From the April issue of CardioSource Interventional News—A close examination of the general population’s most vulnerable subsets may be the key to answering crucial questions regarding acute coronary syndrome (ACS). Most significantly, how important is aggressive risk factor management post-PCI?

PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) tells the big-picture story of coronary atherosclerosis after PCI for ACS. PROSPECT sought to tease out which patients were at risk for sudden cardiac death and MI by trying to determine which lesions were prone to sudden rupture. PROSPECT investigators found that half of all major adverse CV events (MACE) in post-PCI patients with ACS could actually be blamed on non-culprit lesions (NCL).

The latest issue of JACC Cardiovascular Imaging features three new subset analyses—on diabetes mellitus,¹ chronic kidney disease (CKD),² and a breakdown by gender³—which further elucidate the dangers of crucial risk factors while underscoring, yet again, how few patients achieve optimal medical therapy.

Also included in this issue of JACC Cardiovascular Imaging is an editorial by Michael E. Farkouh, MD, and Verghese Mathew, MD, that provides a high-level analysis of the weight that should be given to these sub-analyses and why, along with recommendations to better stratify those at highest risk.⁴ The editorial also proposes that the subset analyses may shed light on possible mechanisms for outcomes observed in larger studies.

High-Risk NCLs in Diabetics versus Non-Diabetics

The subset analyses that found the greatest difference in subjects was that between diabetics versus non-diabetics. It is well established that patients with diabetes are at an increased risk for a wide range of CV events; however, not as much is known about the impact of metabolic syndrome.

In their analysis, Steven P. Marso, MD, and colleagues found that lesion length, plaque burden, necrotic core, and calcium content were significantly higher in the NCLs of those who had diabetes and metabolic syndrome. However, only the necrotic core and calcium were significantly greater in the NCLs of patients with future MACE, the authors found in this subanalysis.

The three-year MACE rate for PROSPECT patients with diabetes was 29.4 percent and 21.3 percent for those with metabolic syndrome, compared with 17.4 percent for patients with regular blood sugar levels. “One of the most intriguing findings is that, in patients with diabetes mellitus, the three-year MACE rates were attributable more so to the NCLs than the index culprit lesion(s),” wrote Drs. Farkouh and Mathew in their editorial. In fact, the frequency of culprit lesion–related MACE in those with diabetes was similar to the entire cohort. However, the rate of NCL–related MACE was twice as high in those with diabetes when compared to those without.

“In a sense this observation is in keeping with our notion of outcomes in diabetic patients after PCI, but is elegantly re-emphasized in the study by Marso et al,” added Dr. Mathew, who is codirector of the cardiac cath lab and professor of medicine at Mayo Clinic College of Medicine in Rochester, Minnesota.

As with any in-depth analysis, more questions arise. In their editorial, Drs. Farkouh and Mathew ask: “Are the diabetic patients who are not meeting risk factor goals, or with more advanced stage/longer duration of diabetes more likely to have NCLs with high-risk features, and therefore more likely to experience MACE?”

Drs. Farkouh and Mathew suggest that further study into the biological differences of atherosclerosis between those with diabetes and those with metabolic syndrome is needed. “This may mean that patients need to be treated more aggressively from a medical standpoint for systemic risk factor modification and stabilization of these lesions, or potentially to have NCLs with multiple plaque characteristics that portend risk treated by novel interventional strategies that are yet to be tested,” they wrote.

Gender-Based Differences

For the gender question, Alexandra J. Lansky, MD, and colleagues found that even though women were older (average age 65) and had more comorbid disease than men, women experienced fewer NCLs overall. Women were more likely to be hospitalized for recurrent angina related to the culprit lesion and were more likely to have at least one high-risk plaque feature, but their atherosclerotic plaques have less necrotic core volume and are less prone to rupture. This may be explained by the fact that the only significant predictor of culprit lesion-related MACE was higher rate of acute procedural results (acute lesion gain), which were much lower in women.

These factors may balance out, which Drs. Farkouh and Mathew state appears to validate the current practice of treating men and women similarly. This may also explain the similar rates of CV events, cardiac death, and MI during PROSPECT’s three-year follow-up. Plaque ruptures were less common in women, which Dr. Lansky and colleagues hypothesize may explain why women present more frequently with chest pain.

CKD and the Benefit from Optimal Medical Therapy

In another analysis, Usman Baber, MD, and colleagues took a closer look at patients with CKD, who were more likely to be older, female, and have diabetes, and found that those with CKD had a higher risk of MACE at the time of ACS. Even post-PCI, those with CKD had more pervasive and more serious atherosclerosis. Also, the plaque in CKD patients is composed of “greater necrotic core and less fibrous tissue” than in non-CKD patients, Dr. Baber reported. This led to “nonsignificantly different rates of NCL-related adverse events, although cardiac death, arrest or MI were more common in patients with CKD,” Dr. Baber and colleagues found.

Drs. Farkouh and Mathew noted that patients with CKD may have an increased risk even if they are treated for their traditional risk factors. Unlike what was found in respect to diabetes, the blame for subsequent events among CKD patients was culprit lesions. “Could this explain the reduced benefit of optimal medical therapy in CKD patients compared to those with diabetes, or is it merely an inability to draw firm conclusions due to the small sample size and inclusion of relatively mild CRF patients?” Drs. Farkouh and Mathew ask. “However, the findings do raise the question as to whether there is a different biology of atherosclerosis for CKD compared to diabetes, which merits further understanding.”

Overall, Drs. Farkouh and Mathew suggest, a “patient-specific, plaque-specific approach” to identify and characterize NCLs that will cause future CV events. Because patients experiencing ACS are not optimally managed with medicine, they urge clinicians to focus on the importance of systemic medical management with pharmacotherapy for treating patients long term post-ACS—keeping in mind that many patients never reach target levels for LDL cholesterol, HDL cholesterol, HbA1c, and BP.

Also, the editorial encourages clinicians to employ complementary coronary imaging aids to assist in identifying NCLs that are more likely to lead to adverse events, suggesting that important baseline characteristics may determine how NCLs are approached in the future. Additionally, the results of the sub-analyses supports future interventional trials to test whether there is benefit in defining and revascularizing high-risk NCLs and using emerging noninvasive strategies such MR, CT and PET to characterize plaque at the extracoronary and coronary level, Drs. Farkouh and Mathew write.

“Moving forward, we need to consider a scoring system to differentiate which patients may be at greatest risk for MACE based on IVUS characterization of NCLs—in the future we may utilize other complementary modalities as well,” Dr. Mathew said. “Testing whether or not directed therapies, such as ‘pre-emptive’ PCI, or other targeted or systemic strategies for high-risk NCLs will impact outcome is critical as we continue to try and ameliorate the risk of subsequent MACE after ACS.”—by Otesa Miles

References

1. Marso SP, et al. JACC Cardiovasc Imaging. 2012;5 Suppl S:S42-52.
2. Baber U, et al. JACC Cardiovasc Imaging. 2012;5 Suppl S:S53-61.
3. Lansky , et al. JACC Cardiovasc Imaging. 2012;5 Suppl S:S62-72.
4. Farkouh ME, Mathew V. JACC Cardiovasc Imaging. 2012;5 Suppl S:S73-75.

“Insights From PROSPECT: Changing the Approach to ACS.” 2012;1(1):28-29.

 

Keywords: Acute Coronary Syndrome, Follow-Up Studies, Atherosclerosis, Cholesterol, LDL, Risk Factors, Cholesterol, HDL, Death, Sudden, Cardiac, Diabetes Mellitus, Calcium

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