Anja Vogt

Effect of Intensive Versus Standard Lipid-Lowering Treatment With Atorvastatin on the Progression of Calcified Coronary Atherosclerosis Over 12 Months: A Multicenter, Randomized, Double-Blind Trial

Background— Recent clinical trials have suggested that intensive versus standard lipid-lowering therapy provides for additional benefit. Electron-beam computed tomography provides the opportunity to quantify the progression of coronary artery calcification (CAC) in serial measurements. Methods and Results— In a multicenter, randomized, double-blind trial, 471 patients (age 61±8 years) who had no history of coronary artery disease and no evidence of high-grade coronary stenoses (>50% diameter reduction) were randomized if they had ≥2 cardiovascular risk factors and moderate calcified coronary atherosclerosis as evidenced by a CAC score ≥30. Patients were assigned to receive 80 mg or 10 mg of atorvastatin per day over 12 months. Progression of CAC volume scores could be analyzed in 366 patients. After pretreatment with 10 mg of atorvastatin for 4 weeks, 12 months of study medication reduced LDL cholesterol from 106±22 to 87±33 mg/dL in the group randomized to receive 80 mg of atorvastatin (P<0.001), whereas levels remained stable in the group randomized to receive 10 mg (108±23 at baseline, 109±28 mg/dL at the end of the study, P=NS). The mean progression of CAC volume scores, corrected for the baseline CAC volume score, was 27% (95% CI 20.8% to 33.1%) in the 80-mg atorvastatin group and 25% (95% CI 19.1% to 30.8%) in the 10-mg atorvastatin group (P=0.65). CAC progression showed no relationship with on-treatment LDL cholesterol levels. Conclusions— We did not observe a relationship between on-treatment LDL cholesterol levels and the progression of calcified coronary atherosclerosis. Over a period of 12 months, intensive atorvastatin therapy was unable to attenuate CAC progression compared with standard atorvastatin therapy. The possibility remains that the time window was too short to demonstrate an effect.

Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events.

Background We investigated in a longitudinal, multicenter, cohort study whether combined lipid apheresis and lipid-lowering medication can reduce extremely high levels of lipoprotein(a) (Lp[a]) and thus prevent major adverse coronary events (MACE) more efficaciously than lipid-lowering medication alone.Methods Eligible patients had coronary artery disease and Lp(a) levels ≥2.14 µmol/l (95th percentile). All patients received lipid-lowering medications alone until maximally tolerated doses were no longer effective, followed by combined lipid apheresis and lipid-lowering medication. The rates of the primary outcome, MACE, were recorded for both periods.Results A total of 120 patients were included. The mean duration of lipid-lowering therapy alone was 5.6±5.8 years, and that of apheresis was 5.0±3.6 years. Median Lp(a) concentration was reduced from 4.00 µmol/l to 1.07 µmol/l with apheresis treatment (P<0.0001); the corresponding mean annual MACE rate per patient was 1.056 versus 0.144 (P<0.0001).Conclusions Lowering of Lp(a) levels by apheresis was efficacious and safe, and we recommend this therapy for patients in whom maximally tolerated doses of medication alone have failed to control coronary artery disease-associated events.

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.

Dyslipidemia in primary care – prevalence, recognition, treatment and control: data from the German Metabolic and Cardiovascular Risk Project (GEMCAS)

