Andrea Lavoie

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

OBJECTIVES The aim of this study was to investigate the relationship between intravascular ultrasound (IVUS)-derived measures of atherosclerosis and cardiovascular outcomes. BACKGROUND IVUS has been used in clinical trials to evaluate the effect of medical therapies on coronary atheroma progression. METHODS 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. RESULTS 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). CONCLUSIONS 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.

The metabolic syndrome, its component risk factors, and progression of coronary atherosclerosis.

BACKGROUND The mechanism that confers adverse cardiovascular prognosis in patients with the metabolic syndrome (MetS) remains unclear. We sought to investigate the association of MetS and its component risk factors with progression of coronary atherosclerosis. METHODS We performed a systematic review of 3459 patients who participated in 7 clinical trials that monitored coronary atheroma progression with intravascular ultrasonography. Patients with or without MetS were compared with regard to clinical characteristics, coronary atheroma burden at baseline, and change on serial evaluation. Relationships between plaque progression (> or =5% increase in percent atheroma volume [PAV]), MetS, and its component risk factors were investigated. RESULTS The metabolic syndrome was highly prevalent and was associated with greater progression of PAV (+0.51% +/- 0.23% vs +0.23% +/- 0.24%; P = .003). Multivariable analysis showed that MetS was associated with a greater likelihood of undergoing progression of PAV (adjusted odds ratio [OR], 1.25; 95% confidence interval [CI], 1.05-1.48; P = .01). When the individual components were used in the model instead of MetS, hypertriglyceridemia (OR, 1.26; 95% CI, 1.06-1.49; P = .008) and a body mass index of 30 or higher (1.18, 1.00-1.40; P = .05) predicted progression of PAV. However, after adjusting for its individual components, MetS was no longer an independent predictor (OR, 1.04; 95% CI, 0.79-1.37; P = .79). CONCLUSION Although accelerated disease progression is observed in the setting of MetS, this is owing to the presence of individual component risk factors rather than to the presence of the syndrome itself.

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

OBJECTIVES 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). BACKGROUND Despite achieving very low levels of LDL-C, many patients continue to demonstrate disease progression and have clinical events. METHODS 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. RESULTS 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). CONCLUSIONS 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.

Lowering the triglyceride/high-density lipoprotein cholesterol ratio is associated with the beneficial impact of pioglitazone on progression of coronary atherosclerosis in diabetic patients: insights from the PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) study.

OBJECTIVES The purpose of this study was to determine the factors associated with the favorable effect of pioglitazone on atheroma progression. BACKGROUND Diabetes mellitus is associated with accelerated coronary atheroma progression. Pioglitazone slowed progression compared with glimepiride in this population. METHODS In all, 360 diabetic patients with coronary artery disease were treated with pioglitazone or glimepiride for 18 months in the PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) study. Coronary atheroma progression was evaluated by serial intravascular ultrasound. The relationship between changes in biochemical parameters, percent atheroma volume, and total atheroma volume was investigated. RESULTS Pioglitazone-treated patients demonstrated greater increases in high-density lipoprotein cholesterol (HDL-C) and reductions in glycated hemoglobin, triglycerides, and C-reactive protein. Significant correlations were observed between changes in percent atheroma volume and triglycerides (r = 0.15, p = 0.04), triglyceride/HDL-C ratio (r = 0.16, p = 0.03), and glycated hemoglobin (r = 0.16, p = 0.03) with pioglitazone, and changes in low-density lipoprotein cholesterol (r = -0.15, p = 0.05), apolipoprotein B (r = -0.16, p = 0.04), and apolipoprotein A-I (r = -0.20, p = 0.01) with glimepiride. Substantial atheroma regression, compared to progression, was associated with greater relative increases in HDL-C (14.2% vs. 7.8%, p = 0.04), relative decreases in triglycerides (-13.3% vs. -1.9%, p = 0.045), triglyceride/HDL-C ratio (-22.5 vs. -9.9%, p = 0.05), and decrease in glycated hemoglobin (-0.6% vs. -0.3%, p = 0.01). Multivariable analysis revealed that pioglitazone-induced effects on triglyceride/HDL-C were associated with changes in percent atheroma volume (p = 0.03) and total atheroma volume (p = 0.02). CONCLUSIONS Favorable effects of pioglitazone on the triglyceride/HDL-C ratio correlated with delayed atheroma progression in diabetic patients. This finding highlights the potential importance of targeting atherogenic dyslipidemia in diabetic patients with coronary artery disease.

Comparison of Rates of Progression of Coronary Atherosclerosis in Patients With Diabetes Mellitus Versus Those With the Metabolic Syndrome

Diabetes mellitus (DM) and metabolic syndrome (MS) are associated with adverse cardiovascular outcomes. However, the extent and progression of coronary atherosclerosis for these conditions have not been directly compared. Three thousand four hundred fifty-nine patients with coronary artery disease underwent serial evaluation of atheroma burden by intravascular ultrasound. Patients with DM, MS, or neither diagnosis were compared with regard to plaque burden, progression, and arterial remodeling. Among the 3 groups, patients with MS had the largest number of individual cardiovascular risk factors. Patients with DM demonstrated more extensive atherosclerosis burden with a greater percent atheroma volume compared to patients with MS or those with neither diagnosis (40.3 +/- 9.0%, 37.6 +/- 8.9%, and 38.1 +/- 9.1%, p <0.001) and total atheroma volume (198.3 +/- 85.9, 190.7 +/- 85.0, and 186.3 +/- 79.1 mm(3), p = 0.05). MS compared to neither diagnosis was accompanied by expansion of the external elastic membrane (501.3 +/- 174.3 vs 484.4 +/- 160.7 mm(3), p = 0.02), whereas DM was associated with lumen constriction (290.6 +/- 111.7 vs 298.1 +/- 105.5 mm(3), p <0.0001). On serial evaluation, DM, but not MS, was associated with greater progression of percent atheroma volume compared to neither diagnosis (+0.8 +/- 0.3, +0.3 +/- 0.2, and +0.1 +/- 0.2%, p <0.0001) and total atheroma volume (-1.0 +/- 1.8, -3.3 +/- 1.8, and -4.0 +/- 1.8 mm(3), p = 0.001). Meeting criteria for MS was not associated with greater disease progression in patients with DM. In conclusion, despite having fewer individual risk factors, DM is associated with greater plaque progression and more constrictive remodeling than MS. This finding highlights the deleterious effects of DM on the arterial wall independent of its associated metabolic abnormalities.

