Longer-Term Efficacy and Safety of Evinacumab in Patients With Refractory Hypercholesterolemia.

Importance: Patients with refractory hypercholesterolemia who do not achieve their guideline-defined low-density lipoprotein cholesterol (LDL-C) thresholds despite treatment with maximally tolerated combinations of lipid-lowering therapies (LLTs) have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Objective: To evaluate longer-term efficacy and safety of evinacumab in patients with refractory hypercholesterolemia. Design, Setting, and Participants: This randomized clinical trial included a 2-week screening period followed by a 16-week double-blind treatment period (DBTP) for subcutaneous regimens (evinacumab, 450 mg, once weekly [QW]; evinacumab, 300 mg, QW; evinacumab, 300 mg, every 2 weeks; or placebo QW) or a 24-week DBTP for intravenous regimens (evinacumab, 15 mg/kg, every 4 weeks [Q4W]; evinacumab, 5 mg/kg, Q4W; or placebo Q4W); a 48-week open-label treatment period (OLTP) for intravenous treatment only; and a 24-week follow-up period. Patients from 85 sites across 20 countries were recruited for the study; patients with primary hypercholesterolemia (defined as heterozygous familial hypercholesterolemia or established clinical ASCVD without familial hypercholesterolemia) who entered the 48-week OLTP were included. In addition, the patients' hypercholesterolemia was refractory to maximally tolerated LLTs. Interventions: All patients entering the OLTP received evinacumab, 15 mg/kg, intravenously Q4W. Main Outcomes and Measures: Efficacy outcomes included change in LDL-C level and other lipid/lipoprotein parameters from baseline to week 72 (end of the OLTP). Safety outcomes included assessment of treatment-emergent adverse events (TEAEs). Results: A total of 96 patients (mean [SD] age, 54.4 [11.3] years; 52 female [54.2%]) entered the OLTP, of whom 88 (91.7%) completed the OLTP. Mean (SD) baseline LDL-C level was 145.9 (55.2) mg/dL. At week 72, evinacumab, 15 mg/kg, reduced mean (SD) LDL-C level from baseline by 45.5% (28.7%) in the overall cohort. Evinacumab, 15 mg/kg, reduced mean (SD) apolipoprotein B (38.0% [22.1%]), non-high density lipoprotein cholesterol (48.4% [23.2%]), total cholesterol (42.6% [17.5%]), and median (IQR) fasting triglyceride (57.2% [65.4%-44.4%]) levels at week 72 from baseline in the overall cohort. TEAEs occurred in 78 of 96 patients (81.3%). Serious TEAEs occurred in 9 of 96 patients (9.4%); all were considered unrelated to study treatment. Conclusions and Relevance: In patients with refractory hypercholesterolemia, evinacumab provided sustained reductions in LDL-C level and was generally well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT03175367.

Evinacumab in Patients with Refractory Hypercholesterolemia.

BACKGROUND: Patients with refractory hypercholesterolemia, who have high low-density lipoprotein (LDL) cholesterol levels despite treatment with lipid-lowering therapies at maximum tolerated doses, have an increased risk of atherosclerosis. In such patients, the efficacy and safety of subcutaneous and intravenous evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, are not known. METHODS: In this double-blind, placebo-controlled, phase 2 trial, we enrolled patients with or without heterozygous familial hypercholesterolemia who had refractory hypercholesterolemia, with a screening LDL cholesterol level of 70 mg per deciliter or higher with atherosclerosis or of 100 mg per deciliter or higher without atherosclerosis. Patients were randomly assigned to receive subcutaneous or intravenous evinacumab or placebo. The primary end point was the percent change from baseline in the LDL cholesterol level at week 16 with evinacumab as compared with placebo. RESULTS: In total, 272 patients were randomly assigned to the following groups: subcutaneous evinacumab at a dose of 450 mg weekly (40 patients), 300 mg weekly (43 patients), or 300 mg every 2 weeks (39 patients) or placebo (41 patients); or intravenous evinacumab at a dose of 15 mg per kilogram of body weight every 4 weeks (39 patients) or 5 mg per kilogram every 4 weeks (36 patients) or placebo (34 patients). At week 16, the differences in the least-squares mean change from baseline in the LDL cholesterol level between the groups assigned to receive subcutaneous evinacumab at a dose of 450 mg weekly, 300 mg weekly, and 300 mg every 2 weeks and the placebo group were -56.0, -52.9, and -38.5 percentage points, respectively (P<0.001 for all comparisons). The differences between the groups assigned to receive intravenous evinacumab at a dose of 15 mg per kilogram and 5 mg per kilogram and the placebo group were -50.5 percentage points (P<0.001) and -24.2 percentage points, respectively. The incidence of serious adverse events during the treatment period ranged from 3 to 16% across trial groups. CONCLUSIONS: In patients with refractory hypercholesterolemia, the use of evinacumab significantly reduced the LDL cholesterol level, by more than 50% at the maximum dose. (Funded by Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03175367.).

