Ulrike Hostalek

Efficacy of vitamin D3 as add-on therapy in patients with relapsing–remitting multiple sclerosis receiving subcutaneous interferon beta-1a: A Phase II, multicenter, double-blind, randomized, placebo-controlled trial

Recent studies have demonstrated the immunomodulatory properties of vitamin D, and vitamin D deficiency may be a risk factor for the development of MS. The risk of developing MS has, in fact, been associated with rising latitudes, past exposure to sun and serum vitamin D status. Serum 25-hydroxyvitamin D [25(OH)D] levels have also been associated with relapses and disability progression. The identification of risk factors, such as vitamin D deficiency, in MS may provide an opportunity to improve current treatment strategies, through combination therapy with established MS treatments. Accordingly, vitamin D may play a role in MS therapy. Small clinical studies of vitamin D supplementation in patients with MS have reported positive immunomodulatory effects, reduced relapse rates and a reduction in the number of gadolinium-enhancing lesions. However, large randomized clinical trials of vitamin D supplementation in patients with MS are lacking. SOLAR (Supplementation of VigantOL(®) oil versus placebo as Add-on in patients with relapsing-remitting multiple sclerosis receiving Rebif(®) treatment) is a 96-week, three-arm, multicenter, double-blind, randomized, placebo-controlled, Phase II trial (NCT01285401). SOLAR will evaluate the efficacy of vitamin D(3) as add-on therapy to subcutaneous interferon beta-1a in patients with RRMS. Recruitment began in February 2011 and is aimed to take place over 1 calendar year due to the potential influence of seasonal differences in 25(OH)D levels.

Evaluation of the safety and tolerability of prolonged-release nicotinic acid in a usual care setting: the NAUTILUS study

ABSTRACT Objective: The main objective was to evaluate the safety and tolerability of prolonged-release nicotinic acid (niacin; Niaspan*) in an usual care setting with patients receiving treatment for dyslipidaemia in Germany: the multiceNtre, open, uncontrolled sAfety and tolerability stUdy of a modified-release nicoTinic acId formuLation in sUbjects with dySlipidaemia and low HDL-cholesterol (NAUTILUS). * Niaspan is a registered trade name of Merck KGaA, Darmstadt, Germany Research design and methods: This was a multicentre, open-label, 15‐week study. Eligible patients had a diagnosis of dyslipidaemia with lipids inadequately controlled by 4 weeks of diet treatment. Additionally, patients had low HDL-cholesterol (< 1.03 mmol/L [< 40 mg/dL]) in men and < 1.29 mmol/L [< 50 mg/dL] in women), and had triglycerides < 9.03 mmol/L (< 800 mg/dL). Exclusion criteria included uncontrolled diabetes (HbA1C > 9%), significant hepatic, vascular or renal disease. The target dose was 2000 mg once daily. Main outcome measures: The main objective was to evaluate the safety and tolerability of prolonged-release nicotinic acid [incidence of adverse events (AE) and serious AE] in the overall population (the safety population). Efficacy parameters (lipid parameters) were also measured in the intent-to-treat population. Results: A total of 566 patients were recruited, mostly with metabolic syndrome (39.4%), mixed hypercholesterolaemia (31.6%), isolated low HDL-cholesterol and markedly elevated cardiovascular risk for other reasons (10.8%), and primary hypercholesterolaemia (8.8%), according to NCEP/ATP III guidelines. The target dose was achieved by 65% of patients. Flushing was the most common side-effect (42%), as expected, and 9.7% withdrew for flushing. Other drug-related AEs occurred at low frequency (18.6%), and 8.7% withdrew for an AE other than flushing. Most AEs were mild or moderate in severity. Serious AEs considered possibly related to treatment occurred in three patients (0.5%); all resolved following treatment withdrawal. There was no hepatotoxicity or serious muscle AE. Conclusions: Prolonged-release nicotinic acid was well tolerated, and these results support its use in the management of patients at elevated cardiovascular risk due to low HDL-cholesterol.

Safety and tolerability of prolonged-release nicotinic acid in statin-treated patients

