William E. Brady

A Community-Based, Randomized Trial of Ezetimibe Added to Statin Therapy to Attain NCEP ATP III Goals for LDL Cholesterol in Hypercholesterolemic Patients: The Ezetimibe Add-On to Statin for Effectiveness (EASE) Trial

OBJECTIVE To determine the extent of reduction in low-density lipoprotein cholesterol (LDL-C) level and improvement in National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) LDL-C goal attainment when ezetimibe was added to ongoing statin therapy in a diverse population of community-based patients. PATIENTS AND METHODS In this multicenter, double-blind, placebo-controlled trial (from January 2003 to August 2003), hypercholesterolemic patients (from 299 US primary care and specialty practices) with LDL-C levels exceeding NCEP ATP III goals were randomized (2:1) to receive ezetimibe (10 mg/d) or placebo in addition to their ongoing statin therapy for 6 weeks. RESULTS In a study of 3030 randomized patients, ezetimibe added to statin therapy significantly reduced the LDL-C level by an additional 25.8% in the total population, compared with an additional 2.7% reduction with placebo plus statin (treatment difference, -23.1%; P<.001); the treatment difference ranged from -19.9% to -24.0% (P<.001) in each NCEP ATP III risk category subgroup. Significantly (P<.001) more patients (71.0%) treated with ezetimibe added to statin reached their NCEP ATP III target LDL-C level compared with those treated with placebo plus statin (20.6%). The addition of ezetimibe also resulted in improvement in other lipid parameters and high-sensitivity C-reactive protein levels. These benefits were consistent across sex, race, age, statin brand, and dose subgroups. Ezetimibe plus statin therapy was well tolerated, with a safety profile similar to placebo plus statin. CONCLUSION Across multiple subgroups, ezetimibe added to statin therapy consistently produced significant additional improvements in LDL-C levels and goal attainment, as well as in other lipoproteins, compared with addition of placebo. The addition of ezetimibe to statin therapy should be considered for patients not achieving their NCEP ATP III LDL-C goals while receiving statin therapy alone.

The effect of a losartan-based treatment regimen on isolated systolic hypertension.

This study was conducted to compare the antihypertensive efficacy and tolerability, over 12 weeks, of a losartan‐based treatment regimen and placebo in patients with isolated systolic hypertension. Three hundred eight patients ≥35 years of age with isolated systolic hypertension, defined as trough sitting blood pressure between 140 and 200 mm Hg systolic and between 70 and 89 mm Hg diastolic, were randomized to losartan 50 mg (n=157) or placebo (n=151) once daily, with titration as necessary to achieve a goal trough sitting systolic blood pressure (SBP) <140 mm Hg. At baseline, mean trough sitting SBP was 140–159 mm Hg in 20.5% of patients, 160–179 mm Hg in 62.7%, and 180–200 mm Hg in 16.9%, and was similar in the two groups (losartan, 165.3 mm Hg; placebo, 166.1 mm Hg). At 12 weeks, mean trough sitting SBP decreased significantly (p<0.001) in both the losartan‐based treatment group (by 19.2 mm Hg) and in the placebo group (by 7.6 mm Hg). The reduction in sitting SBP was significantly greater for losartan than placebo (−11.6 mm Hg; 95% confidence interval, −14.8 to −8.4). In patients with isolated systolic hypertension, a once‐daily losartan‐based treatment regimen significantly lowered SBP. The losartan‐based regimen exhibited antihypertensive efficacy that was superior to that of placebo, with a similar tolerability profile.

Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic patients*

ABSTRACT Objective: To assess the lipid-altering efficacy and safety of ezetimibe/simvastatin single tablet product compared with rosuvastatin at the approved usual starting, next highest, and maximum doses. Research design and methods: Double-blind, multicenter, 6‐week, parallel-group study in hypercholesterolemic patients (n = 2959). Patients were randomized based on stratification by low-density lipoprotein cholesterol (LDL-C) levels to ezetimibe/simvastatin or rosuvastatin, respectively, at the usual starting (10/20 or 10 mg/day), the next highest (10/40 or 20 mg/day), and maximum doses (10/80 or 40 mg/day). Results: At all doses and across doses, ezetimibe/simvastatin reduced LDL‐C levels significantly more (52–61%) than rosuvastatin (46–57%; p ≤ 0.001). Significantly greater percentages of all patients (p < 0.001) and high risk patients (p ≤ 0.005) attained LDL‐C levels < 70 mg/dL (1.8 mmol/L) following ezetimibe/simvastatin treatment compared with rosuvastatin at the prespecified doses and across doses. Ezetimibe/simvastatin also produced significantly greater reductions in total cholesterol ( p < 0.001), non-high-density lipoprotein cholesterol ( p < 0.001), lipid ratios ( p ≤ 0.003), and apolipoprotein B ( p < 0.05). Reductions in triglycerides were significantly greater with ezetimibe/simvastatin than rosuvastatin at the usual starting ( p = 0.004) and next highest ( p = 0.006) doses, and across all doses ( p < 0.001). Increases in high-density lipoprotein cholesterol, and decreases in high sensitivity C reactive protein (hsCRP) were similar between treatment groups. Safety profiles were comparable for both treatments; however, the percent of patients with proteinuria was significantly higher following rosuvastatin treatment than ezetimibe/simvastatin, respectively at 10 mg versus 10/20 mg/day ( p = 0.004) and 40 mg versus 10/80 mg/day ( p < 0.001). Conclusion: Ezetimibe/simvastatin was more effective than rosuvastatin in LDL‐C lowering, and provided greater or comparable improvements in other lipid measures and hsCRP at the approved usual starting, next highest, and maximum doses in hypercholesterolemic patients. Although the doses compared in this study were not equivalent on a milligram basis, the results provide clinically relevant information regarding the use of these drugs for initial therapy and for subsequent use at higher doses when appropriate. Both treatments were generally well-tolerated; however, this study was not powered nor of sufficient duration to assess the prevalence of rare clinical adverse effects. Overall, ezetimibe/simvastatin offers an effective and tolerable treatment option for lipid management. An assessment of its full clinical benefit awaits evaluation in longer-term clinical studies.

Ezetimibe added to ongoing statin therapy improves LDL-C goal attainment and lipid profile in patients with diabetes or metabolic syndrome

This analysis of the Ezetimibe Add-on to Statin for Effectiveness (EASE) trial examined the effectiveness and safety of ezetimibe 10 mg added to ongoing statin therapy in patients with diabetes, metabolic syndrome without diabetes, or neither disorder who had low-density lipoprotein cholesterol (LDL-C) levels exceeding National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) goals. After six weeks of treatment, ezetimibe added to statin reduced LDL-C in patients with diabetes by 28%, metabolic syndrome by 24%, or neither by 26%, compared with a 3% reduction for placebo for each group. In each group, more patients receiving ezetimibe plus statin reached LDL-C goal (67–74%) compared with those receiving placebo plus statin (19–22%). Other parameters demonstrating greater improvement with ezetimibe included triglycerides, apolipoprotein (Apo)B/Apo A-I ratio, high-density lipoprotein cholesterol (HDL-C), and C-reactive protein. Ezetimibe plus statin was well tolerated in each group. Ezetimibe added to ongoing statin therapy offers a new treatment option that is consistently effective in improvement of lipid profiles and attainment of LDL-C goals in patients with or without diabetes or metabolic syndrome.

Lipid altering-efficacy of ezetimibe co-administered with simvastatin compared with rosuvastatin: a meta-analysis of pooled data from 14 clinical trials.

ABSTRACT Objective: Results of direct comparative studies between ezetimibe/simvastatin and rosuvastatin therapies have not been reported. Both of these treatment options offer significant reductions in LDL-C. To evaluate the lipid efficacy of each of these therapies relative to each other, a meta-analysis of data from 14 randomized, double-blind clinical trials that compared the effectiveness of two new options for cholesterol lowering was performed. Data sources: PubMed, EMBASE and BIOSIS databases were searched up to March 14, 2004. Methods of study selection: Efficacy results from clinical trials with the co-administration of ezetimibe 10 mg with simvastatin or with the ezetimibe/simvastatin combination product (ezetimibe/simvastatin 10/10 mg, 10/20 mg, 10/40 mg, and 10/80 mg) were compared with efficacy results from clinical trials of rosuvastatin 5 mg, 10 mg, 20 mg, and 40 mg in patients with primary hypercholesterolemia. Trials in healthy patients, heterozygous familial hypercholesterolemia or combined hyperlipidemia, and pharmacokinetic trials were excluded. Data extraction and synthesis: This analysis used pooled data for LDL-C, HDL-C, non-HDL-C, triglycerides, total cholesterol, apolipoprotein (apo) A-I, and apo B for the two therapies at their lowest doses (ezetimibe/simvastatin 10/10 mg and rosuvastatin 5 mg) through their highest doses (ezetimibe/simvastatin 10/80 mg and rosuvastatin 40 mg), and estimated within-treatment percentage changes in these parameters. Percentage reductions from baseline in LDL-C for the pooled data were 46.2% and 41.8% for ezetimibe/simvastatin 10/10 mg and rosuvastatin 5 mg, respectively; 50.6% and 47.4% for ezetimibe/simvastatin 10/20 mg and rosuvastatin 10 mg, respectively; 55.9% and 52.1% for ezetimibe/simvastatin 10/40 mg and rosuvastatin 20 mg, respectively; and 59.7% and 58.5% for ezetimibe/simvastatin 10/80 mg and rosuvastatin 40 mg, respectively. Conclusions: The results of this meta-analysis suggest greater LDL-C lowering with ezetimibe/simvastatin compared with rosuvastatin. These results need to be confirmed in a head-to-head comparison of both therapies.