Long-term safety and efficacy of alirocumab in South African patients with heterozygous familial hypercholesterolaemia: the ODYSSEY Open-Label Extension study.

BACKGROUND: Alirocumab reduces low-density lipoprotein cholesterol (LDL-C) levels by up to 61%. The ODYSSEY Open-Label Extension study investigated the effect of alirocumab in patients with heterozygous familial hypercholesterolaemia (HeFH) over 144 weeks. METHODS: Eligible patients with HeFH had completed an earlier double-blind, randomised, placebo-controlled parent study. Patients were initiated on 75 mg alirocumab Q2W subcutaneous (SC) unless baseline LDL-C was > 8.9 mmol/l, in which case they received 150 mg alirocumab Q2W. Dose titration to 150 mg Q2W was at the investigator's discretion. RESULTS: The study enrolled 167 patients and the parent study mean (± SD) baseline LDL-C level was 3.65 ± 1.9 mmol/l. Mean LDL-C level was reduced by 48.7% at week 144; mean on-treatment LDL-C was 2.30 ± 1.24 mmol/l. Eight patients reported injection-site reactions, with one treatment discontinuation. Treatment emergent anti-drug antibodies were identified in five patients but these did not affect the efficacy. CONCLUSIONS: Alirocumab effectively and safely reduced LDL-C in these patients.

PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19, 2013. 331 eligible patients (18-80 years of age), who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL cholesterol concentration of 2·6 mmol/L or higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer generated by the study sponsor, implemented by a computerised voice interactive system, and stratified by LDL cholesterol concentration at screening (higher or lower than 4·1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and Amgen study staff were masked to treatment assignments within dosing frequency groups. The coprimary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01763918. FINDINGS: Of 415 screened patients, 331 were eligible and were randomly assigned to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo monthly (n=55). 329 patients received at least one dose of study drug. Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59·2% reduction [95% CI 53·4-65·1], monthly dose: 61·3% reduction [53·6-69·0]; both p<0·0001) and at the mean of weeks 10 and 12 (60·2% reduction [95% CI 54·5-65·8] and 65·6% reduction [59·8-71·3]; both p<0·0001). Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group) and muscle-related adverse events (ten patients [5%] vs 1 [1%]). INTERPRETATION: In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo. FUNDING: Amgen Inc.

Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure.

BACKGROUND: Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. METHODS AND RESULTS: We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-B-type natriuretic peptide and troponin) versus enalapril. CONCLUSIONS: Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Tuberculous pericarditis.

