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Gotberg M, et al. "Spontaneous wave-free ratio versus fractional flow reserve to guide PCI". The New England Journal of Medicine. 2017. 376(19):1813-1823.
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Clinical Question

In patients with stable or unstable coronary artery disease (CAD) undergoing revascularization with intermediate coronary lesions, is instantaneous wave free ratio (iFR) noninferior to fractional flow reserve (FFR) for PCI guidance with regard to all-cause mortality, nonfatal MI, or unplanned revascularization?

Bottom Line

In patients with stable or unstable coronary artery disease (CAD) undergoing revascularization with intermediate coronary lesions, iFR is noninferior to FFR for PCI guidance, with similar rates of all-cause mortality, nonfatal MI, or unplanned revascularization in both groups at 12 months.

Major Points

Fractional flow reserve (FFR) is a method of determining the functional significance of an angiographically borderline epicardial coronary lesion, in which flow is measured both proximal and distal to a lesion while adenosine is administered in order to induce hyperemia and minimize coronary resistance. When distal flow is ≤ 80% of proximal flow using FFR, a coronary lesion is considered physiologically significant. The recent FAME 2 trial demonstrated the superiority of FFR-guided revascularization to standard angiographic guidance in PCI, leading to a significant improvement in rate of death, nonfatal MI, or urgent revascularization driven primarily by a lower rate of urgent revascularization following FFR-guided PCI.

Similar in rationale to the FFR, the iFR is a recently developed method of determining the functional significance of a coronary lesion in which physiologic significance is determined by measuring the resting pressure gradient across the lesion during the portion of diastole when microvascular resistance is spontaneously low and stable. The main advantage of iFR is that it does not require the administration of a hyperemic agent such as adenosine yet potentially provides similar information. A small proof-of-concept study demonstrated that iFR results in largely similar diagnostic information as FFR [1], but a large clinical trial was needed to determine whether iFR performs similarly to FFR with regard to clinical outcomes.

The 2017 Instantaneous Wave-free Ratio versus Fractional Flow Reserve in Patients with Stable Angina Pectoris or Acute Coronary Syndrome (iFR-SWEDEHEART) trial randomized patients with either stable or unstable CAD with an indication for physiologically-guided revascularization (angiographic 40-80% stenosis) to either iFR or FFR guidance and assessed for a primary outcome of death, nonfatal MI, or unplanned revasularization. At 12 months, the rate of the primary outcome was similar in both groups (6.7% with iFR and 6.1% with FFR) with the criteria for noninferiority of iFR met. Interestingly, the iFR approach was associated with a 7% absolute reduction in the number of hemodynamically significant lesions detected, with a correspondingly lower rate of intervention. Adverse events were similar between groups except that only 3% of patients randomized to iFR experienced chest pain during revascularization, while 70% of patients randomized to FFR experienced mild or greater chest pain (a known side effect of adenosine).

The results of iFR-SWEDEHEART provide preliminary evidence that iFR is a viable alternative to FFR as a means of determining physiological significance of epicardial coronary stenoses, with similar clinical event rates using either approach. iFR also has the added benefit of avoiding the use of adenosine, which results in a much lower frequency of chest pain. The lower frequency of detection of hemodynamically significant lesions with correspondingly lower rate of intervention with similar outcomes overall suggests that iFR may be a more specific marker of hemodynamic significance, although this requires further study. Longer term studies are also needed to further investigate possible differences in outcomes between FFR and iFR that may only emerge after several years.


As of May 2017, no guidelines have been published that reflect the results of this trial.


