Reduction in albuminuria with dapagliflozin cannot be predicted by baseline clinical characteristics or changes in most other risk markers.

The sodium glucose co-transporter-2 inhibitor dapagliflozin has been shown to decrease urinary albumin-to-creatinine ratio (UACR). This effect, however, varies among individual patients. In this study, we assessed the baseline characteristics and concurrent changes in other cardiovascular risk markers that might be associated with UACR response to dapagliflozin. A pooled analysis of 11 phase 3 randomized, controlled clinical trials was performed. UACR change from baseline after 24 weeks treatment with dapagliflozin 10 mg/d in 531 patients with type 2 diabetes and UACR ≥30 mg/g at baseline was determined. UACR response was defined as >30% reduction from baseline at 24 weeks, whereas UACR non-response was defined as ≤30% reduction at 24 weeks. A total of 288 (54%) patients were classified as responders and 243 (46%) as non-responders. At 24 weeks, the UACR-adjusted mean change from baseline was -71.2% and 25.9% in responders and non-responders, respectively. Baseline characteristics were similar between both groups. Changes in HbA1c and body weight were comparable across groups. Responders showed a numerically larger reduction in estimated glomerular filtration rate and systolic blood pressure versus non-responders. UACR reduction to dapagliflozin is an individual characteristic that cannot be predicted by baseline clinical features or changes in metabolic variables. Whether UACR response would improve long-term renal and cardiovascular outcomes remains to be determined.

Effect of rosuvastatin therapy on coronary artery stenoses assessed by quantitative coronary angiography: a study to evaluate the effect of rosuvastatin on intravascular ultrasound-derived coronary atheroma burden.

BACKGROUND: Previous studies using quantitative coronary angiography have demonstrated that statin therapy slows the progression of coronary stenoses in proportion to average low-density lipoprotein cholesterol levels during therapy. However, no major statin monotherapy study has demonstrated either halted progression or regression of angiographic disease. A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) assessed whether rosuvastatin could regress coronary atherosclerosis by intravascular ultrasound and quantitative coronary angiography. Intravascular ultrasound showed atheroma volume regression in a single coronary artery with <50% angiographic luminal narrowing. METHODS AND RESULTS: ASTEROID treated 507 coronary disease patients with rosuvastatin 40 mg/d for 24 months. Blinded quantitative coronary angiography analyses of percent diameter stenosis and minimum lumen diameter were performed for up to 10 segments of coronary arteries and major branches with >25% diameter stenosis at baseline. For each patient, the mean of all matched lesions at baseline and study end was calculated. There were 292 patients with 613 matched stenoses. Rosuvastatin reduced low-density lipoprotein cholesterol by 53.3% to 61.1+/-20.3 mg/dL and increased high-density lipoprotein cholesterol by 13.8% to 48.3+/-12.4 mg/dL. Mean+/-SD percent diameter stenosis decreased from 37.3+/-8.4% (median, 35.7%; range, 26% to 73%) to 36.0+/-10.1% (median, 34.5%; range, 8% to 74%; P<0.001). Minimum lumen diameter increased from 1.65+/-0.36 mm (median, 1.62 mm; range, 0.56 to 2.65 mm) to 1.68+/-0.38 mm (median, 1.67 mm; range, 0.76 to 2.77 mm; P<0.001). CONCLUSIONS: Rosuvastatin treatment for 24 months to average low-density lipoprotein cholesterol levels well below 70 mg/dL, accompanied by significant increases in high-density lipoprotein cholesterol, produced regression by decreasing percent diameter stenosis and improving minimum lumen diameter as measured by quantitative coronary angiography in coronary disease patients.

Effect of rosuvastatin therapy on carotid plaque morphology and composition in moderately hypercholesterolemic patients: a high-resolution magnetic resonance imaging trial.

BACKGROUND: Magnetic resonance imaging (MRI) can noninvasively assess changes in atherosclerotic plaque morphology and composition. The ORION trial assessed the effects of rosuvastatin on carotid plaque volume and composition. METHODS: The randomized, double-blind ORION trial used 1.5-T MRI to image carotid atherosclerotic plaques at baseline and after 24 months of treatment. Forty-three patients with fasting low-density lipoprotein cholesterol > or = 100 and < 250 mg/dL and 16% to 79% carotid stenosis by duplex ultrasound were randomized to receive either a low (5 mg) or high (40/80 mg) dose of rosuvastatin. RESULTS: After 24 months, 33 patients had matched serial MRI scans to compare by reviewers blinded to clinical data, dosage, and temporal sequence of scans. Low-density lipoprotein cholesterol was significantly reduced from baseline in both the low- and high-dose groups (38.2% and 59.9%, respectively, both P < .001). At 24 months, there were no significant changes in carotid plaque volume for either dosage group. In all patients with a lipid-rich necrotic core (LRNC) at baseline, the mean proportion of the vessel wall composed of LRNC (%LRNC) decreased by 41.4% (P = .005). CONCLUSIONS: In patients with moderate hypercholesterolemia, both low- and high-dose rosuvastatin were effective in reducing low-density lipoprotein cholesterol. Furthermore, rosuvastatin was associated with a reduction in %LRNC, whereas the overall plaque burden remained unchanged over the course of 2 years of treatment. These findings provide evidence that statin therapy may have a beneficial effect on plaque volume and composition, as assessed by noninvasive MRI.

