Single Ascending Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals With Elevated Plasma Lipoprotein(a) Levels.

Importance: Lipoprotein(a) (Lp[a]) is an important risk factor for atherothrombotic cardiovascular disease and aortic stenosis, for which there are no treatments approved by regulatory authorities. Objectives: To assess adverse events and tolerability of a short interfering RNA (siRNA) designed to reduce hepatic production of apolipoprotein(a) and to assess associated changes in plasma concentrations of Lp(a) at different doses. Design, Setting, and Participants: A single ascending dose study of SLN360, an siRNA targeting apolipoprotein(a) synthesis conducted at 5 clinical research unit sites located in the US, United Kingdom, and Australia. The study enrolled adults with Lp(a) plasma concentrations of 150 nmol/L or greater at screening and no known clinically overt cardiovascular disease. Participants were enrolled between November 18, 2020, and July 21, 2021, with last follow-up on December 29, 2021. Interventions: Participants were randomized to receive placebo (n = 8) or single doses of SLN360 at 30 mg (n = 6), 100 mg (n = 6), 300 mg (n = 6), or 600 mg (n = 6), administered subcutaneously. Main Outcomes and Measures: The primary outcome was evaluation of safety and tolerability. Secondary outcomes included change in plasma concentrations of Lp(a) to a maximum follow-up of 150 days. Results: Among 32 participants who were randomized and received the study intervention (mean age, 50 [SD, 13.5] years; 17 women [53%]), 32 (100%) completed the trial. One participant experienced 2 serious adverse event episodes: admission to the hospital for headache following SARS-CoV-2 vaccination and later for complications of cholecystitis, both of which were judged to be unrelated to study drug. Median baseline Lp(a) concentrations were as follows: placebo, 238 (IQR, 203-308) nmol/L; 30-mg SLN360, 171 (IQR, 142-219) nmol/L; 100-mg SLN360, 217 (IQR, 202-274) nmol/L; 300-mg SLN360, 285 (IQR, 195-338) nmol/L; and 600-mg SLN360, 231 (IQR, 179-276) nmol/L. Maximal median changes in Lp(a) were -20 (IQR, -61 to 3) nmol/L, -89 (IQR, -119 to -61) nmol/L, -185 (IQR, -226 to -163) nmol/L, -268 (IQR, -292 to -189) nmol/L, and -227 (IQR, -270 to -174) nmol/L, with maximal median percentage changes of -10% (IQR, -16% to 1%), -46% (IQR, -64% to -40%), -86% (IQR, -92% to -82%), -96% (IQR, -98% to -89%), and -98% (IQR, -98% to -97%), for the placebo group and the 30-mg, 100-mg, 300-mg, and 600-mg SLN360 groups, respectively. The duration of Lp(a) lowering was dose dependent, persisting for at least 150 days after administration. Conclusions and Relevance: In this phase 1 study of 32 participants with elevated Lp(a) levels and no known cardiovascular disease, the siRNA SLN360 was well tolerated, and a dose-dependent lowering of plasma Lp(a) concentrations was observed. The findings support further study to determine the safety and efficacy of this siRNA. Trial Registration: ClinicalTrials.gov Identifier: NCT04606602; EudraCT Identifier: 2020-002471-35.

Progression of coronary atherosclerosis in stable patients with ultrasonic features of high-risk plaques.

AIM: Large plaque burden, expansive vascular remodelling, and spotty calcification have been considered as important morphologies of high-risk plaques causing acute coronary events. Although non-occlusive rupture of high-risk plaques has been proposed as a mechanism for disease progression in post-mortem studies, the natural history of coronary atherosclerosis in stable patients with high-risk plaques has not been fully elucidated. We sought to evaluate coronary atheroma progression in stable patients with greyscale intravascular ultrasound (IVUS)-derived high-risk plaques. METHODS AND RESULTS: We analysed 4477 patients with stable coronary artery disease underwent serial greyscale IVUS imaging in eight clinical trials. We compared volumetric intravascular ultrasound (IVUS) data in the non-culprit segments between patients with and without high-risk plaques, defined as the combination of per cent atheroma volume (PAV) >63%, positive remodelling and spotty calcification. High-risk plaques were observed in 201 (4.5%) of patients. Patients with high-risk plaques exhibited a greater PAV (47.1 ± 8.4 vs. 37.7 ± 8.7%, P < 0.001) at baseline. On serial evaluation, however, regression of PAV (-0.26 ± 0.39 vs. 0.24 ± 0.32%, P = 0.03) was observed. In patients with high-risk plaques, the non-statin use was associated with the accelerated atheroma progression, whereas atheroma regression was observed under statin therapy (change in PAV: 1.87 ± 0.68% vs. -0.83 ± 0.53%, P = 0.01). CONCLUSIONS: Patients with high-risk plaques exhibit extensive atheroma burden, which is modifiable with anti-atherosclerotic therapies. These findings underscore risk modification using a statin in patients with high-risk plaques.

Attenuated plaque at nonculprit lesions in patients enrolled in intravascular ultrasound atherosclerosis progression trials.

