David R. Sullivan

Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels

BACKGROUND In patients with coronary heart disease and a broad range of cholesterol levels, cholesterol-lowering therapy reduces the risk of coronary events, but the effects on mortality from coronary heart disease and overall mortality have remained uncertain. METHODS In a double-blind, randomized trial, we compared the effects of pravastatin (40 mg daily) with those of a placebo over a mean follow-up period of 6.1 years in 9014 patients who were 31 to 75 years of age. The patients had a history of myocardial infarction or hospitalization for unstable angina and initial plasma total cholesterol levels of 155 to 271 mg per deciliter. Both groups received advice on following a cholesterol-lowering diet. The primary study outcome was mortality from coronary heart disease. RESULTS Death from coronary heart disease occurred in 8.3 percent of the patients in the placebo group and 6.4 percent of those in the pravastatin group, a relative reduction in risk of 24 percent (95 percent confidence interval, 12 to 35 percent; P<0.001). Overall mortality was 14.1 percent in the placebo group and 11.0 percent in the pravastatin group (relative reduction in risk, 22 percent; 95 percent confidence interval, 13 to 31 percent; P<0.001). The incidence of all cardiovascular outcomes was consistently lower among patients assigned to receive pravastatin; these outcomes included myocardial infarction (reduction in risk, 29 percent; P<0.001), death from coronary heart disease or nonfatal myocardial infarction (a 24 percent reduction in risk, P<0.001), stroke (a 19 percent reduction in risk, P=0.048), and coronary revascularization (a 20 percent reduction in risk, P<0.001). The effects of treatment were similar for all predefined subgroups. There were no clinically significant adverse effects of treatment with pravastatin. CONCLUSIONS Pravastatin therapy reduced mortality from coronary heart disease and overall mortality, as compared with the rates in the placebo group, as well as the incidence of all prespecified cardiovascular events in patients with a history of myocardial infarction or unstable angina who had a broad range of initial cholesterol levels.

Effect of a Monoclonal Antibody to PCSK9 on Low-Density Lipoprotein Cholesterol Levels in Statin-Intolerant Patients: The GAUSS Randomized Trial

CONTEXT An estimated 10% to 20% of patients cannot tolerate statins or adequate doses to achieve treatment goals. Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, promoting their degradation and increasing LDL cholesterol levels. In phase 1 studies, a human monoclonal antibody to PCSK9, AMG145, was well tolerated and reduced LDL cholesterol levels. OBJECTIVE To assess the efficacy and tolerability of AMG145 in patients with statin intolerance due to muscle-related side effects. DESIGN, SETTING, AND PATIENTS A 12-week, randomized, double-blind, placebo- and ezetimibe-controlled, dose-ranging study conducted between July 2011 and May 2012 in statin-intolerant adult patients at 33 international sites. INTERVENTION Patients were randomized equally to 1 of 5 groups: AMG145 alone at doses of 280 mg, 350 mg, or 420 mg; AMG145 at 420 mg plus 10 mg of ezetimibe; or 10 mg of ezetimibe plus placebo. AMG145 or placebo was administered subcutaneously every 4 weeks. MAIN OUTCOME MEASURES The primary end point was percentage change from baseline to week 12 in ultracentrifugation-measured LDL cholesterol. Other end points included measures of safety and tolerability of different doses of AMG145 and AMG145 plus ezetimibe. RESULTS Of 236 patients screened, 160 were randomized (mean age, 62 years; 64% female; mean baseline LDL cholesterol, 193 mg/dL); all patients had intolerance to 1 or more statins because of muscle-related events. At week 12, mean changes in LDL cholesterol levels were -67 mg/dL (-41%; 95% CI, -49% to -33%) for the AMG145, 280-mg, group; -70 mg/dL (-43%; 95% CI, -51% to -35%) for the 350-mg group; -91 mg/dL (-51%; 95% CI, -59% to -43%) for the 420-mg group; and -110 mg/dL (-63%; 95% CI, -71% to -55%) for the 420-mg/ezetimibe group compared with -14 mg/dL (-15%; 95% CI, -23% to -7.0%) for the placebo/ezetimibe group (P < .001). Four serious adverse events were reported with AMG145 (coronary artery disease, acute pancreatitis, hip fracture, syncope). Myalgia was the most common treatment-emergent adverse event during the study, occurring in 5 patients (15.6%) in the 280-mg group (n = 32); 1 patient (3.2%) in the 350-mg group (n = 31), 1 patient (3.1%) in the 420-mg group (n = 32), 6 patients (20.0%) receiving 420-mg AMG145/ezetimibe, and 1 patient (3.1%) receiving placebo/ezetimibe. CONCLUSION In this phase 2 study in statin-intolerant patients, subcutaneous administration of a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels and was associated with short-term tolerability. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01375764.