An evaluation of the effects of an angiotensin receptor blocker on health-related quality of life in patients with high-normal blood pressure (prehypertension) in the Trial of Preventing Hypertension (TROPHY).

The Trial of Preventing Hypertension (TROPHY) demonstrated the feasibility of possibly reducing the incidence of hypertension with the angiotensin receptor blocker candesartan compared with placebo. The long-term benefits of pharmacologic therapy in high-normal blood pressure, or prehypertension are not known, and the long-term effect on health-related quality of life (HRQL) has not been determined. An analysis of covariance model was used to assess treatment differences from baseline in the HRQL scores using Short Form (SF)-36, and component measures at subsequent visits. Of the 809 randomized patients, 734 had both baseline and > or =1 HRQL follow-up assessment: 95% (379 of 397) of patients receiving candesartan and 91% (355 of 388) of patients receiving placebo. There were no statistically significant between-group differences in least-squares mean physical component survey and mental component survey scores or the individual scales at each scheduled visit relative to baseline values (P >.05). In TROPHY, patients with prehypertension had relatively high baseline HRQL, and HRQL was maintained with the angiotensin receptor blocker candesartan over both the 2-year treatment period and a total 4-year trial period.

Efficacy and safety of dapagliflozin in Asian patients: A pooled analysis.

BACKGROUND: The efficacy and safety of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, has been demonstrated predominantly in Western populations. This study examined the efficacy and safety of dapagliflozin in Asian patients with type 2 diabetes mellitus (T2DM) from eight Phase IIb/III double-blind trials of up to 24 weeks, treated with placebo (n = 497) or dapagliflozin 5 mg (n = 491) or 10 mg (n = 465). METHODS: Efficacy was assessed in the pooled population receiving dapagliflozin 5, 10 mg or placebo over 24 weeks. Safety and tolerability were assessed by collating data for overall adverse events (AEs) and AEs of special interest over the 24-week period. RESULTS: Demographic and baseline characteristics were comparable across treatment groups. Placebo-corrected adjusted mean changes from baseline at 24 weeks in the dapagliflozin 5 and 10 mg groups, respectively, were -0.52% and -0.58% for HbA1c and -1.34 and -1.80 kg for body weight. Modest reductions in blood pressure were also noted with dapagliflozin. Overall, 56.5%, 53.6%, and 58.7% of patients in the placebo and dapagliflozin 5 and 10 mg groups, respectively, experienced AEs, compared with 2.8%, 4.1%, and 2.4% experiencing serious AEs. Genital infections were more frequent with dapagliflozin 10 mg than placebo, whereas the pattern for urinary tract infections was less clear. A transient reduction in mean estimated glomerular filtration rate was noted with dapagliflozin, but was not associated with an increased frequency of serious renal AEs. In contrast, placebo-corrected reductions in urinary albumin : creatinine ratio in patients with albuminuria at baseline suggest a potential renoprotective effect of dapagliflozin. CONCLUSION: Dapagliflozin was efficacious and well tolerated in Asian patients with T2DM.

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 Cholesterol 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 > or = 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.

A Comparison of Statin Therapies in Hypercholesterolemia in Women: A Subgroup Analysis of the STELLAR Study.

OBJECTIVE: Cardiovascular disease is the leading cause of mortality in women in the United States. Aggressive treatment of modifiable risk factors (e.g., hypercholesterolemia) is essential in reducing disease burden. Despite guidelines recommending the use of statin treatment in hypercholesterolemic women, this patient group is often undertreated. This subgroup analysis of the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial examines the effects of statin therapy in hypercholesterolemic women. METHODS: As part of the STELLAR trial, 1,146 women with elevated low-density lipoprotein cholesterol (LDL-C ≥160 and <250 mg/dL) and triglycerides <400 mg/dL were randomized to rosuvastatin 10-40 mg, atorvastatin 10-80 mg, simvastatin 10-80 mg, or pravastatin 10-40 mg for 6 weeks. RESULTS: LDL-C reduction with rosuvastatin 10 mg, atorvastatin 10 mg, simvastatin 20 mg, and pravastatin 40 mg was 49%, 39%, 37%, and 30%, respectively, after 6 weeks. High-intensity statins (rosuvastatin 20-40 mg and atorvastatin 40-80 mg) reduced LDL-C to the greatest extent: 53% with rosuvastatin 20 mg, 57% with rosuvastatin 40 mg, 47% with atorvastatin 40 mg, and 51% with atorvastatin 80 mg. Similar results were observed for non-high-density lipoprotein cholesterol (non-HDL-C). Increases in HDL-C were greater with rosuvastatin across doses than with other statins. All treatments were well tolerated, with similar safety profiles across dose ranges. CONCLUSIONS: Statin therapies in the STELLAR trial led to reductions in LDL-C, non-HDL-C, and triglycerides and increases in HDL-C among hypercholesterolemic women, with rosuvastatin providing the greatest reductions in LDL-C and non-HDL-C.

Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Hypertension is a common comorbidity in patients with type 2 diabetes mellitus and a major risk factor for microvascular and macrovascular disease. Although the blood pressure-lowering effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors are already established, guidance is needed on how to use these drugs in patients already receiving antihypertensive therapy. We aimed to compare blood pressure and glycaemic effects of the SGLT2 inhibitor dapagliflozin with placebo in patients with inadequately controlled type 2 diabetes mellitus and hypertension. METHODS: In this double-blind, placebo-controlled, phase 3 study we enrolled patients from 311 centres in 16 countries across five continents. Patients had uncontrolled type 2 diabetes (HbA1c 7·0%-10·5%; 53-91 mmol/mol) and hypertension (systolic 140-165 mm Hg and diastolic 85-105 mm Hg at both enrolment and randomisation, and a mean 24 h blood pressure of ≥130/80 mm Hg by ambulatory monitoring within 1 week of randomisation) and were receiving oral antihyperglycaemic drugs, insulin, or both, plus a renin-angiotensin system blocker and an additional antihypertensive drug. Using an interactive voice-response system, we randomly assigned (1:1) patients to dapagliflozin 10 mg once a day or to placebo, with randomisation stratified by additional antihypertensive drug use and insulin use at baseline, in a block size of two. The co-primary endpoints were changes in seated systolic blood pressure and HbA1c measured in the full analysis set, which included all patients who received at least one dose of study drug and had both a baseline and at least one post-baseline measurement of efficacy. This trial is registered with ClinicalTrials.gov, number NCT01195662. FINDINGS: Between Oct 29, 2010, and Oct 4, 2012, we randomly assigned 225 patients to dapagliflozin and 224 to placebo. Seated systolic blood pressure was significantly reduced in the group assigned to dapagliflozin (adjusted mean change from baseline -11·90 mm Hg [95% CI -13·97 to -9·82]) compared with those assigned to placebo (-7·62 mm Hg [-9·72 to -5·51]; placebo-adjusted difference for dapagliflozin -4·28 mm Hg [-6·54 to -2·02]; p=0·0002). Reductions in HbA1c concentrations were also significantly greater in patients assigned to dapagliflozin (adjusted mean change from baseline -0·63% [95% CI -0·76 to -0·50]) than in those assigned to placebo (-0·02% [-0·15 to 0·12]; placebo-adjusted difference -0·61% [-0·76 to -0·46,]; p<0·0001). In a post-hoc analysis, we found difference in blood pressure versus placebo was greater in patients receiving a ß blocker (-5·76 mm Hg [95% CI -10·28 to -1·23]) or a calcium-channel blocker (-5·13 mm Hg, [-9·47 to -0·79]) as their additional antihypertensive drug than in those receiving a thiazide diuretic (-2·38 mm Hg [-6·16 to 1·40]). Adverse events were similar in the dapagliflozin and placebo groups (98 [44%] patients vs 93 [42%], respectively, had at least one adverse event), with few adverse events related to renal function (1% vs <1%) or volume depletion (<1% vs 0%). INTERPRETATION: Dapagliflozin 10 mg significantly improved blood pressure and HbA1c and was tolerated similarly to placebo. Its blood pressure-lowering properties were particularly favourable in patients already receiving a ß blocker or calcium-channel blocker. Dapagliflozin could benefit patients with type 2 diabetes who need a diuretic-like effect to optimise control of blood pressure, adding meaningful efficacy to antihypertensive drug regimens. FUNDING: Bristol-Myers Squibb, AstraZeneca.

Effects of rosuvastatin, atorvastatin, simvastatin, and pravastatin on atherogenic dyslipidemia in patients with characteristics of the metabolic syndrome.

