Baseline Percent Atheroma Volume Research Articles

Usefulness of Coronary Atheroma Burden to Predict Cardiovascular Events in Patients Presenting With Acute Coronary Syndromes (from the PROSPECT Study)

We investigated the relation between overall atheroma burden and clinical events in the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study. In PROSPECT, 660 patients (3,229 nonculprit lesions with a plaque burden ≥ 40% and complete intravascular ultrasound data) were divided into tertiles according to baseline percent atheroma volume (PAV: total plaque/vessel volume). Patients were followed for 3.4 years (median); major adverse cardiac events (MACE: death from cardiac causes, cardiac arrest, myocardial infarction, or rehospitalization because of unstable or progressive angina) were adjudicated to either culprit or nonculprit lesions. Compared with patients in low or intermediate PAV tertiles, patients in the high PAV tertile had the greatest prevalence of plaque rupture and radiofrequency thin-cap fibroatheroma (VH-TCFA) and the highest percentage of necrotic core volume; they were also more likely to have high-risk lesion characteristics: ≥ 1 lesion with minimal luminal area ≤ 4 mm(2), plaque burden >70%, and/or VH-TCFA. Three-year cumulative nonculprit lesion-related MACE was greater in the intermediate and high tertiles than in the low tertile (6.3% vs 14.7% vs 15.1%, low vs intermediate vs high tertiles, p = 0.009). On Cox multivariable analysis, insulin-dependent diabetes (hazard ratio [HR] 3.98, p = 0.002), PAV (HR 1.06, p = 0.03), and the presence of ≥1 VH-TCFA (HR 1.80, p = 0.02) were independent predictors of nonculprit MACE. In conclusion, increasing baseline overall atheroma burden was associated with more advanced, complex, and vulnerable intravascular ultrasound lesion morphology and independently predicted nonculprit lesion-related MACE in patients with acute coronary syndromes after successful culprit lesion intervention.

Atheroma progression in hyporesponders to statin therapy.

Lowering low-density lipoprotein cholesterol (LDL-C) with statins has been demonstrated to slow plaque progression. This antiatherosclerotic effect in patients with minimal LDL-C lowering has not been investigated. Six hundred forty-seven patients with angiographic coronary artery disease who were commenced on statin therapy underwent serial imaging with intravascular ultrasound. Responders were defined as a percentage reduction in LDL-C of <15%. Disease progression was compared in responders (n=517) and hyporesponders (n=130) to statin therapy. Twenty percentage of patients demonstrated minimal changes in LDL-C, despite commencement of statin therapy. Statin hyporesponders were younger (55 versus 57 years; P=0.01), more likely to be male (79% versus 66%; P=0.005), and obese (body mass index, 31.5 ± 6.1 versus 30.3 ± 5.9 kg/m(2); P=0.04) and less likely to have a history of dyslipidemia (50% versus 66%; P<0.001). Baseline levels of systolic blood pressure (127 ± 15 versus 132 ± 17 mm Hg; P=0.01) and LDL-C (2.5 ± 0.6 versus 3.4 ± 0.8 mmol/L; P<0.001) were lower in statin hyporesponders. Baseline percent atheroma volume was similar between statin hyporesponders and responders (36.9 ± 9.8% versus 38.3 ± 9.2%; P=0.13). On serial evaluation, greater progression of percent atheroma volume (1.19 ± 0.48% versus 0.09 ± 0.43%; P=0.003) was observed in statin hyporesponders. After adjusting for baseline clinical characteristics and measures of plaque burden, statin hyporesponders still exhibited greater atheroma progression (+0.83 ± 0.58% versus -0.21 ± 0.52%; P=0.006). A substantial proportion of patients with coronary artery disease fail to achieve effective reductions in LDL-C, despite prescription of statin therapy. Greater progression of atherosclerosis is observed in these patients. Our current study underscores monitoring LDL-C level after the commencement of statin to ensure adequate response to statin therapy.

Antiatherosclerotic effects of long-term maximally intensive statin therapy after acute coronary syndrome: insights from Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin.

