Contrast-induced adverse drug reactions (ADRs), including contrast-induced nephropathy (renal ins... more Contrast-induced adverse drug reactions (ADRs), including contrast-induced nephropathy (renal insufficiency and diabetes), are common among high-risk patients (e.g., patients with diabetes mellitus and renal impairment). These ADRs cause extended hospital stays and additional medication use which lead to increased costs. We examine the cost-effectiveness of the use of 2 contrast media in patients at high risk for contrast-induced nephropathy. METHODS: A decision-analytic model was constructed to estimate the cost-effectiveness of an isosmolar contrast agent, iodixanol, compared to a low-osmolar contrast medium, iohexol, in the UK. Particular emphasis of the model was to avert the incidence of severe ADRs in patients at risk of contrast-induced nephropathy. The analysis is based on a European multi-centre randomised controlled trial, the NEPHRIC trial, of patients receiving iodixanol versus ohexol in which a statistically significant reduction in the incidence of severe ADRs in favour of iodixanol occurred. Patients in the study were adults 18 years of age or older referred for coronary or aortofemoral angiography, had diabetes and stable serum creatinine concentrations (men: 1.5 to 3.5 mg/dL; women: 1.3 to 3.5 mg/dL). ADRs considered included acute renal failure, arrhythmia, cardiovascular events, pulmonary edema, and multiple-organ failure. Resource use, including hospital days, medical visits, contrast medium, medications, laboratory tests and hospital procedures, were obtained from the NEPHRIC clinical trial. Unit costs data were obtained from standard UK costing sources. Costs are reported in 2006 £s. RESULTS: Iodixanol is cost-effective compared to iohexol with both lower costs and better effects related to fewer ADRs. The mean per patient cost difference was Յ555.98 (Յ0.41 and Յ556.39for iodixanol and iohexol, respectively). CONCLUSION: Iodixanol results in fewer ADRs and lower ADR costs per patient for this high risk patient population.
Background The Scandinavian Simvastatin Survival Study (4S) showed that lowering cholesterol leve... more Background The Scandinavian Simvastatin Survival Study (4S) showed that lowering cholesterol levels with simvastatin reduces mortality and morbidity in patients with angina pectoris or previous acute myocardial infarction. Before the widespread use of cholesterol-lowering drugs in such patients is recommended, its cost effectiveness should be demonstrated. We estimated the cost effectiveness of simvastatin treatment to lower cholesterol levels in relation to the age, sex, and cholesterol level before treatment of patients with coronary heart disease. Methods We estimated the cost per year of life gained with simvastatin therapy. To model the increased life expectancy, hazard functions from 4S were used. The costs studied included those of the intervention and the direct and indirect costs associated with morbidity from coronary causes. We prepared separate estimates for men and women at various ages (from 35 to 70 years) and total cholesterol levels before treatment (213 to 309 mg per deciliter). Results In the analysis limited to direct costs, the cost of each year of life gained ranged from $3,800 for 70-year-old men with 309 mg of cholesterol per deciliter to $27,400 for 35-year-old women with 213 mg of cholesterol per deciliter. When we included indirect costs, the results ranged from a savings in the youngest patients to a cost of $13,300 per year of life gained in 70-year-old women with 213 mg of cholesterol per deciliter. Conclusions In patients with coronary heart disease, simvastatin therapy is cost effective among both men and women at the ages and cholesterol levels studied.
OBJECTIVE: To evaluate a dose titration model for recombinant human GH substitution in adult pati... more OBJECTIVE: To evaluate a dose titration model for recombinant human GH substitution in adult patients with GH deficiency, aiming at normal plasma levels of IGF-I. DESIGN AND METHODS: Eighteen patients participated and a start dose of 0.17 mg GH/day was used except by two men who started with 0.33 mg/day. To demonstrate a clear GH effect the patients were first titrated, with steps of 0.17 mg GH/day every 6-8 weeks, to IGF-I levels in the upper range of age-adjusted reference values. The GH dose was then reduced 1 dose step and kept for a further 6 months. For comparison we investigated 17 healthy control subjects. RESULTS: Plasma IGF-I was increased after 2 weeks on the start dose and did not increase further for up to 8 weeks. Women had significantly lower GH sensitivity than men measured as net increment of IGF-I on the start dose of GH. GH sensitivity was not changed by age. The plasma IGF-I levels increased from 76.3+/-47.0 (s.d.) to 237+/-97 microg/l at the end of the study (P&...
We read with great interest the recent article by Kinlay et al. 1 In that article, they emphasize... more We read with great interest the recent article by Kinlay et al. 1 In that article, they emphasized the antiinflammatory effect of high-dose atorvastatin in subjects enrolled in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study, as reflected by lower levels of C-reactive protein (CRP) at 16 weeks. Recent studies showed that helper-T (Th) lymphocytes, which play an important role in the pathogenesis of acute coronary syndrome (ACS), can be divided into Th1 and Th2 cells on the basis of their cytokine profile. Indeed, we recently reported that a Th1 bias in Th1/Th2 immune response may play an important role in ACS patients as measured by the levels of Th1 and Th2 cytokines, such as interleukin (IL)-10, IL-12, and IL-18. 2 Moreover, recent basic studies, so-called "bench" findings, demonstrated that statins exhibit potent immunomodulation of the regulation of Th1/Th2 polarization in animal or in vitro models. 3,4 However, in the clinical setting, the immunomodulating effects of statins of Th1/Th2 polarization in patients with ACS have not been sufficiently determined. We prospectively studied 19 male patients with Braunwald's class III unstable angina (UA) and 21 age-matched male patients with stable angina (SA). The UA patients were randomly assigned to receive treatment with atorvastatin (10 or 20 mg/d) (group A, nϭ10) or conventional therapy (group C, nϭ9) within 24 hours after hospital admission. The group C patients with total cholesterol levels Ն220 mg/dL at 4 weeks after randomization were given colestimide 1.5g bid. Th-cell subsets were analyzed by 3-color flow cytometry after a 4-hour incubation with 25 ng/mL phorbol 12-myristate 13-acetate and 1 g/mL ionomycin in the presence of 10 g/mL Brefeldin A, as described previously. 5 Cytoplasmic cytokines were stained with antibodies against interferon (IFN)-␥ and IL-4. 5 Th1/Th2 ratio, estimated by the ratio of CD4 ϩ IFN-␥ ϩ IL4cells/CD4 ϩ IFN-␥-IL4 ϩ cells, was significantly higher in the UA group than in the SA group (14.0Ϯ7.4 versus 6.1Ϯ2.1, PϽ0.0001). After 16 weeks, the total cholesterol levels were not different (A, 177Ϯ26 mg/dL; C, 192Ϯ32 mg/dL, Pϭ0.2). Nevertheless, the Th1/Th2 ratio significantly decreased in group A relative to group C (A, 14.0Ϯ7.2 to 7.2Ϯ2.3, Pϭ0.01; C, 14.0Ϯ8.4 to 12.1Ϯ4.5, Pϭ0.4; A versus C, Pϭ0.01). Moreover, CRP levels were positively correlated with Th1/Th2 ratio in group A (rϭ0.66, Pϭ0.03). These "bedside" findings firstly demonstrated that early intervention with low-dose atorvastatin also regulates Th1/Th2 imbalance, particularly, Th1 bias in ACS patients. Therefore, we believe that atorvastatin may exert a beneficial effect on ACS through its immunomodulatory property, as shown by the results reported by Kinlay et al. 1
The mortality in coronary heart disease among 50- to 54-year-old men is 4 times higher in Lithuan... more The mortality in coronary heart disease among 50- to 54-year-old men is 4 times higher in Lithuania than in Sweden. It was recently suggested that traditional risk factors could not explain this mortality difference. LDL of Lithuanian men showed, however, a lower resistance to oxidation than that of Swedish men. In addition, the plasma concentration of g-tocopherol, lycopene, and b-carotene were lower in Lithuanian men. In the present investigation, we determined plasma oxysterols in men from Lithuania and Sweden and found that the plasma concentration of 7b-hydroxycholesterol was higher in Lithuanian men, 1265 versus 968 (SD) ng/mL (P50.0011). This oxysterol is a cholesterol autoxidation product and there is no indication that it should have an enzymatic origin. Mean LDL oxidation lag time was shorter in Lithuanian men (75614 versus 90613 minutes, P,0.0001) and the concentration of LDL linoleic acid was lower (249656 versus 292654 mg/mg of LDL protein, P,0.0001). Lipid corrected g-...