The metabolic syndrome (MS) is a constellation of coronary risk factors. Atherogenic dyslipidemia is an important factor in cardiovascular risk in these patients, and treatment of atherogenic dyslipidemia has been identified as an important goal of therapy in patients with MS. This post hoc analysis of data from a 6-week, randomized, open-label, parallel-group, comparative trial (Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin [STELLAR]) assessed the effects of rosuvastatin 10, 20, and 40 mg, atorvastatin 10, 20, 40, and 80 mg, simvastatin 10, 20, 40, and 80 mg, and pravastatin 10, 20, and 40 mg on plasma lipids in hypercholesterolemic patients (low-density lipoprotein cholesterol >/=160 and <250 mg/dl; triglycerides <400 mg/dl) who had >/=3 of the 5 National Cholesterol Education Program Adult Treatment Panel III criteria for MS (body mass index >30 kg/m(2) substituted for waist circumference). Of 2,268 patients, 811 met criteria for MS. Percent reductions in low-density lipoprotein cholesterol ranged from 20% in the pravastatin 10-mg group to 55% in the rosuvastatin 40-mg group. In patients with MS, triglyceride reductions were 22% to 34% with rosuvastatin, 23% to 33% with atorvastatin, 15% to 23% with simvastatin, and 12% to 15% with pravastatin. High-density lipoprotein cholesterol increased by 8% to 11% with rosuvastatin, 5% to 9% with atorvastatin, 8% to 10% with simvastatin, and 3% to 7% with pravastatin. Rosuvastatin, atorvastatin, simvastatin, and pravastatin treatment had favorable effects in hypercholesterolemic patients on the atherogenic dyslipidemia associated with MS. Rosuvastatin had the most favorable effect on the atherogenic lipid profile of MS overall.

Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): a randomised clinical trial.

BACKGROUND: The role of lipid-lowering treatments in renoprotection for patients with diabetes is debated. We studied the renal effects of two statins in patients with diabetes who had proteinuria. METHODS: PLANET I was a randomised, double-blind, parallel-group trial done in 147 research centres in Argentina, Brazil, Bulgaria, Canada, Denmark, France, Hungary, Italy, Mexico, Romania, and the USA. We enrolled patients with type 1 or type 2 diabetes aged 18 years or older with proteinuria (urine protein:creatinine ratio [UPCR] 500-5000 mg/g) and taking stable angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or both. We randomly assigned participants to atorvastatin 80 mg, rosuvastatin 10 mg, or rosuvastatin 40 mg for 52 weeks. The primary endpoint was change from baseline to week 52 of mean UPCR in each treatment group. The study is registered with ClinicalTrials.gov, number NCT00296374. FINDINGS: We enrolled 353 patients: 118 were assigned to rosuvastatin 10 mg, 124 to rosuvastatin 40 mg, and 111 to atorvastatin 80 mg; of these, 325 were included in the intention-to-treat population. UPCR baseline:week 52 ratio was 0·87 (95% CI 0·77-0·99; p=0·033) with atorvastatin 80 mg, 1·02 (0·88-1·18; p=0·83) with rosuvastatin 10 mg, and 0·96 (0·83-1·11; p=0·53) with rosuvastatin 40 mg. In a post-hoc analysis to compare statins, we combined data from PLANET I with those from PLANET II (a similar randomised parallel study of 237 patients with proteinuria but without diabetes; registered with ClinicalTrials.gov, NCT00296400). In this analysis, atorvastatin 80 mg lowered UPCR significantly more than did rosuvastatin 10 mg (-15·6%, 95% CI -28·3 to -0·5; p=0·043) and rosuvastatin 40 mg (-18·2%, -30·2 to -4·2; p=0·013). Adverse events occurred in 69 (60%) of 116 patients in the rosuvastatin 10 mg group versus 79 (64%) of 123 patients in the rosuvastatin 40 mg group versus 63 (57%) of 110 patients in the atorvastatin 80 mg group; renal events occurred in nine (7·8%) versus 12 (9·8%) versus five (4·5%). INTERPRETATION: Despite high-dose rosuvastatin lowering plasma lipid concentrations to a greater extent than did high-dose atorvastatin, atorvastatin seems to have more renoprotective effects for the studied chronic kidney disease population. FUNDING: AstraZeneca.

Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial).

