Hyperlipidemias: Holdaas H

Holdaas H, Fellström B, Jardine AG, Anonymous00166. · No affiliation provided · Am J Transplant. · Pubmed #15888072 No free full text.

This publication has no abstract.

Holdaas H, Wanner C, Abletshauser C, Gimpelewicz C, Isaacsohn J. · Medical Department, National Hospital, University of Oslo, 0027 Oslo, Norway. · Int J Cardiol. · Pubmed #16889855 No free full text.

Abstract: BACKGROUND: Individuals with chronic kidney disease are at high risk for cardiovascular disease and have a high prevalence of hyperlipidemia. Lipid-lowering therapy may help patients with renal disease reduce their risk for cardiovascular events. METHODS: A pooled analysis of 30 completed clinical trials compared the efficacy and safety profiles of fluvastatin in subgroups of patients with moderate to severe renal insufficiency (creatinine clearance < 50 ml/min) and patients with normal renal function or mild renal insufficiency (creatinine clearance > or = 50 ml/min). RESULTS: Changes in lipid parameters with fluvastatin treatment were similar for the compared patient subgroups. Fluvastatin treatment reduced combined cardiac death and myocardial infarction by 41% compared with placebo among patients with moderate to severe renal insufficiency (hazard ratio, 0.59; p=0.007) and by 30% among patients with normal renal function or mild renal insufficiency (hazard ratio, 0.70; p=0.009). The relative reduction in the risk of major adverse cardiac events, a composite endpoint comprising cardiac death, nonfatal myocardial infarction, and coronary intervention procedures, with fluvastatin treatment was not significant for patients with moderate to severe renal insufficiency (hazard ratio, 0.83; p=0.18); in this patient subgroup, the incidence of coronary intervention procedures was similar between treatment groups. The safety profiles were similar for fluvastatin- and placebo-treated patients. CONCLUSIONS: The results of this pooled analysis indicate that fluvastatin is safe and effective for reducing cardiac death and nonfatal myocardial infarction in patients with moderate to severe renal insufficiency. Fluvastatin did not reduce the rate of coronary intervention procedures.

Corsini A, Holdaas H. · Department of Pharmacological Sciences, University of Milan, Milan, Italy. · Ren Fail. · Pubmed #15957541 No free full text.

Abstract: Premature atherosclerotic coronary heart disease driven by multiple risk factors is a major cause of morbidity and mortality among the 6 million patients in the United States with chronic renal failure. Consensus is that kidney failure and renal transplantation patients should be treated aggressively for dyslipidemia. Major medical literature databases were searched for published information about fluvastatin, a HMG-CoA reductase inhibitor, used in patients with impaired renal function. This article characterizes the dyslipidemia observed in these clinical settings and reviews the clinical experience with fluvastatin.

Asberg A, Holdaas H. · Medical Department, National Hospital, Oslo, Norway. · Expert Rev Cardiovasc Ther. · Pubmed #15350166 No free full text.

Abstract: Cardiovascular diseases due to atherosclerosis are the leading causes of mortality in the Western world. Cholesterol-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme Areductase inhibitors (statins) has demonstrated a reduction in cardiovascular morbidity and mortality in diverse populations. Fluvastatin (Lescol, Novartis Pharmaceuticals) was the first totally synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor on the market and has recently become available in an extended-release formulation (Lescol XL, Novartis Pharmaceuticals). Data from several clinical outcome trials have shown substantial benefits from fluvastatin treatment in diverse populations. Fluvastatin exists primarily in its acid form and as inactive metabolites in vivo, while active metabolites as well as the lactone form are only present in small amounts. The demonstration of the safe use of fluvastatin in a wide range of patients may be associated with the predominant acid form of the drug in vivo, as well as its predominant metabolism via the cytochrome P450 2C9 pathway.

Holdaas H, Jardine A. · Department of Medicine, National Hospital, Oslo, Norway. · Minerva Urol Nefrol. · Pubmed #12847415 No free full text.

Abstract: Acute rejection of kidney allografts during the first months following transplantation is one of the most important risk factor for long-term graft failure. Some small open studies have indicated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-Co-A), statins, might act as immunosuppressive agents, and reduce acute rejection rates. Moreover, the use of statin in transplant recipients is quite common, despite no data from prospective large multi-centre studies are available to demonstrate any beneficial effect for acute rejections or long-term cardiovascular protection in this population. In this overview, recent clinical and experimental data will be provided for assessing statins as immunosuppressive agents. Although in vitro studies have provided a theoretical basis for the use of statins as immunosuppressive agents, more recent clinical placebo controlled studies have failed to confirm the initial optimism of this effect of statins.

Fellström BC, Holdaas H, Jardine AG. · Department of Medicine, Western Infirmary, Glasgow, United Kingdom. · Kidney Int Suppl. · Pubmed #12694345 No free full text.

