Plaque Characterization by CTA and Acute Coronary Events
The presence of CTA-based HRP was an independent mid-term predictor of ACS, and all but 2 patients with no plaques were free from ACS. However, non-HRP lesions also developed ACS, and serial CTA analysis revealed the plaques that progressed over time on a volumetric basis and evolved from non-HRP to HRP were the ones more likely to result in ACS. We had previously reported that CTA-verified HRP had a higher risk of developing ACS over a mean follow-up of 2 years in 1,059 patients; ACS developed in 15% of HRP(+) patients and in 0.5% of HRP(−) patients, but did not develop in patients without any plaques.
The present study demonstrated that HRP continued to be an independent predictor of ACS in mid-term follow-up in 3,158 patients (mean follow-up 3.9 ± 2.4 years; ranging from 1 to 10.5 years); ACS frequency was 16% in HRP(+) patients versus 1.6% in HRP(−) patients at baseline CTA assessment. The event rate of ACS in patients without HRP was higher in the current study compared with that reported in the previous study with a 2-year follow-up. The period from CTA to ACS was significantly shorter for those developing events associated with HRP(+) lesions than for patients with ACS at HRP(−) lesions (1.7 ± 1.8 years vs. 3.4 ± 2.4 years; p = 0.0005). Because fewer than 10% of patients had HRP, the cumulative number of ACS arising from HRP lesions, although larger in the first 5 years, was almost matched by the number of ACS arising from the more numerous HRP(−) lesions.
SS, in addition to HRP, was also an independent predictor of ACS. Earlier reports have discussed the prognostic value of CTA-verified stenosis for risk stratification, and a meta-analysis of 18 studies comprising 9,592 patients reported that the risk of adverse cardiac events was associated with the extent and severity of underlying CAD. In the present study, patients with significantly stenotic HRP had higher event rates compared with the non-stenotic HRP or stenotic non-HRP patients; very low event rates were observed in those with non-HRP, non-stenotic plaques or no plaques.
The PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) registry revealed similar data derived from IVUS, with the best predictive values attributed to larger plaque burden (>70%; HR: 5.03; 95% CI: 2.51 to 10.11), presence of thin-cap fibroatheroma (TCFA) (HR: 3.35; 95% CI: 1.77 to 6.36), and lower minimal luminal areas (<4.0 mm; HR: 3.21; 95% CI: 1.61 to 6.42) for the lesions likely to result in an acute event over the 3.4-year follow-up. A related study provided shorter serial imaging data but with results similar to those of the current study. In this IVUS study, plaques characterized as pathological intimal thickening (PIT) evolved into TCFA or thick-cap fibroatheroma (ThCFA) in 10% and 20% of patients over 12 months; 70% of PIT remained unchanged. Conversely, 75% of TCFA stabilized over the next year, and 5% of ThCFA developed high-risk features. Because fewer than 10% of initial lesions were reported as TCFA, the net number of new TCFA produced was similar to the number of TCFA that stabilized over time. None of the plaque characteristics, however, could predict the likelihood of developing TCFA from PIT or ThCFA, or its stabilization. This observational study suggested that atherosclerosis is a diffuse and dynamic process with plaque undergoing biological remodeling and compositional alterations. A recent optical coherence tomography study of 3-vessel imaging revealed that multiple plaques concurrently existed across the coronary tree at different stages of maturation.
The present exploration reveals that because of the much larger number of HRP(−) patients, the total number of ACS arising from non-HRP at the end of follow-up is similar to that of HRP(+) lesions. As detected by serial CTA, PP addresses the development of ACS from non-HRP, at least partially, and emerges as an independent predictor of cardiac events. In the patients with serial CTA, although HRP on CTA-1 was an independent predictor of subsequent cardiac events (15.7% of HRP patients resulted in ACS), 5 of 9 (56%) of ACS developed from originally HRP(−) plaque on CTA-1. Plaque progression at CTA-2 was also an independent predictor of ACS, with adverse events occurring in 8 (14.3%) of 56 patients in the PP(+) group and 1 (0.3%) of 367 in the PP(−) group. Of the 8 ACS patients with PP at CTA-2, HRP was observed in 7 patients on CTA-2; 4 patients had HRP both on CTA-1 and CTA2, and 3 HRP(−) on CTA-1 developed HRP(+) on CTA-2. These results indicate that plaques without high-risk features may evolve to HRP, eventually leading to ACS. On the other hand, patients with HRP on CTA-1, but without PP by CTA-2, remained free of untoward events. These results suggest that serial plaque evaluation may help restratify the risk of cardiac events beyond a single evaluation.
