The ISCHEMIA Algorithm or the FAME-2 Algorithm to Detect Ischemia?

Dear Editors:

Dahal et al¹ claim that the results from the ISCHEMIA trial may be misleading because the algorithm used to detect ischemia with initial non-invasive stress testing is not evidence based. Instead, they suggest an algorithm with computed tomography angiography (CTA), fractional flow reserve computed tomography (FFR_CT), and invasive fractional flow reserve (FFR) in patients with stable coronary artery disease to decide whether revascularization is necessary and which vessel should be revascularized. They based this statement on well-designed studies. However, a word of caution is necessary here. First, performing CTA in all patients, FFR_CT in many, and invasive FFR in some patients seems an unrealistic work-up on patients with chest pain. Not many health systems could afford that. Second, more studies have to be undertaken before considering it an evidence-based algorithm. Importantly, the main weakness of the proposed algorithm is that it is supported by the FAME-2 trial. This trial randomized 888 patients with stable coronary artery disease to optimal medical therapy or FFR-guided percutaneous coronary intervention.^2,3 No differences were found regarding death or myocardial infarction. Only urgent revascularization was decreased with invasive FFR-guided therapy. In other words, urgent revascularization did not implicate either myocardial infarction or death in the FAME-2 trial. A recent meta-analysis comparing both strategies found a reduction of myocardial infarction in favor of the FFR-guided intervention.⁴ However, this meta-analysis included the FAME-2 trial² and two other trials (DANAMI-3-PRIMULTI⁵ and CompareAcute⁶) focused on non-culprit lesions in stabilized patients after acute coronary syndromes, a clinical scenario completely different than that studied in the FAME-2 and ISCHEMIA trials. The ISCHEMIA trial will help many clinicians in their daily practice and sends them the message that optimal medical treatment is the cornerstone in the management of stable patients. If angina cannot be controlled or the patient becomes unstable, proceed to invasive measures. Otherwise, be cautious.

Sincerely,

J. Alberto San Roman, MD, PhD, Hospital Clínico Universitario, Valladolid, CIBERCV, Spain. Email: asanroman@secardiologia.es

Authors’ Response:

We respectfully disagree with the author’s suggestion that we are advocating “performing CTA in all patients, FFR_CT in many, and invasive FFR in some patients.” First, none may need invasive FFR, if results of FFR_CT are already known.  Correlation is quite high, and retesting is likely to be highly redundant. Second, good clinical judgement is necessary and appropriateness of imaging needs to be taken into consideration in any work-up. But before optimal medical therapy can be started in all patients, the etiology of chest pain must be established. It is highly unlikely that statin and antiplatelet therapy will improve non-cardiac chest pain (such as esophageal reflux, musculoskeletal pain, or aortic dissection). Many patients who undergo computed tomography (CT) angiography (once clinically indicated by appropriateness criteria) are found to have normal coronary arteries. In our clinical experience, about 40% of all patients have normal coronaries.These patients can go for treatment of other causes of chest pain. Of those with abnormal CT, many have non-obstructive disease and need only medical therapy (28% of those who qualified for the ISCHEMIA trial by abnormal functional testing had no obstructive disease and were not randomized). Thus, a minority of patients will be found with CT angiography to have moderate to severe coronary disease, and those patients may benefit from FFR_CT. Of those, few will be found with abnormal FFR_CT that warrants revascularization.  In the ADVANCE registry of FFR_CT, only 41.4% of patients with 50%-70% stenosis had an FFR ≤0.8.¹ We agree this algorithm needs further testing, but it is highly likely, based on multiple FFR and FFR_CT studies, to yield positive results, and allow better stratification of patients than functional testing.

Sincerely,

Suraj Dahal, MD and Matthew J. Budoff, MD

1. Dahal S, Budoff MJ. Failed ISCHEMIA trial or failed ischemia testing? J Invasive Cardiol. 2020;32:E83-E85.
2. De Bruyne B, Fearon WF, Pijls NH, et al. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med. 2014;371:1208-1217.
3. Xaplanteris P, Fournier S, Pijls NHJ, et al. Five-year outcomes with PCI guided by fractional flow reserve. N Engl J Med. 2018;379:250-259.
4. Zimmermann FM, Omerovic E, Fournier S, et al. Fractional flow reserve-guided percutaneous coronary intervention vs. medical therapy for patients with stable coronary lesions: meta-analysis of individual patient data. Eur Heart J. 2019;40:180-186. 
5. Engstrøm T, Kelbæk H, Helqvist S, et al; DANAMI-3—PRIMULTI Investigators. Complete revascularisation versus treatment of the culprit lesion only  in patients with ST-segment elevation myocardial infarction and multivessel disease  (DANAMI-3—PRIMULTI): an open-label, randomised controlled trial. Lancet. 2015;386:665-671.
6. Smits PC, Abdel-Wahab M, Neumann FJ, et al. Fractional flow reserve-guided multivessel angioplasty in myocardial infarction. N Engl J Med. 2017;376:1234-1244.

Author Reponse Reference

1. Kitabata H, Leipsic J, Patel MR, et al. Incidence and predictors of lesion-specific ischemia by FFR(CT): learnings from the international ADVANCE registry. J Cardiovasc Comp Tomogr. 2018;12:95-100.