Efficacy and safety of rosuvastatin and atorvastatin in patients with hypercholesterolemia and a high risk of coronary heart disease: a randomized, controlled trial

Background

This double-blind, multicenter, randomized trial compared rosuvastatin and atorvastatin for reducing low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia and a high risk of coronary heart disease.

Methods

After a 6-week dietary lead-in period, patients with LDL-C levels ≥160 and <250 mg/dL and triglyceride levels ≤400 mg/dL were randomly assigned to 24 weeks' treatment in 1 of 3 groups, each with forced dose titrations at 12 and 18 weeks. Starting and titrated doses for each group were rosuvastatin 5, 20, and 80 mg (n = 127); rosuvastatin 10, 40, and 80 mg (n = 128); and atorvastatin 10, 40, and 80 mg (n = 128).

Results

At 24 weeks, LDL-C was reduced significantly more with 80 mg rosuvastatin (combined rosuvastatin group) than with atorvastatin 80 mg (60% vs 52% [P < .001]). At 12 weeks, rosuvastatin 5 and 10 mg reduced LDL-C significantly more than atorvastatin 10 mg (40% [P < .01], 47% [P < .001] vs 35%). At 18 weeks, LDL-C reductions were also significantly greater in both rosuvastatin groups than in the atorvastatin group (52% [P < .01], 59% [P < .001] vs 47%). Consequently, more patients receiving rosuvastatin achieved LDL-C goals. Total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, apolipoproteins B and A-I, and all lipid ratios were more favorably modified by rosuvastatin at 24 weeks (P < .01). Effects of the 2 agents on triglycerides were similar.

Conclusions

Rosuvastatin was more efficacious than atorvastatin in modifying lipids in patients with hypercholesterolemia and a high coronary heart disease risk.     

Differential effects of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I are consistent across hypercholesterolemic patient subgroups

BACKGROUND: In addition to lowering plasma levels of low-density lipoprotein cholesterol (LDL-C), statins also raise high-density lipoprotein cholesterol (HDL-C). HYPOTHESIS: Recent studies have shown that treatment with simvastatin results in larger increases in HDL-C than those seen with atorvastatin. The results of three clinical studies are analyzed, comparing the effects of simvastatin and atorvastatin on HDL-C and apolipoprotein A-I (apo A-I) in the total cohort and in several subgroups of hypercholesterolemic patients. The three studies were all multicenter, randomized clinical trials that included simvastatin (20-80 mg) and atorvastatin (10-80 mg) treatment arms. The subgroup analyses performed were gender; age (< 65 and > or = 65 years); baseline HDL-C (male: < 40 or > or = 40 mg/dl; female: < 45 or > or = 45 mg/dl), baseline LDL-C (< 160 or > or = 160 mg/dl), and baseline triglycerides (< 200 or > or = 200 mg/dl). RESULTS: Both drugs produced similar increases in HDL-C levels at low doses; however, at higher drug doses (40 and 80 mg), HDL-C showed a significantly greater increase with simvastatin than with atorvastatin (p < 0.05 to < 0.001). Therefore, while HDL-C remained consistently elevated across all doses of simvastatin, there appeared to be a pattern of decreasing HDL-C with an increasing dose of atorvastatin. A similar negative dose response pattern was also observed with apo A-I in atorvastatin-treated patients, suggesting a reduction in the number of circulating HDL particles at higher doses. Both drugs reduced LDL-C and triglycerides in a dose-dependent fashion, with atorvastatin showing slightly greater effects. The differential effects of atorvastatin and simvastatin on HDL-C and apo A-I were observed for both the whole study cohorts and all subgroups examined; thus, no consistent treatment-by-subgroup interactions were observed. CONCLUSION: The data presented show that, across different hypercholesterolemic patient subgroups, simvastatin increases HDL-C and apo A-I more than atorvastatin at higher doses, with evidence of a negative dose response effect on HDL-C and apo A-I with atorvastatin, but not simvastatin.     

Effects of switching statins on achievement of lipid goals: measuring effective reductions in cholesterol using rosuvastatin therapy (MERCURY I) study

Background

In a multinational trial (4522IL/0081), we assessed the effects of switching to low doses of rosuvastatin from commonly used doses of atorvastatin, simvastatin, and pravastatin on low-density lipoprotein cholesterol (LDL-C) goal achievement in high-risk patients.

