of anatomicvariation, the PRAMI (Preventive Angioplasty inAcute Myocardial Infarction) trial used a 50%diameter stenosis limit (34), whereas the CvLPRIT(Complete Versus Lesion-Only Primary PCI) trialallowed over 70% in a single view or over 50% in 2views (35). By contrast, the physiology-guided PRI-MULTI trial required 50% diameter nonculprit ste-nosis plus FFR #0.8, or over 90% diameter stenosiswithout FFR (36), and the COMPLETE (Completevs Culprit-only Revascularization to Treat Multi-vessel Disease After Primary PCI for STEMI) trialwill include at least a 50% diameter stenosisplus FFR #0.8, or at least a 70% lesion withoutFFR (37).

Preliminary results demonstrated that 56.5% ofnonculprit lesions of at least 50% diameter stenosishad an FFR >0.8 (38), indicating the same markeddisagreement between anatomy and physiology asthe 38.2% discordance in the acute subset ofthe FAME (Fractional Flow Reserve Versus Angiog-raphy for Multivessel Evaluation) trial (39) orthe 39.1% discordance in the NSTEMI populationof the FAMOUS trial (21). Therefore, 40% to 60%of angiographically significant nonculprit lesionsmay have an FFR >0.8 at the time of acutepresentation.

Although anatomic-functional discordance occursfrequently in both stable and unstable patients, theclinical effect of both high and low FFR values innonculprit lesions in the setting of acute MI remainsto be determined for several reasons. In ACS, mul-tifocal heterogeneous inflammation, endothelial



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dysfunction, coronary spasm, and downstream small-vessel disease may associate with subsequent non-culprit risk not accounted for by FFR. The value ofcoronary physiology in the acute setting may also beopen to question, due to changes during the recoveryphase. Just as the myocardium downstream of aculprit lesion recovers its flow capacity over timeafter STEMI (24), the nonculprit myocardium mayundergo a similar process that changes its capacity toaugment flow. However, empirical data suggest thatsuch changes occur rarely or are only modest andthat nonculprit artery physiology for FFR and IMRremains valid in the acute setting (40,41).

RANDOMIZED OUTCOMES TRIALS USING PHYSIOLOGY

FOR NONCULPRIT LESIONS. Approximately one-thirdof subjects enrolled in the multicenter and interna-tional FAME trial (328 of 1,005 patients) presentedwith unstable angina (UA) or NSTEMI and wereanalyzed in a post hoc substudy (39). Note that FAMEexcluded patients with STEMI in the preceding5 days and UA/NSTEMI with high peak creatinekinase, thus producing a medically stabilized cohortof modest infarct size. FFR measurement was suc-cessful in 93% of lesions in the UA/NSTEMI cohort,which was not significantly different than in the sta-ble population (94%). Although the cohort with acutecoronary disease had a higher event rate than sub-jects with stable angina (24.1% vs. 18.2% after 2 years;p ¼ 0.03), there was no difference between them inthe benefit of FFR-guided treatment on outcomes(relative risk reduction of 19% vs. 18%; p ¼ 0.92).Outcomes in both groups with acute and stable dis-ease favored FFR guidance over angiography. How-ever, due to the smaller size of the UA/NSTEMIcohort, hard endpoints trended lower with an FFRstrategy, but did not reach statistical significance:death 2.7% versus 4.5%, and MI 8.0% versus 13.5%(both p > 0.05). Freedom from angina at 2 years didnot differ between an FFR-guided versus anangiographic-guided strategy in this subgroup withacute disease (60.7% vs. 64.6%; p ¼ 0.54).

The multicenter FAMOUS-NSTEMI trial in theUnited Kingdom focused exclusively on NSTEMI in350 patients with at least one 30% diameter stenosis(21). Importantly, a median of 3 days (interquartilerange: 2 to 5 days) elapsed between the index clinicalepisode and invasive angiography, reflecting the un-derlying health care system. Subjects were random-ized equally between FFR- and angiographic-guidedrevascularization, although all lesions had successfulFFR measurements in 99.7% of cases, with only 2coronary dissections attributed to the pressure wire.After 1 year of clinical follow-up, all-cause death did

not differ significantly between the angiographic- andFFR-guided groups (risk difference 1.1% favoringangiography; 95% CI: �2.4% to 5.0%; p ¼ 0.54), nordid spontaneous MI (risk difference 1.1% favoringangiography; 95% CI: �3.1% to 5.5%; p ¼ 0.69).

Recently, the Danish multicenter PRIMULTI studyenrolled 627 patients with STEMI and a significant(over 50% diameter stenosis) nonculprit lesion in amajor vessel (36). All STEMI culprit lesions weretreated, and nonculprit lesions were randomized tostandard care as per the local routine or to FFR-guided revascularization (unless over 90% diameterstenosis visually, in which case no FFR was required)before hospital discharge, but at least 48 h after theindex procedure. After a minimum follow-up of1 year, all-cause death did not differ significantlybetween the 2 groups (HR: 1.4; 95% CI: 0.63 to 3.00;p ¼ 0.43), but cardiac death trended lower with FFR-guided revascularization of the nonculprit lesion (HR:0.56; 95% CI: 0.19 to 1.70; p ¼ 0.29). Nonfatal MI wasstatistically unchanged (HR: 0.94; 95% CI: 0.47 to1.90; p ¼ 0.87). However, future revascularizationwas lower in the FFR-guided group after discountingthe initial procedure (HR: 0.31; 95% CI: 0.18 to 0.53;p < 0.001). No significant differences existed amongadmissions for significant angina (HR: 1.1; 95% CI:0.75 to 1.70; p ¼ 0.6) or residual angina class.