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.

A new method of scoring coronary angiograms to reflect extent of coronary atherosclerosis and improve correlation with major risk factors

We developed a new angiographic score of the extent of coronary disease (extent score), which we compared with conventional stenosis and vessel scores that emphasize the severity of stenosis. Scores were determined in 132 patients (29 women, 103 men with a mean age of 55 +/- 10 years) who underwent elective coronary angiography. Risk factors were more closely related to the extent score than to either the stenosis or vessel scores (Total R2 = 0.35 versus 0.28 (p less than 0.001) and 0.25 (p less than 0.001), respectively). The extent score was more closely related to age (r = 0.30, p less than 0.05), than was either stenosis (r = 0.21 ns) or vessel score (r = 0.26, p less than 0.05). Apolipoprotein B was the strongest predictor of both extent and stenosis scores but was more closely related to the extent score (r = 0.36, p less than 0.05), even after correction for age and gender. This new angiographic score that assesses the extent of coronary disease is simple to perform and correlates better with age and lipoprotein risk factors than conventional scores do.

Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remain undetected and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non-cholesterol risk factors, and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgement and be adjusted for country-specific and local health care needs and resources.

A multicenter, double-blind, one-year study comparing safety and efficacy of atorvastatin versus simvastatin in patients witb hypercholesterolemia☆

We directly compared the safety and efficacy of atorvastatin and simvastatin in hypercholesterolemic patients. This 1-year, randomized, double-blind study was performed at 9 community- and university-based research hospitals in Australia. One-hundred seventy-seven patients between the ages of 18 and 80 years with baseline low-density-lipoprotein (LDL) cholesterol ≤4.14 and ≤7.76 mmol/L (160 and 300 mg/dl, respectively) and triglycerides ≤4.52 mmol/L (400 mg/dl) received once-daily dosing with atorvastatin (Lipitor) 10 mg or simvastatin (Zocor) 10 mg. At week 16, the dose of medication was titrated to atorvastatin 20 mg or simvastatin 20 mg if patients did not meet LDL cholesterol target of ≤ 3.36 mmol/L (130 mg/dl). Efficacy was reported as percent change from baseline in LDL cholesterol, total cholesterol, very low density lipoprotein cholesterol, total triglycerides, high-density lipoprotein cholesterol, apolipoproteins Al and B, and lipoprotein(a). Atorvastatin caused significantly greater reductions from baseline than did simvastatin for LDL cholesterol, total cholesterol, very low density lipoprotein cholesterol, triglycerides, and apolipoprotein B (p <0.05). No patient in either treatment group had clinically important elevations in creatine phosphokinase, alanine amino-transaminase, or aspartate aminotransaminase. No serious adverse events were considered associated with treatment. With atorvastatin 10 mg, 46% of the patients achieved LDL cholesterol target goal by week 16, whereas only 27% of the simvastatin patients achieved the target goal at the 10-mg dose. This cholesterol-lowering profile affords utility in many patient types.