The primary objective of this 6-week, parallel-group, open-label, randomized, multicenter trial was to compare rosuvastatin with atorvastatin, pravastatin, and simvastatin across dose ranges for reduction of low-density lipoprotein (LDL) cholesterol. Secondary objectives included comparing rosuvastatin with comparators for other lipid modifications and achievement of National Cholesterol Education Program Adult Treatment Panel III and Joint European Task Force LDL cholesterol goals. After a dietary lead-in period, 2,431 adults with hypercholesterolemia (LDL cholesterol > or =160 and <250 mg/dl; triglycerides <400 mg/dl) were randomized to treatment with rosuvastatin 10, 20, 40, or 80 mg; atorvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; or pravastatin 10, 20, or 40 mg. At 6 weeks, across-dose analyses showed that rosuvastatin 10 to 80 mg reduced LDL cholesterol by a mean of 8.2% more than atorvastatin 10 to 80 mg, 26% more than pravastatin 10 to 40 mg, and 12% to 18% more than simvastatin 10 to 80 mg (all p <0.001). Mean percent changes in high-density lipoprotein cholesterol in the rosuvastatin groups were +7.7% to +9.6% compared with +2.1% to +6.8% in all other groups. Across dose ranges, rosuvastatin reduced total cholesterol significantly more (p <0.001) than all comparators and triglycerides significantly more (p <0.001) than simvastatin and pravastatin. Adult Treatment Panel III LDL cholesterol goals were achieved by 82% to 89% of patients treated with rosuvastatin 10 to 40 mg compared with 69% to 85% of patients treated with atorvastatin 10 to 80 mg; the European LDL cholesterol goal of <3.0 mmol/L was achieved by 79% to 92% in rosuvastatin groups compared with 52% to 81% in atorvastatin groups. Drug tolerability was similar across treatments.

Safety, tolerability, pharmacokinetics, and time course of pharmacologic response of the active metabolite of roxifiban, XV459, a glycoprotein IIb/IIIa antagonist, following oral administration in healthy volunteers.

Roxifiban is an esterprodrug that is hydrolyzed, after oral administration, to the active glycoprotein (GP) IIb/IIIa antagonist, XV459. The objectives of the study were to investigate the safety, tolerability, pharmacokinetics, and the time course of the pharmacologic response of XV459 in escalating doses of roxifiban and to assess the effect of age, loading dose of roxifiban, and aspirin pretreatment on XV459 pharmacokinetics, pharmacologic response, and safety profile in a five-part double-blind, placebo-controlled study. Healthy male volunteers (ages 18-46 years) received 7 (0.75-1.5 mg; n = 20) and 10 (0.75-1.0 mg; n = 8) multiple, oral, qd doses of roxifiban or placebo (n = 5). Healthy older male and female volunteers (ages 47-75 years) received roxifiban qd doses (0.5-0.75 mg; n = 8) or placebo (n = 3) for 7 days. Healthy male subjects (ages 18-46 years; n = 16) received a 1.5 or 1.0 mg loading dose either with or without pretreatment of 325 mg aspirin once daily for 3 days followed by single daily doses of 1.0 mg roxifiban for 6 days. Measurable plasma concentrations of XV459 appeared rapidly and were sustained throughout the dosing interval of 24 hours. The pharmacokinetics of XV459 were nonlinear. Systemic exposure of XV459 plateaued at the 1-mg dose level; plasma concentrations approached steady state in 4 to 6 days for doses greater than 1.0 mg. The time course of pharmacologic response as measured by the inhibition of platelet aggregation in response to an ex vivo 10 microM adenosine 5'-diphosphate (ADP) agonist correlated closely to the plasma concentration of XV459. Potent inhibition of ADP-induced platelet aggregation (IPA) persisted over the entire dosing interval. A clear dose response was achieved with roxifiban doses of 0.5 and 1.0 mg. For doses greater than 1.0 mg, a dose-proportional increase in IPA was not observed. Both the pharmacokinetics and pharmacologic response of XV459 exhibited low intraindividual variability (coefficient of variation [CV] < 15%) and higher interindividual variability (CV < 30%). Pretreatment with aspirin and/or a loading dose of 1.5 mg roxifiban had no significant effect on the pharmacokinetics and pharmacologic response of XV459. A dose-related increase in template bleeding time was observed at 1.25- and 1.5-mg doses of roxifiban, as compared to placebo. However, these bleeding time increases in the 1.25- and 1.5-mg dose groups were not significantly different from those at the lower dose groups. Overall, once-daily oral administration of roxifiban was fairly well tolerated and provided sustained systemic drug exposure and pharmacologic response over the entire administration interval.

Comparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin, and pravastatin in achieving lipid goals: results from the STELLAR trial.