Two ongoing randomized outcome trials of non-culprit lesions in STEMI incorporate FFR physiolog-ical assessment. The multicenter, internationalCompareAcute (Comparison Between FFR GuidedRevascularization Versus Conventional Strategy inAcute STEMI Patients With MVD) trial will enroll 885subjects with at least a 50% diameter stenosis in anonculprit vessel (42); baseline data from the first408 subjects were presented in 2014 (38). LikePRIMULTI, all culprit lesions will be treated by PCIwith nonculprit lesions randomized to standard careor FFR-guided revascularization, with a primaryendpoint of all-cause death, MI, any revasculariza-tion, and cerebrovascular accident. The multicenter,international COMPLETE trial will enroll 3,900 sub-jects with either at least a 70% diameter stenosiswithout FFR or 50% to 70% diameter stenosis withFFR #0.8 in a nonculprit vessel (37). Althoughthe randomized groups are as in PRIMULTI andCompareAcute, the primary endpoint includes onlycardiovascular-related death and nonfatal MI. Resultsfrom these 2 new trials are anticipated in 2018.Figure 1 summarizes the existing outcomes trials ofFFR in patients with acute coronary disease.

SUMMARY OF NONCULPRIT PHYSIOLOGICAL

ASSESSMENT TO GUIDE TREATMENT. For the vast

FIGURE 1 FFR in Patients With Acute Coronary Disease

100

95

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70

0 180 360 540 720Days Since Randomization

Surv

ival

Fre

e fr

om M

ACE

(%)

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0 90 180 270 360Days

Cum

ulat

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Even

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e

35

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20

15

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00 12 24 36

Follow-Up (Months)

Even

t Rat

e (%

)

FFR SA (83.6%)

FFR UA/NSTEMI (78.7%)Angio SA (79.9%)

Angio UA/NSTEMI (73.6%)

ARR 3.7%RRR 18%

ARR 5.1%RRR 19%

p=0.92

FAME

FFR–GuidedAngiography–Guided

Log Rank:p=0.796

FAMOUS

Infarct-related artery onlyComplete revascularisation (FFR guided )

HR 0.56 (95% CI 0.38-0.83), p=0.004

PRIMULTI

Number at riskInfarct-related artery only

Complete revascularisation313314

271291

142159

5355

A

B C

Outcomes in randomized trials that studied an FFR-guided strategy. (A) The FAME trial demonstrated the same treatment effect in patients

with acute (dashed lines) and stable (solid lines) coronary disease, with improved outcomes when using an FFR strategy (blue lines) versus an

angiographic strategy (orange lines). Reprinted with permission from Sels et al. (39). (B) The FAMOUS-NSTEMI trial found a trend toward

better outcomes when using an FFR strategy (solid line) instead of an angiographic strategy (dashed line) in an NSTEMI population that

included both culprit and nonculprit lesions. Reprinted with permission from Layland et al. (21). (C) The PRIMULTI trial showed a lower rate of

events when treating nonculprit lesions noted at the time of STEMI using an FFR strategy (orange line) versus standard of care (blue line).

Reprinted with permission from Engstrøm et al. (36). Angio ¼ angiographic; ARR ¼ absolute risk reduction; CI ¼ confidence interval; FFR ¼fractional flow reserve; HR ¼ hazard ratio; MACE ¼major adverse cardiac event(s); NSTEMI ¼ non–ST-segment elevation myocardial infarction;

RRR ¼ relative risk reduction; SA ¼ stable angina; STEMI ¼ ST-segment elevation myocardial infarction; UA ¼ unstable angina.


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majority of patients who stabilize either before orrapidly during the index PCI, assessment of FFRin the acute or semiacute settings has proved to besafe, and its absolute numeric value is acceptablyreproducible. Importantly, a significant discordanceexists between anatomic and physiological assess-ment of nonculprit severity, with 40% to 60% oflesions demonstrating an FFR >0.8, just as for stableCAD (43) (to be reviewed later). Because approxi-mately 50% of patients with acute coronary diseaseundergoing invasive angiography have a noteworthy

nonculprit stenosis, an objective basis for its inter-vention or deferral is essential.

Given the reductions in cardiovascular death andMI seen with routine angiography in patients withacute coronary disease, trials are needed to deter-mine if these same endpoints can be improvedby treating the nonculprit lesion. Hypothesis-generating, yet modestly sized recent trials (<800patients total) using angiographic criteria alonehave suggested marked benefits of 50% to 70%reduction in hard events (34,35). By contrast, recent



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intermediate-sized, FFR-guided trials of nonculpritintervention (<1,500 patients total) indicate moremodest or no benefit, as detailed previously. Thus, wecurrently lack a consistent or plausible signal ofclinical benefit for routine intervention of nonculpritlesions in patients with acute coronary disease.Without a reduction in death or MI, nonculprit PCIat the acute presentation would at least need toimprove symptoms or future quality of life, includingfunctional limitation or urgent revascularization.

In conclusion, large, definitive studies using hardoutcomes are essential to prove any value of physio-logically guided treatment of nonculprit lesionsin patients with acute coronary disease. AlthoughCOMPLETE meets these criteria, it mixes anatomicand physiological criteria, thereby providing lessclarity than either strategy alone.

PATIENTS WITH STABLE

CORONARY DISEASE

Stable CAD patients account for approximately 20% to30% of coronary revascularizations (13,14). However,the total population of patients with stable coronarydisease (approximately 15.5 million Americans haveknown coronary heart disease) dwarfs the numberof patients with acute coronary disease (44). Addi-tionally, those who present with new chest symptomsbut with no elevation in cardiac biomarkers orelectrocardiographic changes comprise a frequentlyencountered category of patients with known orsuspected CAD, which may include patients with orwithout known cardiovascular risk factors. Thus,patients with stable CAD comprise the majorityof clinical practice, but account for a minority ofrevascularizations. Notably, revascularization of pa-tients with stable CAD has failed to improve hardoutcomes, as summarized by the American guidelinesin 2011: “PCI . reduces the incidence of angina . hasnot been demonstrated to improve survival in stablepatients . may increase the short-term risk of MI .does not lower the long-term risk of MI” (45).Nevertheless, a recent study suggests that this spe-cific aspect regarding the potential benefit of revas-cularization or alternative treatment strategies israrely included in informed consent discussionsbetween cardiologists and their patients (46).

