Effect of Evolocumab on Coronary Plaque Composition.

BACKGROUND: Incremental low-density lipoprotein (LDL) cholesterol lowering with the proprotein convertase subtilisin kexin type 9 inhibitor evolocumab regresses coronary atherosclerosis in statin-treated patients. OBJECTIVES: The purpose of this study was to evaluate the effect of adding evolocumab to statin therapy on coronary plaque composition. METHODS: A total of 968 statin-treated coronary artery disease patients underwent serial coronary intravascular ultrasound imaging at baseline and following 76 weeks of treatment with placebo or evolocumab 420 mg monthly. Plaque composition changes were determined in 331 patients with evaluable radiofrequency analysis of the ultrasound backscatter signal. RESULTS: Compared with statin monotherapy, evolocumab further reduced LDL cholesterol (33.5 mg/dl vs. 89.9 mg/dl; p < 0.0001) and induced regression of percent atheroma volume (-1.2% vs. +0.17%; p < 0.0001) and total atheroma volume (-3.6 mm3 vs. -0.8 mm3; p = 0.04). No difference was observed between the evolocumab and placebo groups in changes in calcium (1.0 ± 0.3 mm3 vs. 0.6 ± 0.3 mm3; p = 0.49), fibrous (-3.0 ± 0.6 mm3 vs. -2.4 ± 0.6 mm3; p = 0.49), fibrofatty (-5.0 ± 1.0 mm3 vs. -3.0 ± 1.0 mm3; p = 0.49), and necrotic (-0.6 ± 0.5 mm3 vs. -0.1 ± 0.5 mm3; p = 0.49) volumes. An inverse correlation was observed between changes in LDL cholesterol and plaque calcification (r = -0.15; p < 0.001). CONCLUSIONS: The addition of evolocumab to a statin did not produce differential changes in plaque composition compared with statin monotherapy. This suggests that evaluation of plaque morphology using virtual histology imaging may provide no incremental information about the plaque effects of evolocumab beyond measurement of plaque burden. (GLobal Assessment of Plaque reGression With a PCSK9 antibOdy as Measured by intraVascular Ultrasound [GLAGOV]; NCT01813422).

Effect of Infusion of High-Density Lipoprotein Mimetic Containing Recombinant Apolipoprotein A-I Milano on Coronary Disease in Patients With an Acute Coronary Syndrome in the MILANO-PILOT Trial: A Randomized Clinical Trial.

Importance: Infusing a high-density lipoprotein mimetic containing apolipoprotein A-I Milano demonstrated potential atheroma regression in patients following an acute coronary syndrome. To our knowledge, the effect of infusing a new mimetic preparation (MDCO-216) with contemporary statin therapy is unknown. Objective: To determine the effect of infusing MDCO-216 on coronary atherosclerosis progression. Design, Setting, and Participants: This double-blind, randomized clinical trial conducted in 22 hospitals in Canada and Europe compared the effects of 5 weekly intravenous infusions of MDCO-216 at a dose of 20 mg/kg weekly (n = 59) with placebo (n = 67) in statin-treated patients with an acute coronary syndrome. Main Outcomes and Measures: The primary efficacy measure was the nominal change in percent atheroma volume (PAV) from baseline to day 36 as measured by serial intravascular ultrasonography. The secondary efficacy measures were the nominal changes in normalized total atheroma volume (TAV), atheroma volume in the most diseased 10-mm segment, and the percentage of patients who demonstrated plaque regression. Safety and tolerability were also evaluated. Results: Among 122 randomized patients (mean [SD] age, 61.8 [10.4] years; 93 men [76.2%]; 61 [50.0%] with prior statin use; and a mean [SD] low-density lipoprotein cholesterol [LDL-C] level of 87.6 [40.5] mg/dL [to convert to millimoles per liter, multiply by 0.0259]), 113 (92.6%) had evaluable imaging results at follow-up. The receiving-treatment LDL-C levels were comparable with the placebo and MDCO-216 (68.6 vs 70.5 mg/dL; difference, -2.5 mg/dL; 95% CI, -10.1 to 5.0; P = .51). A reduction in high-density lipoprotein cholesterol levels was observed in MDCO, but not placebo patients (-3.3 vs 3.0 mg/dL [to convert to millimoles per liter, multiply by 0.0259]; difference, -6.3 mg/dL; 95% CI, -8.5 to -4.1; P < .001). Percent atheroma volume, which was adjusted for baseline values, decreased 0.94% with the placebo and 0.21% with MDCO-216 (difference, 0.73%; 95% CI, -0.07 to 1.52; P = .07). Normalized TAV decreased 7.9 mm3 with the placebo and 6.4 mm3 with MDCO-216 (difference, 1.6 mm3; 95% CI, -5.6 to 8.7; P = .67), and atheroma volume in the most diseased segment decreased 1.8 mm3 with the placebo and 2.2 mm3 with MDCO-216 (difference 0.4 mm3; 95% CI, -4.4 to 3.5; P = .83). A similar percentage of patients demonstrated a regression of PAV (67.2% vs 55.8%; P = .21) and TAV (68.9% vs 71.2%; P = .79) in the placebo and MDCO-216 groups, respectively. Conclusions and Relevance: Among patients with an acute coronary syndrome, infusing MDCO-216 did not produce an incremental plaque regression in the setting of contemporary statin therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02678923.

Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial.

Importance: Reducing levels of low-density lipoprotein cholesterol (LDL-C) with intensive statin therapy reduces progression of coronary atherosclerosis in proportion to achieved LDL-C levels. Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors produce incremental LDL-C lowering in statin-treated patients; however, the effects of these drugs on coronary atherosclerosis have not been evaluated. Objective: To determine the effects of PCSK9 inhibition with evolocumab on progression of coronary atherosclerosis in statin-treated patients. Design, Setting, and Participants: The GLAGOV multicenter, double-blind, placebo-controlled, randomized clinical trial (enrollment May 3, 2013, to January 12, 2015) conducted at 197 academic and community hospitals in North America, Europe, South America, Asia, Australia, and South Africa and enrolling 968 patients presenting for coronary angiography. Interventions: Participants with angiographic coronary disease were randomized to receive monthly evolocumab (420 mg) (n = 484) or placebo (n = 484) via subcutaneous injection for 76 weeks, in addition to statins. Main Outcomes and Measures: The primary efficacy measure was the nominal change in percent atheroma volume (PAV) from baseline to week 78, measured by serial intravascular ultrasonography (IVUS) imaging. Secondary efficacy measures were nominal change in normalized total atheroma volume (TAV) and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated. Results: Among the 968 treated patients (mean age, 59.8 years [SD, 9.2]; 269 [27.8%] women; mean LDL-C level, 92.5 mg/dL [SD, 27.2]), 846 had evaluable imaging at follow-up. Compared with placebo, the evolocumab group achieved lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL; difference, -56.5 mg/dL [95% CI, -59.7 to -53.4]; P < .001). The primary efficacy parameter, PAV, increased 0.05% with placebo and decreased 0.95% with evolocumab (difference, -1.0% [95% CI, -1.8% to -0.64%]; P < .001). The secondary efficacy parameter, normalized TAV, decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab (difference, -4.9 mm3 [95% CI, -7.3 to -2.5]; P < .001). Evolocumab induced plaque regression in a greater percentage of patients than placebo (64.3% vs 47.3%; difference, 17.0% [95% CI, 10.4% to 23.6%]; P < .001 for PAV and 61.5% vs 48.9%; difference, 12.5% [95% CI, 5.9% to 19.2%]; P < .001 for TAV). Conclusions and Relevance: Among patients with angiographic coronary disease treated with statins, addition of evolocumab, compared with placebo, resulted in a greater decrease in PAV after 76 weeks of treatment. Further studies are needed to assess the effects of PCSK9 inhibition on clinical outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT01813422.

Impact of PCSK9 inhibition on coronary atheroma progression: Rationale and design of Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV).