In the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial, the efficacy of rosuvastatin calcium (Crestor) was compared with that of atorvastatin (Lipitor), simvastatin (Zocor), and pravastatin (Pravachol) for lowering plasma low-density lipoprotein cholesterol (LDL-C) after 6 weeks of treatment. In this multicenter, parallel-group, open-label trial, adults with hypercholesterolemia were randomized to treatments with rosuvastatin 10, 20, 40, or 80 mg, atorvastatin 10, 20, 40, or 80 mg, simvastatin 10, 20, 40, or 80 mg, or pravastatin 10, 20, or 40 mg. Efficacy and safety results from this trial have been previously published. The additional analyses included in this report show that 53% (83/156) to 80% (125/157) of patients in the rosuvastatin 10- to 40-mg groups achieved LDL-C levels < 100 mg/dl (< 2.6 mmol/l), compared with 18% (28/158) to 70% (115/165) of patients who received atorvastatin, 8% (13/165) to 53% (86/163) of patients who received simvastatin, and 1% (1/160) to 8% (13/161) of patients who received pravastatin. Other additional analyses showed that more patients in the rosuvastatin 10- to 40-mg groups than in the comparator groups who were at high risk of coronary heart disease according to National Cholesterol Education Program Adult Treatment Panel (ATP) III, Joint European Societies, or Canadian guidelines achieved the LDL-C goals of < 100 mg/dl (< 2.6 mmol/l) (55% to 77% compared with 0 to 64%), < 3.0 mmol/l (< 116 mg/dl) (76% to 94% compared with 6% to 81%), and < 2.5 mmol/l (< 97 mg/dl) (47% to 69% compared with 0 to 53%), respectively. Results favoring rosuvastatin versus the comparators were also reported for patients: (a) who had triglycerides > or = 200mg/dl (> or = 2.3 mmol/l), and achieved both ATP III LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) goals (80% to 84% versus 15% to 84%); (b) overall who achieved the Canadian LDL-C goals of < 2.5 (< 97 mg/dl) to < 5.0 mmol/l (< 193 mg/dl) (85% to 91% versus 44% to 86%); and (c) who achieved all 3 Canadian goals for LDL-C, triglycerides (< 3.0 mmol/l [< 266 mg/dl] to < 2.0 mmol/l [< 177 mg/dl]), and the total cholesterol/high-density lipoproteincholesterol ratio (< 4 to < 7) (70% to 83% versus 35% to 79%).

The use of roxifiban (DMP754), a novel oral platelet glycoprotein IIb/IIIa receptor inhibitor, in patients with stable coronary artery disease.

INTRODUCTION: Intravenous platelet glycoprotein (GP) IIb/IIIa receptor inhibitors have a significant beneficial impact on the outcomes of patients undergoing high-risk coronary interventions and in the stabilization of patients with unstable angina pectoris refractory to conventional medical treatment. The role of long-term treatment with oral platelet GP IIb/IIIa receptor inhibitors in patients with coronary artery disease is unproven. This study examined the dose-response effect on inhibition of platelet aggregation by roxifiban (DMP754), a novel oral platelet GP IIb/IIIa receptor inhibitor, and its safety and tolerability in patients with a history of chronic stable angina pectoris. METHODS: Ninety-eight patients were randomized to receive either a placebo or 1 of 8 oral dosages of roxifiban. Twenty-two patients were enrolled in multiple-dose regimens, bringing the total study population to 120. The oral dosages were 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, or 2.5 mg/day for up to 30 days. RESULTS: Pharmacodynamic response of roxifiban was clearly dose-dependent. Platelet aggregation inhibition in response to 10 micromol/L slope adenosine diphosphate was sustained throughout the study period (up to 1 month). No serious adverse events, including significant major bleeding events, were associated with roxifiban treatment. Minor bleeding was reported in 5% of participants in the placebo group (1 of 21 cases) versus 26% in the study group (26 of 99 cases). Incidence of minor bleeding associated with roxifiban 2 and 2.5 mg/day was significantly (p < or = 0.05) greater than that with placebo. Adverse events, including gastrointestinal disorders, platelet and clotting disorders, and urinary tract disorders, were observed in 1 of 21 cases (5%) in the placebo group and in 12 of 99 cases (12%) in the study group. Reversible thrombocytopenia without other complications developed in two patients. CONCLUSIONS: Roxifiban-induced inhibition of platelet aggregation was dose-dependent and sustained throughout the study period: higher drug dosages correlated with higher levels of platelet inhibition and higher incidence of minor bleeding events. No serious adverse events were observed at any dosage. Thus, roxifiban appears to be a potent oral platelet GP IIb/IIIa receptor inhibitor that is clinically well-tolerated and deserves further study as a new treatment strategy in patients with chronic stable angina pectoris.

Efficacy, safety and effect on biomarkers related to cholesterol and lipoprotein metabolism of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg vs. simvastatin 40 or 80 mg plus ezetimibe 10 mg in high-risk patients: Results of the GRAVITY randomized study.