Abstract: BACKGROUND: The risk of cardiovascular complications is markedly increased in patients on dialysis treatment. This includes cardiac disease, stroke, and peripheral vascular disease. The mortality in dialysis patients is markedly higher compared to a nonuremic population. There are several cardiovascular (CV) risk factors that are unique to this population, one of which is dyslipidemia. Uremic patients do not usually develop hypercholesterolemia, but rather are characterized by high levels of very low density lipoprotein (VLDL) triglycerides, low high density lipoprotein (HDL) cholesterol, and elevated levels of modified low density lipoprotein (LDL) particles, which are particularly harmful to the vascular wall. HMG-CoA reductase inhibitors (statins) have been proven to be very efficient in reducing CV events in a nonrenal population. There are several landmark trials that have demonstrated that statins reduce the mortality in cardiovascular disease (CVD) in populations with normal, or close to normal, renal function. There are some observational registry data indicating that this may also be true in hemodialysis (HD) patients, but no prospective controlled trial has been performed to date. METHODS: We present the rationale for, and a brief outline of, a randomized placebo-controlled trial using a novel drug, rosuvastatin, in HD patients, to target cardiovascular events (the AURORA study). This study will include close to 3000 male and female HD patients, aged 50-80 years. The study is event driven and it has been estimated that it will run for a follow-up time close to four years. CONCLUSION: There is a sound rationale for making a randomized placebo-controlled statin trial in HD patients, with the objective to demonstrate an effect on CV mortality and morbidity.

Ballantyne CM, Corsini A, Davidson MH, Holdaas H, Jacobson TA, Leitersdorf E, März W, Reckless JP, Stein EA. · Center for Cardiovascular Disease Prevention, Baylor College of Medicine, 6565 Fannin, Mail Station A601, Suite A656, Houston, TX 77030, USA. · Arch Intern Med. · Pubmed #12622602 links to  free full text

Abstract: Emerging data suggest that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) offer important benefits for the large population of individuals at high risk for coronary heart disease. This population encompasses a sizable portion of individuals who are also at high risk for drug-drug interactions due to their need for multiple medications. In general, statins are associated with a very small risk for myopathy (which may progress to fatal or nonfatal rhabdomyolysis); however, the potential for drug-drug interactions is known to increase this risk in specific high-risk groups. The incidence of myopathy associated with statin therapy is dose related and is increased when statins are used in combination with agents that share common metabolic pathways. Of particular concern is the potential for interactions with other lipid-lowering agents such as fibrates and niacin (nicotinic acid), which may be used in patients with mixed lipidemia, and with immunosuppressive agents, such as cyclosporine, which are commonly used in patients after transplantation. Clinicians should be alert to the potential for drug-drug interactions to minimize the risk of myopathy during long-term statin therapy in patients at high risk for coronary heart disease.

Jardine A, Holdaas H. · Department of Medicine and Therapeutics, Western Infirmary, Glasgow, U.K. · J Clin Pharm Ther. · Pubmed #10651972 No free full text.

Abstract: Cardiovascular disease remains a significant cause of morbidity and mortality in patients who have undergone renal transplantation, with one of the main risk factors being post-transplantation hyperlipidaemia. To date, however, optimal management of elevated lipid levels in such patients has been hindered by the lack of both effective and safe treatments, coupled with concerns over probable interactions with immunosuppressive therapy, particularly cyclosporin. Numerous studies confirm that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, such as fluvastatin, are effective lipid-lowering agents in renal transplant recipients, supporting findings in other patients' groups. Moreover, based on investigations of metabolic profile and clinical observation, fluvastatin (at dosages of up to 80 mg/day) is well tolerated in renal transplant recipients receiving cyclosporin. In clinical trials to date, no instances of rhabdomyolysis have been observed during co-administration of fluvastatin and cyclosporin. The potential of fluvastatin for improving survival in renal transplant recipients, in terms of both cardiovascular mortality and graft rejection, is currently being investigated in two ongoing studies: ALERT (Assessment of Lescol [fluvastatin] in Renal Transplantation) and SOLAR (Study of Lescol [fluvastatin] in Acute Rejection). The results of these landmark studies should confirm the safe utility of fluvastatin in the renal transplantation setting.

Holdaas H, Fellström B, Holme I, Nyberg G, Fauchald P, Jardine A, Grönhagen-Riska C, Madsen S, Neumayer HH, Cole E, Maes B, Weinreich T, Olsson AG, Pedersen TR, Benghozi R, Hartmann A, Anonymous00351. · Department of Medicine, National Hospital, N-0027 Oslo, Norway. · J Cardiovasc Risk. · Pubmed #11324372 No free full text.