Patients with acute coronary syndromes (ACS) display diffuse coronary atheroma instability and heightened risk of early and late recurrent coronary events. We compared the long-term antiatherosclerotic efficacy of high-intensity statins in patients with ACS when compared with stable disease. Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) used serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. The overall effect of high-intensity statins on the change in coronary percent atheroma volume and major adverse cardiovascular events (death/nonfatal myocardial infarction/coronary revascularization) were evaluated in this post hoc analysis. When compared with non-ACS patients (n=678), patients with ACS (n=361) were younger, actively smoking, and have had a previous myocardial infarction (all P<0.001). At baseline, patients with ACS exhibited lower high-density lipoprotein cholesterol (43.5±11 versus 45.8±11 mg/dL; P=0.002), a higher apolipoprotein B: apolipoprotein A-1 ratio (0.90±0.24 versus 0.83±0.24; P<0.001) and greater percent atheroma volume (37.3±8.5% versus 35.9±8.1%; P=0.01) when compared with non-ACS patients. Despite similar achieved levels of lipid and inflammatory markers after high-intensity statin therapy, patients with ACS demonstrated greater percent atheroma volume regression than non-ACS patients (-1.46±0.14 versus -0.89±0.13; P=0.003). After propensity-weighted multivariable adjustment, baseline percent atheroma volume (P<0.001) and an ACS clinical presentation (P=0.02) independently associated with plaque regression. The 24-month major adverse cardiovascular events-free survival was similar between patients with ACS and non-ACS (90.6 versus 92.9%; P=0.25). Long-term high-intensity statin therapy caused greater plaque regression and comparable major adverse cardiovascular events rates in ACS when compared with non-ACS patients. Despite a higher clinical risk profile, patients with ACS harbor a more modifiable disease substrate and seem to benefit the most from potent statin therapy.

Sex-Related Differences of Coronary Atherosclerosis Regression Following Maximally Intensive Statin Therapy: Insights From SATURN

ObjectivesThe study sought to explore sex-related differences in coronary atheroma regression following high-intensity statin therapy. BackgroundGuidelines now recommend high-intensity statins in all individuals with atherosclerotic cardiovascular disease. MethodsSATURN (Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin) employed serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. The treatment groups did not differ significantly in change from baseline of percent atheroma volume (PAV) or total atheroma volume (TAV) on intravascular ultrasound, nor in safety or clinical outcomes. ResultsCompared with men (n = 765), women (n = 274) were older (p < 0.001) and more likely to have hypertension (p < 0.001), diabetes (p = 0.002), and higher low-density lipoprotein cholesterol (LDL-C) (p = 0.01), high-density lipoprotein cholesterol (p < 0.001), and C-reactive protein (CRP) (p = 0.004) levels. At follow-up, women had higher high-density lipoprotein cholesterol (p < 0.001) and CRP (p < 0.001), but similar LDL-C (p = 0.46) levels compared with men. Compared with men, women had lower baseline PAV (34.0 ± 8.0% vs. 37.2 ± 8.2%, p < 0.001) and TAV (122.4 ± 55 mm3 vs. 151.9 ± 63 mm3, p < 0.001), yet demonstrated greater PAV regression (–1.52 ± 0.18% vs. –1.07 ± 0.10%, p = 0.03) and TAV regression (–8.27 ± 0.9 mm3 vs. –6.59 ± 0.50 mm3, p = 0.11) following treatment. Greater PAV regression in women versus men occurred with rosuvastatin (p = 0.004), those with diabetes (p = 0.01), stable coronary disease (p = 0.01), higher baseline LDL-C (p = 0.02), and higher CRP (p = 0.04) levels. On multivariable analysis, female sex was independently associated with PAV regression (p = 0.01), and a sex-treatment interaction was found (p = 0.036). For participants with on-treatment LDL-C levels <70 mg/dl, women achieved greater PAV regression (–1.81 ± 0.22% vs. –1.12 ± 0.13%, p = 0.007) and TAV regression (–10.1 ± 1.1 mm3 vs. –7.16 ± 0.65 mm3, p = 0.023) than men, whereas PAV and TAV regression did not differ by sex, with LDL-C levels ≥70 mg/dl. ConclusionsWomen with coronary disease demonstrate greater coronary atheroma regression than men when empirically prescribed guideline-driven potent statin therapy. This benefit appears in the setting of lower on-treatment LDL-C levels. (CRESTOR Athero Imaging Head to Head IVUS Study [SATURN]; NCT000620542)

Coronary atheroma volume and cardiovascular events during maximally intensive statin therapy