Methods

Hypercholesterolemic patients (n = 3140) with coronary heart disease, atherosclerosis, or type 2 diabetes were randomized to open-label rosuvastatin 10 mg, atorvastatin 10 or 20 mg, simvastatin 20 mg, or pravastatin 40 mg for 8 weeks. Patients either remained on these treatments for another 8 weeks or switched treatments from atorvastatin 10 mg, simvastatin 20 mg, and pravastatin 40 mg to rosuvastatin 10 mg or from atorvastatin 20 mg to rosuvastatin 10 or 20 mg. The primary efficacy measure was the proportion of patients reaching the Joint European Societies' LDL-C goal (<116 mg/dL) at week 16. For measures of cholesterol goal achievement, treatment arms were compared using logistic-regression analysis.

Results

Significant improvement in LDL-C goal achievement was found for patients who switched to rosuvastatin 10 mg, compared with patients who remained on atorvastatin 10 mg (86% vs 80%, P < .05), simvastatin 20 mg (86% vs 72%, P < .0001), and pravastatin 40 mg (88% vs 66%, P < .0001), and between patients switched to rosuvastatin 20 mg and those who remained on atorvastatin 20 mg (90% vs 84%, P < .01). Similar results were found for achievement of the European combined LDL-C and total cholesterol goals and National Cholesterol Education Program Adult Treatment Panel III LDL-C goals. All statins were well tolerated over 16 weeks.

Conclusions

We demonstrated that switching to a more efficacious statin is an effective strategy to improve lipid goal achievement in patients requiring lipid-lowering therapy.     

Achieving LDL cholesterol, non-HDL cholesterol, and apolipoprotein B target levels in high-risk patients: Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY (MERCURY) II

Background

National Cholestesrol Education Program Adult Treatment Panel III guidelines for patients at a high risk of coronary heart disease set a low-density lipoprotein cholesterol (LDL-C) target of <100 mg/dL. This target can be difficult to attain with diet and current therapy.

Methods

In a 16-week multinational trial, 1993 high-risk patients were randomized to rosuvastatin 20 mg, atorvastatin 10 mg, atorvastatin 20 mg, simvastatin 20 mg, or simvastatin 40 mg for 8 weeks. Patients either remained on starting treatment or switched to lower or milligram-equivalent doses of rosuvastatin for 8 more weeks.

Results

At 16 weeks, more patients achieved their LDL-C target by switching to rosuvastatin 10 mg than staying on atorvastatin 10 mg (66% vs 42%, P < .001) or simvastatin 20 mg (73% vs 32%, P < .001). Changing to rosuvastatin 20 mg brought more patients to their LDL-C target than staying on atorvastatin 20 mg (79% vs 64%, P < .001) or simvastatin 40 mg (84% vs 56%, P < .001). More very high risk patients achieved an LDL-C target of <70 mg/dL when changed to rosuvastatin from atorvastatin or simvastatin (within-arm comparisons P < .01). More hypertriglyceridemic patients (triglycerides ≥200 mg/dL) met LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B targets by changing to rosuvastatin. Switching to rosuvastatin produced greater reductions in LDL-C, total cholesterol, non-HDL-C, apolipoprotein B, and lipid ratios. All treatments were well tolerated, with no differences among treatment groups in skeletal muscle, hepatic, or renal toxicity.

Conclusion

Rosuvastatin 10 or 20 mg is an effective and safe therapeutic option for high-risk patients to achieve their lipid and apolipoprotein targets.     

Effects of switching statins on lipid and apolipoprotein ratios in the MERCURY I study

BACKGROUND: Lipid ratios are clinically useful markers of coronary artery disease (CAD) risk. The effects of rosuvastatin, atorvastatin, simvastatin, and pravastatin on lipid ratios were investigated in the Measuring Effective Reductions in Cholesterol Using Rosuvastatin TherapY (MERCURY) I trial. METHODS: This trial was conducted in 3140 hypercholesterolemic patients with CAD, atherosclerosis, type 2 diabetes mellitus, or a 20% 10-year risk for CAD. Patients were randomized to rosuvastatin 10 mg, atorvastatin 10 or 20 mg, simvastatin 20 mg, or pravastatin 40 mg for 8 weeks; all patients except those receiving rosuvastatin 10 mg either were switched to rosuvastatin 10 or 20 mg or remained on initial treatment for 8 more weeks. RESULTS: At 8 weeks, reductions in total cholesterol (TC):high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol:HDL-C, non-HDL-C:HDL-C, and apolipoprotein (apo) B:apo A-I ratios with rosuvastatin 10 mg were significantly greater than those with atorvastatin 10 mg, atorvastatin 20 mg, simvastatin 20 mg, and pravastatin 40 mg (P<0.0001 for all). At week 16, switching to rosuvastatin 10 mg from atorvastatin 10 mg, simvastatin 20 mg, and pravastatin 40 mg and to rosuvastatin 20 mg from atorvastatin 20 mg produced significantly greater reductions in all lipid ratios (P< or =0.0001 for all). Switching to rosuvastatin 10 mg from atorvastatin 20 mg produced significantly greater reductions in TC:HDL-C (P<0.025) and apo B:apo A-I (P<0.01). CONCLUSIONS: Rosuvastatin 10 mg reduces lipid ratios more than equivalent and higher doses of other statins; switching to equal or lower doses of rosuvastatin produces significantly improved reductions in lipid ratios.     

Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin

Background

Despite the efficacy of statins in lowering low-density lipoprotein cholesterol (LDL-C) levels, many patients who are at high risk for heart disease with hypercholesterolemia require additional LDL-C level reduction. The cholesterol absorption inhibitor, ezetimibe, has been shown to provide significant incremental reductions in LDL-C levels when co-administered with statins. This study was performed to compare the efficacy and safety of ezetimibe (10 mg) plus response-based atorvastatin titration versus response-based atorvastatin titration alone in the attainment of LDL-C goals in subjects who are at high risk for coronary heart disease (CHD) and are not at their LDL-C goal on the starting dose of atorvastatin.

Methods

This was a 14-week, multicenter, randomized, double-blind, active-controlled study conducted in 113 clinical research centers in 21 countries. Participants were adults with heterozygous familial hypercholesterolemia (HeFH), CHD, or multiple (≥2) cardiovascular risk factors, and a LDL-C level ≥130 mg/dL after a 6- to10-week dietary stabilization and atorvastatin (10 mg/day) open-label run-in period. Eligible subjects continued to receive atorvastatin (10 mg) and were randomized to receive blinded treatment with ezetimibe (10 mg/day; n = 305) or an additional 10 mg/day of atorvastatin (n = 316). The atorvastatin dose in both groups was doubled after 4 weeks, 9 weeks, or both when the LDL-C level was not at its goal (≤100 mg/dL), so that patients receiving combined therapy could reach 40 mg/day and patients receiving atorvastatin alone could reach 80 mg/day. The primary end point was the proportion of subjects achieving their LDL-C level goal at week 14. A secondary end point was the change in LDL-C level and other lipid parameters at 4 weeks after ezetimibe co-administration with 10 mg/day of atorvastatin versus 20 mg/day of atorvastatin monotherapy.

Results

The proportion of subjects reaching their target LDL-C level goal of ≤100 mg/dL was significantly higher in the co-administration group than in the atorvastatin monotherapy group (22% vs 7%; P <.01). At 4 weeks, levels of LDL-C, triglycerides, and non-high-density lipoprotein cholesterol were reduced significantly more by combination therapy than by doubling the dose of atorvastatin (LDL-C −22.8% versus −8.6%; P <.01). The combination regimen had a safety and tolerability profile similar to that of atorvastatin alone.

Conclusions

The addition of ezetimibe to the starting dose of 10 mg/day of atorvastatin followed by response-based atorvastatin dose titration to a maximum of 40 mg/day provides a more effective means for reducing LDL-C levels in patients at high risk for CHD than continued doubling of atorvastatin as high as 80 mg/day alone.     

Efficacy and safety of statins in hypercholesterolemia with emphasis on lipoproteins

Information of the effect of statin on lipoproteins such as apolipoprotein (apo) A-I, lipoprotein (a) [Lp (a)], or apolipoprotein B levels is limited. This investigation was a crossover study designed to evaluate the efficacy and safety of atorvastatin and simvastatin in patients with hyperlipidemia. Sixty-six patients were involved in the study. Group I consisted of 32 patients, who were first treated with atorvastatin (10 mg) then switched to simvastatin (10 mg). Group II consisted of 34 patients, who were first treated with simvastatin then switched to atorvastatin. Each regimen was used for 3 months (phase I), stopped for 2 months, and then restarted for another 3 months (phase II). Both statins effectively reduced total cholesterol, low-density lipoprotein cholesterol (LDL-C), apo B, and Lp (a) (P < 0.001 in all comparisons). A significant increase in the high-density lipoprotein cholesterol (HDL-C) was noted after both statin treatments (P < 0.05 in all comparisons). Both statins caused an increase in the apo A-I levels, and the extent of changes in apo A-I revealed no difference between the two drugs. Compared to the simvastatin group, there were more patients in the atorvastatin group achieving the National Cholesterol Education Program ATP-III LDL-C goal (P < 0.05) and European LDL-C goal (P < 0.001). Both treatments were well tolerated; no patient was withdrawn from the study. This study demonstrates that both statins can effectively improve lipid profiles in patients with hyperlipidemia. Atorvastatin is more effective in helping patients reach the ATP-III and European LDL-C goals than simvastatin at the same dosage.     