In the future, how will coronary physiology as-sessments affect the diagnosis and managementof stable CAD patients? For clinical care and trialsalike, an important conceptual step separates“harder” outcomes of death and MI from “softer”outcomes of angina relief and recurrent procedures. Aphysiological risk-benefit continuum exists that may

profoundly affect the magnitude, as well as themethod of revascularization (5,47). Coronary physi-ology already provides objective and quantitativetools for patient care that may further refine recruit-ment into outcomes trials of meaningful clinicalendpoints for validation of beneficial treatments.Prospective randomized trials on the basis of theseconcepts are feasible, despite associated practical andeconomic challenges (5).

PHYSIOLOGICAL CONTINUUM OF RISK. Outcomesdata over the past several years have identified aconsistent relationship between coronary physiolog-ical measurements and subsequent clinical events.The broadest data have been acquired using eitherinvasive FFR or noninvasive CFR, although prog-nostic data is now emerging for several parametersthat combine measurements. Noninvasive CFR equalsthe ratio of absolute coronary flow or myocardialperfusion between hyperemia and rest, and can beassessed using a variety of technologies, although thebroadest data exists for positron emission tomogra-phy (PET) (48). Developed as a relative CFR (49),invasive FFR practically equals the ratio of coronaryto aortic pressure during hyperemia.

In addition to being distinct, yet complimentaryphysiological measures of CAD severity, FFR andnoninvasive CFR differentially emphasize revascu-larization as an outcome. The published prognosticdata on FFR has been more highly influenced by theuse of revascularization, as opposed to noninvasiveCFR, with generally hard endpoints that have moreominous prognostic implications. As a final distinc-tion between them, FFR-guided PCI reduces subse-quent major adverse cardiac events in randomizedtrials compared with angiographic-guided PCI andcompared with medical treatment alone. No suchtrials exist for CFR. Here, we summarize the existingstudies on the FFR (Figure 2) and CFR (Figure 3)severity-risk continuum as the basis for discussingtheir clinical implications in the next section, whichprofoundly reorders assessment of CAD severity fromanatomy to physiology.

A meta-analysis of FFR outcomes studies included9,173 study-level lesions and 6,961 patient-levellesions from predominately observational publisheddata (47). Both types of analysis supported a contin-uous, inverse relationship between the numeric FFRvalue and adverse outcomes, with a parallel increasein the absolute risk for medically treated lesionsassociated with a larger absolute benefit from revas-cularization. The medical treatment and revasculari-zation curves generally crossed in the 0.75 to0.80 range, but the source data was primarily limited

FIGURE 2 Risk Versus Benefit Continuum of FFR

P=0.014

64

14.5

11.1

6.8

highest

medium

low

0%0.0 low threshold high 1.0

Fractional Flow Reserve (FFR)

Subs

eque

nt E

vent

Rat

e (%

)

PCI probably increasesevents at high FFR

Optimal thresholdRevascularized

PCI decreases eventrate most at low FFR

Medically treated

Conceptual plot for FFR as continuous marker of riskMeta-analysis- 9,173 study-level lesions- 6,961 patient-level lesionsFAME 2 (abstract)- 1,027 lesionsIRIS DEFER (preliminary)- 3,534 lesionsAalst (abstract)- 1,459 lesionsSt Louis- 882 lesions

A B

C

40%

30%

20%

10%

0%

Fractional Flow Reserve (FFR)

5,979 patients with a total of258 deaths163 non-fatal MI552 revascularizations

FFR 0.75-0.80

0.67

0.75

medically treated

medically treated

PCI/CABG

PCI/CABG

Cox

Mod

el 1-

Year

MAC

E (%

)

40%

30%

20%

10%

0%0.4 0.5 0.6 0.7 0.8 0.9 1.0

Mean Cohort FFR

Norm

aliz

ed 1-

Year

MAC

E (%

)

8,418 patients from90 cohorts with a total of

458 deaths235 non-fatal MI326 revascularizations

MACE-Rate per FFR strata

Pts with Revascularisation (n=449)

Pts with MT (n=1010)

0.70 0.71 0.72 0.73 0.74 0.75 0.76 0.77 0.78 0.79 0.80 0.81 0.82 0.83 0.84 0.850

5

10

15

20

25

30

FFR

MAC

E at

5 Y

ears

%

Repeated Intervention at 2 Years (per vessel)

% from K-M estimates

D

0.4 0.5 0.6 0.7 0.8 0.9 1.0

Revascularization better Medical therapy better

30

25

20

15

10

5

0Stenting <0.70 0.71-0.75 0.76-0.80 0.81-0.85 0.86-0.90 >0.90

4.9 6.1

22

46.1 5.4

2.2 1.5

P=0.077 P=0.76 P=0.44 P=0.044 P=0.18

Deferral Revascularization

0.80

(A) Five published reports, with a total of approximately 15,000 lesions, support the concept that FFR displays a continuous relationship with outcomes, both when

treated medically (blue line) and after revascularization (orange line), such that the largest benefit accrues for the most severe lesions. Reprinted with permission from

Johnson et al. (47). (B) Supporting data from a study- and patient-level meta-analysis of mostly observational publications. Reprinted with permission from Johnson

et al. (47). (C) Supporting data from a retrospective, observational study. Reprinted with permission from Adjedj et al. (54). (D) Preliminary supporting data from an

ongoing observational study. Reprinted with permission from Park et al. (53). CABG ¼ coronary artery bypass graft; K-M ¼ Kaplan-Meier; MI ¼ myocardial infarction;

MT ¼ medical therapy; PCI ¼ percutaneous coronary intervention; Pts ¼ patients; other abbreviations as in Figure 1.


2779

due to confounding by indication. FFR measuredimmediately after PCI also showed an inverse rela-tionship with clinical outcomes, likely reflectingresidual diffuse disease.

A retrospective, single-center analysis of 882deferred lesions explored predictive variables forsubsequent intervention (50). In a multivariablemodel, the numeric FFR value remained a signifi-cant predictor of future revascularization, of which65% were urgent. For every 0.05 decrease in theFFR value, the hazard increased by 21% (HR: 1.21;95% CI: 1.03 to 1.42; p ¼ 0.02) after adjusting forother factors.