Efficacy and Safety of Longer-Term Administration of Evolocumab (AMG 145) in Patients With Hypercholesterolemia 52-Week Results From the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) Randomized Trial

Background— Evolocumab (AMG 145), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) in phase 2 studies of 12 weeks’ duration. The longer-term efficacy and safety of PCSK9 inhibition remain undefined. Methods and Results— Of 1359 randomized and dosed patients in the 4 evolocumab phase 2 parent studies, 1104 (81%) elected to enroll into the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study. Regardless of their treatment assignment in the parent study, patients were randomized 2:1 to receive either open-label subcutaneous evolocumab 420 mg every 4 weeks with standard of care (SOC) (evolocumab+SOC, n=736) or SOC alone (n=368). Ninety-two percent of patients in the evolocumab+SOC group and 89% of patients in the SOC group completed 52 weeks of follow-up. Patients who first received evolocumab in OSLER experienced a mean 52.3% [SE, 1.8%] reduction in LDL-C at week 52 (P<0.0001). Patients who received 1 of 6 dosing regimens of evolocumab in the parent studies and received evolocumab+SOC in OSLER had persistent LDL-C reductions (mean reduction, 50.4% [SE, 0.8%] at the end of the parent study versus 52.1% [SE, 1.0%] at 52 weeks; P=0.31). In patients who discontinued evolocumab on entry into OSLER, LDL-C levels returned to near baseline levels. Adverse events and serious adverse events occurred in 81.4% and 7.1% of the evolocumab+SOC group patients and 73.1% and 6.3% of the SOC group patients, respectively. Conclusion— Evolocumab dosed every 4 weeks demonstrated continued efficacy and encouraging safety and tolerability over 1 year of treatment in the largest and longest evaluation of a PCSK9 inhibitor in hypercholesterolemic patients to date. Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique identifier: NCT01439880.Background— Evolocumab (AMG 145), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) in phase 2 studies of 12 weeks’ duration. The longer-term efficacy and safety of PCSK9 inhibition remain undefined. Methods and Results— Of 1359 randomized and dosed patients in the 4 evolocumab phase 2 parent studies, 1104 (81%) elected to enroll into the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study. Regardless of their treatment assignment in the parent study, patients were randomized 2:1 to receive either open-label subcutaneous evolocumab 420 mg every 4 weeks with standard of care (SOC) (evolocumab+SOC, n=736) or SOC alone (n=368). Ninety-two percent of patients in the evolocumab+SOC group and 89% of patients in the SOC group completed 52 weeks of follow-up. Patients who first received evolocumab in OSLER experienced a mean 52.3% [SE, 1.8%] reduction in LDL-C at week 52 ( P <0.0001). Patients who received 1 of 6 dosing regimens of evolocumab in the parent studies and received evolocumab+SOC in OSLER had persistent LDL-C reductions (mean reduction, 50.4% [SE, 0.8%] at the end of the parent study versus 52.1% [SE, 1.0%] at 52 weeks; P =0.31). In patients who discontinued evolocumab on entry into OSLER, LDL-C levels returned to near baseline levels. Adverse events and serious adverse events occurred in 81.4% and 7.1% of the evolocumab+SOC group patients and 73.1% and 6.3% of the SOC group patients, respectively. Conclusion— Evolocumab dosed every 4 weeks demonstrated continued efficacy and encouraging safety and tolerability over 1 year of treatment in the largest and longest evaluation of a PCSK9 inhibitor in hypercholesterolemic patients to date. Clinical Trial Registration— URL: . Unique identifier: [NCT01439880][1]. # CLINICAL PERSPECTIVE {#article-title-27} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01439880&atom=%2Fcirculationaha%2F129%2F2%2F234.atom

Oral L-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary artery disease.