Coronary heart disease mortality is four times higher in Lithuanian compared to Swedish middle-ag... more Coronary heart disease mortality is four times higher in Lithuanian compared to Swedish middle-aged men. Using the same equipment (Acuson XP10 with 5 MHz linear transducer) and staff, we compared the amount of atherosclerosis in carotid and femoral arteries in 100 randomly sampled 50-year-old men in each of the cities Vilnius, Lithuania and Linkö ping, Sweden. Atherosclerotic plaques were more abundant in Vilnius men compared to Linkö ping men (53 versus 28% in the common carotid artery, 73 versus 37% in the common femoral artery, PB 0.001 for both). Plaques were thicker and more extended in arteries of Vilnius men, and an ultrasound atherosclerosis score was higher in both carotid and femoral arteries (P B0.001 for all). More Vilnius men had a maximal intima-media thickness of the common femoral artery above 1 mm (P B 0.005). Stiffness in the common carotid artery was higher in Vilnius men (PB0.001). In a linear regression model of the pooled material, after adjustment for city was made, smoking, systolic blood pressure, low density lipoprotein cholesterol and b-carotene (inversely) significantly contributed to a high total ultrasound score (r 2 = 0.32). These findings show that the higher coronary mortality noted in Lithuanian men goes together with a higher prevalence of early peripheral atherosclerosis.
Background The NASDAC study was designed to evaluate the safety and efficacy of atorvastatin at s... more Background The NASDAC study was designed to evaluate the safety and efficacy of atorvastatin at starting doses of 10, 20, 40, and 80 mg. Methods After an 8-week placebo washout period, 919 patients who were candidates for lipid-lowering therapy according to the National Cholesterol Education Program's Adult Treatment Panel III guidelines were randomized to 1 of 4 atorvastatin treatment groups: 10 mg (n = 229), 20 mg (n = 228), 40 mg (n = 231), and 80 mg (n = 231). Results Atorvastatin reduced low-density lipoprotein cholesterol (LDL-C) levels dose dependently across the 10-to 80-mg-dose range (35.7%-52.2%). Each of the 20-, 40-, and 80-mg doses provided significantly greater decreases in LDL-C than all lower doses (P b .01). All doses also reduced total cholesterol, the LDL-C/high-density lipoprotein cholesterol ratio, apolipoprotein B, and triglycerides from baseline. An increase in high-density lipoprotein cholesterol was observed in all dose groups. Most participants, regardless of their level of coronary heart disease risk, attained their National Cholesterol Education Program's Adult Treatment Panel III LDL-C goal by the end of the study. Patients in all risk groups were more likely to achieve the NCEP LDL-C goal at higher starting doses. Atorvastatin was well tolerated at all dose levels. Conclusions Atorvastatin initiated at doses of 10, 20, 40, and 80 mg is effective and safe for the treatment of patients with dyslipidemia. Depending on the percentage reduction needed to achieve an LDL-C goal, patients with or at risk of coronary heart disease may benefit from starting therapy at a higher dose of atorvastatin.
To assess the long-term cost-effectiveness of various doses of rosuvastatin (R) versus relevant d... more To assess the long-term cost-effectiveness of various doses of rosuvastatin (R) versus relevant doses of simvastatin (S) (R20 mg versus S40 mg (primary analysis), R10 versus S20 and R10 versus S40) in a patient population with high risk of cardiovascular events (10-year Framingham CVD risk ≥ 20%). METHODS: A Monte Carlo simulation model was developed based on the JUPITER (Justifi cation for the Use of statins in Primary prevention: an Intervention Trial evaluating Rosuvastatin, NCT00239681) trial fi ndings and includes modeling of cardiovascular events and death over the lifetime of patients. The relative effi cacy of S20, S40 and R10 compared with R20 (as observed in JUPITER) was estimated by computing relative 10-year Framingham cardiovascular event risks based on reported differences in Total Cholesterol/High-Density Lipoprotein cholesterol ratio. Epidemiological data specifi c for the Swedish setting were utilized to model post-event mortality and long-term overall mortality in event-free patients. Incremental effectiveness was primarily measured as quality-adjusted life-years (QALYs) gained. Cost-effectiveness was assessed based upon direct costs. All effects and costs (in 2008/09 Swedish unit prices) were discounted at annual 3%. RESULTS: The model estimated that treating a cohort of 100,000 patients (66 years, 60% males) with R20 mg avoided 2642 CVD events over lifetime compared with S40 mg. This translated into an estimated gain of 9515 years in full health (QALYs). The incremental cost per QALY gained was SEK161,712 (16,434). The cost per QALY gained was SEK228,655 (c23,237) for R10 versus S20, and SEK234,932 (c23,875) for R10 versus S40. Probabilistic sensitivity analyses supported base-case results. CONCLUSIONS: Treatment with rosuvastatin 10 and 20 mg is cost-effective compared with relevant doses of simvastatin in the primary prevention of CVD for patients with high baseline cardiovascular risk (10-year Framingham CVD risk ≥ 20%).