Southern Saskatchewan Ticagrelor Registry experience.

Background As ticagrelor enters into clinical use for acute coronary syndrome, it is important to understand patient/physician behavior in terms of appropriate use, adherence, and event rates. Methods The Southern Saskatchewan Ticagrelor Registry is a prospective, observational, multicenter cohort study that identifies consecutive patients started on ticagrelor. We aimed to evaluate both on- and off-label use, identify characteristics of patients who prematurely stop ticagrelor, and describe patient/physician behavior contributing to inappropriate stoppage of this medication. Results From April 2012 to September 2013, 227 patients were initiated on ticagrelor, with a mean age of 62.2±12.1 years. The participants were 66% men and had a mean follow up of 157.4±111.7 days. Seventy-four patients (32.4%) had off-label indications. Forty-seven patients (20.7%) prematurely stopped ticagrelor and were more likely to be older, women, nonwhite, present with shock, and complain of dyspnea. Twenty-six of the 47 patients stopped ticagrelor inappropriately because of patient nonadherence (18 patients) and physician advice (eight patients). A composite outcome event of death from vascular causes, myocardial infarction, or stroke occurred in 8.8% of the entire cohort and was more likely to occur in those older then 65 years, those presenting with cardiogenic shock, and those who prematurely stopped ticagrelor. Conclusion In this real-world registry of patients started on ticagrelor, a third have off-label indications and a fifth prematurely stop the medication. Premature discontinuation was an independent predictor of major life-threatening bleeding and increased composite event rate of death from vascular causes, myocardial infarction, or stroke.

Plaque Progression in Coronary Arteries With Minimal Luminal Obstruction in Intravascular Ultrasound Atherosclerosis Trials

The relation among the burden of disease, progression of atherosclerosis, and remodeling in angiographically minimally diseased coronary arteries has not been defined. The present analysis included 1,906 patients who participated in 5 prospective clinical trials examining atheroma progression using intravascular ultrasonography. For the present analysis, the patients were stratified according to baseline quantitative coronary angiographic stenosis: <20%, 20% to 35%, and >35%. Patients with a lesser degree of luminal stenosis had less atherosclerosis. However, in the arteries with minimal angiographic stenosis, a large percentage of images contained atheroma, demonstrating the diffuse nature of coronary atherosclerosis. All 3 groups showed evidence of disease progression. The serial changes in vessel dimensions revealed that both the external elastic membrane and lumen volumes decreased in all 3 subgroups, in keeping with vessel and luminal constriction. In conclusion, these findings have demonstrated that patients with at least one luminal stenosis have diffuse atherosclerosis that progressed during 18 to 24 months, making them a target for therapeutic intervention. These minimally diseased arteries demonstrated evidence of vessel and luminal constriction, regardless of the angiographic appearance.

Future requirement for arterial wall imaging modalities in the evaluation of novel anti-atherosclerotic therapies.

Abstract Background: While arterial wall imaging has been used to characterize progression of atherosclerosis, there remain limitations to this approach. Scope: A selective overview of emerging modalities to image the artery wall and highlight how they may be used to evaluate emerging anti-atherosclerotic agents. Findings: Ongoing developments appear to enable assessment of composition and molecular properties of plaque in addition to quantitation of burden. Non-invasiveness and correlation with clinical outcome remains a challenge. Conclusion: New developments in imaging should enhance the ability to provide early characterization of the potential therapeutic efficacy of experimental agents.

Rationale and approach to evaluation of the impact of medical therapies on progression of atherosclerosis with arterial wall imaging.

Abstract Background: Despite the benefit of medical therapies, there remains a substantial residual risk of cardiovascular events. Atherosclerosis imaging has been used to assess new therapies. Scope: A selective review of current imaging techniques used to evaluate novel anti-atherosclerotic therapies. Findings: Noninvasive and invasive arterial wall imaging permits characterization of the quantity and composition of atherosclerotic plaque. Serial imaging enables assessment of the impact of therapies on the natural history of disease progression. Conclusion: Both noninvasive and invasive imaging modalities can be used in development programs to provide an early assessment of the impact of novel anti-atherosclerotic agents.

Findings of clinical trials that evaluate the impact of medical therapies on progression of atherosclerosis.

Abstract Background: Arterial wall imaging has been increasingly employed in clinical trials to evaluate the impact of medical therapies on progression of atherosclerosis. Scope: A selective overview of major findings from clinical trials that assessed the impact of medical therapies on atherosclerosis progression. Findings: Targeting established risk factors including LDL cholesterol, HDL cholesterol and blood pressure has a beneficial impact on disease progression. Conclusion: As a result, vascular imaging has been employed in the early evaluation of experimental therapies.