  • Prospective, open-label, randomized controlled clinical trial
  • N=2037
    • iFR (n=1019)
    • FFR (n=1018)
  • Setting: 13 centers in Sweden, 1 center in Denmark, and 1 center in Iceland
  • Enrollment: May 2014 to October 2015
  • Duration follow-up: 1 year
  • Analysis: Intention-to-treat
  • Primary outcome: death, nonfatal MI, and unplanned revascularization


Inclusion Criteria

  • Age ≥ 18 years
  • Suspected stable angina or unstable angina/NSTEMI
    • Scheduled to undergo coronary angiography
    • Angiographic stenosis grade 40-80%

Exclusion Criteria

  • Previous CABG with patent grafts to interrogated vessel
  • Life expectancy < 1 year
  • Multivessel CAD with ACS and inability to determine culprit lesion
  • Unstable hemodynamics (Kilip class III-IV)
  • Inability to tolerate adenosine
  • Heavily calcified or tortuous vessels where inability to cross the lesion with a pressure wire is expected

Baseline Characteristics

From the iFR group

  • Demographics: age 67.6, male 74.2%, BMI 27.6
  • Indication for angiography: stable angina 62.0%, unstable angina 20.7%, NSTEMI 17.3%
  • Angina: class I 24.2%, class II 56.3%, class III 7.8%, class IV 0%
  • Co-morbidities: DM 22.8%, HTN 71.6%, HLD 71.9%, smoker 15.6%, previous MI 33.1%, previous CABG 4.8%, previous PCI 42.1%
  • Angiography: nonobstructive CAD 20.0%, 1-vessel disease 44.3%, 2-vessel disease 25.1%, 3-vessel disease 10.6%


  • Randomized 1:1 to iFR or FFR
  • In patients with suspected stable angina, any lesion could be assessed. In patients with ACS, only nonculprit lesions could be assessed
  • In both groups, intracoronary nitroglycerin was administered before lesion assessment
  • iFR and FFR measurements were obtained with the use of a coronary-pressure guidewire
  • In FFR, hyperemia was induced using intravenous or intracoronary adenosine, in accordance with the clinical practice at each center
  • Revascularization of the investigated vessel was mandated if the iFR < 0.9 or FFR ≤ 0.8
  • Revascularization (either PCI or CABG) was performed in accordance with standard clinical practice
  • At the conclusion of the procedure, the treating physician asked the patient to assess level of chest pain on a four-point scale (none to severe)
  • Type of P2Y12 inhibitor administered during and after PCI was left to the discretion of the treating physician
  • Lifelong treatment with ASA was mandated
  • Death and MI events were adjudicated by an independent committee unaware of group assignments
  • Unplanned revascularization and secondary angiographic events were assessed by an independent experienced observer unaware of group assignments


Comparisons are iFR vs. FFR

Primary Outcomes

Death, nonfatal MI, or unplanned revascularization
68 (6.7%) vs. 61 (6.1%) [HR 1.12, 95% CI 0.79-1.58, p=0.53]

Secondary Outcomes

All-cause death
15 (1.5%) vs. 12 (1.2%) [HR 1.25, 95% CI 0.58-2.66, p=0.57]
Myocardial infarction
22 (2.2%) vs. 17 (1.7%) [HR 1.29, 95% CI 0.68-2.44, p=0.42]
Unplanned revascularization
47 (4.6%) vs. 46 (4.6%) [HR 1.04, 95% CI 0.69-1.57, p=0.84]
19 (1.9%) vs. 18 (1.8%) [HR 1.05, 95% CI 0.55-2.01, p=0.87]

Subgroup Analysis

  • No significant heterogeneity of treatment effect was detected in subgroup analyses

Adverse Events

Any chest discomfort
30 (3.0%) vs. 688 (68.3%) [p<0.001]


  • Open-label nature of the study allows for ascertainment bias (e.g., patients randomized iFR more likely to undergo routine coronary angiography resulting in detection of an asymptomatic lesion resulting in unplanned revascularization).
  • Open-label nature of the study allows for bias in outcomes assessment, although this is mitigated somewhat by blinded outcomes adjudication.
  • Given noninferiority margin of 3.2%, a difference in outcomes with iFR vs. FFR smaller than 3.2% cannot be ruled out.


  • Study supported by an unrestricted research grant from Philips Volcano to the Uppsala Clinical Research Center

Further Reading