To assess the long-term cost-effectiveness of various doses of rosuvastatin (R) versus relevant d... more To assess the long-term cost-effectiveness of various doses of rosuvastatin (R) versus relevant doses of simvastatin (S) (R20 mg versus S40 mg (primary analysis), R10 versus S20 and R10 versus S40) in a patient population with high risk of cardiovascular events (10-year Framingham CVD risk ≥ 20%). METHODS: A Monte Carlo simulation model was developed based on the JUPITER (Justifi cation for the Use of statins in Primary prevention: an Intervention Trial evaluating Rosuvastatin, NCT00239681) trial fi ndings and includes modeling of cardiovascular events and death over the lifetime of patients. The relative effi cacy of S20, S40 and R10 compared with R20 (as observed in JUPITER) was estimated by computing relative 10-year Framingham cardiovascular event risks based on reported differences in Total Cholesterol/High-Density Lipoprotein cholesterol ratio. Epidemiological data specifi c for the Swedish setting were utilized to model post-event mortality and long-term overall mortality in event-free patients. Incremental effectiveness was primarily measured as quality-adjusted life-years (QALYs) gained. Cost-effectiveness was assessed based upon direct costs. All effects and costs (in 2008/09 Swedish unit prices) were discounted at annual 3%. RESULTS: The model estimated that treating a cohort of 100,000 patients (66 years, 60% males) with R20 mg avoided 2642 CVD events over lifetime compared with S40 mg. This translated into an estimated gain of 9515 years in full health (QALYs). The incremental cost per QALY gained was SEK161,712 (16,434). The cost per QALY gained was SEK228,655 (c23,237) for R10 versus S20, and SEK234,932 (c23,875) for R10 versus S40. Probabilistic sensitivity analyses supported base-case results. CONCLUSIONS: Treatment with rosuvastatin 10 and 20 mg is cost-effective compared with relevant doses of simvastatin in the primary prevention of CVD for patients with high baseline cardiovascular risk (10-year Framingham CVD risk ≥ 20%).
This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NH... more This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn.
To the Editor: Tsimikas et al hypothesized that in the MIRACL (Myocardial Ischemia Reduction with... more To the Editor: Tsimikas et al hypothesized that in the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) study statins induced a net efflux of oxidized phospholipids (OxPL) from the vessel wall, which is reflected by an increased OxPL/apoB ratio, representing enrichment in OxPL of apoB particles. 1 We would like to suggest an alternative interpretation. The oxidized low-density lipoprotein (OxLDL)-E06 assay used captures apoB-containing particles from the plasma sample. Because plasma lipoprotein(a) (Lp(a)) increased and LDL decreased during statin treatment, more Lp(a) and fewer LDL particles were captured after statin treatment. Because OxPL are predominantly associated with Lp(a), 2 the increased OxPL/apoB ratio could be explained by the shift in the Lp(a)/LDL ratio. Similarly, in the placebo-treated group the decreased OxPL/apoB ratio results from a decrease in Lp(a) relative to LDL. It is therefore unlikely that the OxPL/apoB ratio is a surrogate marker of net removal of OxPL from the vessel wall. Moreover, the observed 30% decrease in total plasma apoB-OxPL also argues against an increased net efflux of OxPL from the vessel wall. Recently, using the OxLDL assay from Mercodia in which an oxidation epitope associated with apoB is detected with monoclonal antibody 4E6, we found that atorvastatin (80 mg/d) and simvastatin (40 mg/d) reduced total plasma Ox-apoB (Ϫ43% and Ϫ35%, respectively) in patients with familial hypercholesterolemia from the ASAP study. 3 Interestingly, we observed no change in the Ox-apoB/apoB ratio when we used the noncompetitive version of the kit, in which the immobilized antibody captures Ox-apoB from the sample. We did, however, observe a small increase in the Ox-apoB/apoB ratio (18% for atorvastatin, 13% for simvastatin) when we used the competitive version, which unlike the noncompetitive version is sensitive to the number of oxidation epitopes associated with apoB. In addition, the increase in Ox-apoB/apoB ratio can be explained by an increase in Lp(a) relative to LDL. To further address this question, measurements of OxLDL with E06 and 4E6 in welldesigned assays (eg, in isolated Lp(a) particles) at different time points after the start of statin treatment are required.
Journal of the American Heart Association, Jan 10, 2017
Aldosterone may have adverse effects in the myocardium and vasculature. Treatment with an aldoste... more Aldosterone may have adverse effects in the myocardium and vasculature. Treatment with an aldosterone antagonist reduces cardiovascular risk in patients with acute myocardial infarction complicated by heart failure (HF) and left ventricular systolic dysfunction. However, most patients with acute coronary syndrome do not have advanced HF. Among such patients, it is unknown whether aldosterone predicts cardiovascular risk. To address this question, we examined data from the dal-OUTCOMES trial that compared the cholesteryl ester transfer protein inhibitor dalcetrapib with placebo, beginning 4 to 12 weeks after an index acute coronary syndrome. Patients with New York Heart Association class II (with LVEF <40%), III, or IV HF were excluded. Aldosterone was measured at randomization in 4073 patients. The primary outcome was a composite of coronary heart disease death, nonfatal myocardial infarction, stroke, hospitalization for unstable angina, or resuscitated cardiac arrest. Hospitaliz...
Journal of the American Heart Association, Jan 28, 2013
In acute coronary syndromes, C-reactive protein (CRP) strongly relates to subsequent death, but s... more In acute coronary syndromes, C-reactive protein (CRP) strongly relates to subsequent death, but surprisingly not to recurrent myocardial infarction. Other biomarkers may reflect different processes related to these outcomes. We assessed 8 inflammatory and vascular biomarkers and the risk of death and recurrent nonfatal cardiovascular events in the 16 weeks after an acute coronary syndrome. We measured blood concentrations of CRP, serum amyloid A (SAA), interleukin-6 (IL-6), soluble intercellular adhesion molecule (ICAM), soluble vascular cell adhesion molecule (VCAM), E-selectin, P-selectin, and tissue plasminogen activator antigen (tPA) 24 to 96 hours after presentation with acute coronary syndrome in 2925 subjects participating in a multicenter study. Biomarkers were related to the risk of death, and recurrent nonfatal acute coronary syndromes (myocardial infarction or unstable angina) over 16 weeks using Cox proportional hazard models. On univariate analyses, baseline CRP (P=0.00...