The effect of baseline physical activity on cardiovascular outcomes and new-onset diabetes in patients treated for hypertension and left ventricular hypertrophy: the LIFE study

Objectives.  Physical activity (PA) is a preventive strategy for cardiovascular disease and for managing cardiovascular risk factors. There is little information on the effectiveness of PA for the prevention of cardiovascular outcomes once cardiovascular disease is present. Thus, we studied the relationship between PA at baseline and cardiovascular events in a high‐risk population.

Effectiveness of Ezetimibe Added to Ongoing Statin Therapy in Modifying Lipid Profiles and Low-Density Lipoprotein Cholesterol Goal Attainment in Patients of Different Races and Ethnicities: A Substudy of the Ezetimibe Add-On to Statin for Effectiveness Trial

OBJECTIVE To examine whether the improvements in lipid profiles and low-density lipoprotein cholesterol (LDL-C) goal attainment found in the Ezetimibe Add-On to Statin for Effectiveness trial occurred equally in the black, Hispanic, and white patient populations enrolled in the study. PATIENTS AND METHODS In this double-blind, placebo-controlled study, patients were recruited from 299 community-based practices across the United States (January to August 2003). Patients with, hypercholesterolemia and LDL-C levels exceeding National Cholesterol Education Program Adult Treatment Panel III goals were randomized (2:1) to receive either ezetimibe (10 mg/d) or placebo in addition to their ongoing statin therapy for 6 weeks. RESULTS A total of 5802 patients were screened at baseline for the Ezetimibe Add-On to Statin for Effectiveness study. Of these, 2772 were excluded, and the remaining 3030 eligible patients were randomized. Ezetimibe, compared with placebo, added to statin therapy significantly reduced LDL-C levels from statin-treated baseline by 23.0% (white patients), 23.0% (black patients), and 21.0% (Hispanic patients). This effect was consistent across race and ethnicity groups (P > .50 for treatment-by-race interactions). Ezetimibe added to statin therapy also statistically significantly (P < .001) increased the percentage of patients attaining their LDL-C goal for their National Cholesterol Education Program Adult Treatment Panel III risk category in black (63.0%), Hispanic (64.8%), and white (72.3%) patients compared with placebo plus statin (32.9% black patients, 19.0% Hispanic patients, and 19.7% white patients). Ezetimibe treatment improved other lipid parameters across groups, including triglyceride, high-density lipoprotein cholesterol, non-high-density ilpoprotein cholesterol, and total cholesterol levels. Finally, the addition of ezetimibe reduced high-sensitivity C-reactive protein levels overall, and no significant interaction of treatment by race occurred (P = .83), Indicating a consistent effect across races. Ezetimibe was generally well tolerated, and no detectable differences occurred in the adverse event profile by race or ethnicity. CONCLUSION Ezetimibe added to statin therapy is effective and well tolerated for improving the lipid profile and LDL-C goal attainment of patients regardless of race or ethnicity.

A multicenter, randomized, double-blind, placebo-controlled, 8-week trial of the efficacy and tolerability of once-daily losartan 100 mg/hydrochlorothiazide 25 mg and losartan 50 mg/hydrochlorothiazide 12.5 mg in the treatment of moderate-to-severe essential hypertension.

