Fractional flow reserve and non-hyperemic indices: Essential tools for percutaneous coronary interventions

Table 1 Coronary hyperemic agents

Agent		Dose	Side effects
Adenosine	Intravenous	140 µg/kg/min IV; > 40 µg RCA; > 80 µg LCA	Transient AV block, chest pain, shortness of breath, hypotension, headache, flushing
	Intracoronary
Regadenoson		400 µg singe bolus central or peripheral IV	Rhythm or conduction abnormalities, rare gastrointestinal side effects, less frequent chest pain and dyspnea
Papaverine		10-12 mg in RCA; 15-20 mg in LCA	Abdominal symptoms, headache, flushing of face, increase in heart rate, QTc prolongation, ventricular tachyarrhythmias

AV bloc: Atrioventricular block; IV: Intravenous; RCA: Right coronary artery; LCA: Left coronary artery. Table 1 summarizes the hyperemic agents used for fractional flow reserve measurements and gives the dose and potential side effects of each agent. One has to choose in function of the clinical parameters of the patient.

Table 2 Diagnostic performance of different non-invasive stress tests

Test	Anatomically Significant CAD		Functionally significant CAD
	Specificity (95%CI)	Sensitivity (95%CI)	Specificity (95%CI)	Sensitivity (95%CI)
Stress ECG	62 (54-69)	58 (46-69)	73 (55-86)	68 (60-75)
Stress echo	82 (72-89)	85 (80-89)
CCTA	78 (67-86)	97 (93-99)	53 (37-68)	93 (89-96)
SPECT	70 (63-76)	87 (83-90)	83 (71-90)	73 (62-82)
PET	85 (78-90)	90 (78-96)	85 (81-88)	89 (82-93)
Stress CMR	80 (69-88)	90 (83-94)	87 (83-91)	89 (85-92)

CAD: Coronary artery disease; CCTA: Coronary Computed Tomography Angiography; CMR: Cardiac Magnestic Resonance; ECG: Electrocardiogram; echo: echocardiography; SPECT: Single-Photon Emission Computerized Tomography; PET: Positron Emission tomography. The Table 2 summarize the multiple non-invasive stress tests available at this day for coronary artery disease screening. Each exam is characterized by its specificity and sensibility. The exam choice depends on the patient’s clinical situation.

Table 3 Studies that evaluated the outcomes of fractional flow reserve in intermediate coronary artery disease

Author or Study	Single or MVD CAD	Study design	FFR value defining ischemia	No. of patients	Survival %	Event-free survival %	Follow up, mo	Primary outcome rate %
DEFER[37]	Single	Randomized, prospective, multicenter	0.75	91/144	93/91	80/63	60
FAME[10]	MVD	Randomized, prospective, multicenter	0.80	509/1005	37/509	73	12
Hamilos et al[50]	LM	Prospective, single center	0.80	136/73	89.8/85.4	74.2/82.8	35
FLOWER MI[51]	MVD	Randomized, prospective, multicenter	0.80	590/1171	5.5/4.2	98.5/98.3	12.36
PHANTOM[52]	NR	Prospective, multicenter	0.75	39/21	100/100	97/76	12
FAME 2[9]	Single + MVD	Randomized, prospective, multicenter	0.80	447/1220			60	8.7
FAME 3[53]	MVD	Randomized, prospective, multicenter	0.80	757/1500			12	10.6

CAD: Coronary artery disease; MVD: Multivessel disease; FFR: Fractional flow reserve; mo: Months; LM: Left main; No: Number. Table 3 represents the multiple studies that evaluated the fractional flow reserve through years. These diverse trials had different end points but generally converged to the common conclusion that fractional flow reserve guided- percutaneous interventions (PCI) has better outcomes than angiography-guided PCI. FFR clinical threshold has been chosen upon these studies.

Table 4 Summary of main instantaneous wave free ratio trials

Trial	Study population	Mean FFR value +/-SD	Mean iFR-value +/-SD	iFR cut-off	P value for non-inferiority	Correlation	Sensitivity %	Specificity %
DEFINE-FLAIR[13]	2492	0.83 +/-0.09	0.91+/- 0.09	0.89	< 0.001
iFR SWEDEHEART[12]	2037	0.82 +/-0.10	0.91+/- 0.10	0.89	0.007
ADVISE study[59]	131	0.72+/- 0.2		0.83		0.9 (P < 0.001)	85	91
VERIFY[65]	206			0.83		0.67	54 (49-60)	96 (95-99)
JUSTIFY-CFR[61]	186	0.74+/- 0.17	0.81+/- 0.21	0.89		0.68 0.60-0.76	73	74

FFR: Fractional flow reserve; SD: Standard deviation. Table 4 summarize the primary studies evaluating the instantaneous wave free ratio (iFR). These trials have evaluated the correlation rate between iFR and FFR value and showed that iFR guided- percutaneous interventions (PCI) could be an alternative to FFR guided-PCI.

Table 5 Non-hyperemic pressure ratio indices

Acronym	Full name	Manufacturer	Method	Threshold	Evidence
iFR	Instantaneous wave-free ratio	Philips Heathcare	Mean five Pd/Pa during the WFP	0.89	DEFINE FLAIR[13], SWEDEHAEART TRIAL[12]
RFR	Resting full-cycle ratio	Abbott	Lowest value of Pd/Pa across the whole cardiac cycle	0.89	VALIDATE RFR[68], RE-VALIDATE RFR[69]
DFR	Diastolic hyperemia-free ratio	Boston Scientific	Average 5 consecutive cardiac cycles Pd/Pa ratio over the approximateda diastolic period	0.89	Comparison of different diastolic resting indexes to iFR[15]
dPR	Diastolic pressure ratio	ACIST/Opsens Medical	Average 5 beats Pd/Pa ratio at the pressure peak-to-peak midpoint	0.89	Diastolic pressure ratio: New approach and validation vs the iFR[69]
Resting Pd/Pa		Not proprietary technology	Pd/Pa averaged over the entire cardiac cycle	0.91

^aDiastole approximated as negatively sloped segment of tracing where Pa falls below mean Pa. Pd: Distal coronary artery pressure; Pa: Aortic pressure; WFP: Wave Free Period. This table represents the multiple non-hyperemic pressure ratios available at this day. Each manufacturer has led its trial to support the use of its non-hyperemic pressure ratios (NHPR) indices. These studies compared the new calculations methods to the instantaneous wave free ratio (iFR) and showed good correlation between NHPR. These indices have the same cut-off value of 0.89 below which a coronary artery stenosis is considered functionally significant.