Circulation. Cardiovascular genetics, Jan 11, 2015
Background-Dalcetrapib did not improve clinical outcomes, despite increasing high-density lipopro... more Background-Dalcetrapib did not improve clinical outcomes, despite increasing high-density lipoprotein cholesterol by 30%. These results differ from other evidence supporting high-density lipoprotein as a therapeutic target. Responses to dalcetrapib may vary according to patients' genetic profile. Methods and Results-We conducted a pharmacogenomic evaluation using a genome-wide approach in the dal-OUTCOMES study (discovery cohort, n=5749) and a targeted genotyping panel in the dal-PLAQUE-2 imaging trial (support cohort, n=386). The primary endpoint for the discovery cohort was a composite of cardiovascular events. The change from baseline in carotid intima-media thickness on ultrasonography at 6 and 12 months was evaluated as supporting evidence. A single-nucleotide polymorphism was found to be associated with cardiovascular events in the dalcetrapib arm, identifying the ADCY9 gene on chromosome 16 (rs1967309; P=2.41×10-8), with 8 polymorphisms providing P<10-6 in this gene. Considering patients with genotype AA at rs1967309, there was a 39% reduction in the composite cardiovascular endpoint with dalcetrapib compared with placebo (hazard ratio, 0.61; 95% confidence interval, 0.41-0.92). In patients with genotype GG, there was a 27% increase in events with dalcetrapib versus placebo. Ten single-nucleotide polymorphism in the ADCY9 gene, the majority in linkage disequilibrium with rs1967309, were associated with the effect of dalcetrapib on intima-media thickness (P<0.05). Marker rs2238448 in ADCY9, in linkage disequilibrium with rs1967309 (r 2 =0.8), was associated with both the effects of dalcetrapib on intima-media thickness in dal-PLAQUE-2 (P=0.009) and events in dal-OUTCOMES (P=8.88×10-8 ; hazard ratio, 0.67; 95% confidence interval, 0.58-0.78). Conclusions-The effects of dalcetrapib on atherosclerotic outcomes are determined by correlated polymorphisms in the ADCY9 gene.
Background Renal transplant recipients are at increased risk of premature cardiovascular disease.... more Background Renal transplant recipients are at increased risk of premature cardiovascular disease. Although statins reduce cardiovascular risk in the general population, their efficacy and safety in renal transplant recipients have not been established. We investigated the effects of fluvastatin on cardiac and renal endpoints in this population. Methods We did a multicentre, randomised, double-blind, placebo-controlled trial in 2102 renal transplant recipients with total cholesterol 4•0-9•0 mmol/L. We randomly assigned patients fluvastatin (n=1050) or placebo (n=1052) and follow up was for 5-6 years. The primary endpoint was the occurrence of a major adverse cardiac event, defined as cardiac death, nonfatal myocardial infarction (MI), or coronary intervention procedure. Secondary endpoints were individual cardiac events, combined cardiac death or non-fatal MI, cerebrovascular events, non-cardiovascular death, all-cause mortality, and graft loss or doubling of serum creatinine. Analysis was by intention to treat. Findings After a mean follow-up of 5•1 years, fluvastatin lowered LDL cholesterol concentrations by 32%. Risk reduction with fluvastatin for the primary endpoint (risk ratio 0•83 [95% CI 0•64-1•06], p=0•139) was not significant, although there were fewer cardiac deaths or non-fatal MI (70 vs 104, 0•65 [0•48-0•88] p=0•005) in the fluvastatin group than in the placebo group. Coronary intervention procedures and other secondary endpoints did not differ significantly between groups. Interpretation Although cardiac deaths and non-fatal MI seemed to be reduced, fluvastatin did not generally reduce rates of coronary intervention procedures or mortality. Overall effects of fluvastatin were similar to those of statins in other populations.
Effect of fluvastatin on renal end points in the Assessment of Lescol in Renal Transplant (ALERT)... more Effect of fluvastatin on renal end points in the Assessment of Lescol in Renal Transplant (ALERT) trial. Background. Hyperlipidemia is a risk factor for long-term renal transplant dysfunction, but no prospective clinical trials have investigated the effects of statin treatment on graft function in renal transplant recipients. The aim of the present study was to evaluate the effect of fluvastatin on long-term renal transplant function and development of chronic allograft nephropathy in the ALERT (Assessment of Lescol in Renal Transplantation) study. Methods. ALERT was a randomized, double-blind, placebocontrolled study of the effect of fluvastatin, 40 mg and 80 mg daily, in renal transplant recipients. Patients were randomized to receive either fluvastatin (N = 1050) or placebo (N = 1052) and followed for five to six years. Renal end points included graft loss or doubling of serum creatinine or death; glomerular filtration rate (GFR) was also measured during follow-up in a subset of patients (N = 439). Results. There were 283 patients (13.5%) with graft loss, mainly due to chronic rejection (82%), yielding an annual rate of 2.4%. Fluvastatin treatment significantly lowered mean lowdensity lipoprotein (LDL)-cholesterol levels by 32% (95% CI −33 to −30) compared with placebo, but had no significant effect on the incidence of renal graft loss or doubling of serum creatinine, or decline in GFR throughout follow-up in the whole study population. Neither was any treatment effect by fluvastatin found in any of the subgroups analyzed. Conclusion. Fluvastatin treatment significantly improves lipid values in renal transplant recipients but has no effect on graft loss or doubling of serum creatinine.
Journal of the American College of Cardiology, 2010
Background: To evaluate the effect of high dose statin therapy on lipoprotein associated phosphol... more Background: To evaluate the effect of high dose statin therapy on lipoprotein associated phospholipase A2 (Lp-PLA2) and secretory phospholipase A2 (sPLA2) in acute coronary syndrome (ACS). Lp-PLA2 and sPLA2 are biomarkers of increased cardiovascular risk and targets of emerging therapeutic agents but the effect of statin therapy on their levels in patients with ACS is not established. Methods: Lp-PLA2 and sPLA2 mass and activity were measured in the Myocardial Ischemia Reduction with Acute Cholesterol Lowering (MIRACL) trial at baseline and after 16 weeks of atorvastatin 80 mg/day or placebo. Results: Compared to placebo in a Wilcoxon rank-sum test, atorvastatin treatment resulted in significant(p<0.001) reductions in median Lp-PLA2 (mass:-35.7 vs.-6.1%; activity:-24.5 vs. 5.5%) and sPLA2 (mass:-32.2 vs.-23.1%, activity:-29.6 vs.-19.2%). Baseline levels of Lp-PLA2 mass and activity correlated modestly (r=0.46, p<0.001), whereas sPLA2 mass and activity correlated strongly (r=0.79, p<-0.001). Baseline and 16 week sPLA2 activity, but not sPLA2 mass, was weakly correlated with Lp-PLA2 activity (r=0.12, p<0.001) and mass (r=0.18, p<0.001). The baseline levels of Lp-PLA2 and sPLA2 mass and activity were not associated with subsequent ischemic events. However, subjects with subsequent ischemic events had significantly smaller reductions in Lp-PLA2 mass (-15.5 vs.-20.6% p=0.01), sPLA2 mass (-18.9 vs.-28.8% p<0.001) and sPLA2 activity (-16.8 vs.-25.2% p<0.001) compared to those without ischemic events. The difference remained significant after adjusting for change in LDL-C and baseline sPLA2 or Lp-PLA2. Conclusions: High dose atorvastatin treatment significantly reduces Lp-PLA2 and sPLA2 mass and activity in patients with ACS. A blunted reduction in Lp-PLA2 mass or sPLA2 mass and activity in response to atorvastatin was associated with increased risk of ischemic events.
Journal of the American College of Cardiology, 2013
Background: Studies show that renal function improves with statin therapy in coronary patients wi... more Background: Studies show that renal function improves with statin therapy in coronary patients with CKD, but few studies show a relationship between cholesterol and CKD. As many patients with CKD have dyslipidemia there is a need to evaluate the relationship between lipoproteins and CKD.