Preliminary data from the randomized, interna-tional, and multicenter FAME 2 trial focused on thenatural history of 1,027 lesions treated medically inthe FFR #0.8 group and the FFR >0.8 registry (51).Again, a significant and inverse relationship existedbetween the FFR value and a clinical composite ofdeath, MI, and target lesion revascularization. Forevery 0.05 decrease in the FFR value, the risk (espe-cially target lesion revascularization) increased by31% (HR: 1.308; 95% CI: 1.219 to 1.403; p < 0.001)after adjusting for other factors.

A multicenter registry in South Korea enrolled de-ferred coronary lesions of over 30% diameter stenosis

by visual estimation with an FFR >0.8 (52). A total of5,006 patients have been enrolled, for whom pre-liminary results were presented from 3,534 lesionsthat had at least 6 months of clinical follow-up afterdeferral from revascularization (53). The 2-year ratesof cardiac death (1.0%) and nonfatal MI (0.9%) high-light the low-risk natural history of lesions with ahigh FFR value. As in other studies, a significant, in-verse relationship existed between the numericFFR value and repeated interventions at 2 years.

Another retrospective, single-center analysis of1,459 patients with FFR lesions between 0.70 and0.85 compared clinical outcomes after medical ther-apy versus revascularization (54). Among medicallytreated lesions, a significant, inverse relationship wasseen between the numeric FFR value and a compositeoutcome of death, MI, and revascularization. Themedical therapy and revascularization curves crossedat an FFR of 0.80, a threshold again biased due toconfounding by indication. All-cause death alone washigher for medically treated lesions between FFR0.70 to 0.80 than for FFR 0.81 to 0.85 (HR: 2.62; 95%CI: 1.28 to 6.8; p < 0.001).

Noninvasive CFR (occasionally termed myocardialflow or perfusion reserve, although we prefer CFR toemphasize the fundamental and common physiology)

FIGURE 3 Risk Continuum of Noninvasive CFR

20%

15%

10%

5%

0%0 1 2 3

Years

Card

iac

Mor

talit

y

N = 2,783 patients137 (5%) CV deaths adjusted hazard ratios

5.55 (95%CI 2.5-12.4)3.40 (95%CI 1.5-7.7)

CFR<1.5

CFR=1.5-2.0

CFR>2.0

N = 224 patients33 (15%) events

adjusted hazard ratio2.93 (95%CI 1.3-6.7)

MFR ≥2.11

MFR <2.11

P =0.001

1

0.75

0.50

0.25

0

0 200 400 600 800Time After PET/CT (d)

Cum

ulat

ive

Even

t-Fr

ee S

urvi

val

30.027.525.022.520.017.515.012.510.0

7.55.02.50.0

SSS < 4 SSS ≥ 4-7 SSS ≥ 8

Perc

ent o

f MAC

E (%

)



3.8

CFR≥2.0

7.81.5-2.0

11.1CFR<1.5 8.0

20.0

*26.5

10.5

23.325.4** 1.0

0.8

0.6

0.4

0.2

0.0

Surv

ival

-Fre

e of

MAC

E

0.0 2.0 4.0 6.0 8.0 10.0Follow-Up (Years)

CFRnormal (n)abnormal (n)

127102

11382

10869

10260

9756

9756



normalCFR ≥2.0

abnormalCFR <2.0

A B

C D

Montage of supporting data from cardiac PET. *p ¼ 0.028 for SSS$4 to 7 and CFR<1.5 versus CFR$2. **p ¼ 0.002 for SSS$8 and CFR<1.5 versus CFR$2. Adapted with

permission from (A) Murthy et al. (59); (B) Fukushima et al. (57); (C) Ziadi et al. (56); and (D) Herzog et al. (55). CFR ¼ coronary flow reserve; CT ¼ computed to-

mography; CV ¼ cardiovascular; MFR ¼ myocardial flow reserve; PET ¼ positron emission tomography; SSS ¼ summed stress score. other abbreviations as in Figure 1.



2780

as a binary prognostic variable has been assessed inseveral single-center series using cardiac PET or car-diac magnetic resonance. Binary CFR <2 identified ahigher risk of cardiac death alone or when combinedwith MI, revascularization, and cardiac hospitaliza-tion in 229 patients over approximately 5 years afterinitial medical treatment, even when adjusting forother variables (55). Similarly, in 677 patients afterinitial medical treatment, CFR <2 was an indepen-dent predictor of both hard events of cardiac deathplus MI alone, and when combined with revascu-larization and cardiac hospitalization (56). BothCFR <2.11 and absolute stress flow <1.90 ml/min/g(derived from the median values in the population)significantly separated risk in 224 patients over about1 year after initial medical treatment, although onlyCFR remained significant in a multivariable model

(57). A substudy of 222 subjects in MESA demon-strated an inverse relationship between the predicted10-year risk of coronary heart disease and absolutestress flow and CFR (p < 0.0001 for trend) (58).

Global CFR physiologically quantifies the globalburden of diffuse CAD over a spectrum of severitythat directly relates to a continuum of risk. This riskmight be modifiable by revascularization (5). GlobalCFR <1.5 by PET is associated with a high risk ofcoronary events, as compared with global CFR over2.0 carrying relatively lower risk, and with an inter-mediate risk in between (59,60). As shown in Figure 4,coronary artery bypass graft (CABG), but not PCI, inpatients with global CFR <1.6 may modify this high-risk natural history (61). However, neither PCI norCABG had any effect on the natural history of patientswith global CFR $1.6, and the overall cohort was of

FIGURE 4 Potential Benefit of Revascularization for Low CFR

12.5

10.0

7.5

5.0

2.5

0.0

Adju

sted

Ann

ualiz

edEv

ent R

ate

(%)

CFR High/No Revasc

(n=79)

CFR High/PCI

(n=70)

CFR High/CABG(n=17)

CFR Low/No Revasc

(n=57)

CFR Low/PCI

(n=84)

CFR Low/CABG(n=22)

6.04%p=0.22

p=0.32

3.83%

p=0.48

2.16%

11.52%

p=0.17

7.38%

0.88%

p=0.001

p=0.006

p=0.37

Adjusted for pretest clinical score, LV ejection fraction, LV ischemia, and coronary artery disease prognostic index.CFR denotes coronary flow reserve: high (≥1.6), low (<1.6).Early revascularization strategy denotes revascularization with percutaneous coronary intervention (PCI), coronary artery bypass grafting(CABG), or neither (No Revasc), within 90 days of noninvasive imaging.