Abstract: BACKGROUND: Recent clinical trials of primary and secondary prevention of cardiovascular disease have demonstrated that lowering plasma cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors ('statins') reduces morbidity and mortality from coronary heart disease in diverse patient populations. STUDY AIMS: The aim of the present ALERT (Assessment of Lescol in Renal Transplantation) study is to determine whether renal transplant recipients would also benefit from statin therapy. ALERT is a multicentre, randomized, double-blind, placebo-controlled trial to assess the effect of fluvastatin in renal transplant recipients with mild-to-moderate hypercholesterolaemia. The primary objective is to investigate the effects of fluvastatin on major adverse cardiac events (MACE). In addition, the effects on cardiovascular and all-cause mortality, as well as renal function, will be addressed. STUDY POPULATION: The study population contains patients with functioning renal allografts of more than 6 months' duration, recruited from 75 centres in Northern Europe and Canada. Patients of both sexes, aged 30-75 years, with a total cholesterol level of 4.0-9.0 mmol/l (155-348 mg/dl) were included, except for those with a history of myocardial infarction, where the upper limit for inclusion was 7.0 mmol/l (270 mg/dl). STUDY DESIGN: A total of 2100 patients were recruited by the end of October 1997 and will be followed for up to 6 years. This report presents the design features of the study (recruitment, follow-up, sample size, data analysis and study organization), along with baseline results. ALERT is the first large-scale prospective, randomized, double-blind study to address the prevention of cardiovascular mortality in renal transplant patients receiving an HMGCoA reductase inhibitor.

Soveri I, Holdaas H, Jardine A, Gimpelewicz C, Staffler B, Fellström B. · Department of Medical Sciences, Uppsala University Hospital, entr 40, 75185, Uppsala, Sweden. · Nephrol Dial Transplant. · Pubmed #16574686 links to  free full text

Abstract: BACKGROUND: Renal transplant recipients (RTR) mainly die of premature cardiovascular disease. Traditional cardiovascular disease risk factors are prevalent in RTR. Additionally, non-traditional risk factors seem to contribute to the high risk. The impact of renal dysfunction was compared with traditional risk factors for cardiovascular morbidity and mortality in 1052 placebo-treated patients of the ALERT trial. METHODS: All patients were on cyclosporine-based immunosuppressive therapy, follow-up was 5-6 years and captured endpoints included cardiac death, non-cardiovascular death, all-cause mortality, major adverse cardiac event (MACE), non-fatal myocardial infarction (MI) and stroke. RESULTS: A calculated 84 micromol/l increase in serum creatinine was needed to double the risk for cardiac death, an increase of 104 micromol/l to double the risk for non-cardiovascular death and an increase of 92 micromol/l to double the risk for all-cause mortality. MACE risk was doubled if serum creatinine was elevated by 141 micromol/l, age was increased by 23 years, or LDL-cholesterol by 2 mmol/l. Diabetes increased the incidences of cardiac death, all-cause mortality, MACE, stroke and non-fatal MI. A serum creatinine increase of approximately 130 micromol/l, or approximately 20 years increase in age was calculated as similar in risk for cardiac death, all-cause mortality and MACE, and comparable to risk of diabetes in RTR. CONCLUSION: An increase in serum creatinine of 80-100 micromol/l doubles the risk for cardiac death, non-cardiovascular death and all-cause mortality in RTR. An increase of 130 micromol/l in serum creatinine or approximately 20 years increase in age is comparable to risk of diabetes.

Jardine AG, Fellström B, Logan JO, Cole E, Nyberg G, Grönhagen-Riska C, Madsen S, Neumayer HH, Maes B, Ambühl P, Olsson AG, Pedersen T, Holdaas H. · University of Glasgow, UK. · Am J Kidney Dis. · Pubmed #16129216 No free full text.

Abstract: BACKGROUND: Renal transplantation is associated with an increased risk for premature cardiovascular disease. We analyzed the data in the placebo arm of Assessment of Lescol in Renal Transplantation (ALERT) to improve our understanding of the relationship between cardiovascular risk factors and outcomes in this unique population. METHODS: We performed Cox survival analysis for myocardial infarction, cardiac death, and noncardiac death in 1,052 patients recruited to the placebo arm of ALERT. These subjects were aged 30 to 75 years, had stable graft function at least 6 months after transplantation, had a serum total cholesterol level between 155 and 348 mg/dL (4 and 9 mmol/L), and were receiving cyclosporine-based immunosuppression. RESULTS: The results confirm previous studies. In multivariate analysis, preexisting coronary heart disease (hazard ratio [HR], 3.69; P < 0.001), total cholesterol level (HR, 1.55 per 50 mg/dL; P = 0.0045), and prior acute rejection (HR, 2.36; P = 0.0023) were independent risk factors. Conversely, independent risk factors for cardiac death were age (HR, 1.58 per decade; P = 0.0033), diabetes (HR, 3.35; P = 0.0002), ST-T changes on the ECG (HR, 3.17; P = 0.0004), and serum creatinine level (HR, 2.65 per milligram per deciliter; P < 0.0001). CONCLUSION: This analysis confirms that renal transplant recipients share risk factors for myocardial infarction and cardiac death with the general population. However, the pattern of risk factors and their relationship with outcomes is atypical, highlighting the unique nature of cardiovascular risk in transplant recipients.

Holdaas H, Julian D. · No affiliation provided · Nephrol Dial Transplant. · Pubmed #12147814 links to  free full text

This publication has no abstract.