BackgroundCurrent guidelines from the European Society of Cardiology (ESC) define low thresholds for the diagnosis of dyslipidemia using total cholesterol (TC) and LDL-cholesterol (LDL-C) to guide treatment. Although being mainly a prevention tool, its thresholds are difficult to meet in clinical practice, especially primary care.MethodsIn a nationwide study with 1,511 primary care physicians and 35,869 patients we determined the prevalence of dyslipidemia, its recognition, treatment, and control rates. Diagnosis of dyslipidemia was based on TC and LDL-C. Basic descriptive statistics and prevalence rate ratios, as well as 95% confidence intervals were calculated.ResultsDyslipidemia was highly frequent in primary care (76% overall). 48.6% of male and 39.9% of female patients with dyslipidemia was diagnosed by the physicians. Life style intervention did however control dyslipidemia in about 10% of patients only. A higher proportion (34.1% of male and 26.7% female) was controlled when receiving pharmacotherapy. The chance to be diagnosed and subsequently controlled using pharmacotherapy was higher in male (PRR 1.15; 95%CI 1.12–1.17), in patients with concomitant cardiovascular risk factors, in patients with hypertension (PRR 1.20; 95%CI 1.05–1.37) and cardiovascular disease (PRR 1.46; 95%CI 1.29–1.64), previous myocardial infarction (PRR 1.32; 95%CI 1.19–1.47), and if patients knew to be hypertensive (PRR 1.18; 95%CI 1.04–1.34) or knew about their prior myocardial infarction (PRR 1.17; 95%CI 1.23–1.53).ConclusionThresholds of the ESC seem to be difficult to meet. A simple call for more aggressive treatment or higher patient compliance is apparently not enough to enhance the proportion of controlled patients. A shift towards a multifactorial treatment considering lifestyle interventions and pharmacotherapy to reduce weight and lipids may be the only way in a population where just to be normal is certainly not ideal.

Single lipoprotein apheresis session improves cardiac microvascular function in patients with elevated lipoprotein(a): detection by stress/rest perfusion magnetic resonance imaging.

The aim of this study was to explore the effects of a single lipoprotein apheresis session on myocardial stress/rest (S/R) perfusion in patients with elevated lipoprotein(a) (Lp(a)) and coronary artery disease using cardiac magnetic resonance imaging. Twenty patients with Lp(a) > 60 mg/dL and coronary artery disease were randomized into a control or a treatment group. Both groups underwent cardiac magnetic resonance imaging with assessment of left ventricular function, perfusion and viability, and the treatment group underwent lipoprotein apheresis immediately afterwards. Repeat magnetic resonance imaging was performed at 24 h for both groups and at 96 h for just the treatment group. The transmyocardial perfusion gradient (i.e. endo‐epi ratio [EER]) was determined and a comprehensive parameter of resting and adenosine‐induced stress perfusion was derived (EER‐S/R). While the hematocrit remained unchanged, apheresis reduced lipoproteins and rheological parameters: Lp(a) − 55.1%, total cholesterol − 34.5%, low density lipoprotein (LDL) − 54.6%, Lp(a)‐corrected LDL − 54.3%, high density lipoprotein − 17.4%, apolipoprotein B − 39.2%, plasma viscosity − 10.7%, and fibrinogen − 30.6% at 24 h (P < 0.05 for all). At 96 h these parameters, except for plasma viscosity, apolipoprotein B and Lp(a)‐corrected LDL, recovered but did not reach baseline values (P < 0.05 for all). The EER‐S/R at 24 h was lowered by therapy (ΔEER‐S/R 5%; P < 0.03), whereas this effect disappeared at 96 h. The ejection fraction (EF) was slightly improved at 24 h (67.07 ± 6.28% vs. 64.89 ± 6.39%; ΔEF 2.2%, P < 0.05) and returned to baseline at 96 h. In the control group no corresponding changes were detected. In conclusion, cardiac magnetic resonance imaging detects subtle treatment‐related changes in regional myocardial perfusion in patients with elevated Lp(a) and coronary artery disease undergoing lipoprotein apheresis.

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.

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

Response to Letter Regarding Article, “Effect of Intensive Versus Standard Lipid-Lowering Treatment With Atorvastatin on the Progression of Calcified Coronary Atherosclerosis Over 12 Months: A Multicenter, Randomized, Double-Blind Trial”

We thank Drs Romanens and Miserez for their interest in our study.1 We completely agree with their conclusion that our study cannot be used to argue against the predictive ability of coronary artery calcification (CAC) scores regarding cardiovascular events. The predictive ability of CAC has been demonstrated in numerous studies (please see References 14 and 23 in our article for further reading), and it should be viewed independent of the progression of CAC over 12 months under the effects of lipid-lowering therapy with different intensity. The statistical power calculations underlying our …