*†

‡

Adjusted annualized rates of cardiovascular death and heart failure admission among patients referred for coronary angiography by CFR and

early revascularization (Revasc) strategy (CABG, PCI, or neither). No difference in event rates was seen in patients with high CFR (light blue,

orange, or gray), regardless of the revascularization strategy pursued. In patients with low CFR, those who underwent CABG (aqua) had

lower event rates than those who underwent PCI (purple; p ¼ 0.006) or no revascularization (maroon; p ¼ 0.001), and had event rates similar

to those with high CFR who underwent CABG (gray). Annualized event rates were adjusted for pre-test clinical score, LV ejection fraction,

LV ischemia, and coronary artery disease prognostic index. Reprinted with permission from Taqueti et al. (61). LV ¼ left ventricular; other

abbreviations as in Figures 2 and 3.


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modest size, at 329 patients. These retrospective ob-servations require randomized outcomes trialsof revascularization or novel medical treatment,but for now they suggest that the risk/benefit con-tinuum may be modified by physiology-guidedrevascularization.

Finally, some studies have explored the prognosticcontinuum for combined invasive FFR and invasiveCFR measurements. A retrospective, single-centeranalysis examined the outcomes of 157 lesionstreated with initial medical therapy (62). Lesions withboth FFR >0.8 and CFR >2 experienced the lowestrates of approximately 30% combined death, MI, andrevascularization over the subsequent decade offollow-up. Lesions with FFR #0.8, but CFR >2 had aslightly higher event rate at 40%, whereas the highestevent rate of 80% occurred in lesions with FFR >0.8,but CFR #2 (although revascularizations dominated).On the basis of these and related findings (63), amulticenter international pilot study is examining thehypothesis that PCI in lesions with CFR >2, despiteFFR #0.8, can be safely deferred and treated withmedical therapy alone (64).IMPLICATIONS OF THE SEVERITY-RISK CONTINUUM

ON HARD OUTCOMES. Disease severity and its

associated risk represent a continuum that challengesthe patient-specific selection of diagnostic testingand management. Precision medicine focuses thera-pies on those most likely to derive the greatestbenefit. Accordingly, it is helpful to view the designand interpretation of clinical trials through the con-tinuum lens. Because fully informed patient consentincludes a “discussion of the pros and cons of thealternatives” as well as “the uncertainties associatedwith the decision” (46), the risk continuum also haspractical implications for clinical care. Moreover, inthe absence of trials proving reduced MI and death,the common belief by patients and physicians thatPCI will reduce either of these events (65) might beconsidered a fundamental violation of true informedconsent. This potential becomes realistic because in areal-world analysis of discussions with cardiologists,better-informed patients were less likely to selectinvasive angiography and potential PCI (46). Forexample, between an FFR of 0.75 and 0.80, themodestly elevated risk from the stenosis physiologywarrants consideration of other factors, such as theamount of distal myocardium, severity and pattern ofsymptoms, technical feasibility of revascularization,and ability to tolerate antianginal and dual

FIGURE 5 Severity Stratification for Randomized Trials or Informed Interventional

Decisions

Severity Stratified Randomized Trial For MI or Death

Focal stenosis (+)Global diffuse (-)Schema S. Randomizeto PCI/CABG or Med RxLikely MI/death

Focal stenosis (+)Global diffuse (+)Schema SD. Randomizeto PCI/CABG or Med Rx

Likely ± MI/death

Mixedmoderate focal

+global diffuse CADPCI/CABG ± MI/death

in currenttrials

Focal stenosis (-)Global diffuse (-)Medical Rx only

Focal stenosis (-)Global diffuse (+)

Schema D. Randomizeto PCI/CABG or Med Rx

Likely ± MI/death

None (-) Threshold (+) WorstQuantitative Severity of Diffuse CAD

None

(-)

Thre

shol

d

(+)

Wor

st

Quan

titat

ive

Foca

l Ste

nosis

Consequences of different severities of stenosis and diffuse CAD for informed interven-

tional decisions or randomized trial design to determine whether PCI reduces MI or

mortality. Light blue denotes low risk; orange signals high risk;maroon notes the presence

of diffuse disease. Reprinted with permission from Gould et al. (5). CABG ¼ coronary artery

bypass surgery; CAD ¼ coronary artery disease; Rx ¼ prescription; S ¼ discrete stenosis;

Schema D ¼ diffuse disease with minimal local stenosis; SD ¼ stenosis and diffuse disease;

other abbreviations as in Figure 2.



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antiplatelet medications. However, the greatlyelevated risk from an FFR <0.60 should tilt the bal-ance strongly toward revascularization if all otherfactors remain equal. We already make these contin-uous and integrative decisions for blood pressure,dyslipidemia, and ejection fraction; thus, the appli-cation to lesion physiology is a natural extension.

No trial comparing optimal medical therapy torevascularization in patients with stable CAD hasconclusively demonstrated a statistically significantreduction in hard outcomes of death or MI. Untilrevascularization trials prove a reduction in hardevents by selecting more severe focal and diffuse CADthan previously, the risk/benefit continuum remainsthe only valid basis for personalized decision-makingwith informed consent. This view will likely play suchan important future role in both clinical practiceand trial design that a further discussion of currenttrials in stable CAD is essential for revealing thiscommonly-overlooked interpretation of what theirdata actually shows.

The FAME 2 trial showed a nonsignificantreduction in death and MI from 8.2% after 2 yearswith initial medical therapy to 6.5% with upfrontPCI (HR: 0.79; 95% CI: 0.49 to 1.29; p ¼ 0.35) forlesions with FFR #0.8 (66). Using these event ratesplus standard assumptions for a power calculation(2-sided, <0.05 significance, 80% power) yields atrial size of 3,784 patients (5)—over 4-fold higherthan the 888 patients randomized in FAME 2, andlarger than any contemporary revascularization trialin patients with stable coronary disease: 408 inMASS II (Medicine, Angioplasty, or Surgery Study)(67), 1,605 in BARI 2D (Bypass Angioplasty Revas-cularization Investigation 2 Diabetes) (68), and 2,287in COURAGE (69). Given the current recruitmenttrajectory of ISCHEMIA (now at n ¼ 2,851 [10] of atarget 8,000 after 3 years of enrollment), random-izing 3,784 patients with stable coronary diseasewith FFR #0.8 does not seem feasible within cur-rent research frameworks.

