Fractional Flow Reserve (FFR)

Definition

Fractional flow reserve (FFR) is a pressure wire-based physiologic index measuring the ratio of maximum achievable coronary flow distal to a stenosis to the theoretical maximum without the stenosis, expressed as distal coronary pressure (Pd) divided by aortic pressure (Pa) during maximum hyperemia (induced by adenosine). A value of ≤0.80 is the established ischemic threshold warranting revascularization; values >0.80 favour medical management or deferral. FFR is validated as superior to angiography alone for identifying hemodynamically significant coronary stenoses in stable and chronic coronary artery disease, but its role in the ACS setting is more complex.

Key Concepts

Physiology

• Requires pharmacologic hyperemia (IV or intracoronary adenosine) to minimise microvascular resistance and isolate the pressure gradient across the epicardial stenosis
• FFR ≤0.80 = hemodynamically significant (ischemia-producing); FFR >0.80 = defer revascularization safely
• Unlike quantitative coronary angiography, FFR accounts for lesion length, shape, location, and the downstream microvascular territory
• Critical limitation: FFR measures current flow limitation only — it cannot detect plaque vulnerability (thin fibrous cap, large lipid core) or assess risk of future MI from plaque rupture

Validation in Stable and Chronic Coronary Artery Disease

• DEFER trial: FFR-guided deferral safe in stable CAD — 5-year MACE comparable to normal coronary arteries when FFR >0.75
• FAME trial (NEJM 2009): FFR-guided vs angiography-guided PCI in multivessel stable CAD — fewer stents, lower MACE at 1 year
• FAME-2 trial (NEJM 2014): FFR-guided PCI vs medical therapy in stable CAD — lower urgent revascularization; no all-cause mortality benefit
• Current guideline position: Class I recommendation (ESC) for intermediate stenoses 50–90% in stable/chronic CAD (sources/CCS-AHA-2023, rating: high)

FFR in ACS — Culprit vs Nonculprit Assessment

• FFR of the culprit vessel acutely is unreliable: microvascular dysfunction elevates resistance → overestimates FFR → false-negative (may miss ischemia-producing stenosis)
• FFR of nonculprit vessels is considered reliable acutely and comparable to repeat measurement at 35 days (WAVE study; Ntalianis 2010)
• This distinction underpins all ACS FFR trials: culprit PCI is guided angiographically; only nonculprit assessment uses FFR

FFR-Guided Complete Revascularization in ACS — FULL REVASC Trial

• Design: 1,542 patients with STEMI or very-high-risk NSTEMI and multivessel CAD; 1:1 FFR-guided complete revascularization vs culprit-only PCI; 32 centres, 7 countries; median 4.8-year follow-up (sources/ffrpci-mi-fullrevasc-nejm-2024, rating: very high)
• Primary outcome (death/MI/unplanned revascularization): 19.0% vs 20.4%; HR 0.93 (95% CI 0.74–1.17); P=0.53 — not superior
• Death or MI: HR 1.12 (NS); Unplanned revascularization: HR 0.76 (NS)
• Any revascularization: 10.2% vs 16.5% (HR 0.59) — fewer total procedures with FFR strategy
• Stent thrombosis: 2.5% vs 0.9% (HR 2.80) — significantly higher with FFR-guided complete revascularization
• Key FFR finding: 40% of complete-revascularization patients had ALL nonculprit lesions deferred (FFR >0.80); only 47% of tested vessels had FFR ≤0.80
• Trial terminated early (74% power) after COMPLETE trial publication (sources/ffrpci-mi-fullrevasc-nejm-2024, rating: very high)

FFR vs Angiography Guidance — A Critical Distinction in ACS

• COMPLETE trial (NEJM 2019; n=4,041): Angiography-guided complete revascularization → 26% lower risk of CV death/MI; benefit driven by stenoses ≥80% by visual estimation or ≥60% by QCA; FFR used in <1% of patients
• FULL REVASC trial (NEJM 2024; n=1,542): FFR-guided complete revascularization → neutral (HR 0.93, P=0.53) (sources/ffrpci-mi-fullrevasc-nejm-2024, rating: very high)
• Mechanistic hypothesis for divergence: Angiography-guided approach treats high-grade stenoses (≥60–80%) that are not only flow-limiting but also harbor vulnerable plaques — FFR defers some of these because FFR >0.80, yet these plaques carry future MI risk that FFR cannot detect
• COMPLETE OCT substudy confirmed vulnerable plaque features in nonculprit lesions, independent of stenosis severity
• The ongoing COMPLETE-2 trial is directly comparing physiology-guided vs angiography-guided complete revascularization in ACS

FFR vs iFR

• Both measure hemodynamic significance via intracoronary pressure wire
• iFR uses resting diastolic pressure ratio (no adenosine); FFR uses hyperemic ratio (adenosine required)
• Validated equivalent for MACE in stable CAD (DEFINE-FLAIR, iFR-SWEDEHEART, NEJM 2017)
• iFR may have a higher false-positive rate (~11%) in STEMI due to elevated resting flow; FFR requires adenosine which may cause transient AV block, dyspnoea, chest discomfort
• iFR-guided immediate complete revascularization in STEMI was also neutral vs deferred MRI-guided approach at 3 years (iMODERN, NEJM 2026; HR 0.95, P=0.81)
• See concepts/Instantaneous-Wave-Free-Ratio