OBJECTIVES: We investigated attenuated plaque (hypoechoic plaque with deep ultrasonic attenuation despite absence of bright calcium) in nonculprit lesions. BACKGROUND: Recent intravascular ultrasound (IVUS) studies describe acoustic shadowing behind large, echolucent, acute culprit lesion sites in the absence of bright calcium. Such "attenuated plaque" is considered a characteristic of high-risk lesions, but its prevalence in stable nonculprit lesions is incompletely known. METHODS: We reviewed IVUS pullback data from nonculprit vessels in 159 patients from the ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden) trial. We identified attenuated plaque and compared volumetric IVUS data in the segments with and without attenuation. In addition, we described plaque morphology in segments with attenuation at baseline and follow-up. RESULTS: Attenuated plaque was found in 17 of 159 patients (10.7%, 95% confidence interval: 6% to 17%). At baseline, there were no significant differences in clinical presentation and cardiovascular risk factors between patients with and without attenuation. Other than a greater plaque eccentricity index (p = 0.008), there were no significant differences between segments with and without attenuation. In segments with attenuated plaque, expansive remodeling was observed in 53%, and calcified plaque adjacent to the attenuation site in 70% of patients. During follow-up, attenuation remained stable, and no events occurred in the patients with attenuation. CONCLUSIONS: Attenuated plaque is present in a significant number of nonculprit segments in patients enrolled in IVUS progression trials and remains stable during follow-up. There is a relationship with mixed calcified lesions. These findings challenge the prior assumption that attenuated plaque is a finding limited to culprit lesions associated with acute clinical presentation.

Beta-blockers and progression of coronary atherosclerosis: pooled analysis of 4 intravascular ultrasonography trials.

BACKGROUND: In patients with myocardial infarction, beta-adrenergic blockers reduce recurrent myocardial infarction and total mortality rates. However, whether a direct influence of beta-blockers on coronary atherosclerosis contributes to reduced recurrent myocardial infarction and total mortality rates is not known. OBJECTIVE: To assess whether beta-blocker therapy is associated with reduced atheroma progression in adults with known coronary artery disease. DESIGN: Post hoc, pooled analysis of individual patient data from 4 intravascular ultrasonography (IVUS) trials. SETTING: Four IVUS trials conducted in the United States, Europe, and Australia. PATIENTS: 1515 patients with coronary artery disease. INTERVENTION: The original trials used 3 different statins, a calcium-channel blocker, an angiotensin-converting enzyme inhibitor, or an acyl coenzyme A-cholesterol acyltransferase inhibitor. MEASUREMENTS: Changes in atheroma volume, as determined by IVUS after adjustment for possible confounders by using linear mixed-effects models, were compared in patients who did and did not receive concomitant beta-blocker treatment. RESULTS: Patients who received beta-blockers (n = 1154) were more likely to have histories of myocardial infarction, angina, and hypertension than were patients who did not receive beta-blockers (n = 361). The estimated annual change in atheroma volume was statistically significantly less in patients who received beta-blockers. This was true for univariate and multivariable analyses that controlled for history of myocardial infarction, angina, and hypertension (mean [+/-SE] atheroma volume, -2.4 +/- 0.5 mm3/y in treated patients vs. -0.4 +/- 0.8 mm3/y in untreated patients; P = 0.034). Accordingly, atheroma volume statistically significantly decreased at follow-up IVUS in patients who received beta-blockers (P < 0.001) and did not change in patients who did not receive beta-blockers (P = 0.86). Additional adjustments for low-density lipoprotein cholesterol level, concomitant medications, and clinical trial did not change the results. LIMITATIONS: Patients were not randomly assigned to beta-blocker therapy, and interventions other than beta-blocker therapy could have influenced the changes in atheroma volume. Whether progression rate of atherosclerosis as detected by IVUS predicts cardiovascular outcomes is unknown. CONCLUSIONS: The analysis demonstrates that beta-blockers can slow progression of coronary atherosclerosis. The findings provide additional support for the current clinical guidelines advocating long-term use of beta-blockers to treat most forms of coronary artery disease.

Effects of normal, pre-hypertensive, and hypertensive blood pressure levels on progression of coronary atherosclerosis.

OBJECTIVES: The purpose of this study was to evaluate the effects of normal blood pressure (BP), pre-hypertension, and hypertension on progression of coronary atherosclerosis. BACKGROUND: The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) classifies BP as normal, pre-hypertension, and hypertension. The effects of these categories on progression of coronary atherosclerosis are unknown. METHODS: The 274 patients who completed the intravascular ultrasound (IVUS) substudy of the CAMELOT (Comparison of Amlodipine Versus Enalapril to Limit Occurrences of Thrombosis) trial were included. The entry criteria were > or =1 angiographic coronary stenosis >20% and diastolic BP <100 mm Hg. Patients underwent a baseline coronary IVUS, which was repeated after 2 years of amlodipine, enalapril, or placebo therapy. The BP was evaluated periodically, and the averages of the measurements were used in the analyses. RESULTS: Mean BP throughout the study was 127.0 +/- 12.0/75.5 +/- 6.8 mm Hg. In multivariable analysis, significant determinants of progression included systolic BP (r = 0.16; p = 0.006) and pulse pressure (r = 0.14; p = 0.02). Patients with "hypertensive" average BP had a 12.0 +/- 3.6 mm3 (least-square mean +/- SE) increase in atheroma volume, those with "pre-hypertensive" BP had no major change (0.9 +/- 1.8 mm3), and those with "normal" BP had a decrease of 4.6 +/- 2.6 mm(3) (p < 0.001 by analysis of covariance; p < 0.05 for comparison of all pairs). CONCLUSIONS: The most favorable rate of progression of coronary atherosclerosis is observed in patients whose BP falls within the "normal" JNC-7 category (i.e., systolic BP <120 mm Hg and diastolic BP <80 mm Hg). This study suggests that in patients with coronary artery disease, the optimal BP goal may be substantially lower than the <140/90 mm Hg level.

