What is the role of Instantaneous Flow Reserve (IFR) in the latest trials for managing Acute Coronary Syndrome (ACS)?

IFR in Acute Coronary Syndrome: Latest Evidence

Both instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) are equally recommended for guiding revascularization decisions in patients with acute coronary syndromes and angiographically intermediate stenoses, with iFR offering the practical advantage of not requiring adenosine while maintaining equivalent clinical outcomes. 1

Guideline Recommendations for IFR in ACS

Class I Recommendation (Strongest Evidence)

• In patients with ACS, undocumented ischemia, and angiographically intermediate stenoses (typically 40-90% for non-left main stenoses), the use of iFR or FFR is recommended to guide the decision to proceed with PCI. 1
• Both the 2021 ACC/AHA/SCAI and 2024 ESC guidelines provide Class I, Level A recommendations for iFR use in ACS, placing it on equal footing with FFR. 1

Key Trial Evidence Supporting IFR in ACS

• The DEFINE-FLAIR and iFR-SWEDEHEART trials specifically enrolled patients with acute coronary syndromes and demonstrated that iFR-guided PCI was noninferior to FFR-guided PCI for clinical outcomes. 1
• These landmark trials included both stable angina and ACS patients, providing robust evidence for iFR use across the spectrum of coronary disease presentations. 1

Clinical Outcomes and Safety Data

Short-Term Outcomes (1 Year)

• In the pooled analysis of DEFINE-FLAIR and iFR-SWEDEHEART trials, major adverse cardiac events (MACE) rates were similar between iFR and FFR groups at 1 year (4.12% vs. 4.05%; HR 1.13,95% CI 0.72-1.79, p=0.60). 2
• When revascularization was deferred based on iFR >0.89 or FFR >0.80, both strategies showed equally low event rates, confirming the safety of deferral with either index. 2

Long-Term Outcomes (5 Years)

• A critical finding emerged at 5-year follow-up: meta-analyses revealed a 2% absolute increase in all-cause mortality in patients managed with iFR compared to FFR. 1
• However, this mortality difference was not associated with increased rates of unplanned revascularization or non-fatal myocardial infarction, suggesting the mechanism remains unclear. 1
• Importantly, iFR-based deferral remained as safe as FFR-based deferral up to 5 years, with no difference in outcomes among deferred patients specifically. 3

Practical Advantages of IFR in ACS

Procedural Benefits

• iFR does not require adenosine administration, eliminating hyperemic agent-related adverse effects, procedural time, and cost. 1
• In the DEFINE-FLAIR and iFR-SWEDEHEART trials, iFR use was associated with lower rates of procedure-related chest pain and shorter procedural time compared to FFR. 1

Deferral Patterns

• iFR resulted in more frequent deferral of revascularization compared to FFR (50% vs. 45%, p<0.01), potentially reducing unnecessary interventions. 2
• This higher deferral rate with iFR did not translate into worse outcomes, supporting its safety profile. 2

Important Caveats for ACS Patients

Higher Risk in ACS vs. Stable Disease

• Patients with ACS who had revascularization deferred based on physiologic assessment had significantly higher MACE rates compared to stable angina patients (5.91% vs. 3.64%; adjusted HR 0.61 favoring stable disease, p=0.04). 2
• This finding emphasizes that while iFR and FFR are equally safe in ACS, the overall risk remains higher in ACS patients even when lesions are deemed non-significant by physiology. 2

Timing Considerations

• Current guidelines suggest FFR/iFR assessment is useful in ACS patients with intermediate lesions 5 days after the index event for non-culprit lesions. 1
• For culprit lesions in NSTEMI, the FAMOUS-NSTEMI trial demonstrated that FFR measurement was feasible and safe, with FFR retaining diagnostic validity in medically stabilized NSTEMI patients. 1

Diagnostic Thresholds and Accuracy

Cut-off Values

• iFR ≤0.89 indicates hemodynamically significant stenosis requiring revascularization. 1
• iFR >0.89 supports deferral of PCI in stable patients with intermediate stenoses. 1

Diagnostic Performance

• Meta-analysis of 16 studies comprising 5,756 lesions showed iFR has excellent diagnostic accuracy referenced to FFR ≤0.80: sensitivity 0.78, specificity 0.83, and area under the ROC curve 0.87. 4
• iFR shows stronger correlation with coronary flow velocity reserve (CFVR) compared to FFR (ρ=0.68 vs. ρ=0.50, p<0.001), suggesting it may better reflect underlying coronary physiology. 5

Clinical Decision Algorithm for IFR Use in ACS

When to Use IFR in ACS

1. Intermediate stenoses (40-90% diameter stenosis by visual estimate) in non-culprit vessels or stabilized culprit vessels where ischemia documentation is lacking. 1
2. Multivessel disease in ACS where determining which non-culprit lesions require treatment is uncertain. 1
3. Left main intermediate stenoses (40-70%) where physiologic assessment is particularly valuable, though IVUS should also be considered. 1

When NOT to Perform PCI Despite Angiographic Appearance

• Do not perform PCI in stable ACS patients with iFR >0.89, as this carries a Class III (No Benefit), Level B-R recommendation. 1
• Only stenoses >90% by visual estimate reliably predict hemodynamic significance without physiologic testing (96% accuracy). 1

Emerging Concerns and Ongoing Questions

The 5-Year Mortality Signal

• The unexplained 2% mortality increase with iFR at 5 years requires cautious interpretation, as it was not accompanied by increased MI or revascularization rates. 1
• Initial hypotheses suggested this could relate to higher inappropriate deferral rates with iFR (50% vs. 45% with FFR), but subsequent analyses showed deferral itself was equally safe with both indices. 1, 3
• Until this mortality signal is better understood, some operators may prefer FFR for long-term prognostic assessment, particularly in younger patients or those with longer life expectancy. 1

Limitations in ACS-Specific Validation

• While iFR has been validated in mixed populations including ACS, concerns exist about microvascular dysfunction and blunted adenosine response in acute settings potentially affecting FFR more than iFR. 6
• The resting nature of iFR may theoretically provide more stable measurements in the acute phase when microvascular function is impaired. 6