BACKGROUND Many patients with moderate-to-severe hypertension require multiple drug therapy to achieve blood-pressure goals. Fixed-dose combination therapy with losartan and hydrochlorothiazide may be useful in this population. OBJECTIVE This study was conducted to obtain additional data on the antihypertensive efficacy and tolerability of once-daily, fixed-dose combinations of losartan and hydrochlorothiazide. METHODS This was a multicenter, randomized, double-blind, parallel-group, placebo-controlled trial. Patients > or = 21 years of age with moderate-to-severe essential hypertension, defined as a mean trough sitting diastolic blood pressure (SiDBP) of 105 to 115 mm Hg, were randomly assigned in a 2:2:1 ratio to receive losartan 100 mg/hydrochlorothiazide 25 mg (L100/25), losartan 50 mg/hydrochlorothiazide 12.5 mg (L50/12.5), or placebo (PBO) once daily for 8 weeks. The primary efficacy measurement was the mean change from baseline in trough SiDBP in the L100/25 versus L50/12.5 treatment groups. Responders were defined as patients with mean trough SiDBP <90 mm Hg or a > or = 10-mm Hg decrease in mean trough SiDBP. RESULTS A total of 446 patients were randomly assigned to receive L100/25 (n = 173), L50/12.5 (n = 184), or PBO (n = 89). At week 8, mean trough SiDBP was significantly lower than at baseline in the L100/25 (-17.5 mm Hg), L50/12.5 (-15.2 mm Hg), and PBO groups (-8.5 mm Hg) (all P < 0.001). The difference between the active-treatment groups was statistically significant (-2.2 mm Hg; 95% Cl, range -3.8 to -0.6) (P = 0.006), as was the difference between the L100/25 and PBO groups (-9.0 mm Hg; 95% CI, range -I1.0 to -7.0) (P < 0.001) and the L50/12.5 and PBO groups (-6.7 mm Hg; 95% CI, range -8.7 to -4.8) (P < 0.001). At week 8, the percentages of responders were 86.7% (144 of 166), 78.9% (142 of 180), and 50.0% (42 of 84) in the L100/25, L50/12.5, and PBO groups, respectively. The incidence of adverse experiences (AEs) was 34.7% (60 of 173) in the L100/25 group, 23.9% (44 of 184) in the L50/12.5 group, and 32.6% (29 of 89) in the PBO group. The incidence of drug-related AEs was similar among the treatment groups (L100/25, 7.5% [13 of 173]; L50/12.5, 7.1% [13 of 184]; and PBO, 11.2% [10 of 89]). CONCLUSIONS This study demonstrates the antihypertensive efficacy and tolerability of the once-daily, fixed-dose combination L50/12.5 in patients with moderate-to-severe essential hypertension. In this study, L100/25 provided additional anti-hypertensive efficacy beyond that of L50/12.5 (and both were more efficacious than PBO). Approximately 4 of 5 patients (78.9%) treated with L50/12.5 responded to therapy, as did nearly 9 of 10 patients (86.7%) treated with L100/25. The tolerability profiles of L50/12.5 and L100/25 were similar to that of PBO.

Losartan Benefits over Atenolol in Non-Smoking Hypertensive Patients with Left Ventricular Hypertrophy: The LIFE Study

We studied the impact of smoking in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, which showed superiority of losartan over atenolol for reduction of composite risk of cardiovascular death, stroke and myocardial infarction in hypertensives with left ventricular hypertrophy. We compared hazard ratios in 4656 never-smokers, and 3033 previous and 1499 current smokers, adjusting for gender, age, alcohol intake, exercise and race. Composite endpoint rate was higher in previous (28/1000 years), as well as current (39/1000 years) smokers than in never-smokers (21/1000 years). Composite (hazard ratio 0.78, 95% CI 0.65-0.94, p < 0.01) and stroke (hazard ratio 0.61, 95% CI 0.47-0.80], p < 0.001) risks were lower with losartan than atenolol in never-smokers, but not significantly in previous smokers. Drug regimens did not differ in current smokers (composite hazard ratio 0.99, stroke hazard ratio 0.94). Smoking-treatment interactions were non-significant, but a borderline significant trend (p = 0.05) suggested decreasing benefit of losartan vs atenolol for stroke prevention from never- to previous to current smoking status. Smoking increased cardiovascular risk markedly in the LIFE study. The benefit of losartan vs atenolol is consistent with the overall conclusion of the LIFE study, although the treatment effect appeared largest in non-smokers.