The Prognostic Value of Coronary Flow Reserve in Patients with Non-obstructive Coronary Artery Disease and Microvascular Dysfunction: a Systematic Review and Meta-analysis with Focus on Imaging Modality and Sex Difference

To clarify prognosis of patients with non-obstructive coronary artery disease (NOCAD) and coronary microvascular disease (CMD) assessed as low coronary flow reserve (CFR) according to imaging modalities and sex difference. Comprehensive systematic literature review and meta-analyses were conducted. Risk of death and major adverse cardiac events (MACE) were pooled and compared in patients with abnormally low versus normal CFR using cut-off limits 2.0-2.5. Random effects model used for estimation of odds ratios (OR) and hazard ratios (HR) with 95% confidence interval (CI). Nineteen eligible observational studies provided data for death and MACE, publication bias was insignificant, p = 0.62. Risk of death and MACE were significantly higher in patients with low (n = 4.612, 29%) than normal CFR (n = 11.367, 71%): using transthoracal echocardiography (TTE) (OR 4.25 (95% CI 2.94, 6.15) p < 0.001) and (OR 6.98 (95% CI 2.56, 19.01) p < 0.001), positron emission tomography (PET) (OR 2.51 (CI 95%: 1.40, 4..49) p = 0.002) and (OR 2.87 (95% CI 2.16, 3.81) p < 0.001), and invasive intracoronary assessment (OR 2.23 (95% CI 1.15, 4.34) p < 0.018), and (OR 4.61 (95% CI 2.51, 8.48) p < 0.001), respectively. Pooled adjusted HR for death and MACE were (HR 2.45(95% CI 1.37, 3.53) p < 0.001) and (HR 2.08 (95% CI 1.54, 2.63) p < 0.001) respectively. Studies comparing men and women with abnormally low CFR demonstrated similar worse prognosis in both sexes. Low CFR is associated with poorer prognosis in patients with NOCAD regardless of sex. TTE may overestimate risk of death and MACE, while PET seems to be more appropriate. Future studies are needed to consolidate the current evidence.