The ideal test for evaluating coronary artery disease (CAD) should incorporate both anatomic and physiologic data regarding coronary artery stenosis. Traditionally, ischemia has been evaluated with stress testing followed by invasive coronary angiography (ICA) or by invasive angiography with fractional flow reserve (FFR) assessment using a coronary pressure wire.

The PROMISE trial reported similar outcomes using either coronary computed tomography angiography (CTA) or stress testing for assessing the severity of coronary artery stenosis, but the specificity of CTA was low.¹ The emergence of FFR_CT, in which FFR is calculated from CTA data, has provided a noninvasive test that yields both anatomic and functional data. Several recent studies have evaluated the effectiveness of FFR_CT for assessing coronary lesion severity.

The PROMISE trial investigators assessed whether FFR_CT added to CTA was a better predictor of coronary revascularization and outcomes than CTA alone in patients with stable chest pain referred to ICA after CTA.² This retrospective sub-study included 181 patients who underwent CTA, ICA and FFR_CT. They found that patients with an FFR_CT ≤0.80 were significantly more likely to have coronary revascularization and to meet the composite endpoint of major adverse cardiac events (MACE) or revascularization than those with FFR_CT >0.80. An FFR_CT ≤0.80 was a significantly better predictor of the composite endpoint compared with severe CTA stenosis (hazard ratio, 4.31 vs. 2.90; p = 0.033). The study also showed that reserving ICA for patients with FFR_CT ≤0.80 could reduce the rate of performing ICA after CTA by 28 percent, decrease the rate of ICA without ≥50 percent stenosis by 44 percent and increase the rate of ICA leading to revascularization by 24 percent.

The emergence of FFR_CT, in which FFR is calculated from CTA data, has provided a noninvasive test that yields both anatomic and functional data.

FFR_CT was compared with CTA alone for assessment of lesion severity and patient management in 200 patients with stable chest pain in the FFR_CT RIPCORD study.³ The patients underwent CTA and FFR_CT was calculated. Three interventional cardiologists assessed the CTA data for each patient and developed a management plan by consensus. The four management options were: optimal medical therapy (OMT) alone; PCI plus OMT; CABG plus OMT; or more information about ischemia required. The FFR_CT data were then revealed and the cardiologists again decided on a management plan by consensus. They also recorded the FFR_CT results for each vessel that was considered ischemic. The endpoint was the difference between management plans based on the CTA alone or FFR_CT data. After assessing the FFR_CT data, the cardiologists changed the management plan for 72 patients (36 percent) based on assessment of lesion severity. Including changes in the PCI target vessel, treatment decisions were changed in 44 percent of patients.

In the PLATFORM study, 584 patients were allocated to noninvasive or invasive coronary angiography cohorts.⁴ Each cohort was divided into standard of care and FFR_CT guided care groups. The 90-day primary endpoint of invasive catheterization without obstructive CAD occurred in significantly fewer patients with FFR_CT-guided care vs. usual care in both cohorts. Of the 584 patients, 581 completed one-year follow-up. The one-year endpoints were MACE, total medical costs and quality of life (QOL). At one year, two MACE occurred in each arm of the planned invasive cohort and one occurred in the usual care group of the planned noninvasive cohort. No events occurred in the 117 patients whose planned ICA was cancelled due to CT/FFR_CT results. Median costs were lower with FFR_CT vs. usual care (p < 0.01) in the invasive cohort and similar in the noninvasive cohort (p = 0.82). QOL scores improved at one year, with similar improvements in both care groups.

Coenen and colleagues investigated the individual and combined accuracy of FFR_CT and dynamic CT myocardial perfusion imaging (CT MPI) in 74 patients in whom ICA and invasive FFR were planned.⁵ A total of 142 vessels were studied. The sensitivity and specificity of CTA were 78 percent and 49 percent respectively. The sensitivity, specificity and diagnostic accuracy were 73 percent (95 percent CI, 61-86 percent), 68 percent (95 percent CI, 56-80 percent) and 70 percent (95 percent CI, 62-79 percent) for CT MPI and 82 percent (95 percent CI, 72-92 percent), 60 percent (95 percent CI, 48-72 percent) and 70 percent (63-80 percent) for FFR_CT. The diagnostic accuracy for CT MPI integrated with FFR_CT was 79 percent (95 percent CI, 71-87 percent). The diagnostic accuracy was 77 percent for a simulated stepwise work-up of FFR_CT with selective use of CT MPI. CT MPI and FFR_CT demonstrated comparable accuracy in identifying functionally significant CAD. Diagnostic accuracy was improved with a combination of both methods.

A real-world study of the clinical utility of FFR_CT for decision making in patients with stable CAD was conducted in all patients with new-onset chest pain referred for CTA over 12 months.⁶ Based on the CTA results, the patients were referred to ICA (n = 82), FFR_CT (n = 189) or MPI (n = 44). Conclusive FFR_CT results were obtained in 185 patients. FFR_CT was ≤0.80 in 57 patients and >0.80 in 128 patients. ICA was performed in 53 of these patients, with FFR (19 percent) or instantaneous wave-free ratio (iFR) (1 percent). FFR_CT ≤0.80 accurately classified 73 percent of patients and 70 percent of vessels using an FFR ≤0.80 or iFR ≤0.90. No cardiac events were reported among patients with FFR_CT >0.80 who were deferred from ICA during a median follow-up period of 12 months.