Contrast-induced adverse drug reactions (ADRs), including contrast-induced nephropathy (renal ins... more Contrast-induced adverse drug reactions (ADRs), including contrast-induced nephropathy (renal insufficiency and diabetes), are common among high-risk patients (e.g., patients with diabetes mellitus and renal impairment). These ADRs cause extended hospital stays and additional medication use which lead to increased costs. We examine the cost-effectiveness of the use of 2 contrast media in patients at high risk for contrast-induced nephropathy. METHODS: A decision-analytic model was constructed to estimate the cost-effectiveness of an isosmolar contrast agent, iodixanol, compared to a low-osmolar contrast medium, iohexol, in the UK. Particular emphasis of the model was to avert the incidence of severe ADRs in patients at risk of contrast-induced nephropathy. The analysis is based on a European multi-centre randomised controlled trial, the NEPHRIC trial, of patients receiving iodixanol versus ohexol in which a statistically significant reduction in the incidence of severe ADRs in favour of iodixanol occurred. Patients in the study were adults 18 years of age or older referred for coronary or aortofemoral angiography, had diabetes and stable serum creatinine concentrations (men: 1.5 to 3.5 mg/dL; women: 1.3 to 3.5 mg/dL). ADRs considered included acute renal failure, arrhythmia, cardiovascular events, pulmonary edema, and multiple-organ failure. Resource use, including hospital days, medical visits, contrast medium, medications, laboratory tests and hospital procedures, were obtained from the NEPHRIC clinical trial. Unit costs data were obtained from standard UK costing sources. Costs are reported in 2006 £s. RESULTS: Iodixanol is cost-effective compared to iohexol with both lower costs and better effects related to fewer ADRs. The mean per patient cost difference was Յ555.98 (Յ0.41 and Յ556.39for iodixanol and iohexol, respectively). CONCLUSION: Iodixanol results in fewer ADRs and lower ADR costs per patient for this high risk patient population.
Background The Scandinavian Simvastatin Survival Study (4S) showed that lowering cholesterol leve... more Background The Scandinavian Simvastatin Survival Study (4S) showed that lowering cholesterol levels with simvastatin reduces mortality and morbidity in patients with angina pectoris or previous acute myocardial infarction. Before the widespread use of cholesterol-lowering drugs in such patients is recommended, its cost effectiveness should be demonstrated. We estimated the cost effectiveness of simvastatin treatment to lower cholesterol levels in relation to the age, sex, and cholesterol level before treatment of patients with coronary heart disease. Methods We estimated the cost per year of life gained with simvastatin therapy. To model the increased life expectancy, hazard functions from 4S were used. The costs studied included those of the intervention and the direct and indirect costs associated with morbidity from coronary causes. We prepared separate estimates for men and women at various ages (from 35 to 70 years) and total cholesterol levels before treatment (213 to 309 mg per deciliter). Results In the analysis limited to direct costs, the cost of each year of life gained ranged from $3,800 for 70-year-old men with 309 mg of cholesterol per deciliter to $27,400 for 35-year-old women with 213 mg of cholesterol per deciliter. When we included indirect costs, the results ranged from a savings in the youngest patients to a cost of $13,300 per year of life gained in 70-year-old women with 213 mg of cholesterol per deciliter. Conclusions In patients with coronary heart disease, simvastatin therapy is cost effective among both men and women at the ages and cholesterol levels studied.
OBJECTIVE: To evaluate a dose titration model for recombinant human GH substitution in adult pati... more OBJECTIVE: To evaluate a dose titration model for recombinant human GH substitution in adult patients with GH deficiency, aiming at normal plasma levels of IGF-I. DESIGN AND METHODS: Eighteen patients participated and a start dose of 0.17 mg GH/day was used except by two men who started with 0.33 mg/day. To demonstrate a clear GH effect the patients were first titrated, with steps of 0.17 mg GH/day every 6-8 weeks, to IGF-I levels in the upper range of age-adjusted reference values. The GH dose was then reduced 1 dose step and kept for a further 6 months. For comparison we investigated 17 healthy control subjects. RESULTS: Plasma IGF-I was increased after 2 weeks on the start dose and did not increase further for up to 8 weeks. Women had significantly lower GH sensitivity than men measured as net increment of IGF-I on the start dose of GH. GH sensitivity was not changed by age. The plasma IGF-I levels increased from 76.3+/-47.0 (s.d.) to 237+/-97 microg/l at the end of the study (P&...
We read with great interest the recent article by Kinlay et al. 1 In that article, they emphasize... more We read with great interest the recent article by Kinlay et al. 1 In that article, they emphasized the antiinflammatory effect of high-dose atorvastatin in subjects enrolled in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study, as reflected by lower levels of C-reactive protein (CRP) at 16 weeks. Recent studies showed that helper-T (Th) lymphocytes, which play an important role in the pathogenesis of acute coronary syndrome (ACS), can be divided into Th1 and Th2 cells on the basis of their cytokine profile. Indeed, we recently reported that a Th1 bias in Th1/Th2 immune response may play an important role in ACS patients as measured by the levels of Th1 and Th2 cytokines, such as interleukin (IL)-10, IL-12, and IL-18. 2 Moreover, recent basic studies, so-called "bench" findings, demonstrated that statins exhibit potent immunomodulation of the regulation of Th1/Th2 polarization in animal or in vitro models. 3,4 However, in the clinical setting, the immunomodulating effects of statins of Th1/Th2 polarization in patients with ACS have not been sufficiently determined. We prospectively studied 19 male patients with Braunwald's class III unstable angina (UA) and 21 age-matched male patients with stable angina (SA). The UA patients were randomly assigned to receive treatment with atorvastatin (10 or 20 mg/d) (group A, nϭ10) or conventional therapy (group C, nϭ9) within 24 hours after hospital admission. The group C patients with total cholesterol levels Ն220 mg/dL at 4 weeks after randomization were given colestimide 1.5g bid. Th-cell subsets were analyzed by 3-color flow cytometry after a 4-hour incubation with 25 ng/mL phorbol 12-myristate 13-acetate and 1 g/mL ionomycin in the presence of 10 g/mL Brefeldin A, as described previously. 5 Cytoplasmic cytokines were stained with antibodies against interferon (IFN)-␥ and IL-4. 5 Th1/Th2 ratio, estimated by the ratio of CD4 ϩ IFN-␥ ϩ IL4cells/CD4 ϩ IFN-␥-IL4 ϩ cells, was significantly higher in the UA group than in the SA group (14.0Ϯ7.4 versus 6.1Ϯ2.1, PϽ0.0001). After 16 weeks, the total cholesterol levels were not different (A, 177Ϯ26 mg/dL; C, 192Ϯ32 mg/dL, Pϭ0.2). Nevertheless, the Th1/Th2 ratio significantly decreased in group A relative to group C (A, 14.0Ϯ7.2 to 7.2Ϯ2.3, Pϭ0.01; C, 14.0Ϯ8.4 to 12.1Ϯ4.5, Pϭ0.4; A versus C, Pϭ0.01). Moreover, CRP levels were positively correlated with Th1/Th2 ratio in group A (rϭ0.66, Pϭ0.03). These "bedside" findings firstly demonstrated that early intervention with low-dose atorvastatin also regulates Th1/Th2 imbalance, particularly, Th1 bias in ACS patients. Therefore, we believe that atorvastatin may exert a beneficial effect on ACS through its immunomodulatory property, as shown by the results reported by Kinlay et al. 1
The mortality in coronary heart disease among 50- to 54-year-old men is 4 times higher in Lithuan... more The mortality in coronary heart disease among 50- to 54-year-old men is 4 times higher in Lithuania than in Sweden. It was recently suggested that traditional risk factors could not explain this mortality difference. LDL of Lithuanian men showed, however, a lower resistance to oxidation than that of Swedish men. In addition, the plasma concentration of g-tocopherol, lycopene, and b-carotene were lower in Lithuanian men. In the present investigation, we determined plasma oxysterols in men from Lithuania and Sweden and found that the plasma concentration of 7b-hydroxycholesterol was higher in Lithuanian men, 1265 versus 968 (SD) ng/mL (P50.0011). This oxysterol is a cholesterol autoxidation product and there is no indication that it should have an enzymatic origin. Mean LDL oxidation lag time was shorter in Lithuanian men (75614 versus 90613 minutes, P,0.0001) and the concentration of LDL linoleic acid was lower (249656 versus 292654 mg/mg of LDL protein, P,0.0001). Lipid corrected g-...