However, the continuum of risk implies a largertreatment benefit for more severe lesions. Assume thatlowering the inclusion criterion from FFR#0.8 to#0.7would increase both the relative benefit (from 0.79 to0.7 with upfront PCI) and the absolute event rate (from8.2% to 9%withmedical therapy). Now the sample sizefalls from 3,784 to 1,670—a decrease of about 55%—

resulting in a trial comparable in size to BARI 2D andsmaller than COURAGE (Clinical Outcomes UtilizingRevascularization and Aggressive Drug Evaluation).Not only has sample size decreased, but so too theabsolute number of death and MI events: 277 in thelarger trial to 116 in the smaller trial (5). Thus, exam-ining for a potential benefit of PCI on hard outcomes inmore severe patients makes a clinical trial bothfeasible and more ethical. Figure 5 provides a generalframework for this trial.

Additionally, the typical FFR values around 0.83seen in a recent diagnostic accuracy study from in-vestigators seeking to avoid hyperemia (70) (such thatapproximately 2 of 3 patients had an FFR >0.8, andprobably 8 of 10 patients had an FFR >0.75) fallon the flat portion of the risk/benefit continuum,thereby reducing event rates and hence hamperingthe ability to exclude a clinically meaningful inferi-ority when using resting metrics. In this range ofmild physiology, a more vigorous upstream trial ofmedical therapy, coupled with a higher symptom ornoninvasive testing threshold, could likely avoidinvasive angiography completely, without compro-mising outcomes.

Finally, the risk continuum has implications fornoninvasive physiological testing. Advanced imagingtools all have similar and high diagnostic


2783

performance versus FFR #0.8: PET (sensitivity 89%,specificity 84% [71]), cardiac magnetic resonance(sensitivity 90%, specificity 87% [72]), and phy-siological simulation of FFR on the basis of CTangiography (sensitivity 89%, specificity 71% [73]).However, FFR as a reference standard of severity canreasonably be challenged due to substantial discor-dance from adequate or normal quantitative coronaryflow capacity (63) or in patients with insignificant orno coronary stenosis (43), historically at low risk.Although a complete description of stenosis physi-ology requires both pressure and flow measurements(48), the risk continuum at very low FFR or CFRidentifies lesions with a worse natural historypotentially benefited by revascularization. At theselower FFR and CFR values, lesion severity is rarelyunderestimated by advanced imaging, with pressureflow concordance for optimally guiding revasculari-zation to reduce hard endpoints.

MATCHING REVASCULARIZATION STRATEGY TO

PHYSIOLOGY PROFILE. At its most general, 3 optionsexist for treating stable CAD: medical therapy, PCI,and CABG. Medical therapy forms the foundation oftreatment, although patients differ in their abilityto tolerate and adhere to optimal management. PCIrelieves a focal stenosis, providing improved anginarelief compared with medical therapy (74), but at acost of small (but nonzero) procedural risk (18) andthe need for dual antiplatelet therapy of potentiallylonger duration (75). CABG may excel at treatingdiffuse and complex CAD (76), but with a higherprocedural risk (18) and without the need for dualantiplatelet therapy.

Historically, the benefit of PCI rested on assump-tions that are now challenged by the following 2 re-alizations. First, visual estimation of stenosis severityperforms poorly compared with coronary physiology(43). Second, unrecognized and unquantified diffusedisease carries a similar risk to focal disease (61,77).This was also illustrated in the PROSPECT study,wherein nonculprit lesions accounted for a compa-rable frequency of events versus culprit lesions afteran ACS (11.6% vs. 12.9% over 3 years, respectively)(11), and in a pooled analysis of post-PCI measure-ments of FFR that found an inverse relationshipwith outcomes due to residual diffuse disease (48).Although a series of randomized trials has alreadymoved the evaluation of stenosis severity fromangiography to physiology, specifically by using FFR(66,78,79), the awareness regarding diffuse andmicrovascular disease is only now emerging.

Matching the strengths of each treatment tothe individual patient implies PCI for focal disease

of sufficient physiological severity as detailed previ-ously, but without extreme anatomic complexity (76)or severe diffuse disease, which may be better treatedby CABG or medical therapy, depending on anatomicand patient specifics (5). Distinguishing focal fromdiffuse disease thus takes on heightened importance,and 2 general physiological techniques exist. Inva-sively, a pressure pullback along the length of theepicardial artery can separate focal drops in pressurefrom diffuse, gradual pressure loss (80). However, adistal FFR measurement will overestimate the rela-tive flow increase from treating a focal stenosis inthe presence of diffuse disease, thereby uncouplingFFR from relative CFR. Noninvasively, a global CFRor absolute stress flow reduction in the absence ofa relative regional perfusion defect identifies diffusedisease and/or microvascular dysfunction (63). Theparticular strength of CFR using absolute perfusionmeasurements resides in its common units forboth focal stenosis and diffuse disease, therebyquantifying their relative importance or weight foroptimizing the revascularization method (5).

Identifying the physiological pattern affects bothpatient care and the design of clinical trials to guideinformed consent. Treating a focal and severe angio-graphic stenosis that is physiologically mild exposespatients to procedural risk and heightened antith-rombotic therapy without improving symptoms orreducing the risk of hard events (78,79). Treating amildfocal stenosis in a vessel with low FFR due mainly todiffuse disease leaves the patient at increased residualrisk (47). It is possible that both of these physiology-to-treatment mismatches took place in prior outcometrials that failed to find benefit of revascularizationcompared with medical therapy (69).