A prospective study by Gaur and colleagues assessed the performance of FFR_CT for the diagnosis of lesion-specific ischemia in nonculprit vessels of 60 patients with recent STEMI and multivessel CAD.⁷ Coronary CTA was performed one month after STEMI. FFR_CT was calculated and lesion-specific ischemia was defined as FFR_CT ≤0.80. The patients underwent ICA one day after CTA and FFR was performed in 168 vessels, including 124 nonculprit vessels. FFR_CT compared with CTA alone improved accuracy (72 vs. 64 percent; p = 0.033), specificity (66 vs. 49 percent; p < 0.001) and positive predictive value (56 vs. 48 percent; p = 0.032). There was no difference between FFR_CT and ICA estimates. There was moderate agreement between FFR_CT and FFR. The median volume-to-mass ratio was lower than in patients with stable angina, which influenced the diagnostic performance of FFR_CT. Because of the moderate diagnostic performance of FFR_CT, the investigators concluded that the routine use of FFR_CT in post-STEMI patients is not supported.

"The demonstrated clinical applicability of invasive FFR determined over 20 years of research cannot simply be transplanted to its noninvasive counterpart. That privilege must be earned." — Justin E. Davies, MBBS, BSc, PhD, and Christopher M. Cook, MD

In an editorial comment on the FFR_CT PROMISE trial, Subha V. Raman, MD, MSEE, FACC, and Karolina M. Zareba, MD, state that the distribution of pretest likelihood of CAD in the PROMISE cohort facilitates translation of the results to daily practice – if FFR_CT results are available, they should be used for revascularization decision making.⁸ In an editorial comment on the RIPCORD trial, William F. Fearon, MD, FACC, and Jang Hoon Lee, MD, agree that the addition of FFR_CT significantly improves the diagnostic accuracy of CTA compared with invasively measured FFR.⁹ They pointed out the effect that FFR_CT has had on decision making even when used routinely in a consecutive group of patients, noting that if the technique was only used in cases with abnormal CTA, even more dramatic differences in the treatment plan would be expected.

The success of FFR_CT studies has led to the widespread expectation that it will enter the mainstream soon, state Justin E. Davies, MBBS, BSc, PhD, and Christopher M. Cook, MD, in an editorial.¹⁰ “However, enthusiasm for FFR_CT must be tempered by an appreciation of some of the limitations intrinsic to the technique,” they added.

Among the limitations described by these and other reviewers are the need for thicker slice collimation in obese patients, the high cost of the proprietary FFR_CT software and the need for faster turnaround of results. In addition, algorithmic improvements are needed to make FFR_CT available to a broader patient population. Davies and Cook note the major limitation of FFR_CT is that “uniform and constant values of microvascular resistance and coronary flow do not exist.” The failure of the study using FFR_CT to diagnose lesion-specific ischemia in nonculprit vessels to demonstrate high diagnostic accuracy of FFR_CT in recent STEMI patients was likely due to the substantially lower total coronary vessel lumen volume relative to left ventricular volume to mass ratio compared with patients with stable angina. James K. Min, MD, FACC, Y. S. Chandrashekhar, MD, FACC, and Jagat Narula, MD, PhD, MACC, speculated that the presence of severe coronary calcification and blooming artifacts from partial volume effects may have confounded FFR_CT accuracy in the recent STEMI population.¹¹

Importantly, FFR_CT has not been evaluated in a direct comparison with invasive FFR in a prospective patient outcomes study. “The demonstrated clinical applicability of invasive FFR determined over 20 years of research cannot simply be transplanted to its noninvasive counterpart. That privilege must be earned,” write Davies and Cook.

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References

1. Douglas PS, Hoffman U, Patel MR, et al. N Engl J Med 2015;372:1291-300.
2. Lu MT, Ferencik M, Roberts RS, et al. JACC Cardiovasc Imaging 2017;April 7:[Epub ahead of print].
3. Curzen NP, Nolan J, Zaman AG, et al. JACC Cardiovasc Imaging 2016;9:1188-94.
4. Douglas PS, De Bruyne B, Pontone G, et al. J AM Coll Cardiol 2016;68:434-45.
5. Coenen A, Rossi A, Lubbers, et al. JACC Cardiovasc Imaging 2017;10:760-70.
6. Norgaard BL, Hjort J, Gaur S, et al. JACC Cardiovasc Imaging 2017;10:541-50.
7. Gaur S, Taylor CA, Jensen JM, et al. JACC Cardiovasc Imaging 2017;10:424-33.
8. Raman SV, Zareba K. JACC Cardiovasc Imaging 2017;10:April 7:[Epub ahead of print].
9. Fearon WF, Lee JH. JACC Cardiovasc Imaging 2016:9:1195-97.
10. Davies JE, Cook CM. JACC Cardiovasc Imaging 2017;10:434-6.
11. Min JK, Chandrashekhar Y, Narula J. JACC Cardiovasc Imaging 2017;10:500-2.

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Keywords: ACC Publications, Cardiology Magazine, Coronary Angiography, Myocardial Perfusion Imaging, Coronary Artery Disease, Angina, Stable, Prospective Studies, omega-Chloroacetophenone, Retrospective Studies, Constriction, Pathologic, Myocardial Infarction, Coronary Stenosis, Catheterization

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