BACKGROUND: Statin-mediated low-density lipoprotein cholesterol (LDL-C) lowering fails to prevent more than half of cardiovascular events in clinical trials. Serial plaque imaging studies have highlighted the benefits of aggressive LDL-C lowering, with plaque regression evident in up to two-thirds of patients with achieved LDL-C levels <70 mg/dL. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors permit LDL-C-lowering by a further 54% to 75% in statin-treated patients. The impact of achieving very low LDL-C levels with PCSK9 inhibitors on coronary atherosclerosis has not been investigated. AIMS: To test the hypothesis that incremental LDL-C lowering with the PCSK9 inhibitor, evolocumab, will result in a significantly greater change from baseline in coronary atheroma volume than placebo in subjects receiving maximally tolerated statin therapy. METHODS: A phase 3, multicenter, double-blind, randomized, placebo-controlled trial evaluating the impact of evolocumab on coronary atheroma volume as assessed by serial coronary intravascular ultrasound at baseline in patients undergoing a clinically indicated coronary angiogram with angiographic evidence of coronary atheroma, and after 78 weeks of treatment. Subjects (n = 968) were randomized 1:1 into 2 groups to receive monthly either evolocumab 420 mg or placebo subcutaneous injections. CONCLUSIONS: The GLAGOV trial will explore whether greater degrees of plaque regression are achievable with ultrahigh-intensity LDL-C lowering after combination statin-PCSK9 inhibitor therapy. GLAGOV will provide important mechanistic, safety, and efficacy data prior to the eagerly anticipated clinical outcomes trials testing the PCSK9 inhibitor hypothesis (www.clinicaltrials.gov identifier NCT01813422).

Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial.

BACKGROUND: REG1 is a novel anticoagulation system consisting of pegnivacogin, an RNA aptamer inhibitor of coagulation factor IXa, and anivamersen, a complementary sequence reversal oligonucleotide. We tested the hypothesis that near complete inhibition of factor IXa with pegnivacogin during percutaneous coronary intervention, followed by partial reversal with anivamersen, would reduce ischaemic events compared with bivalirudin, without increasing bleeding. METHODS: We did a randomised, open-label, active-controlled, multicentre, superiority trial to compare REG1 with bivalirudin at 225 hospitals in North America and Europe. We planned to randomly allocate 13,200 patients undergoing percutaneous coronary intervention in a 1:1 ratio to either REG1 (pegnivacogin 1 mg/kg bolus [>99% factor IXa inhibition] followed by 80% reversal with anivamersen after percutaneous coronary intervention) or bivalirudin. Exclusion criteria included ST segment elevation myocardial infarction within 48 h. The primary efficacy endpoint was the composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularisation by day 3 after randomisation. The principal safety endpoint was major bleeding. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, identifier NCT01848106. The trial was terminated early after enrolment of 3232 patients due to severe allergic reactions. FINDINGS: 1616 patients were allocated REG1 and 1616 were assigned bivalirudin, of whom 1605 and 1601 patients, respectively, received the assigned treatment. Severe allergic reactions were reported in ten (1%) of 1605 patients receiving REG1 versus one (<1%) of 1601 patients treated with bivalirudin. The composite primary endpoint did not differ between groups, with 108 (7%) of 1616 patients assigned REG1 and 103 (6%) of 1616 allocated bivalirudin reporting a primary endpoint event (odds ratio [OR] 1·05, 95% CI 0·80-1·39; p=0·72). Major bleeding was similar between treatment groups (seven [<1%] of 1605 receiving REG1 vs two [<1%] of 1601 treated with bivalirudin; OR 3·49, 95% CI 0·73-16·82; p=0·10), but major or minor bleeding was increased with REG1 (104 [6%] vs 65 [4%]; 1·64, 1·19-2·25; p=0·002). INTERPRETATION: The reversible factor IXa inhibitor REG1, as currently formulated, is associated with severe allergic reactions. Although statistical power was limited because of early termination, there was no evidence that REG1 reduced ischaemic events or bleeding compared with bivalirudin. FUNDING: Regado Biosciences Inc.