L-Arginine is the physiological substrate for nitric oxide synthesis by the vascular endothelium. In hypercholesterolaemic rabbits, oral L-arginine reduces atheroma, improves endothelium-dependent dilatation and reduces monocyte/endothelial cell adhesion. The effect of oral L-arginine on endothelial physiology is unknown, however, in humans with established atherosclerosis. In a prospective, double-blind, randomised crossover trial, ten men aged 41 +/- 2 years with angiographically proven coronary atherosclerosis took L-arginine (7 g three times per day) or placebo for 3 days each, with a washout period of 10 days. After L-arginine, compared to placebo, plasma levels of arginine were increased (318 +/- 18 vs. 124 +/- 9 mumol/l, P < 0.01) and endothelium-dependent dilatation of the brachial artery (measured as the change in diameter in response to reactive hyperaemia, using external vascular ultrasound) was improved (4.7 +/- 1.1 vs. 1.8 +/- 0.7%, P < 0.04). No changes were seen in endothelium-independent dilatation of the brachial artery (measured as the change in diameter in response to sublingual nitroglycerine), blood pressure, heart rate or fasting lipid levels. Serum from six of the ten subjects after L-arginine and placebo was then added to confluent monolayers of human umbilical vein endothelial cells for 24 h, before human monocytes obtained by countercurrent centrifiguation elutriation were added and cell adhesion assessed by light microscopy. Adhesion was reduced following L-arginine compared to placebo (42 +/- 2 vs. 50 +/- 1%, P < 0.01). In young men with coronary artery disease, oral L-arginine improves endothelium-dependent dilatation and reduces monocyte/endothelial cell adhesion.

Cholesterol-lowering effects of plant sterol esters differ in milk, yoghurt, bread and cereal.

Objective: To measure the relative effects of each of four phytosterol ester-enriched low-fat foods (bread, breakfast cereal, milk and yoghurt) on serum lipids, plasma phytosterols and carotenoids.Design: Three research centres undertook a randomised, incomplete crossover, single-blind study consisting of four treatment periods of 3 weeks each, one of which was a control period. Each sterol-enriched test food provided 1.6 g/day of phytosterols as sterol esters.Setting: General Community.Subjects: In all 58, free-living men and women with mean age (s.d.) 54 (8) y, moderately elevated plasma total cholesterol 6.2 (0.7) mmol/l and body mass index 26.2 (3.0) kg/m2.Main outcome measures: Serum lipids, plasma phytosterols and carotenoids.Results: Serum total and LDL cholesterol levels were significantly lowered by consumption of phytosterol-enriched foods: milk (8.7 and 15.9%) and yoghurt (5.6 and 8.6%). Serum LDL cholesterol levels fell significantly by 6.5% with bread and 5.4% with cereal. They were both significantly less efficacious than sterol-enriched milk (P<0.001). Plasma sitosterol increased by 17–23% and campesterol by 48–52% with phytosterol-enriched milk and bread. Lipid-adjusted β-carotene was lowered by 5–10% by sterols in bread and milk, respectively.Conclusions: This is the first study to demonstrate that cholesterol-lowering effects of plant sterol esters may differ according to the food matrix. Plant sterols in low-fat milk was almost three times more effective than in bread and cereal. Despite phytosterol-enriched cereal products resulting in lower serum cholesterol reductions compared to sterol-enriched milk, the detection of similar changes in plasma phytosterols demonstrated that such products still delivered and released phytosterols to the gut.

Plasma PCSK9 Concentrations Correlate with LDL and Total Cholesterol in Diabetic Patients and Are Decreased by Fenofibrate Treatment

BACKGROUND Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the LDL receptor (LDLr) in hepatocytes, and its expression in mouse liver has been shown to decrease with fenofibrate treatment. METHODS We developed a sandwich ELISA using recombinant human PCSK9 protein and 2 affinity-purified polyclonal antibodies directed against human PCSK9. We measured circulating PCSK9 concentrations in 115 diabetic patients from the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study before and after fenofibrate treatment. RESULTS We found that plasma PCSK9 concentrations correlate with total (r = 0.45, P = 0.006) and LDL (r = 0.54, P = 0.001) cholesterol but not with triglycerides or HDL cholesterol concentrations in that cohort. After 6 weeks of treatment with comicronized fenofibrate (200 mg/day), plasma PCSK9 concentrations decreased by 8.5% (P = 0.041 vs pretreatment). This decrease correlated with the efficacy of fenofibrate, as judged by a parallel reduction in plasma triglycerides (r = 0.31, P = 0.015) and LDL cholesterol concentrations (r = 0.27, P = 0.048). CONCLUSIONS We conclude that this decrease in PCSK9 explains at least in part the LDL cholesterol-lowering effects of fenofibrate. Fenofibrate might be of interest to further reduce cardiovascular risk in patients already treated with a statin.