On the basis of the 2010 Appropriateness Use Criteria for Cardiac Computed Tomography, the appropriateness of CTA for asymptomatic high-risk patients with unknown CAD is uncertain. Additionally, guidelines have not recommended treatment or management of HRP on the basis of CTA; the 2010 Expert Consensus Document on coronary CTA ruled that documentation of noncalcified coronary plaques, atherosclerotic burden, and vulnerable plaques provided uncertain clinical utility. As evidence unfolds with regard to documented HRP on CTA, expert consensus statements may require updated guidance on directed management of these patients. Moreover, clinical trial evidence would definitively inform evidentiary standards on guideline-directed care. The current study demonstrated that dyslipidemia, BMI >25 kg/m, previous ACS, HRP, and severe stenosis were independent predictors of ACS, and BMI >25 kg/m and HRP were associated with PP. Also, patients with a history of ACS have been reported to show higher coronary event rates than those without. On the basis of these results, patients with HRP or previous ACS might be candidates for serial CTA. However, radiation dose, use of contrast media, and cost effectiveness would need to be considered. The appropriate number and frequency of serial scans remains undetermined. The current exploration combined with evidence from previous reports underscores that although significant advances have been made in understanding the biology of HRP, our focus must remain on the entire atherosclerotic process and prevention of diffuse disease. Our data support the statement that seeking individual plaques may not provide the ultimate answer.
First, this is a retrospective cohort study. Of 4,423 patients who underwent CTA, 590 (13%) were excluded because of the lack of 1-year follow-up. Second, individual physicians determined indications for repeat CTA, making selection bias a distinct possibility; thus, the data presented here should only be considered hypothesis generating. Third, in assessing serial CTA, differences in imaging platforms from 16- and 64- to 320-slice scanners could have affected image quality and comparability. However, all CTA images were interpreted by 2 cardiologists blinded to the patient's clinical information. Fourth, it is difficult to evaluate the lumen stenosis and the presence of HRP in calcified lesions, and in such areas, luminal stenoses are likely to be overestimated and HRP underestimated. Finally, because we focused on the plaque characteristics associated with ACS, we included only those patients whose culprit plaques could be identified. However, the plaque characteristics of the patients who died without having invasive coronary angiography and of those with ACS who did not have the culprit lesion identified might have affected the considerations of the likelihood of ACS on the basis of CTA plaque characteristics. Thus, the patients without invasive coronary angiography could have added to our current understanding of HRP and incident ACS. Importantly, a prognostic analysis including these patients in a Cox model did not alter our presented findings.
Discussion
The presence of CTA-based HRP was an independent mid-term predictor of ACS, and all but 2 patients with no plaques were free from ACS. However, non-HRP lesions also developed ACS, and serial CTA analysis revealed the plaques that progressed over time on a volumetric basis and evolved from non-HRP to HRP were the ones more likely to result in ACS. We had previously reported that CTA-verified HRP had a higher risk of developing ACS over a mean follow-up of 2 years in 1,059 patients; ACS developed in 15% of HRP(+) patients and in 0.5% of HRP(−) patients, but did not develop in patients without any plaques.
The present study demonstrated that HRP continued to be an independent predictor of ACS in mid-term follow-up in 3,158 patients (mean follow-up 3.9 ± 2.4 years; ranging from 1 to 10.5 years); ACS frequency was 16% in HRP(+) patients versus 1.6% in HRP(−) patients at baseline CTA assessment. The event rate of ACS in patients without HRP was higher in the current study compared with that reported in the previous study with a 2-year follow-up. The period from CTA to ACS was significantly shorter for those developing events associated with HRP(+) lesions than for patients with ACS at HRP(−) lesions (1.7 ± 1.8 years vs. 3.4 ± 2.4 years; p = 0.0005). Because fewer than 10% of patients had HRP, the cumulative number of ACS arising from HRP lesions, although larger in the first 5 years, was almost matched by the number of ACS arising from the more numerous HRP(−) lesions.
SS, in addition to HRP, was also an independent predictor of ACS. Earlier reports have discussed the prognostic value of CTA-verified stenosis for risk stratification, and a meta-analysis of 18 studies comprising 9,592 patients reported that the risk of adverse cardiac events was associated with the extent and severity of underlying CAD. In the present study, patients with significantly stenotic HRP had higher event rates compared with the non-stenotic HRP or stenotic non-HRP patients; very low event rates were observed in those with non-HRP, non-stenotic plaques or no plaques.
The PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) registry revealed similar data derived from IVUS, with the best predictive values attributed to larger plaque burden (>70%; HR: 5.03; 95% CI: 2.51 to 10.11), presence of thin-cap fibroatheroma (TCFA) (HR: 3.35; 95% CI: 1.77 to 6.36), and lower minimal luminal areas (<4.0 mm; HR: 3.21; 95% CI: 1.61 to 6.42) for the lesions likely to result in an acute event over the 3.4-year follow-up. A related study provided shorter serial imaging data but with results similar to those of the current study. In this IVUS study, plaques characterized as pathological intimal thickening (PIT) evolved into TCFA or thick-cap fibroatheroma (ThCFA) in 10% and 20% of patients over 12 months; 70% of PIT remained unchanged. Conversely, 75% of TCFA stabilized over the next year, and 5% of ThCFA developed high-risk features. Because fewer than 10% of initial lesions were reported as TCFA, the net number of new TCFA produced was similar to the number of TCFA that stabilized over time. None of the plaque characteristics, however, could predict the likelihood of developing TCFA from PIT or ThCFA, or its stabilization. This observational study suggested that atherosclerosis is a diffuse and dynamic process with plaque undergoing biological remodeling and compositional alterations. A recent optical coherence tomography study of 3-vessel imaging revealed that multiple plaques concurrently existed across the coronary tree at different stages of maturation.
The present exploration reveals that because of the much larger number of HRP(−) patients, the total number of ACS arising from non-HRP at the end of follow-up is similar to that of HRP(+) lesions. As detected by serial CTA, PP addresses the development of ACS from non-HRP, at least partially, and emerges as an independent predictor of cardiac events. In the patients with serial CTA, although HRP on CTA-1 was an independent predictor of subsequent cardiac events (15.7% of HRP patients resulted in ACS), 5 of 9 (56%) of ACS developed from originally HRP(−) plaque on CTA-1. Plaque progression at CTA-2 was also an independent predictor of ACS, with adverse events occurring in 8 (14.3%) of 56 patients in the PP(+) group and 1 (0.3%) of 367 in the PP(−) group. Of the 8 ACS patients with PP at CTA-2, HRP was observed in 7 patients on CTA-2; 4 patients had HRP both on CTA-1 and CTA2, and 3 HRP(−) on CTA-1 developed HRP(+) on CTA-2. These results indicate that plaques without high-risk features may evolve to HRP, eventually leading to ACS. On the other hand, patients with HRP on CTA-1, but without PP by CTA-2, remained free of untoward events. These results suggest that serial plaque evaluation may help restratify the risk of cardiac events beyond a single evaluation.
On the basis of the 2010 Appropriateness Use Criteria for Cardiac Computed Tomography, the appropriateness of CTA for asymptomatic high-risk patients with unknown CAD is uncertain. Additionally, guidelines have not recommended treatment or management of HRP on the basis of CTA; the 2010 Expert Consensus Document on coronary CTA ruled that documentation of noncalcified coronary plaques, atherosclerotic burden, and vulnerable plaques provided uncertain clinical utility. As evidence unfolds with regard to documented HRP on CTA, expert consensus statements may require updated guidance on directed management of these patients. Moreover, clinical trial evidence would definitively inform evidentiary standards on guideline-directed care. The current study demonstrated that dyslipidemia, BMI >25 kg/m, previous ACS, HRP, and severe stenosis were independent predictors of ACS, and BMI >25 kg/m and HRP were associated with PP. Also, patients with a history of ACS have been reported to show higher coronary event rates than those without. On the basis of these results, patients with HRP or previous ACS might be candidates for serial CTA. However, radiation dose, use of contrast media, and cost effectiveness would need to be considered. The appropriate number and frequency of serial scans remains undetermined. The current exploration combined with evidence from previous reports underscores that although significant advances have been made in understanding the biology of HRP, our focus must remain on the entire atherosclerotic process and prevention of diffuse disease. Our data support the statement that seeking individual plaques may not provide the ultimate answer.
Study Limitations
First, this is a retrospective cohort study. Of 4,423 patients who underwent CTA, 590 (13%) were excluded because of the lack of 1-year follow-up. Second, individual physicians determined indications for repeat CTA, making selection bias a distinct possibility; thus, the data presented here should only be considered hypothesis generating. Third, in assessing serial CTA, differences in imaging platforms from 16- and 64- to 320-slice scanners could have affected image quality and comparability. However, all CTA images were interpreted by 2 cardiologists blinded to the patient's clinical information. Fourth, it is difficult to evaluate the lumen stenosis and the presence of HRP in calcified lesions, and in such areas, luminal stenoses are likely to be overestimated and HRP underestimated. Finally, because we focused on the plaque characteristics associated with ACS, we included only those patients whose culprit plaques could be identified. However, the plaque characteristics of the patients who died without having invasive coronary angiography and of those with ACS who did not have the culprit lesion identified might have affected the considerations of the likelihood of ACS on the basis of CTA plaque characteristics. Thus, the patients without invasive coronary angiography could have added to our current understanding of HRP and incident ACS. Importantly, a prognostic analysis including these patients in a Cox model did not alter our presented findings.
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