The impact of baseline coronary plaque burden on the clinical outcome in patients receiving aggressive low-density lipoprotein cholesterol (LDL-C) lowering therapy to levels <70 mg/dL is unknown. We assessed the prognostic significance of baseline coronary plaque burden following high-intensity statin therapy. SATURN used serial intravascular ultrasound (IVUS) to measure coronary atheroma volume in 1039 patients before and after 24 months of treatment with rosuvastatin 40 mg or atorvastatin 80 mg. This post hoc analysis compared the relationship between baseline percent atheroma volume (PAV) and major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, coronary revascularization, hospitalization for unstable angina) in patients with baseline PAV less than (n = 519) or greater than (n = 520) the median. Patients with a higher baseline PAV had a similar LDL-C compared with those with a lower baseline PAV at baseline (119.0 ± 29 vs. 121.0 ± 27 mg/dL, P = 0.09) and at follow-up (65.3 ± 23 vs. 65.8 ± 22 mg/dL, P = 0.47). In multivariable analysis, each standard deviation increase in baseline PAV was associated with a 28% increase in MACE [HR 1.28 (1.05, 1.57), P = 0.01]. Those with the highest quartile of baseline PAV (>41.8%) had a 2-year cumulative MACE rate of 12%, which was significantly higher (log-rank P = 0.001) than MACE rates of all lower PAV quartiles (MACE: quartile 3, 2, and 1 were 5.7, 7.9, and 5.1%, respectively). LDL-C levels at baseline [HR 0.96 (0.79, 1.18), P = 0.73] and on-treatment [HR 1.19 (0.83, 1.73), P = 0.35] were not associated with MACE. Following 2 years of high-intensity statin therapy, a baseline coronary atheroma volume predicted MACE, despite the achievement of very low on-treatment LDL-C levels.

Factors underlying regression of coronary atheroma with potent statin therapy

Statins can inhibit the progression of coronary atherosclerosis. We aimed to characterize clinical factors that associate with differing measures of coronary atheroma volume following potent statin therapy. SATURN employed serial intravascular ultrasound (IVUS) to monitor changes in measures of coronary atheroma burden [total atheroma volume (TAV) and per cent atheroma volume (PAV)] in 1039 patients with coronary artery disease, treated with rosuvastatin (40 mg) or atorvastatin (80 mg) daily for 24 months. Rosuvastatin-treated patients demonstrated greater reductions in low-density lipoprotein cholesterol (LDL-C, 47 vs. 40%, P < 0.001) and greater increases in high-density lipoprotein cholesterol (HDL-C, 13 vs. 10%, P = 0.02). These alterations in the lipid profile associated with greater TAV (-6.4 vs. -4.4 mm(3), P = 0.01), but not PAV (-1.22 vs. -0.99%, P = 0.17) regression. Greater TAV reductions with rosuvastatin vs. atorvastatin occurred in patients with diabetes (P = 0.01, treatment by diabetic status interaction P-value 0.05). Greater PAV reductions with rosuvastatin were evident in females (P = 0.01, treatment by sex interaction P-value 0.03) and in those with greater than or equal to median baseline LDL-C (P = 0.02, treatment by LDL-C group interaction P-value 0.03) or HDL-C levels (P = 0.02, treatment by HDL-C group interaction P-value 0.04). On multivariable analysis assessing change in TAV and PAV, both higher baseline TAV and PAV independently associated with TAV and PAV regression, respectively (standardized estimates: TAV -0.25, P < 0.001; PAV -0.23, P < 0.001). Higher-risk patients, particularly those with greater baseline coronary atheroma volume, are more likely to experience less disease progression with potent statin therapy.

Analysis of Missing Mechanism in IVUS Imaging Clinical Trials with Missing Covariates

Intravascular ultrasound (IVUS) is a clinical imaging procedure used to assess drug effects on the progression of coronary atherosclerosis in clinical trials. It is an invasive medical procedure of measuring coronary artery atheroma (plaque) volume, and leads to high missing rates (often over 30%). This paper uses an IVUS Phase II clinical trial data to explore the missing mechanism of IVUS endpoint, the percent atheroma volume (PAV). We proposed a moving-window method to examine the relationship between continuous covariates such as lipid endpoint and the probability of missing IVUS values, which provides a general approach for missing mechanism exploration. The moving-window method is more intuitive and provides a fuller picture about the relationship. In the example, some covariates such as lipid measures also have high missing rates after 12 months because of compliance issues probably caused by fatigue of blood drawing. We found that if the method of last observation carried forward (LOCF) is used to impute the lipid endpoints, it leads to biologically unexplainable results. Using the multiple imputation approach for the missing covariates results in a more reasonable conclusion about the IVUS missing mechanism. Age, race, and baseline PAV are identified as key potential contributors to the probability of missing IVUS endpoint. This finding can be used to reduce missing values in future IVUS trials by setting up appropriate inclusion and exclusion criteria at the trial design stages.