Effects of statin treatment on uric acid homeostasis in patients with primary hyperlipidemia

Background

Epidemiologic studies have shown that serum uric acid is a risk factor of coronary artery disease. In addition to fenofibrate, there is some evidence that atorvastatin may have a hypouricemic action, but the underlying mechanisms remain speculative.

Methods

This randomized trial was conducted to investigate the effects of atorvastatin and simvastatin on uric acid homeostasis in patients treated for primary hyperlipidemia. A total of 180 patients were enrolled; patients were randomly assigned to 40 mg/d of either atorvastatin or simvastatin. Serum lipid and metabolic parameters were measured at baseline and at 6 and 12 weeks of treatment; random urine samples were simultaneously obtained for creatinine, sodium, and uric acid determinations.

Results

Baseline serum uric acid levels correlated positively with the body mass index, serum insulin, creatinine, and triglyceride levels and inversely with serum HDL cholesterol levels. Both statins caused a favorable effect on lipids and a significant decrease in fibrinogen and high-sensitivity CRP levels. However, only atorvastatin reduced serum uric acid levels (from 5.6 ± 1.7 to 4.9 ± 1.5 mg/dL, P < .0001) by augmenting its urinary fractional excretion (from 10.4% ± 7.9% to 12.0% ± 7.4%, P < .01). In a multivariate logistic regression analysis, the reduction of uric acid levels was independently associated with baseline serum uric acid concentration but not to other variables, including lipid parameters (OR, 1.65; 95% CI, 1.14 to 2.40; P = .008).

Conclusions

Atorvastatin (but not simvastatin) significantly lowered serum uric acid levels. This result may be in favor of a preferable choice of atorvastatin for the treatment of hyperlipidemic patients presenting with hyperuricemia.     

Short term dietary sodium restriction decreases HDL cholesterol, apolipoprotein A-I and high molecular weight adiponectin in healthy young men: Relationships with renal hemodynamics and RAAS activation

Background and aims

We aimed to determine the effect of short-term dietary sodium restriction on plasma total cholesterol, LDL-C, HDL-C, triglycerides, apolipoprotein (apo) A-I, apo B and high molecular weight (HMW) adiponectin in non-obese, normotensive young men. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), plasma renin activity (PRA) and aldosterone were also measured.

Methods and results

Sixty-five men, aged 23 ± 7 years, were randomly studied on a high sodium intake (HS, 228 ± 77 mmol Na+/24 h) and a low sodium intake (LS, 36 ± 27 mmol Na+/24 h), each period lasting 1 week. LS decreased GFR and ERPF and increased PRA and aldosterone (p < 0.0001 for all). LS also induced a decrease in HDL-C (3.8 ± 10.8%), apo A-I (3.7 ± 6.5%) and HMW-adiponectin (13.6 ± 40.5%) (p < 0.05 for all), but plasma total cholesterol, LDL-C, triglycerides and apo B did not significantly change. The changes in HDL-C and apo A-I were correlated negatively to the changes in effective renal plasma flow (p < 0.05), whereas the changes in HMW adiponectin were correlated negatively to the changes in PRA and aldosterone (p < 0.05 for both).

Conclusion

Short term sodium restriction modestly decreases HDL-C, apo A-I and HMW-adiponectin in healthy men. Changes in GFR and ERPF and in the renin-angiotensin-aldosterone system as induced by LS may be involved in these responses.     

Comparison of effects of ezetimibe/simvastatin versus simvastatin versus atorvastatin in reducing C-reactive protein and low-density lipoprotein cholesterol levels