Coronary heart disease mortality is four times higher in Lithuanian compared to Swedish middle-ag... more Coronary heart disease mortality is four times higher in Lithuanian compared to Swedish middle-aged men. Using the same equipment (Acuson XP10 with 5 MHz linear transducer) and staff, we compared the amount of atherosclerosis in carotid and femoral arteries in 100 randomly sampled 50-year-old men in each of the cities Vilnius, Lithuania and Linkö ping, Sweden. Atherosclerotic plaques were more abundant in Vilnius men compared to Linkö ping men (53 versus 28% in the common carotid artery, 73 versus 37% in the common femoral artery, PB 0.001 for both). Plaques were thicker and more extended in arteries of Vilnius men, and an ultrasound atherosclerosis score was higher in both carotid and femoral arteries (P B0.001 for all). More Vilnius men had a maximal intima-media thickness of the common femoral artery above 1 mm (P B 0.005). Stiffness in the common carotid artery was higher in Vilnius men (PB0.001). In a linear regression model of the pooled material, after adjustment for city was made, smoking, systolic blood pressure, low density lipoprotein cholesterol and b-carotene (inversely) significantly contributed to a high total ultrasound score (r 2 = 0.32). These findings show that the higher coronary mortality noted in Lithuanian men goes together with a higher prevalence of early peripheral atherosclerosis.
Background The NASDAC study was designed to evaluate the safety and efficacy of atorvastatin at s... more Background The NASDAC study was designed to evaluate the safety and efficacy of atorvastatin at starting doses of 10, 20, 40, and 80 mg. Methods After an 8-week placebo washout period, 919 patients who were candidates for lipid-lowering therapy according to the National Cholesterol Education Program's Adult Treatment Panel III guidelines were randomized to 1 of 4 atorvastatin treatment groups: 10 mg (n = 229), 20 mg (n = 228), 40 mg (n = 231), and 80 mg (n = 231). Results Atorvastatin reduced low-density lipoprotein cholesterol (LDL-C) levels dose dependently across the 10-to 80-mg-dose range (35.7%-52.2%). Each of the 20-, 40-, and 80-mg doses provided significantly greater decreases in LDL-C than all lower doses (P b .01). All doses also reduced total cholesterol, the LDL-C/high-density lipoprotein cholesterol ratio, apolipoprotein B, and triglycerides from baseline. An increase in high-density lipoprotein cholesterol was observed in all dose groups. Most participants, regardless of their level of coronary heart disease risk, attained their National Cholesterol Education Program's Adult Treatment Panel III LDL-C goal by the end of the study. Patients in all risk groups were more likely to achieve the NCEP LDL-C goal at higher starting doses. Atorvastatin was well tolerated at all dose levels. Conclusions Atorvastatin initiated at doses of 10, 20, 40, and 80 mg is effective and safe for the treatment of patients with dyslipidemia. Depending on the percentage reduction needed to achieve an LDL-C goal, patients with or at risk of coronary heart disease may benefit from starting therapy at a higher dose of atorvastatin.
To assess the long-term cost-effectiveness of various doses of rosuvastatin (R) versus relevant d... more To assess the long-term cost-effectiveness of various doses of rosuvastatin (R) versus relevant doses of simvastatin (S) (R20 mg versus S40 mg (primary analysis), R10 versus S20 and R10 versus S40) in a patient population with high risk of cardiovascular events (10-year Framingham CVD risk ≥ 20%). METHODS: A Monte Carlo simulation model was developed based on the JUPITER (Justifi cation for the Use of statins in Primary prevention: an Intervention Trial evaluating Rosuvastatin, NCT00239681) trial fi ndings and includes modeling of cardiovascular events and death over the lifetime of patients. The relative effi cacy of S20, S40 and R10 compared with R20 (as observed in JUPITER) was estimated by computing relative 10-year Framingham cardiovascular event risks based on reported differences in Total Cholesterol/High-Density Lipoprotein cholesterol ratio. Epidemiological data specifi c for the Swedish setting were utilized to model post-event mortality and long-term overall mortality in event-free patients. Incremental effectiveness was primarily measured as quality-adjusted life-years (QALYs) gained. Cost-effectiveness was assessed based upon direct costs. All effects and costs (in 2008/09 Swedish unit prices) were discounted at annual 3%. RESULTS: The model estimated that treating a cohort of 100,000 patients (66 years, 60% males) with R20 mg avoided 2642 CVD events over lifetime compared with S40 mg. This translated into an estimated gain of 9515 years in full health (QALYs). The incremental cost per QALY gained was SEK161,712 (16,434). The cost per QALY gained was SEK228,655 (c23,237) for R10 versus S20, and SEK234,932 (c23,875) for R10 versus S40. Probabilistic sensitivity analyses supported base-case results. CONCLUSIONS: Treatment with rosuvastatin 10 and 20 mg is cost-effective compared with relevant doses of simvastatin in the primary prevention of CVD for patients with high baseline cardiovascular risk (10-year Framingham CVD risk ≥ 20%).