CORONARY PHYSIOLOGY TO DIAGNOSE SYMPTOMS

AND GUIDE TREATMENT. Apart from the questions ofaltering hard endpoints of death and MI in stableCAD, we frequently encounter patients with symp-toms who want to feel better. Of patients withoutknown CAD who present with new chest pain symp-toms, only a small minority has a coronary etiology.For example, in the ROMICAT-II (Rule Out MyocardialInfarction/Ischemia Using Computer Assisted Tomo-graphy) trial of 1,000 patients presenting to theemergency department with symptoms suggestive ofan ACS, but with an initial negative troponin and nosignificant changes on electrocardiography, 8% ofpatients were diagnosed with an ACS (81). Further-more, 89% of patients with symptoms promptingemergency medical evaluation in this study hadnoncardiac or noncoronary chest pain. The similarlylow rates of revascularization after 90 days seen in



2784

the PROMISE (Prospective Multicenter Imaging Studyfor Evaluation of Chest Pain) trial of 10,003 out-patients referred for noninvasive testing (3.2%with functional testing vs. 6.2% with anatomictesting; p < 0.001) (82) parallel the findings in theemergency department, and both studies excludedpatients with known CAD (81,82).

Thus, on the basis of the selected populationsdescribed in the preceding text, patients with stablecoronary disease without known CAD have a pre-testprobability of approximately 5% for a coronary etiol-ogy of their chest symptoms. This figure mirrors theprevalence of angina pectoris at just over 3% ofthe entire adult population in the United States,resulting in 22,000 hospital discharges each year (44).Although these figures imply a small population withsymptomatic, stable epicardial coronary disease, suchpatients comprise a significant portion of cardiologypractice and resource utilization due to diagnostictesting, clinic visits, hospital admissions, medicationprescriptions plus associated adverse reactions,and revascularization procedures plus associatedcomplications. Coronary physiology may play 2important roles in symptomatic, patients with stablecoronary disease. First, it may help to separate thesmall minority of patients with a coronary etiology forpresenting chest pain from the background majoritywith noncoronary or noncardiac diagnoses. Unlikeindex CT screening (81,82), upfront physiologicaltesting can likely screen without increasing unnec-essary downstream procedures. Second, it mayhelp to select patients likely to experience superiorangina relief with revascularization compared withmedical therapy, as reported in the FAME 2 (66) andCOURAGE (69) trials.

A wide body of evidence supports invasive quan-tification of coronary physiology to identify symp-tomatic fixed stenosis and guide improvement usingrevascularization. By comparing FFR against a mul-titest reference standard of exercise electrocardiog-raphy, exercise single-photon emission computedtomography perfusion, and dobutamine echocardi-ography, both before and after revascularization,the threshold of 0.75 was established almost 20 yearsago in symptomatic patients with “uncertainty aboutwhether the chest pain was related to reversibleischemia caused by the moderate stenosis” (49). ForFFR >0.75 lesions in the DEFER trial, upfront PCIcompared with medical therapy did not improveangina burden or need for antianginal medicationsduring the subsequent 5 years (78). From 1 month to5 years, upfront PCI for these stenoses did not in-crease the proportion of patients with CanadianCardiovascular Society (CCS) class I angina (57% vs.

67% actually favoring medical therapy; p > 0.05).Conversely, the FAME 2 trial demonstrated superiorangina relief when treating FFR #0.8 lesions withPCI compared with medical therapy (66). From 1 to24 months, upfront PCI for these stenoses reducedCCS class II to IV angina by about 50% to 60%compared with initial medical therapy (risk ratios:0.36, 0.41, 0.39, and 0.49 at 1, 6, 12, and 24 months,respectively; p # 0.002 at all time points), despitean approximate 40% crossover to revascularization inpatients treated medically.

However, the improvement in angina after revas-cularization noted in FAME 2 and other studies mayoverestimate benefit due to unblinding of patients andtheir physicians (83). Thus, ORBITA (Comparison ofCoronary Angioplasty and Optimum Medical TherapyVersus Optimal Medical Therapy in the Stable Angina),an ongoing multicenter study in the United Kingdom,will randomize a total of 200 patients with stableangina to real versus sham PCI under blinded condi-tions (84). Baseline coronary physiology measure-ments will occur before PCI in all patients, with aprimary endpoint of treadmill exercise time after 6weeks. The coronary physiology data will providevaluable predictors for identifying patients whoseangina improves with real PCI, providing an evidence-based evaluation of the added value for hyperemiabecause stable angina occurs with stress, not at rest.

Noninvasive physiological measurements duringangina provide quantitative limits that could form thebasis for future randomized outcomes trials. A study of1,674 cardiac PET scans imaged absolute stress flowand CFR with vasodilation using, as the independentstandard, a new or worse perfusion defect duringvasodilation in conjunction with significant ST-segment depression and/or severe angina requiringpharmacological treatment (85). Absolute stress flowsof 0.91 ml/min/g and CFR of 1.74 demonstratedexcellent diagnostic performance (area under ROCcurves of 0.98 and 0.91, respectively) for identifyingthis well-defined ischemia. A multicenter and inter-national study of 330 patients who underwent bothcardiac PET and invasive angiography with frequentFFR used an over 90% diameter stenosis or FFR #0.8as its reference standard (71). Although we should bearin mind that a complete description of stenosis phys-iology requires both pressure and flow measurements(48), absolute stress flow of 2.3 ml/min/g and CFR of2.5 showed good diagnostic performance (per-vesselaccuracy 85% and 81%, respectively), and these flowlevels have been associated with low risk (59–61).

Noninvasive simulations and resting physiologicalpredictions of hyperemic conditions assume a uni-form, predictable, biological response to stress in


2785

proportion to resting measurements. Documentedbiological variability fundamentally contravenes suchassumptions (86), which can be generally classified asdue to heterogeneous responses to hyperemia (thecapacity to increase flow varies greatly and unpre-dictably among patients) or imperfect resolution(in the case of physiological simulation of FFR frominvasive or noninvasive imaging of anatomy). As a neteffect, these nonstress tools have demonstrated animperfect pooled 79% per-vessel accuracy from the3 major FFRCT diagnostic accuracy studies (87–89), bythe approximate 80% per-lesion accuracy of invasiveresting physiology (70,90,91) to predict invasiveFFR #0.8, and by the Bland-Altman SD for bothtechniques of 0.10 to 0.15 compared with invasiveFFR (86,90). For example, a predicted FFR of 0.85(via invasive resting gradient or noninvasive simula-tion) could overlap with actual FFR values from 0.70to 1.0, whose prognosis and treatment differ widely.Therefore, such resting tools rely on assumptionsthat may not be valid when compared with actualphysiological measurements necessary for accuratepersonalized therapy.