The lowering effects of ezetimibe/simvastatin combination therapy on low-density lipoprotein (LDL) cholesterol and high-sensitivity C-reactive protein (CRP) were compared with those of simvastatin or atorvastatin monotherapy in a large cohort of patients with primary hypercholesterolemia. To compare ezetimibe/simvastatin with simvastatin, data were combined from 3 identical, prospective 12-week trials in which patients were randomized to receive placebo; ezetimibe 10 mg; ezetimibe 10 mg added to simvastatin 10, 20, 40, or 80 mg; or simvastatin 10, 20, 40, or 80 mg. To compare ezetimibe/simvastatin with atorvastatin, data were analyzed from a phase III double-blind, active-controlled study in which patients were randomized equally to receive ezetimibe/simvastatin 10/10, 10/20, 10/40, or 10/80 mg or atorvastatin 10, 20, 40, or 80 mg for 6 weeks. When averaged across doses, ezetimibe/simvastatin produced significantly greater reductions compared with simvastatin alone in LDL cholesterol (52.5% vs 38.0%, respectively) and CRP levels (31.0% vs 14.3%, respectively). At each individual simvastatin dose, co-administration with ezetimibe produced significant further CRP reductions versus simvastatin alone. Ezetimibe/simvastatin was significantly more effective at lowering LDL cholesterol than atorvastatin when pooled across doses (53.4% vs 45.3%, respectively) and in each milligram-equivalent dose comparison. Reductions in CRP of similar magnitude were observed with ezetimibe/simvastatin and atorvastatin when averaged across doses and at each milligram-equivalent statin dose comparison. In conclusion, the lipid-modulating and anti-inflammatory effects of ezetimibe/simvastatin provide additional benefits not realized by statin monotherapy alone.     

Effects of Statins on High-Density Lipoproteins: A Potential Contribution to Cardiovascular Benefit

PURPOSE: The objective was to systematically review clinical trial data on the effects of statins on high-density lipoproteins (HDL) and to examine the possibility that this provides cardiovascular benefits in addition to those derived from reductions in low-density lipoproteins (LDL). METHODS: The PubMed database was searched for publications describing clinical trials of atorvastatin, pravastatin, rosuvastatin, and simvastatin. On the basis of predefined criteria, 103 were selected for review. RESULTS: Compared with placebo, statins raise HDL, measured as HDL-cholesterol (HDL-C) and apolipoprotein A-I (apo A-I); these elevations are maintained in the long-term. In hypercholesterolemia, HDL-C is raised by approximately 4% to 10%. The percentage changes are greater in patients with low baseline levels, including those with the common combination of high triglycerides (TG) and low HDL-C. These effects do not appear to be dose-related although there is evidence that, with the exception of atorvastatin, the changes in HDL-C are proportional to reductions in apo B-containing lipoproteins. The most likely explanation is a reduced rate of cholesteryl ester transfer protein (CETP)-mediated flow of cholesterol from HDL. There is some evidence that the statin effects on HDL reduce progression of atherosclerosis and risk of cardiovascular disease independently of reductions in LDL. CONCLUSION: Statins cause modest increases in HDL-C and apo A-I probably mediated by reductions in CETP activity. It is plausible that such changes independently contribute to the cardiovascular benefits of the statin class but more studies are needed to further explore this possibility.     

Increased levels of pregnancy-associated plasma protein-A in patients with hypercholesterolemia: the effect of atorvastatin treatment

Background

Serum levels of pregnancy-associated plasma protein-A (PAPP-A) have recently been linked to plaque instability and are increased in acute coronary syndromes. The relation between PAPP-A levels and coronary risk factors, namely blood lipids, has not been studied to date. We have therefore investigated whether serum PAPP-A levels are increased in asymptomatic hypercholesterolemic subjects and whether PAPP-A levels are influenced by atorvastatin therapy.

Methods

We examined 27 subjects with isolated hypercholesterolemia free of manifest vascular disease and 29 age-matched healthy control subjects. Patients were examined at baseline and after 10 weeks of atorvastatin treatment (20 mg/d).

Results

In untreated hypercholesterolemic subjects, PAPP-A levels were significantly higher than in control subjects (8.02 ± 1.86 mU/L vs 6.50 ± 2.54 mU/L, P = .018). There was no correlation between PAPP-A levels and serum lipid levels. Atorvastatin treatment reduced total and LDL-cholesterol by 31% and 40%, respectively. Despite this profound lipid lowering, there was no significant change in the serum PAPP-A levels.

Conclusions

PAPP-A levels are elevated in hypercholesterolemic subjects without clinical signs of atherosclerosis. PAPP-A may therefore not only reflect plaque instability but also serve as a marker of total atherosclerotic burden in asymptomatic subjects with hyperlipidemia. However, PAPP-A levels are not influenced by atorvastatin treatment.     

Long-Term Efficacy of Adding Fenofibric Acid to Moderate-Dose Statin Therapy in Patients with Persistent Elevated Triglycerides

Objective

The objective of this study was to evaluate the long-term efficacy of adding fenofibric acid to moderate-dose statin therapy in patients at goal for low-density lipoprotein cholesterol (LDL-C) but with persistent hypertriglyceridemia.