ABSTRACT Objective: To evaluate the safety and tolerability of prolonged-release nicotinic acid (Niaspan*) added to statin therapy in patients at increased cardiovascular risk. Methods: This was a 6-month, prospective, observational, multicentre, open-label evaluation of prolonged-release nicotinic acid (maximum dose 2000 mg/day) in statin-treated patients with cardiovascular disease and/or type 2 diabetes. The primary endpoint was the safety and tolerability of prolonged-release nicotinic acid, with special regard to treatment-related adverse drug reactions (ADRs). Secondary endpoints were changes in lipids and 10-year cardiovascular risk (Prospective Cardiovascular Münster (PROCAM) score). Results: The study population included 1053 patients: 50% had hypertension, diabetes and/or metabolic syndrome (National Cholesterol Education Program/Adult Treatment Panel III criteria) and 80% had cardiovascular disease. Flushing (mostly mild or moderate) occurred in 430 patients (40.8%). Other ADRs occurred in 125 patients (12.5%), most commonly pruritus (2.7%), gastrointestinal symptoms (3.8%) and nervous system-related complaints (3.8%). Serious ADRs were uncommon (0.6%). All patients recovered completely from these ADRs after treatment discontinuation. In total, 11.1% of the patients discontinued study medication for flushing and 8.4% for other ADRs. There was no evidence of hepatotoxicity or myopathy. New-onset hyperglycaemia was negligible. Overall tolerability of prolonged-release nicotinic acid treatment (n = 734 patients at closeout) was ‘very good’ in 130 (17.7%), ‘good’ in 262 (35.7%), and ‘acceptable’ in 144 (19.6%) patients. High-density lipoprotein (HDL) cholesterol increased by 23%, triglycerides decreased by 15% and LDL-C decreased by 4%. Conclusions: Prolonged-release nicotinic acid was safe and generally well tolerated and effective in combination with statin therapy in patients at high risk of cardiovascular events, with a side-effect profile consistent with previous clinical experience.

Prolonged-release nicotinic acid for the management of dyslipidemia: an update including results from the NAUTILUS study

Low HDL-cholesterol (<1.02 mmol/L [40 mg/dL] in men or <1.29 mmol/L [50 mg/dL] in women) occurs in about one-third of European patients with dyslipidemia and is an independent cardiovascular risk factor. Simultaneous correction of low HDL-cholesterol and high total-cholesterol and LDL-cholesterol may provide reductions in cardiovascular morbidity and mortality beyond those possible with statins alone. Nicotinic acid (niacin in the US) is the most effective means of increasing HDL-cholesterol available and has been shown to reduce cardiovascular event rates significantly. Niaspan® (prolonged-release nicotinic acid) provides a convenient, once-daily means of administering nicotinic acid. Clinical studies with Niaspan® have demonstrated marked, long-term increases in HDL-cholesterol with additional useful benefits on triglycerides, LDL-cholesterol, and lipid sub-profiles. The NAUTILUS study demonstrated the beneficial efficacy and tolerability profiles of Niaspan® in a usual-care setting. The most common side-effect of Niaspan® is flushing, which infrequently causes treatment discontinuation and which usually subsides over continued treatment. The ARBITER 2 and ARBITER 3 studies showed 1–2 years of treatment with Niaspan® plus a statin induced regression of atherosclerosis in patients with coronary artery disease. The effect of Niaspan®-statin treatment, relative to a statin alone, on clinical cardiovascular outcomes is currently under evaluation. Niaspan® represents a practical means of correcting low HDL-cholesterol, an independent risk factor for adverse cardiovascular outcomes.

Correction of low HDL cholesterol to reduce cardiovascular risk: practical considerations relating to the therapeutic use of prolonged‐release nicotinic acid (Niaspan®)

Background:  Substantial residual cardiovascular risk persists despite effective LDL lowering treatment in populations at elevated risk for adverse cardiovascular outcomes. Low HDL cholesterol is an independent cardiovascular risk factor and occurs in about one‐third of patients treated for dyslipidaemia in Europe. Moreover, randomised intervention studies have shown that increasing HDL cholesterol improves cardiovascular outcomes. Correcting low HDL cholesterol therefore presents a rational and proven strategy for intervention to produce further reductions in cardiovascular risk beyond those possible with a statin alone. Nicotinic acid (niacin in the USA) is the most effective agent currently available for increasing levels of HDL cholesterol.

Hydrogen Cyanide Poisoning in a Prison Environment: A Case Report

Cyanide poisoning is an important source of morbidity and mortality from smoke exposure in structural fires. This case involved administration of a cyanide antidote to a prisoner (male, 23 years) in France, discovered in cardiorespiratory arrest after about 30 minutes exposure to smoke from a burning mattress during an apparent suicide attempt. Smoke exposure, circulatory failure during initial resuscitation, and elevated blood cyanide and lactate led to the diagnosis of cyanide poisoning. Hydroxocobalamin (Cyanokit®, 5 g intravenous) was given immediately and on arrival at the hospital. Cardiopulmonary resuscitation restored cardiovascular function after 33 minutes. There were no neurological or other sequelae. Timely hydroxocobalamin administration contributed to full recovery from cardiorespiratory arrest secondary to cyanide poisoning from smoke inhalation. Hydroxocobalamin should be available to emergency medical teams attending fire scenes.

