Investigating the Lowest Threshold of Vascular Benefits from LDL Cholesterol Lowering with a PCSK9 mAb Inhibitor (Alirocumab) in Patients with Stable Cardiovascular Disease (INTENSITY-HIGH): protocol and study rationale for a randomised, open label, parallel group, mechanistic study.

INTRODUCTION: Elevated low-density lipoprotein cholesterol (LDL-C) is a strong independent risk predictor of cardiovascular (CV) events, while interventions to reduce it remain the only evidence-based approach to reduce CV morbidity and mortality. Secondary prevention statin trials in combination with ezetimibe and/or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors showed that there is no 'J shaped curve' in LDL-C levels with regard to CV outcomes. The lowest threshold beyond which reduction of LDL-C confers no further CV benefits has not been identified.The INTENSITY-HIGH study seeks to explore physiological mechanisms mediating CV benefits of LDL-C lowering by PCSK9 inhibition in patients with established cardiovascular disease (CVD). The study examines the changes in measures of endothelial function and vascular inflammation imaging following intervention with PCSK9 and against standard of care. METHODS AND ANALYSIS: This is a single-centre, randomised, open label, parallel group, mechanistic physiological study. It will include approximately 60 subjects with established CVD, with LDL-C of <4.1 mmol/L on high-intensity statins. All eligible participants will undergo 18-fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) scanning of the aorta and carotid arteries, as well as baseline endothelial function assessment. Subsequently, they will be randomised on a 1:1 basis to either alirocumab 150 mg or ezetimibe 10 mg/day. Repeat FDG-PET/CT scan and vascular assessments will be undertaken after 8 weeks of treatment. Any changes in these parameters will be correlated with changes in lipid levels and systemic inflammation biomarkers. ETHICS AND DISSEMINATION: The study received a favourable opinion from the Wales Research Ethics Committee 4, was registered on clinicaltrials.gov and conformed to International Conference for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice. The results of this study will be reported through peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: NCT03355027.

Investigating the lowest threshold of vascular benefits from LDL cholesterol lowering with a PCSK9 mAb inhibitor (alirocumab) in healthy volunteers - a mechanistic physiological study (INTENSITY-LOW): protocol and study rationale.

Objective: Whether reducing low density lipoprotein cholesterol (LDL-C) is associated with cardiovascular benefits in low risk normocholesterolaemic subjects is unknown. The INTENSITY LOW [Investigating the lowest threshold of vascular benefits from LDL-cholesterol lowering with a PCSK9 mAb inhibitor (alirocumab) in healthy volunteers] study aims to assess whether lowering LDL-C by alirocumab monotherapy can improve endothelial-dependent vascular function compared with placebo (primary objective) in low-risk normocholesterolaemic healthy individuals. Changes in endothelial-dependent or endothelial-independent vascular function, arterial stiffness and biomarkers of systemic inflammation by alirocumab, atorvastatin or their combination are secondary objectives. Study design and methods: This is a single-center, randomized, two-period, single-blind, placebo-controlled clinical trial. The study was registered on clinicaltrials.gov (N03273972). It will include 30 healthy low-risk subjects with LDL-C < 4.1 mmol/l. After passing the screening visit (Visit 1), eligible participants will be randomized 1:1 to either subcutaneous alirocumab 150 mg or placebo. These will be administered as single doses in 2 visits 14 days apart (Visits 2 and 3). Atorvastatin 20 mg once nightly will be prescribed for 14 days at Visit 3 in both groups through to Visit 4. At baseline (Visit 2) and during all post-dose visits (Visits 3-4), endothelial function will be assessed using venous occlusion plethysmography. Specifically, changes in forearm blood flow responses to intra-arterial infusions of acetylcholine, sodium nitroprusside and L-NG-monomethyl-arginine acetate will be assessed as surrogates of endothelial-dependent and -independent vasodilatation. Additionally, arterial stiffness and carotid intima-media thickness will be evaluated at the same timepoints. The above-mentioned changes will be correlated with changes in lipid and systemic inflammation biomarkers.

Left bundle branch block with acute thrombotic occlusion is associated with increased myocardial jeopardy score and poor clinical outcomes in primary percutaneous coronary intervention activations.

OBJECTIVE: To assess the utility of left bundle branch block (LBBB) as an activation criterion for primary percutaneous coronary intervention (PPCI). DESIGN: Retrospective observational cohort study. SETTING: Single UK heart attack centre. PATIENTS: Consecutive patients referred for PPCI September 2008-December 2011 (n=2192). INTERVENTIONS: Demographic and outcome data were obtained by review of case notes, angiograms and interrogation of local/national databases. MAIN OUTCOME MEASURES: Angiographic culprit lesion assessment defined appropriate and inappropriate activations. Patients outcomes were assessed by Major adverse cardiac events (MACE), defined as a composite of mortality and unplanned revascularisation at 1-year. RESULTS: LBBB-activation occurred in 120 patients (5.5%), of whom 21 (17.5%) had acute coronary occlusion angiographically, and were adjudicated appropriately. Compared with appropriate activations for ST segment elevation, appropriate LBBB-activations were older (71.0 ± 9.6 vs 64.2 ± 12.4 years, p=0.01) and more likely to be in cardiogenic shock (19.0% vs 4.3%, p<0.01). Extent of disease quantified by the SYNTAX score did not differ (median 21.5, IQR 11.0-27.0 vs 19, 11.0-25.5, p=0.66), but amount of myocardium at-risk was higher in appropriate LBBB-activations (culprit jeopardy score median 4, IQR 2-6 vs 2, 2-4, p=0.02). Final diagnoses for LBBB-activations were acute coronary syndrome (39.2%), non-acute coronary syndrome cardiac chest pain (33.3%) and non-cardiac chest pain (27.5%). In appropriate LBBB-activations 1-year mortality and MACE were higher (23.8% vs 6.6%, p=0.002 and 28.6% vs 10.5%, p=0.007, respectively). CONCLUSIONS: Our data suggests that despite its poor specificity for identifying acute coronary occlusion, LBBB should at the present time remain an activation criterion for PPCI and such patients should continue to be transferred to heart attack centres for assessment and treatment.