Methods

This is a post hoc analysis of a subset of patients (N?=?92) with mixed dyslipidemia treated with moderate-dose statin (rosuvastatin 20 mg, simvastatin 40 mg, or atorvastatin 40 mg) for 12 weeks in three controlled trials who had achieved LDL-C <100 mg/dL but whose triglycerides remained >200 mg/dL, and had fenofibric acid 135 mg added to the moderate-dose statin in a 52-week open-label extension study. Lipid and apolipoprotein (Apo) values and the proportion of patients meeting individual and combined treatment targets with combination therapy were determined at scheduled visits during the 52-week study and compared with baseline (start of extension study).

Results

Addition of fenofibric acid to moderate-dose statin for 52 weeks resulted in significant (P?P?=?0.007), and LDL-C?+?non–HDL-C?+?ApoB?+?HDL-C?+?triglycerides (25.6% vs 0.0%) than at baseline.

Conclusions

The addition of fenofibric acid to moderate-dose statin in patients whose LDL-C was optimal but whose triglycerides remained >200 mg/dL led to additional improvements in non–HDL-C, ApoB, HDL-C, and triglycerides that resulted in greater proportions of patients attaining optimal levels of the individual parameters as well as simultaneously achieving optimal levels of these parameters and LDL-C.

     

Vascular basis for the treatment of myocardial ischemia study: trial design and baseline characteristics

Background

Increased low-density lipoprotein (LDL) and oxidized LDL cholesterol levels adversely affect endothelial function in patients with stable coronary artery disease (CAD). Statin drugs are efficacious in primary and secondary prevention of clinical CAD events, but they have not been extensively studied as a treatment for ischemia during routine daily activities or during exercise, indicators of high-risk in patients with stable CAD. The purpose of the Vascular Basis for the Treatment of Myocardial Ischemia study is to determine whether aggressive lowering of LDL cholesterol level with atorvastatin, with or without supplemental antioxidant vitamins C and E, can improve endothelial function and ischemia during ambulatory electrocardiogram (AECG) monitoring and exercise treadmill testing (ETT).

Methods

Patients are eligible when they have ischemia during an ETT and AECG monitoring and when their fasting total cholesterol level is ≤250 mg/dL. Eligible patients are randomized to receive 1 of 3 treatments: intensive atorvastatin to reduce LDL cholesterol level to ≤80 mg/dL, intensive atorvastatin to reduce LDL cholesterol level to ≤80 mg/dL plus antioxidant vitamins C and E, and control of diet and low-dose lovastatin, when needed, to reduce LDL cholesterol level ≤ to 130 mg/dL. Patients undergo endothelial function testing, 48-hour AECG monitoring, and ETT at randomization and at 6 and 12 months.

Results

A total of 300 patients have been randomized: 101 to receive atorvastatin alone, 103 to receive atorvastatin plus antioxidant vitamins, and 96 to receive placebo. Baseline characteristics are similar across treatment groups.

Conclusions

The Vascular Basis study will provide important insight on the effects of aggressive management of dyslipidemia with statin drugs and antioxidant vitamins in patients with stable but high-risk CAD.     

Influence of age, gender, and race on the efficacy of adding ezetimibe to atorvastatin vs. atorvastatin up-titration in patients at moderately high or high risk for coronary heart disease

Background

Age, gender, and race are factors that influence atherosclerotic coronary heart disease (CHD) risk and may conceivably affect the efficacy of lipid-altering drugs.

Methods

Post hoc analysis of two multicenter, 6-week, double-blind, randomized, parallel-group trials assessed age (< 65 and ≥ 65 years), gender, and race (white, black, and other) effects on atorvastatin plus ezetimibe versus up-titration of atorvastatin in hypercholesterolemic patients with CHD risk. High CHD risk subjects with low-density lipoprotein (LDL) cholesterol levels ≥ 70 mg/dL (~ 1.81 mmol/L) during stable atorvastatin 40 mg therapy were randomized to atorvastatin 40 mg plus ezetimibe 10 mg, or up-titrated to atorvastatin 80 mg. Moderately high CHD risk subjects with LDL cholesterol levels ≥ 100 mg/dL (~ 2.59 mmol/L) with atorvastatin 20 mg were randomized to atorvastatin 20 mg plus ezetimibe 10 mg, or atorvastatin 40 mg.