Effect of the BET Protein Inhibitor, RVX-208, on Progression of Coronary Atherosclerosis: Results of the Phase 2b, Randomized, Double-Blind, Multicenter, ASSURE Trial.

BACKGROUND: Bromodomain and extra-terminal (BET) proteins regulate transcription of lipoprotein and inflammatory factors implicated in atherosclerosis. The impact of BET inhibition on atherosclerosis progression is unknown. METHODS: ASSURE was a double-blind, randomized, multicenter trial in which 323 patients with angiographic coronary disease and low high-density lipoprotein cholesterol (HDL-C) levels were randomized in a 3:1 fashion to treatment with the BET protein inhibitor RVX-208 200 mg or placebo for 26 weeks. Plaque progression was measured with serial intravascular ultrasound imaging. Lipid levels, safety, and tolerability were also assessed. RESULTS: During treatment, apolipoprotein (apo)A-I increased by 10.6% with placebo (P < 0.001 compared with baseline) and 12.8% with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.18. HDL-C increased by 9.1% with placebo (P < 0.001 compared with baseline) and 11.1% with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.24. Low-density lipoprotein cholesterol (LDL-C) decreased by 17.9% with placebo (P < 0.001 compared with baseline) and 15.8% with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.55. The primary endpoint, the change in percent atheroma volume, decreased 0.30% in placebo-treated patients (P = 0.23 compared with baseline) and 0.40% in the RVX-208 group (P = 0.08 compared with baseline), between groups P = 0.81. Total atheroma volume decreased 3.8 mm(3) in the placebo group (P = 0.01 compared with baseline) and 4.2 mm(3) in the RVX-208 group (P < 0.001 compared with baseline), P = 0.86 between groups. A greater incidence of elevated liver enzymes was observed in RVX-208-treated patients (7.1 vs. 0%, P = 0.009). CONCLUSION: Administration of the BET protein inhibitor RVX-208 showed no greater increase in apoA-I or HDL-C or incremental regression of atherosclerosis than administration of placebo. TRIAL REGISTRATION: ClinicalTrials.gov identifier-NCT01067820.

ApoA-I induction as a potential cardioprotective strategy: rationale for the SUSTAIN and ASSURE studies.

BACKGROUND: Considerable interest has focused on the development of therapies that target the functionality of high-density lipoproteins (HDL). Upregulation of endogenous synthesis of the major protein on HDL particles, apolipoprotein A-I (apoA-I), represents a novel approach to generation of new HDL particles. The Study of Quantitative Serial Trends in Lipids with Apolipoprotein A-I Stimulation (SUSTAIN, NCT01423188) study aims to evaluate the lipid efficacy, safety and tolerability of an apoA-I inducer (RVX-208). The ApoA-I Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation (ASSURE, NCT01067820) study aims to evaluate the effect of RVX-208 on plaque burden. METHODS: In SUSTAIN, 172 patients with low levels of HDL-C will be randomized to receive RVX-208 100 mg bid or placebo for 24 weeks. The primary efficacy parameter will be the percentage change in HDL-C levels. In ASSURE, 310 patients with angiographic coronary artery disease and low HDL-C levels will be randomized to receive RVX-208 100 mg bid or placebo for 26 weeks. The primary efficacy parameter will be the nominal change in percent atheroma volume (PAV), determined by analysis of intravascular ultrasound (IVUS) images of matched coronary artery segments acquired at baseline and at 26-week follow-up. The effect of RVX-208 on other lipid and inflammatory markers, safety and tolerability will also be assessed in both studies. CONCLUSION: ApoA-I induction represents a potential novel strategy to reduce cardiovascular risk, by generating nascent HDL particles. These studies will provide early evaluation of the effects of RVX-208 on lipids and atherosclerotic plaque.

Effect of two intensive statin regimens on progression of coronary disease.