To assess the long-term cost-effectiveness of various doses of rosuvastatin (R) versus relevant d... more To assess the long-term cost-effectiveness of various doses of rosuvastatin (R) versus relevant doses of simvastatin (S) (R20 mg versus S40 mg (primary analysis), R10 versus S20 and R10 versus S40) in a patient population with high risk of cardiovascular events (10-year Framingham CVD risk ≥ 20%). METHODS: A Monte Carlo simulation model was developed based on the JUPITER (Justifi cation for the Use of statins in Primary prevention: an Intervention Trial evaluating Rosuvastatin, NCT00239681) trial fi ndings and includes modeling of cardiovascular events and death over the lifetime of patients. The relative effi cacy of S20, S40 and R10 compared with R20 (as observed in JUPITER) was estimated by computing relative 10-year Framingham cardiovascular event risks based on reported differences in Total Cholesterol/High-Density Lipoprotein cholesterol ratio. Epidemiological data specifi c for the Swedish setting were utilized to model post-event mortality and long-term overall mortality in event-free patients. Incremental effectiveness was primarily measured as quality-adjusted life-years (QALYs) gained. Cost-effectiveness was assessed based upon direct costs. All effects and costs (in 2008/09 Swedish unit prices) were discounted at annual 3%. RESULTS: The model estimated that treating a cohort of 100,000 patients (66 years, 60% males) with R20 mg avoided 2642 CVD events over lifetime compared with S40 mg. This translated into an estimated gain of 9515 years in full health (QALYs). The incremental cost per QALY gained was SEK161,712 (16,434). The cost per QALY gained was SEK228,655 (c23,237) for R10 versus S20, and SEK234,932 (c23,875) for R10 versus S40. Probabilistic sensitivity analyses supported base-case results. CONCLUSIONS: Treatment with rosuvastatin 10 and 20 mg is cost-effective compared with relevant doses of simvastatin in the primary prevention of CVD for patients with high baseline cardiovascular risk (10-year Framingham CVD risk ≥ 20%).
This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NH... more This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn.
To the Editor: Tsimikas et al hypothesized that in the MIRACL (Myocardial Ischemia Reduction with... more To the Editor: Tsimikas et al hypothesized that in the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) study statins induced a net efflux of oxidized phospholipids (OxPL) from the vessel wall, which is reflected by an increased OxPL/apoB ratio, representing enrichment in OxPL of apoB particles. 1 We would like to suggest an alternative interpretation. The oxidized low-density lipoprotein (OxLDL)-E06 assay used captures apoB-containing particles from the plasma sample. Because plasma lipoprotein(a) (Lp(a)) increased and LDL decreased during statin treatment, more Lp(a) and fewer LDL particles were captured after statin treatment. Because OxPL are predominantly associated with Lp(a), 2 the increased OxPL/apoB ratio could be explained by the shift in the Lp(a)/LDL ratio. Similarly, in the placebo-treated group the decreased OxPL/apoB ratio results from a decrease in Lp(a) relative to LDL. It is therefore unlikely that the OxPL/apoB ratio is a surrogate marker of net removal of OxPL from the vessel wall. Moreover, the observed 30% decrease in total plasma apoB-OxPL also argues against an increased net efflux of OxPL from the vessel wall. Recently, using the OxLDL assay from Mercodia in which an oxidation epitope associated with apoB is detected with monoclonal antibody 4E6, we found that atorvastatin (80 mg/d) and simvastatin (40 mg/d) reduced total plasma Ox-apoB (Ϫ43% and Ϫ35%, respectively) in patients with familial hypercholesterolemia from the ASAP study. 3 Interestingly, we observed no change in the Ox-apoB/apoB ratio when we used the noncompetitive version of the kit, in which the immobilized antibody captures Ox-apoB from the sample. We did, however, observe a small increase in the Ox-apoB/apoB ratio (18% for atorvastatin, 13% for simvastatin) when we used the competitive version, which unlike the noncompetitive version is sensitive to the number of oxidation epitopes associated with apoB. In addition, the increase in Ox-apoB/apoB ratio can be explained by an increase in Lp(a) relative to LDL. To further address this question, measurements of OxLDL with E06 and 4E6 in welldesigned assays (eg, in isolated Lp(a) particles) at different time points after the start of statin treatment are required.
Journal of the American Heart Association, Jan 10, 2017
Aldosterone may have adverse effects in the myocardium and vasculature. Treatment with an aldoste... more Aldosterone may have adverse effects in the myocardium and vasculature. Treatment with an aldosterone antagonist reduces cardiovascular risk in patients with acute myocardial infarction complicated by heart failure (HF) and left ventricular systolic dysfunction. However, most patients with acute coronary syndrome do not have advanced HF. Among such patients, it is unknown whether aldosterone predicts cardiovascular risk. To address this question, we examined data from the dal-OUTCOMES trial that compared the cholesteryl ester transfer protein inhibitor dalcetrapib with placebo, beginning 4 to 12 weeks after an index acute coronary syndrome. Patients with New York Heart Association class II (with LVEF <40%), III, or IV HF were excluded. Aldosterone was measured at randomization in 4073 patients. The primary outcome was a composite of coronary heart disease death, nonfatal myocardial infarction, stroke, hospitalization for unstable angina, or resuscitated cardiac arrest. Hospitaliz...
Journal of the American Heart Association, Jan 28, 2013
In acute coronary syndromes, C-reactive protein (CRP) strongly relates to subsequent death, but s... more In acute coronary syndromes, C-reactive protein (CRP) strongly relates to subsequent death, but surprisingly not to recurrent myocardial infarction. Other biomarkers may reflect different processes related to these outcomes. We assessed 8 inflammatory and vascular biomarkers and the risk of death and recurrent nonfatal cardiovascular events in the 16 weeks after an acute coronary syndrome. We measured blood concentrations of CRP, serum amyloid A (SAA), interleukin-6 (IL-6), soluble intercellular adhesion molecule (ICAM), soluble vascular cell adhesion molecule (VCAM), E-selectin, P-selectin, and tissue plasminogen activator antigen (tPA) 24 to 96 hours after presentation with acute coronary syndrome in 2925 subjects participating in a multicenter study. Biomarkers were related to the risk of death, and recurrent nonfatal acute coronary syndromes (myocardial infarction or unstable angina) over 16 weeks using Cox proportional hazard models. On univariate analyses, baseline CRP (P=0.00...