Results

Although some variability existed, age, gender, and race subgroups did not substantially differ from the entire patient population with regard to lipid-altering findings. Ezetimibe plus atorvastatin produced greater percent reductions in LDL cholesterol, total cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B than up-titration of atorvastatin for all subgroups. HDL cholesterol and apolipoprotein AI changes were small and variable.

Conclusion

Treatment efficacy in age, gender, and race subgroups did not substantially differ from the entire study population. Ezetimibe combined with atorvastatin generally produced greater incremental reductions in LDL cholesterol and several other key lipid parameters compared with doubling the atorvastatin dose in hypercholesterolemic patients with high or moderately high CHD risk. These results suggest that co-administration of ezetimibe with statins is a useful therapeutic option for treatment of dyslipidemia in differing patient populations.     

International noninterventional study of acarbose treatment in patients with type 2 diabetes mellitus

Aim

To obtain data on efficacy, safety and tolerability of acarbose monotherapy or combination therapy during daily-life treatment.

Methods

This prospective, non-controlled, observational study enrolled patients with type 2 diabetes, whose physician decided that acarbose treatment was appropriate, from China, Middle East, Indonesia, Morocco, Pakistan, Philippines, Poland and Taiwan. The observation period included an initial visit and up to three follow-up visits; an extension of 2 years was realized in Pakistan and Poland.

Results

Of 14,574 patients enrolled, 14,418 comprised the intent-to-treat population. At the initial visit, 74.1% of patients had been treated with a glucose-lowering agent. Fasting blood glucose was reduced from 175.2 mg/dL at the initial visit to 133.7 mg/dL at the last visit (mean of 11.3 weeks after initial visit; P < 0.0001). Mean 2-h postprandial blood glucose decreased from 244.7 mg/dL to 172.4 mg/dL (P < 0.0001). HbA1c reduced from 8.4% to 7.4% (P < 0.0001). Glycemic efficacy was maintained over the 2-year extension period. There were 432 adverse events in 293 patients (2.03%), mainly gastrointestinal. Physicians assessed efficacy as “very good”/“good” in 85.1% of patients, and were “very satisfied”/“satisfied” with acarbose therapy in 94.3% of cases.

Conclusion

Acarbose therapy was efficacious and well tolerated in daily life in patients with type 2 diabetes.     

Statin-associated rhabdomyolysis: is there a dose-response relationship?

Background

Statins have a well-established role in prevention of vascular events but are associated with muscle-related adverse events. The dose relationship with these adverse events is unclear. We present an original analysis of Canadian and US case reports of statin-associated rhabdomyolysis with a focus on dose response. A typical clinical case is also summarized.

Methods

All cases of statin-associated rhabdomyolysis reported to Health Canada's Canadian Vigilance Program and to the US Food and Drug Administration's Adverse Event Reporting System from 2004-2008 were analyzed by severity and dose equivalence. Canadian national statin utilization data from 2002-2007 were used to estimate the dose-related incidence of rhabdomyolysis corrected for levels of utilization.

Results

The clinical case illustrates well the potential severity of statin-induced rhabdomyolysis. Combined Canadian/US data revealed an average of 812 cases of statin-induced rhabdomyolysis reported annually with a mean patient age of 64.4 years (35.5% female). The worst outcomes reported were renal dysfunction in 17.0%, acute renal failure in 19.8%, dialysis in 5.2%, and death in 7.6%. Using 10 mg atorvastatin per day as the reference dose, the odds ratios of rhabdomyolysis were 3.8 (95% CI 2.3-6.6) for 40 mg/day atorvastatin dose equivalent and 11.3 (95% CI 6.4-20.4) for 80 mg/day atorvastatin dose equivalent.

Conclusions

The results of our adverse drug analysis suggest a dose-response relationship. Given the widespread use of statins, the ability to predict which patients will experience serious muscle-related harm is a research priority.     

Economic evaluation of high-dose (80 mg/day) atorvastatin treatment compared with standard-dose (20 mg/day to 40 mg/day) simvastatin treatment in Canada based on the Incremental Decrease in End-Points Through Aggressive Lipid-Lowering (IDEAL) trial

BACKGROUND:

The Incremental Decrease in End-Points Through Aggressive Lipid-Lowering (IDEAL) trial demonstrated incremental cardiovascular benefit of treatment with high-dose atorvastatin (80 mg/day) versus standard-dose simvastatin (20 mg/day to 40 mg/day) in 8888 patients with a previous myocardial infarction (MI) over a median follow-up period of 4.8 years.

OBJECTIVES:

To assess the cost-effectiveness of high-dose atorvastatin versus standard-dose simvastatin treatment in patients with a history of MI from a Canadian societal perspective.