OBJECTIVES: Combination therapy may help high-risk patients achieve low-density lipoprotein cholesterol (LDL-C) goals. Impact of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg (RSV10/EZE10 and RSV20/EZE10) has not been fully characterized previously. GRAVITY (NCT00525824) compared efficacy, safety and effect on biomarkers of RSV10/EZE10 and RSV20/EZE10 vs. simvastatin 40 mg and 80 mg plus EZE10 (SIM40/EZE10 and SIM80/EZE10) in patients with coronary heart disease (CHD) or CHD risk equivalent. METHODS: Adult patients (n = 833) were randomized to RSV10/EZE10, RSV20/EZE10, SIM40/EZE10 or SIM80/EZE10. Following a 6-week dietary lead-in, patients received 6 weeks' statin monotherapy followed by same statin dose plus ezetimibe for 6 more weeks. Primary endpoint was LDL-C change from baseline to 12 weeks. RESULTS: Significantly greater (p < 0.05) reductions in LDL-C and other atherogenic lipids were observed with RSV20/EZE10 vs. SIM40/EZE10 and SIM80/EZE10 and with RSV10/EZE10 vs. SIM40/EZE10. A significantly greater proportion of patients achieved LDL-C goals of <100 mg/dl and <70 mg/dl with RSV20/EZE10 vs. SIM40/EZE10 and SIM80/EZE10 and with RSV10/EZE10 vs. SIM40/EZE10. LDL-C was reduced ∼10-14% further with combination therapy vs. monotherapy. Statin monotherapy reduced cholesterol and bile acid synthesis biomarkers, ezetimibe reduced ß-sitosterol (sterol absorption marker), and combination therapy achieved additive reductions in lipoprotein-associated phospholipase A2 mass and activity, free cholesterol and 7-ketocholesterol. Safety profiles of rosuvastatin/ezetimibe and simvastatin/ezetimibe combinations were comparable. CONCLUSION: Co-administration of rosuvastatin 10 or 20 mg plus ezetimibe achieved significant improvements in lipid profiles in high-risk patients vs. simvastatin 40 or 80 mg plus ezetimibe.

Alteration of relation of atherogenic lipoprotein cholesterol to apolipoprotein B by intensive statin therapy in patients with acute coronary syndrome (from the Limiting UNdertreatment of lipids in ACS With Rosuvastatin [LUNAR] Trial).

The low-density lipoprotein (LDL) cholesterol goal of <70 mg/dl, recommended for patients with acute coronary syndrome, typically requires intensive therapy with high-dose statins. The secondary goals of non-high-density lipoprotein (non-HDL) cholesterol <100 mg/dl and apolipoprotein B (ApoB) <80 mg/dl have been recommended to reduce excess cardiovascular risk not captured by LDL cholesterol. The present post hoc analysis from the Limiting UNdertreatment of lipids in Acute coronary syndrome with Rosuvastatin (LUNAR) study examined the relation of ApoB with LDL cholesterol and non-HDL cholesterol at baseline and during treatment with intensive statin therapy. The LUNAR participants had acute coronary syndrome and received rosuvastatin 40 mg/day or 20 mg/day or atorvastatin 80 mg/day for 12 weeks. Linear regression analyses were used to compare ApoB, direct LDL cholesterol, and non-HDL cholesterol at baseline and during therapy. Of the 682 patients included in the analysis, 220 had triglycerides ≥200 mg/dl. Linear regression analysis showed that correlation of ApoB and non-HDL cholesterol was stronger than that of ApoB and LDL cholesterol and stronger with statin therapy than at baseline (R(2) = 0.93 for ApoB vs non-HDL cholesterol with statins). The target of ApoB of 80 mg/dl correlated with LDL cholesterol of 90 mg/dl and non-HDL cholesterol of 110 mg/dl at baseline and with LDL cholesterol of 74 mg/dl and non-HDL cholesterol of 92 mg/dl with statin therapy. For high-triglyceride patients, the corresponding on-treatment targets were LDL cholesterol of 68 mg/dl and non-HDL cholesterol of 92 mg/dl. In conclusion, non-HDL cholesterol is an adequate surrogate of ApoB during statin therapy, independent of triglyceride status. However, to match LDL cholesterol and ApoB treatment goals in the very-high-risk category, the current non-HDL cholesterol goal should be lowered by 8 to 10 mg/dl.

Renal safety of intensive cholesterol-lowering treatment with rosuvastatin: a retrospective analysis of renal adverse events among 40,600 participants in the rosuvastatin clinical development program.

