Background: Cardiovascular events still occur at intermediate stenosis with fractional flow reserve (FFR) ≥0.81, underscoring the additional measure to evaluate this residual risk. A reduction in distal coronary artery pressure/aortic pressure from baseline to hyperemia (i.e., change in Pd/Pa) reflects lipidic burden within vessel walls. We hypothesized that this physiological measure might stratify the risk of future cardiac events at deferrable lesions. Methods: Lesion- (899 intermediate lesions) and patient-based (899 deferred patients) analyses in those with FFR ≥0.81 were conducted to investigate the association between change in Pd/Pa and target lesion failure (TLF) and major adverse cardiac events (MACE) at 7 years, respectively. Results: The occurrence of TLF and MACE was 6.7% and 13.4%, respectively. The incidence of target lesion-related non-fatal myocardial infarction was 0.6%. Lesions with TLF had greater change in Pd/Pa (0.11±0.03 vs. 0.09±0.04; P=0.002), larger diameter stenosis (51.0±9.2% vs. 46.4±12.4%; P=0.048), and smaller FFR (0.84 (0.82-0.87) vs. 0.86 (0.83-0.90); P=0.02). Change in Pd/Pa (per 0.01 increase) predicted TLF (odds ratio, 1.16; 95% confidence interval (CI), 1.05-1.28; P=0.002) and MACE (odds ratio, 1.08; 95% CI, 1.01-1.16; P=0.03). Lesions with change in Pd/Pa ≥0.10 had 2.94- and 1.85-fold greater likelihood of TLF (95% CI, 1.30-6.69; P=0.01) and MACE (95% CI, 1.08-3.17; P=0.03), respectively. Lesions with FFR ≤0.85 had substantially higher likelihood of TLF when change in Pd/Pa ≥0.10 (12.4% vs. 2.9%; hazard ratio, 3.60, 95% CI, 1.01-12.80; P=0.04). However, change in Pd/Pa did not affect TLF risk in lesions with FFR ≥0.86 (3.8% vs. 3.7%; hazard ratio, 0.56; 95% CI, 0.06-5.62; P=0.62). Conclusions: Despite deferrable FFR values, lesions and patients with change in Pd/Pa ≥0.10 had higher cardiovascular risk. Change in Pd/Pa might help stratify lesion- and patient-level risk of future cardiac events in those with FFR ≥0.81.