BACKGROUND: Statins reduce adverse cardiovascular outcomes and slow the progression of coronary atherosclerosis in proportion to their ability to reduce low-density lipoprotein (LDL) cholesterol. However, few studies have either assessed the ability of intensive statin treatments to achieve disease regression or compared alternative approaches to maximal statin administration. METHODS: We performed serial intravascular ultrasonography in 1039 patients with coronary disease, at baseline and after 104 weeks of treatment with either atorvastatin, 80 mg daily, or rosuvastatin, 40 mg daily, to compare the effect of these two intensive statin regimens on the progression of coronary atherosclerosis, as well as to assess their safety and side-effect profiles. RESULTS: After 104 weeks of therapy, the rosuvastatin group had lower levels of LDL cholesterol than the atorvastatin group (62.6 vs. 70.2 mg per deciliter [1.62 vs. 1.82 mmol per liter], P<0.001), and higher levels of high-density lipoprotein (HDL) cholesterol (50.4 vs. 48.6 mg per deciliter [1.30 vs. 1.26 mmol per liter], P=0.01). The primary efficacy end point, percent atheroma volume (PAV), decreased by 0.99% (95% confidence interval [CI], -1.19 to -0.63) with atorvastatin and by 1.22% (95% CI, -1.52 to -0.90) with rosuvastatin (P=0.17). The effect on the secondary efficacy end point, normalized total atheroma volume (TAV), was more favorable with rosuvastatin than with atorvastatin: -6.39 mm(3) (95% CI, -7.52 to -5.12), as compared with -4.42 mm(3) (95% CI, -5.98 to -3.26) (P=0.01). Both agents induced regression in the majority of patients: 63.2% with atorvastatin and 68.5% with rosuvastatin for PAV (P=0.07) and 64.7% and 71.3%, respectively, for TAV (P=0.02). Both agents had acceptable side-effect profiles, with a low incidence of laboratory abnormalities and cardiovascular events. CONCLUSIONS: Maximal doses of rosuvastatin and atorvastatin resulted in significant regression of coronary atherosclerosis. Despite the lower level of LDL cholesterol and the higher level of HDL cholesterol achieved with rosuvastatin, a similar degree of regression of PAV was observed in the two treatment groups. (Funded by AstraZeneca Pharmaceuticals; ClinicalTrials.gov number, NCT000620542.).

Impact of statins on progression of atherosclerosis: rationale and design of SATURN (Study of Coronary Atheroma by InTravascular Ultrasound: effect of Rosuvastatin versus AtorvastatiN).

BACKGROUND: Previous imaging studies have demonstrated that the beneficial impact of high-dose statins on the progression of coronary atherosclerosis associates with their ability to lower levels of low-density lipoprotein cholesterol (LDL-C) and C-reactive protein (CRP) and to raise high-density lipoprotein cholesterol (HDL-C). The Study of Coronary Atheroma by InTravascular Ultrasound: Effect of Rosuvastatin versus AtorvastatiN (SATURN, NCT00620542) aims to compare the effects of high-dose atorvastatin and rosuvastatin on disease progression. METHODS: A total of 1385 subjects with established coronary artery disease (CAD) on angiography were randomized to receive rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. The primary efficacy parameter will be the nominal change in percent atheroma volume (PAV), determined by analysis of intravascular ultrasound (IVUS) images of matched coronary artery segments acquired at baseline and at 24-month follow-up. The effect of statin therapy on plasma lipids and inflammatory markers, and the incidence of clinical cardiovascular events will also be assessed. The study does not have the statistical power to directly compare the treatment groups with regard to clinical events. CONCLUSION: Serial IVUS has emerged as a sensitive imaging modality to assess the impact of treatments on arterial structure. In this study, IVUS will be used to determine whether high-dose statins have different effects on plaque progression.

Efficacy and safety of a novel oral inducer of apolipoprotein a-I synthesis in statin-treated patients with stable coronary artery disease a randomized controlled trial.