Circulation. Cardiovascular genetics, Jan 11, 2015
Background-Dalcetrapib did not improve clinical outcomes, despite increasing high-density lipopro... more Background-Dalcetrapib did not improve clinical outcomes, despite increasing high-density lipoprotein cholesterol by 30%. These results differ from other evidence supporting high-density lipoprotein as a therapeutic target. Responses to dalcetrapib may vary according to patients' genetic profile. Methods and Results-We conducted a pharmacogenomic evaluation using a genome-wide approach in the dal-OUTCOMES study (discovery cohort, n=5749) and a targeted genotyping panel in the dal-PLAQUE-2 imaging trial (support cohort, n=386). The primary endpoint for the discovery cohort was a composite of cardiovascular events. The change from baseline in carotid intima-media thickness on ultrasonography at 6 and 12 months was evaluated as supporting evidence. A single-nucleotide polymorphism was found to be associated with cardiovascular events in the dalcetrapib arm, identifying the ADCY9 gene on chromosome 16 (rs1967309; P=2.41×10-8), with 8 polymorphisms providing P<10-6 in this gene. Considering patients with genotype AA at rs1967309, there was a 39% reduction in the composite cardiovascular endpoint with dalcetrapib compared with placebo (hazard ratio, 0.61; 95% confidence interval, 0.41-0.92). In patients with genotype GG, there was a 27% increase in events with dalcetrapib versus placebo. Ten single-nucleotide polymorphism in the ADCY9 gene, the majority in linkage disequilibrium with rs1967309, were associated with the effect of dalcetrapib on intima-media thickness (P<0.05). Marker rs2238448 in ADCY9, in linkage disequilibrium with rs1967309 (r 2 =0.8), was associated with both the effects of dalcetrapib on intima-media thickness in dal-PLAQUE-2 (P=0.009) and events in dal-OUTCOMES (P=8.88×10-8 ; hazard ratio, 0.67; 95% confidence interval, 0.58-0.78). Conclusions-The effects of dalcetrapib on atherosclerotic outcomes are determined by correlated polymorphisms in the ADCY9 gene.
Background Renal transplant recipients are at increased risk of premature cardiovascular disease.... more Background Renal transplant recipients are at increased risk of premature cardiovascular disease. Although statins reduce cardiovascular risk in the general population, their efficacy and safety in renal transplant recipients have not been established. We investigated the effects of fluvastatin on cardiac and renal endpoints in this population. Methods We did a multicentre, randomised, double-blind, placebo-controlled trial in 2102 renal transplant recipients with total cholesterol 4•0-9•0 mmol/L. We randomly assigned patients fluvastatin (n=1050) or placebo (n=1052) and follow up was for 5-6 years. The primary endpoint was the occurrence of a major adverse cardiac event, defined as cardiac death, nonfatal myocardial infarction (MI), or coronary intervention procedure. Secondary endpoints were individual cardiac events, combined cardiac death or non-fatal MI, cerebrovascular events, non-cardiovascular death, all-cause mortality, and graft loss or doubling of serum creatinine. Analysis was by intention to treat. Findings After a mean follow-up of 5•1 years, fluvastatin lowered LDL cholesterol concentrations by 32%. Risk reduction with fluvastatin for the primary endpoint (risk ratio 0•83 [95% CI 0•64-1•06], p=0•139) was not significant, although there were fewer cardiac deaths or non-fatal MI (70 vs 104, 0•65 [0•48-0•88] p=0•005) in the fluvastatin group than in the placebo group. Coronary intervention procedures and other secondary endpoints did not differ significantly between groups. Interpretation Although cardiac deaths and non-fatal MI seemed to be reduced, fluvastatin did not generally reduce rates of coronary intervention procedures or mortality. Overall effects of fluvastatin were similar to those of statins in other populations.
Effect of fluvastatin on renal end points in the Assessment of Lescol in Renal Transplant (ALERT)... more Effect of fluvastatin on renal end points in the Assessment of Lescol in Renal Transplant (ALERT) trial. Background. Hyperlipidemia is a risk factor for long-term renal transplant dysfunction, but no prospective clinical trials have investigated the effects of statin treatment on graft function in renal transplant recipients. The aim of the present study was to evaluate the effect of fluvastatin on long-term renal transplant function and development of chronic allograft nephropathy in the ALERT (Assessment of Lescol in Renal Transplantation) study. Methods. ALERT was a randomized, double-blind, placebocontrolled study of the effect of fluvastatin, 40 mg and 80 mg daily, in renal transplant recipients. Patients were randomized to receive either fluvastatin (N = 1050) or placebo (N = 1052) and followed for five to six years. Renal end points included graft loss or doubling of serum creatinine or death; glomerular filtration rate (GFR) was also measured during follow-up in a subset of patients (N = 439). Results. There were 283 patients (13.5%) with graft loss, mainly due to chronic rejection (82%), yielding an annual rate of 2.4%. Fluvastatin treatment significantly lowered mean lowdensity lipoprotein (LDL)-cholesterol levels by 32% (95% CI −33 to −30) compared with placebo, but had no significant effect on the incidence of renal graft loss or doubling of serum creatinine, or decline in GFR throughout follow-up in the whole study population. Neither was any treatment effect by fluvastatin found in any of the subgroups analyzed. Conclusion. Fluvastatin treatment significantly improves lipid values in renal transplant recipients but has no effect on graft loss or doubling of serum creatinine.
Journal of the American College of Cardiology, 2010
Background: To evaluate the effect of high dose statin therapy on lipoprotein associated phosphol... more Background: To evaluate the effect of high dose statin therapy on lipoprotein associated phospholipase A2 (Lp-PLA2) and secretory phospholipase A2 (sPLA2) in acute coronary syndrome (ACS). Lp-PLA2 and sPLA2 are biomarkers of increased cardiovascular risk and targets of emerging therapeutic agents but the effect of statin therapy on their levels in patients with ACS is not established. Methods: Lp-PLA2 and sPLA2 mass and activity were measured in the Myocardial Ischemia Reduction with Acute Cholesterol Lowering (MIRACL) trial at baseline and after 16 weeks of atorvastatin 80 mg/day or placebo. Results: Compared to placebo in a Wilcoxon rank-sum test, atorvastatin treatment resulted in significant(p<0.001) reductions in median Lp-PLA2 (mass:-35.7 vs.-6.1%; activity:-24.5 vs. 5.5%) and sPLA2 (mass:-32.2 vs.-23.1%, activity:-29.6 vs.-19.2%). Baseline levels of Lp-PLA2 mass and activity correlated modestly (r=0.46, p<0.001), whereas sPLA2 mass and activity correlated strongly (r=0.79, p<-0.001). Baseline and 16 week sPLA2 activity, but not sPLA2 mass, was weakly correlated with Lp-PLA2 activity (r=0.12, p<0.001) and mass (r=0.18, p<0.001). The baseline levels of Lp-PLA2 and sPLA2 mass and activity were not associated with subsequent ischemic events. However, subjects with subsequent ischemic events had significantly smaller reductions in Lp-PLA2 mass (-15.5 vs.-20.6% p=0.01), sPLA2 mass (-18.9 vs.-28.8% p<0.001) and sPLA2 activity (-16.8 vs.-25.2% p<0.001) compared to those without ischemic events. The difference remained significant after adjusting for change in LDL-C and baseline sPLA2 or Lp-PLA2. Conclusions: High dose atorvastatin treatment significantly reduces Lp-PLA2 and sPLA2 mass and activity in patients with ACS. A blunted reduction in Lp-PLA2 mass or sPLA2 mass and activity in response to atorvastatin was associated with increased risk of ischemic events.
Journal of the American College of Cardiology, 2013
Background: Studies show that renal function improves with statin therapy in coronary patients wi... more Background: Studies show that renal function improves with statin therapy in coronary patients with CKD, but few studies show a relationship between cholesterol and CKD. As many patients with CKD have dyslipidemia there is a need to evaluate the relationship between lipoproteins and CKD.
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