FFR vs Angiography-Based vFFR — FAST III Trial

• Design: 2,235 patients with intermediate lesions (30–80% stenosis); chronic or acute coronary syndrome; 37 European centers; 1:1 vFFR-guided vs FFR-guided revascularization; 1-year follow-up (sources/vffr-fastiii-nejm-2026, rating: very high)
• vFFR (vessel FFR; Pie Medical Imaging) derives an FFR equivalent from 3D quantitative coronary angiography using two angiographic projections — no intracoronary wire and no adenosine required; same ≤0.80 threshold as wire FFR
• Primary endpoint (death/MI/revascularization at 1 year): 7.5% (vFFR) vs 7.5% (FFR); risk difference −0.02 pp (95% CI −2.25 to 2.21); P=0.004 for noninferiority — vFFR noninferior to FFR (sources/vffr-fastiii-nejm-2026, rating: very high)
• vFFR identified more functionally significant lesions (40.9% vs 31.3%) and led to more revascularizations (45.0% vs 36.0%), yet clinical outcomes were equivalent; procedure time was ~5 min shorter with vFFR and intraprocedural complications were lower (3.7% vs 6.0%)
• The higher lesion detection rate with vFFR reflects its reliance on assumed geometric flow rather than actual measured hyperemic flow — angiography-based tools do not account for microvascular resistance, demand, or patient-specific hyperemia responses
• See concepts/Angiography-Based-Coronary-Physiology for full detail including FAVOR III Europe vs FAST III comparison

Guideline Positions — FFR in ACS

• ESC 2023 ACS Guidelines: Angiographic severity is the primary basis for nonculprit PCI in STEMI; functional invasive evaluation "may be considered" — not mandated; functional evaluation recommended for nonculprit lesions in NSTEMI
• AHA/ACC 2025 ACS Guidelines: FFR "may be useful" to guide nonculprit PCI for intermediate stenoses in STEMI (Class IIa); complete revascularization remains Class I recommendation (without mandating FFR)
• TAVI candidates with CAD: FFR ≤0.80 or ≥90% angiographic stenosis — PCI reduces MACE (NOTION-3, NEJM 2024) (sources/PCI-TAVI-NOTION3-NEJM-2024, rating: very high)

Contradictions / Open Questions

• FFR-guided vs angiography-guided complete revascularization in ACS: COMPLETE shows angiography-guided strategy reduces CV death/MI (HR ~0.74); FULL REVASC shows FFR-guided strategy is neutral (HR 0.93, P=0.53). Whether FFR-guided deferral systematically under-treats patients with vulnerable high-grade lesions (FFR >0.80 but rupture-prone) is the central unanswered question. COMPLETE-2 (ongoing) will directly compare the two approaches (sources/ffrpci-mi-fullrevasc-nejm-2024, rating: very high)
• Stent thrombosis excess (HR 2.80) with FFR-guided complete revascularization: Each additional nonculprit stent in an ACS patient carries thrombotic risk that may not be offset by ischemia prevention when FFR borderline. The 40% deferral rate in FULL REVASC still left 60% with additional stents, driving excess stent thrombosis without commensurate outcome benefit (sources/ffrpci-mi-fullrevasc-nejm-2024, rating: very high)
• FIRE trial contradiction (NEJM 2023): Physiology-guided complete revascularization in elderly STEMI/NSTEMI (≥75yr) showed 36% lower CV death/MI at 1 year — directly contradicts FULL REVASC's neutral result at 4.8 years. Key differences: older/sicker FIRE population, multiple physiology tools (not FFR alone), shorter follow-up, and different composite endpoint dynamics
• Optimal FFR threshold in ACS: The ≤0.80 cutoff was established in stable CAD; whether a lower threshold (e.g., ≤0.75) would improve specificity in the ACS setting and avoid the vulnerable-plaque problem remains unexplored
• vFFR detects more lesions than FFR (FAST III): vFFR classified 40.9% vs 31.3% of lesions as functionally significant, driving a 9 pp higher revascularization rate (45% vs 36%) with equivalent outcomes. Whether this indicates vFFR better identifies prognostically relevant lesions, or systematically over-detects, adding stents without benefit, is unresolved — prespecified cost-effectiveness analysis pending (sources/vffr-fastiii-nejm-2026, rating: very high)

Connections

• Related to concepts/Angiography-Based-Coronary-Physiology — wire-free alternative; vFFR noninferior to FFR (FAST III, NEJM 2026)
• Related to concepts/Instantaneous-Wave-Free-Ratio — resting pressure-wire alternative to FFR
• Related to concepts/Multivessel-PCI-STEMI-Timing — FFR vs angiography guidance in STEMI nonculprit decisions
• Related to concepts/PCI-Before-TAVI — FFR threshold used in NOTION-3 trial
• Related to concepts/Myocardial-Viability — physiologic vs imaging approaches to assessing myocardial significance

Sources

• sources/ffrpci-mi-fullrevasc-nejm-2024
• sources/PCI-TAVI-NOTION3-NEJM-2024
• sources/vffr-fastiii-nejm-2026