OBJECTIVES: The purpose of this study was to investigate the safety, tolerability, and efficacy of RVX-208, the first oral agent designed to enhance apolipoprotein (apo) A-I synthesis. BACKGROUND: No agent that selectively induces synthesis of apoA-I has reached an advanced stage of clinical development. METHODS: A total of 299 statin-treated patients with coronary artery disease were treated with placebo or with RVX-208 at a dose of 50, 100, or 150 mg twice daily for 12 weeks. Changes in lipid-related biomarkers, in addition to safety and tolerability, of RVX-208 were investigated. RESULTS: For each dose of RVX-208, individual pairwise comparisons of apoA-I changes with placebo, the primary end point, did not achieve statistical significance. However, treatment with RVX-208 was associated with a dose-dependent increase in apoA-I levels by up to 5.6% (p = 0.035 for trend). Administration of RVX-208 resulted in significant increases in levels of high-density lipoprotein cholesterol (HDL-C) ranging from 3.2% to 8.3% (p = 0.02), and large HDL particles increased by 11.1% to 21.1% (p = 0.003). ApoA-I levels increased rapidly from 8 to 12 weeks, suggesting that peak pharmacological effect has not been achieved by the end of the 12-week study. Transient and reversible elevations in liver transaminases >3 times the upper limit of normal were observed in 18 patients treated with RVX-208, with no associated increase in bilirubin levels. CONCLUSIONS: Administration of RVX-208 for 12 weeks was associated with increases in apoA-I, HDL-C, and concentration of large HDL particles, consistent with facilitation of cholesterol mobilization. Maximal increases in apoA-I may require longer exposure. An increase in liver enzymes was observed with active treatment. (Clinical Trial for Dose Finding and Safety of RVX000222 in Subjects With Stable Coronary Artery Disease; NCT01058018).

Utility of sirolimus-eluting Cypher stents to reduce 12-month target vessel revascularization in saphenous vein graft stenoses: results of a multicenter 350-patient case-control study.

BACKGROUND: Although the increased utilization of drug-eluting stents is well supported by multiple studies with clinical trial data for many patient and lesion subsets, their use to treat diseased saphenous vein graft (SVG) lesions is much less well substantiated. We sought to ascertain and compare 12-month target vessel revascularization (TVR) rates for sirolimus-eluting Cyphertrade mark stents and bare-metal stents (BMS) when utilized to treat stenoses in diseased SVGs. METHODS: Therefore, we conducted a multicenter matched-control study in patients treated for de novo SVG lesions with Cypher or BMS, matching for reference vessel diameter, stent length, diabetes and number of stents utilized. The primary study endpoint was TVR at 12 months. RESULTS: Three hundred and fifty patients were matched, with patient age = 69 +/- 9 years, 77% male, 39% diabetics, SVG age = 119 +/- 75 months, reference vessel diameter = 3.3 +/- 0.4 mm, target lesion length = 17.4 +/- 8.4 mm (p = NS for all between-group comparisons). Twelve-month TVR was modestly reduced with Cypher stenting (6.8% vs. 11.8%; p = 0.14) due to a trend toward a reduction in binary restenosis (7.4% vs. 13.6%; p = 0.08). Twelve-month survival was 95.3% and 96.4% in the Cypher and BMS groups, respectively (p = 0.79). CONCLUSIONS: Cypher stents appear to modestly reduce TVR without apparent safety risk compared with BMS when applied to the treatment of diseased SVGs. In conjunction with other available studies, these data support Cypher stent use in this setting.

What is the metabolic syndrome? Prediabetes and cardiovascular risk.

The metabolic syndrome has been referred to as a clustering of cardiovascular risk factors, including abdominal obesity, atherogenic dyslipidemia, increased blood pressure, insulin resistance, proinflammatory state, and a prothrombotic state. The metabolic syndrome has become one of the leading clinical issues discussed by physicians and the media, leading to increased public awareness to this potentially catastrophic multiplex risk factor for cardiovascular disease. With increasing prevalence in the United States, the metabolic syndrome has been equated to cigarette smoking as a contributing factor to premature cardiovascular heart disease and one of the underlying causes of type 2 diabetes. The identification and modification of the root causes, overweight/obesity, physical inactivity, and the closely associated condition, insulin resistance, needs to be one of the initial strategies that are addressed by the clinician.