Prolonged-Release Nicotinic Acid in Patients with Atherosclerotic Disease in The Netherlands

Objectives: High-density lipoprotein (HDL) cholesterol elevation is associated with an improved outcome in patients with atherosclerotic disease. Niaspan®, a prolonged-release nicotinic acid, was evaluated during the Niaspan-Induced HDL Elevation for Optimizing Risk Control (NEMO) study in The Netherlands. Methods: NEMO was a 6-month, prospective, observational, multicentre, open-label study. Niaspan was prescribed in statin-treated patients with known or suspected atherosclerotic disease. The main outcome measures were treatment-related adverse drug reactions (ADRs) and effects on lipids and cardiovascular-risk score based on the algorithm derived from the Prospective Cardiovascular Münster study. Results: 612 patients were included in The Netherlands. Flushing was the most common ADR (29% of patients during the first month of treatment). The main reasons for treatment discontinuation were flushing (10.5%), patient request (8.0%) and being lost to follow-up (6.0%). About half of all patients (52%) continued treatment after the study. Tolerability was rated ‘good’ or ‘very good’ in 54% of these patients. HDL cholesterol increased by 23% from baseline, and triglycerides were reduced by 16%, with little change in low-density lipoprotein or total cholesterol. Cardiovascular risk score was reduced by 3.3 points. Conclusions: The use of the prolonged-release nicotinic acid Niaspan in patients with or at risk for atherosclerotic disease showed good tolerability, a marked increase in HDL cholesterol and a reduced cardiovascular risk score.

Influence of the timing of low-dose aspirin on tolerability of prolonged-release nicotinic acid in patients at elevated cardiovascular risk

ABSTRACT Objectives: To investigate the effect of low-dose aspirin administered in the morning or evening on the rate of discontinuation of prolonged-release nicotinic acid (Niaspan*) due to flushing in patients at elevated cardiovascular risk. Research design and methods: This was an observational, non-interventional study in patients at elevated cardiovascular risk due to cardiovascular disease or type 2 diabetes. Patients received prolonged-release nicotinic acid and aspirin under the usual care of their physician for 15 weeks. Main outcome measures: The main outcome measure was the rate of treatment discontinuation for flushing. Other adverse drug reactions (ADRs) were also recorded. Lipid parameters were also measured. Results: The patient population included 539 subjects (70% male); 36% had type 2 diabetes, 80% had prior cardiovascular disease, and 37% had a family history of cardiovascular disease. The rate of treatment discontinuation due to flushing did not differ ( p = 0.3375) between the morning aspirin group (10.6%) and the evening aspirin group (13.8%). The overall incidence of flushing was 57%. Most flushes were of mild or moderate severity and decreases occurred over time in both frequency and intensity. ADRs unrelated to flushing occurred in 6.6% of the morning aspirin group and 7.4% of the evening aspirin group. HDL-cholesterol increased by +21.3% in the overall population, together with moderate improvements in other lipid parameters. Conclusions: Flushing was the most common ADR with prolonged-release nicotinic acid treatment, as expected. The timing of aspirin administration did not influence the rate of treatment discontinuations for flushing. Marked increases in HDL-cholesterol were observed.

NAUTILUS (Safety and tolerability of Niaspan® ): a subgroup analysis in patients with diabetes

The multiceNtre, open, uncontrolled sAfety and tolerability stUdy of a modified-release nicoTinic acId formuLation in sUbjects with dySlipidaemia and low HDL-cholesterol (NAUTILUS) trial was designed to evaluate the safety and tolerability of prolongedrelease nicotinic acid (Niaspan®) in patients treated for dyslipidaemia in a usual care setting in Germany. The dyslipidaemia was inadequately controlled by diet, including low high-density lipoprotein cholesterol (HDL-C) (< 1.0 mmol/L [< 40 mg/dL] in men and < 1.2 mmol/L [<46 mg/dL] in women). This analysis focuses on the tolerability and safety of Niaspan® in patients with diabetes. Diabetic and non-diabetic subjects reported similar incidences of all-cause adverse events (AE; 59.9% vs. 60.8%, respectively), serious AE (SAE; 4.0% vs. 3.4%, respectively) and withdrawals for AE (17.6% vs. 16.4%). Flushing was the most common side effect, as expected (42% of patients in each group), but < 10% withdrew for flushing. There was no indication of hepatotoxicity or serious muscle toxicity in diabetic or non-diabetic subjects. Changes in glycaemic parameters were small (mean changes in diabetic subjects of +0.2% HbA1C and +0.4 mmol/L [+8 mg/dL] for fasting plasma glucose), despite marked reductions in the intensity of antidiabetic therapy in about one third of patients. Niaspan® was equally effective in diabetic or non-diabetic subjects in increasing HDL-C (+24% in each group) and decreasing triglycerides (-12% and -13%, respectively). Niaspan® was well tolerated in patients with type 2 diabetes and the results of NAUTILUS support its use for correction of low HDL-C in this population. Br J Diabetes Vasc Dis 2006;6:127‐33