Reduction in vascular access site bleeding in sequential abciximab coronary intervention trials.

We analyzed vascular access site bleeding from the EPIC, EPILOG, and EPISTENT trials to quantify the decrease in vascular bleeding complications in these three trials, especially those attributable to abciximab. The incidence of combined major and minor vascular access site bleeding in nonabciximab (heparin plus placebo) patients progressively decreased from EPIC (8.2%) to EPILOG (2.9%) to EPISTENT (1.7%; P < 0.001). Combined major and minor vascular access site bleeding in abciximab (heparin plus abciximab) patients decreased from EPIC (20%) to EPILOG (5.8%) to EPISTENT (2.2%; P < 0.001). There were more major vascular access site bleeds with abciximab compared to placebo in EPIC (odds ration 3.2; P < 0.001) but not in EPILOG or EPISTENT. Modified abciximab and heparin dosing and improved vascular access site management strategies have decreased the risk of vascular access bleeding during coronary intervention and have essentially eliminated the excess access site bleeding associated with abciximab.

Effect of abciximab on angiographic complications during percutaneous coronary stenting in the Evaluation of Platelet IIb/IIIa Inhibition in Stenting Trial (EPISTENT).

In the Evaluation of Platelet IIb/IIIa Inhibition in Stenting Trial (EPISTENT), abciximab reduced ischemic complications of stent implantation at 30 days and 6 months. The responsible mechanisms remain unclear. We sought to determine if abciximab decreases ischemic complications by decreasing the incidence of angiographic complications during coronary stenting. In EPISTENT, patients were randomized to stenting with abciximab (abciximab group), stenting with placebo (placebo group), or balloon angioplasty with abciximab. Angiographic complications (including major or minor dissection, distal embolization, thrombus postprocedure, side branch or other vessel occlusion, residual stenosis >50%, transient coronary occlusion, and Thrombolysis In Myocardial Infarction final flow <3) were recorded prospectively. Creatine kinase (CK)-MB enzyme levels after intervention were measured at 6-hour intervals. We analyzed angiographic complications and CK-MB elevations in the abciximab group (n = 784) and the placebo group (n = 803). Angiographic complications were 29% less frequent in the abciximab group compared with the placebo group (17.0% vs 23.8%; p = 0.001). In patients with angiographic complications, there was a nonsignificant reduction in the incidence of CK-MB elevation >3 times normal with abciximab therapy (19.7% vs 24.5% in placebo group; p = 0.314). Abciximab (compared with placebo) significantly reduced the incidence of CK-MB elevation >3 times normal in those without any angiographic complications (6.5% vs 10.7%; p = 0.007). In summary, abciximab (compared with placebo) significantly reduced angiographic complications during coronary stenting. Abciximab also prevented CK-MB elevations in patients without angiographic complications.

Glycoprotein IIb-IIIa inhibition with abciximab and postprocedural risk assessment: lessons from the evaluation of platelet IIb/IIIa inhibitor for stenting trial and implication for ad hoc use of glycoprotein IIb-IIIa antagonists.

BACKGROUND: Angiographic features of vessels in which stents have been deployed can be used to predict the risk of postprocedural ischemic events. The purpose of this study was to compare the effects of abciximab in patients with and without high-risk postprocedure features. METHODS AND RESULTS: Protocol-mandated stent implantation was performed in 1586 patients in the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting trial, 783 of whom received abciximab, and was successful in 97% of the patients. High-risk features were defined as the presence of Thrombolysis In Myocardial Infarction (TIMI) flow <3, presence of thrombus or major dissection, or residual stenosis >10%. The primary endpoint was a composite of death, myocardial infarction, and urgent target vessel revascularization at 30 days. High-risk features were present in 21% of the patients. In patients without high-risk features after stent placement, abciximab reduced the primary endpoint from 9.0% to 3.9% (P <.001) compared with 16.2% to 8.6% (P =.046) in patients in whom high-risk features were present. There was no statistical evidence of interaction between abciximab treatment and the presence or absence of high-risk features. CONCLUSION: Glycoprotein IIb-IIIa antagonism with abciximab is equally effective in prevention of a composite of ischemic events in patients with and without high-risk features after stent placement. However, patients in whom high-risk features are present after stent placement are at increased risk of ischemic cardiac events even with abciximab treatment.