OBJECTIVE: Intensive lowering of low-density lipoprotein cholesterol (LDL-C) with statins reduces cardiovascular risk but can cause liver-, muscle-, and possibly renal-related adverse events (AEs). We assessed the effects of rosuvastatin on the risk of developing renal impairment or renal failure among participants in the rosuvastatin clinical development program. METHODS: The analysis was based on AE data reported by investigators from 36 studies that included 40,600 participants who did not have advanced, pre-existing renal disease. Rates of renal AEs were determined based on time to first occurrence of renal impairment or renal failure. RESULTS: Renal impairment or renal failure was reported in 536 study participants during 72,488 patient-years of follow-up. Renal event rates were higher in patients with history of heart failure (n = 5011), hypertension (n = 21,864), diabetes (n = 5165), or estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) (n = 9507) at baseline but did not differ with rosuvastatin compared with placebo or with rosuvastatin 40 mg compared with rosuvastatin 10mg. Relative risk (RR) estimates obtained from pooled analysis of placebo-controlled trials were RR: 1.03 (95% CI: 0.86-1.23, p = 0.777) for any reported renal impairment or renal failure event, RR: 1.02 (95% CI: 0.76-1.37, p = 0.894) for serious renal AEs, and RR: 0.70 (95% CI: 0.36-1.35, p = 0.282) for renal AEs leading to death. CONCLUSION: These findings suggest that intensive LDL-C-lowering treatment with rosuvastatin does not affect the risk of developing renal insufficiency or renal failure in patients who do not have advanced, pre-existing renal disease.

Safety and efficacy of achieving very low low-density lipoprotein cholesterol levels with rosuvastatin 40 mg daily (from the ASTEROID Study).

Clinical trial evidence supports the use of intensive statin therapy for patients with coronary artery disease. High doses of potent statins have shown the greatest clinical benefit, but concerns persist regarding the efficacy and safety of achieving very low levels of low-density lipoprotein (LDL) cholesterol. We grouped patients treated with 40 mg of rosuvastatin daily by the LDL cholesterol achieved according to previous work (<40, 40 to <60, 60 to <80, 80 to <100, and > or =100 mg/dl) and by National Cholesterol Education Program targets (<70, 70 to <100, and > or =100 mg/dl) in A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID). The rates of key safety end points, including death, hemorrhagic stroke, and liver and muscle enzyme elevations, and key efficacy end points (atheroma burden) were compared using chi-square testing or Fisher's exact testing. The analysis included 471 patients who had had their LDL cholesterol measured at 3 months, of whom 340 (72.2%) had LDL cholesterol of <70 mg/dl, exhibiting excellent achievement of even the most stringent guideline-based goals. Of these 471 subjects, 192 (40.8%) had LDL cholesterol > or =40 mg/dl but <60 mg/dl, and 57 (12.1%) had LDL cholesterol <40 mg/dl. Adverse events occurred infrequently during the trial, and no pattern appeared relating the frequency of any adverse event to the achieved LDL cholesterol. Similarly, the on-treatment atheroma volume, change in atheroma volume, and high percentage of subjects with atheroma regression did not differ by the achieved LDL cholesterol. In conclusion, although the power to detect such changes was limited, these data showed no clear relation between the LDL cholesterol achieved by intensive statin therapy with rosuvastatin and adverse effects. Atheroma regression occurred in most patients and was not linked to the LDL cholesterol achieved.

Statin therapy alters the relationship between apolipoprotein B and low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol targets in high-risk patients: the MERCURY II (Measuring Effective Reductions in Cholesterol Using Rosuvastatin) trial.

OBJECTIVES: The purpose of this analysis was to compare concentrations of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (apoB) before and during statin therapy. BACKGROUND: Reducing LDL-C to a pre-determined goal may still leave an excess of atherogenic lipoproteins, as reflected in apoB levels. METHODS: The MERCURY II (Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY II) trial examined the effects of statin treatment in patients with high coronary heart disease (CHD) risk, LDL-C > or =130 and <250 mg/dl, and triglycerides <400 mg/dl. Therapy consisted of rosuvastatin (10 or 20 mg), atorvastatin (10 or 20 mg), or simvastatin (20 or 40 mg). The apoB and LDL-C or non-HDL-C at baseline and after 16 weeks of therapy were compared using linear regression. RESULTS: In untreated patients, the apoB target of <90 mg/dl was roughly equivalent to an LDL-C level <100 mg/dl and a non-HDL-C level <130 mg/dl, which is consistent with existing apoB and lipoprotein guidelines. However, during statin therapy, to reach an apoB target of <90 mg/dl it was necessary to reduce non-HDL-C to <100 mg/dl or to reduce LDL-C to <70 mg/dl (in high-triglyceride patients) or <80 mg/dl (in lower-triglyceride patients). The tight correlation seen for non-HDL-C with apoB while on statin therapy (R(2) = 0.92) implies that non-HDL-C may be an acceptable surrogate for direct apoB measurement. CONCLUSIONS: These data are consistent with the more aggressive cholesterol goals suggested for CHD patients, because achieving such targets also reduced apoB to the recommended level. (Mercury II-Compare the Efficacy and Safety of Lipid Lowering Agents Atorvastatin and Simvastatin With Rosuvastatin in High Risk Subjects With Type IIa and IIb Hypercholesterolemia; NCT00654407).