Clinical Predictors of Plaque Progression Despite Very Low Levels of Low-Density Lipoprotein Cholesterol

The purpose of this study was to characterize the determinants of plaque progression despite achieving very low levels of low-density lipoprotein cholesterol (LDL-C). Despite achieving very low levels of LDL-C, many patients continue to demonstrate disease progression and have clinical events. A total of 3,437 patients with coronary artery disease underwent serial intravascular ultrasound examination in 7 clinical trials. Patients who achieved an on-treatment LDL-C level of <or=70 mg/dl (n = 951) were stratified as progressors (n = 200) and nonprogressors (n = 751) and compared. Despite achieving LDL-C <or=70 mg/dl, >20% of patients continued to progress. There were no demographic differences between groups. Progressors demonstrated higher baseline levels of glucose (117.1 +/- 42.5 mg/dl vs. 112.1 +/- 40.0 mg/dl, p = 0.02), triglycerides (157.5 mg/dl vs. 133.0 mg/dl, p = 0.004), and a smaller decrease of apolipoprotein B (-25.1 +/- 3.4 mg/dl vs. -27.4 +/- 3.35 mg/dl, p = 0.01) at follow-up. Multivariable analysis revealed that independently associated risk factors of progression in patients with LDL-C <or=70 mg/dl included baseline percent atheroma volume (p = 0.001), presence of diabetes mellitus (p = 0.02), increase in systolic blood pressure (p = 0.001), less increase in high-density lipoprotein cholesterol (p = 0.01), and a smaller decrease in apolipoprotein B levels (p = 0.001), but not changes in C-reactive protein (p = 0.78) or LDL-C (p = 0.84). Residual risk factors are associated with the likelihood of disease progression in patients who achieve very low LDL-C levels. In addition, the association between apolipoprotein B and atheroma progression highlights the potential importance of LDL particle concentration in patients with optimal LDL-C control. This finding highlights the need for intensive modification of global risk in patients with coronary artery disease.

Intravascular Ultrasound-Derived Measures of Coronary Atherosclerotic Plaque Burden and Clinical Outcome

The aim of this study was to investigate the relationship between intravascular ultrasound (IVUS)-derived measures of atherosclerosis and cardiovascular outcomes. IVUS has been used in clinical trials to evaluate the effect of medical therapies on coronary atheroma progression. Coronary plaque progression was evaluated in 4,137 patients in 6 clinical trials that used serial IVUS. The relationship between baseline and change in percent atheroma volume (PAV) and total atheroma volume with incident major adverse cardiovascular events (MACE) was investigated. PAV increased by 0.3% (p < 0.001), and 19.9% of subjects experienced MACE (0.9% death, 1.8% myocardial infarction, 18.9% coronary revascularization). Greater baseline PAVs were observed in patients who experienced myocardial infarctions (42.2 +/- 9.6% vs. 38.6 +/- 9.1%, p = 0.001), coronary revascularization (41.2 +/- 9.3% vs. 38.1 +/- 9.0%, p < 0.001), or MACE (41.3 +/- 9.2% vs. 38.0 +/- 9.0%, p < 0.001). Each standard deviation increase in PAV was associated with a 1.32-fold (95% confidence interval: 1.22 to 1.42; p < 0.001) greater likelihood of experiencing a MACE. During follow-up (21.1 +/- 3.7 months), greater increases in PAV, but not total atheroma volume, were observed in subjects who experienced MACE compared with those who did not (0.95 +/- 0.19% vs. 0.46 +/- 0.16%, p < 0.001). Each standard deviation increase in PAV was associated with a 1.20-fold (95% confidence interval: 1.10 to 1.31; p < 0.001) greater risk for MACE. Multivariate analysis revealed that factors associated with MACE included baseline PAV (p < 0.0001), change in PAV (p = 0.002), smoking (p = 0.0002) and hypertension (p = 0.01). A direct relationship was observed between the burden of coronary atherosclerosis, its progression, and adverse cardiovascular events. The relationship between disease progression and outcomes largely reflected the need for coronary revascularization. These data support the use of atherosclerosis imaging with IVUS in the evaluation of novel antiatherosclerotic therapies.