BACKGROUND: The incidence of tuberculous pericarditis is increasing in Africa as a result of the human immunodeficiency virus (HIV) epidemic. The primary objective of this article was to review and summarize the literature on the pathogenesis, diagnosis, and management of tuberculous pericarditis. METHODS AND RESULTS: We searched MEDLINE (January 1966 to May 2005) and the Cochrane Library (Issue 1, 2005) for information on relevant references. A "definite" diagnosis of tuberculous pericarditis is based on the demonstration of tubercle bacilli in pericardial fluid or on a histological section of the pericardium; "probable" tuberculous pericarditis is based on the proof of tuberculosis elsewhere in a patient with otherwise unexplained pericarditis, a lymphocytic pericardial exudate with elevated adenosine deaminase levels, and/or appropriate response to a trial of antituberculosis chemotherapy. Treatment consists of the standard 4-drug antituberculosis regimen for 6 months. It is uncertain whether adjunctive corticosteroids are effective in reducing mortality or progression to constriction. Surgical resection of the pericardium remains the appropriate treatment for constrictive pericarditis. The timing of surgical intervention is controversial, but many experts recommend a trial of medical therapy for noncalcific pericardial constriction, and pericardiectomy in nonresponders after 4 to 8 weeks of antituberculosis chemotherapy. CONCLUSIONS: Research is needed to improve the diagnosis, assess the effectiveness of adjunctive steroids, and determine the impact of HIV infection on the outcome of tuberculous pericarditis.

The use of adenosine deaminase and interferon-gamma as diagnostic tools for tuberculous pericarditis.

BACKGROUND: Traditional diagnostic tests for pericardial tuberculosis (TB) are insensitive and often require long culture periods, and this has led to more emphasis being placed on biochemical tests such as the pericardial adenosine deaminase (ADA) test. However, controversy exists as to its diagnostic utility. In addition, the use of interferon (IFN)-gamma, which is a reliable indicator of pleural and peritoneal TB, has not been explored in pericardial effusions. We investigated ADA and IFN-gamma levels in pericardial effusions of different etiologies. METHODS AND RESULTS: A prospective study was carried out from February 1995 to February 1998 at Tygerberg Hospital (South Africa), with pericardial taps being performed under echocardiographic guidance. During this period, 110 consecutive patients presenting with large pericardial effusions were included in the study. Diagnoses were made according to predetermined criteria, and they included TB (n = 64), malignancy (n = 12), nontuberculous infections (n = 5), other effusions (n = 19), and effusions of uncertain origin (n = 10). The median ADA level in the tuberculous group was 71.7 U/L (range, 10.3 to 303.6 U/L), which was significantly higher than that in any other group (p < 0.05). With a cutoff level for ADA activity of 30 U/L, sensitivity was 94%, specificity was 68%, and positive predictive value was 80%. IFN-gamma levels were determined in 30 subjects. The median IFN-gamma concentration in the tuberculous group was > 1,000 pg/L, which was significantly higher than in any other diagnostic group (p < 0.0005). A cutoff value of 200 pg/L for IFN-gamma resulted in a sensitivity and specificity of 100% for the diagnosis of pericardial TB. CONCLUSION: Pericardial fluid levels of ADA and IFN-gamma are useful in the diagnosis of tuberculous pericarditis.

Role of biochemical tests in the diagnosis of large pericardial effusions.

STUDY OBJECTIVES: To determine the biochemical characteristics of large pericardial effusions in various disease states, and to assess their utility as diagnostic tools. SETTING: An academic university hospital in the Western Cape, South Africa. DESIGN: Consecutive, prospective case series. PATIENTS: One hundred ten hospital patients > 12 years old, who presented to the echocardiography department with large pericardial effusions, and 12 control subjects who underwent open-heart surgery (coronary artery bypass graft or aortic valve replacement). MEASUREMENTS: Fluid was sent for examination of biochemistry, adenosine deaminase, microbiology, hematology, and cytology. The etiology of each pericardial fluid sample was established using predetermined criteria. RESULTS: The biochemistry of pericardial exudates differed significantly from pericardial transudates. Light' s criteria (whereby an exudate is defined as having one or more of the following: pleural fluid/serum protein ratio > 0.5; pleural fluid/serum lactate dehydrogenase [LDH] ratio > 0.6; and/or pleural fluid LDH level > 200 U/L) were applied to pericardial fluids and demonstrated to be the most reliable diagnostic tool for identifying pericardial exudates. The corresponding sensitivity was 98%. CONCLUSION: Although laboratory tests are a useful guideline when assessing the etiology and pathophysiology of pericardial effusions, the majority of large, clinically significant pericardial effusions result from exudative causes.