DIAGNOSIS AND TREATMENT OF ANGINA WITHOUT

OBSTRUCTIVE EPICARDIAL CAD. Two scenariosoccasionally arise that are distinct from classic stableangina due to a physiologically severe stenosis, aspreviously discussed. First, atypical angina can occurat rest or inconsistently with activity. Chest symp-toms that occur at rest in patients with stable coro-nary disease are unlikely to arise solely from a fixedcoronary stenosis. Typically, such complaints areeither noncoronary or result from a variable combi-nation of fixed stenosis plus functional disease (e.g.,abnormal blood pressure or heart rate, adrenergicmedications, endothelial dysfunction, or coronaryspasm). As an advantage, vasodilator imaging andinvasive measurements minimize physiologicalvariability to reveal the severity of fixed diseasealone, whereas exercise stress or dobutamine infu-sion stimulate physiology severity over and beyondthe fixed structural component (92). Because thevast majority of functional coronary disease (e.g.,vasospasm, myocardial bridging, or endothelialdysfunction) can be treated with widely available,generally well-tolerated, and relatively inexpensivemedications (e.g., beta-blockers, calcium-blockers,and nitrates), it has received less attention thanrevascularization of fixed coronary disease. Howev-er, it is increasingly recognized that such conven-tional therapies do not lead to similar symptomcontrol as that seen in patients with focal epicardialstenosis.

Beyond symptoms, the presence of angina withangiographically nonobstructive or normal coronaryarteries may not necessarily associate with low clin-ical risk. Indeed, a large European registry demon-strated that patients with angina and normalcoronary arteries or nonobstructive CAD were asso-ciated with a 52% and 85% increased risk of com-bined cardiovascular mortality, hospitalization forMI, heart failure, or stroke, and with 29% and 52%increased risk of all-cause mortality, respectively,with no differences between men and women (93).Similar physiological observations were seen instudies using invasive (94) or noninvasive (95) CFRassessment.

Second, classic angina may present without a sig-nificant stenosis. Interestingly, the group of patientswith angina but FFR >0.75 to 0.80 has a clear subsetwith refractory symptoms, despite medical therapy.In both the DEFER and FAME 2 trials, lesions withhigh FFR had inferior angina relief compared withlow FFR lesions that underwent PCI. Specifically, theFFR <0.75 cohort treated by initial PCI in the DEFERtrial reached a 72% freedom from angina, whereasboth FFR $0.75 cohorts had lower levels, at 67% and57% free of angina (p ¼ 0.028) (78). Similarly, the FFR>0.8 registry of the FAME 2 trial had a similar anginaburden at baseline that improved by 1 month, butthereafter remained worse than the FFR #0.8 cohorttreated by PCI (risk ratios: 0.47, 0.38, and 0.40 at6, 12, and 24 months, respectively, favoring lowFFR with PCI; all p # 0.002) despite 12% crossoverto PCI (66).

These subgroup analyses highlight other mecha-nisms for angina that are separate from a severeepicardial stenosis. Such functional coronary diseasemay be elucidated through a variety of physiolog-ical techniques, such as noninvasive quantificationof global CFR (61), Doppler-derived (62) or bolusthermodilution-based (20) measures of myocardialresistance, pressure or flow interrogation of myocar-dial bridges (96), or provocation testing for endothe-lial dysfunction (97).

However, currently, only hypothesis-generatingstudies suggest potential links to existing thera-pies. Additionally, many of these therapies cost littleand could thus be tried anyway in patients withresidual symptoms, after excluding significant fixedepicardial disease. Novel systemic therapies forcardiovascular disease, such as methotrexate andPCSK9 inhibitors, are currently being tested in gen-eral populations, and coronary physiology mayprovide a risk stratification tool to refine theircost-effective use.



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CONCLUSIONS

We conclude by summarizing a vision for the futureof coronary physiology. Given the prominent role ofACS and invasive procedures in cardiology, ourschema focuses on those themes. Nonetheless, many(if not most) patients now undergoing interventionalcardiovascular procedures may not meet the severitycriteria for intervention to reduce death and MIbeyond what modern medical treatment can achieve.It is our view that new interventional trials driven byquantitatively severe focal and diffuse disease mayhelp to define the roles of integrated diagnostictesting and intervention for reducing hard outcomes.

Of course, no clinical diagnostic test stands apartfrom an associated therapy. The future of invasiveFFR, noninvasive CFR, and other related physiolog-ical measurements rests firmly on establishingmeaningful links to effective treatments and im-proved clinical outcomes. For patients with acutecoronary disease, coronary physiology may poten-tially refine treatment of the culprit lesion. Here,endpoints of death and MI will dominate clinical

trials, just as they have in the past for ACS. For bothpatients with stable and acute coronary disease withnonculprit disease, reducing death and MI withrevascularization potentially occurs at the severe endof the focal physiological spectrum, an area under-represented in existing trials. We can use the con-tinuum of risk clarified by coronary physiology totailor our discussions with patients to achieve trulyinformed consent regarding risks and benefits fromtherapy. For the large number of patients with chestsymptoms, physiology measurements identify thesmall proportion of them who have coronary diseasewith focal severity likely to benefit from revasculari-zation in addition to medical therapy. Nonepicardialdisease and diffuse CAD remain underexplored as-pects of coronary physiology for testing of noveltreatments.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Nils P. Johnson, Weatherhead PET Center, McGov-ern Medical School at UTHealth, 6431 Fannin Street,Room MSB 4.256, Houston, Texas 77030. E-mail:[email protected].

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KEY WORDS coronary flow reserve,coronary physiology, fractional flow reserve




























































































































































































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