METHODS:

In a within-trial analysis, end point-related events, resources used and productivity losses occurring during the IDEAL trial were aggregated by treatment arm on an intention-to-treat basis to calculate the incremental cost per event avoided. Additionally, quality-adjusted survival was projected using a lifetime Markov model. Transition probabilities, workdays lost, use of study medication and cardiovascular hospitalization rates were based on IDEAL trial data. Hospitalization, study medication and productivity costs were included. Probabilistic and deterministic sensitivity analyses were performed.

RESULTS:

Compared with standard-dose simvastatin, atorvastatin 80 mg led to 0.099 fewer events per patient and cost savings over 4.8 years of treatment. Over a lifetime horizon, atorvastatin 80 mg led to 0.023 quality-adjusted life years (QALYs) gained per patient at an incremental cost of $26,795/QALY gained. The incremental cost-effectiveness ratio remained below $50,000/QALY in 78% of 1000 simulations. Exclusion of indirect costs resulted in an incremental cost-effectiveness ratio of $38,834/QALY. Results were relatively sensitive to baseline age, but robust with respect to sex, baseline low-density lipoprotein cholesterol levels, diabetes status and hospitalization costs.

CONCLUSION:

From a Canadian societal perspective, high-dose atorvastatin is cost-effective compared with standard-dose simvastatin in patients with a previous MI.     

Aspirin resistance and adverse clinical events in patients with coronary artery disease

Purpose

We sought to determine the clinical significance of aspirin resistance measured by a point-of-care assay in stable patients with coronary artery disease (CAD).

Methods

We used the VerifyNow Aspirin (Accumetrics Inc, San Diego, Calif) to determine aspirin responsiveness of 468 stable CAD patients on aspirin 80 to 325 mg daily for ≥4 weeks. Aspirin resistance was defined as an Aspirin Reaction Unit ≥550. The primary outcome was the composite of cardiovascular death, myocardial infarction (MI), unstable angina requiring hospitalization, stroke, and transient ischemic attack.

Results

Aspirin resistance was noted in 128 (27.4%) patients. After a mean follow-up of 379 ± 200 days, patients with aspirin resistance were at increased risk of the composite outcome compared to patients who were aspirin-sensitive (15.6% vs 5.3%, hazard ratio [HR] 3.12, 95% confidence intervals [CI], 1.65-5.91, P < .001). Cox proportional hazard regression modeling identified aspirin resistance, diabetes, prior MI, and a low hemoglobin to be independently associated with major adverse long-term outcomes (HR for aspirin resistance 2.46, 95% CI, 1.27-4.76, P = .007).

Conclusions

Aspirin resistance, defined by an aggregation-based rapid platelet function assay, is associated with an increased risk of adverse clinical outcomes in stable patients with CAD.     

Prognostic implication of creatine kinase release after elective percutaneous coronary intervention in the pre-IIb/IIIa antagonist era

Background

The significance of mild elevations in cardiac enzymes after an elective percutaneous coronary intervention (PCI) still remains controversial. We evaluated the significance of creatine phosphokinase level (CPK) elevations in a large cohort of patients who had undergone an elective PCI before the IIb/IIIa receptor antagonist era.

Methods

All patients enrolled in the Emory databank from 1981 to 1996 who had an elective PCI were evaluated. We identified 15,637 patients who met our inclusion and exclusion criteria. Patients were divided into 4 groups on the basis of the magnitude of the CPK elevation noted in the post-PCI period: group I (CPK <250 mg/dL, n = 14,512); group II (CPK 250-500 mg/dL, n = 715); group III (CPK 500-750 mg/dL, n = 164); and group IV (CPK >750 mg/dL, n = 246).

Results

CPK elevations were associated with a significant increase in the periprocedure angiographic complications. Angiographic complication rates were 14.6%, 30.5%, 40.2%, and 43.5% in groups I, II, III, and IV, respectively (P < .001). Long-term survival also correlated inversely with the magnitude of CPK elevations. The 10-year survival rates were 73%, 71%, 69%, and 55% in groups I, II, III, and IV, respectively (P < .0001). After multivariate analysis to correct for clinical factors, a CPK elevation of at least 3-times normal (group IV) was found to be an independent predictor of diminished 30-day and long-term survival (hazard ratio 1.84, 95% CI 1.41-2.41, P < .0001). Elevations in CPK <3-times normal (groups II and III) were not independently predictive of poor long-term survival.

Conclusion

A CPK level >3-times normal after an elective PCI is a strong independent predictor of poor long-term prognosis.