Statin Therapy With or Without Ezetimibe in Patients at High Risk for Cardiovascular Disease

Linda Brookes, MSc

Disclosures

July 28, 2006

Editorial Collaboration

Medscape &

The results of 2 studies presented at the 2006 symposium of the International Society of Atherosclerosis in Rome, Italy, have demonstrated the benefit of adding the cholesterol absorption inhibitor ezetimibe to high-dose statin therapy in patients at high risk for cardiovascular disease. Both studies showed that 6 weeks of treatment with ezetimibe 10 mg administered with rosuvastatin 40 mg or as fixed-dose combination therapy with simvastatin 80 mg allowed more than 90% of patients to achieve US and European low-density lipoprotein (LDL)-cholesterol goals and unprecedented 60% to 70% reductions in LDL-cholesterol levels.

However, the doses of the statins used -- rosuvastatin 40 mg and simvastatin 80 mg -- are the highest approved for the market and, some investigators noted, are not widely prescribed by general practitioners.

Rosuvastatin in Combination With Ezetimibe vs Rosuvastatin Monotherapy

The EXamination of Potential Lipid-modifying effects Of Rosuvastatin in combination with Ezetimibe versus Rosuvastatin alone (EXPLORER) trial (supported by AstraZeneca, London, United Kingdom) was a 6-week, open-label study comparing daily treatment with rosuvastatin 40 mg alone or in combination with ezetimibe 10 mg.[1] Eligible patients had hypercholesterolemia, which was defined as LDL-cholesterol levels from 4.1 mmol/L to < 6.5 mmol/L (160 mg/dL to < 250 mg/dL), triglycerides < 4.52 mmol/L (400 mg/dL), and either a history of coronary heart disease (CHD), clinical evidence of atherosclerosis, or a CHD risk equivalent (10-year CHD risk > 20%). After recruitment at 58 centers in the United States, Europe, and South Africa, a total of 469 patients were randomized to treatment (230 to rosuvastatin monotherapy and 239 to rosuvastatin plus ezetimibe).

After 6 weeks, LDL-cholesterol levels, which were the same in both treatment groups at the start of the study, were lower in the patients on rosuvastatin plus ezetimibe compared with the patients on rosuvastatin monotherapy (Table 1).

Table 1. Mean Lipid Levels (mmol/L [mg/dL]) at Baseline and After 6 Weeks of Treatment
LDL Cholesterol Rosuvastatin 40 mg
+ Ezetimibe 10 mg
Rosuvastatin
40 mg
Baseline 4.89 (189.2) 4.93 (190.8)
6 weeks 1.47 (56.9) 2.11 (81.5)
LDL = low-density lipoprotein

The reduction in LDL cholesterol with rosuvastatin plus ezetimibe was significantly greater than with rosuvastatin monotherapy (69.8% vs 57.1%, P < .001) (Table 2). Significantly greater reductions in total cholesterol, as well as the various subfractions and subfraction ratios, were also seen with combination therapy compared with rosuvastatin monotherapy. There was no difference, however, between the 2 treatments' effects on high-density lipoprotein (HDL) cholesterol.

Table 2. Change (%) in Lipids and Lipoproteins After 6 Weeks
Lipid Parameter Rosuvastatin 40 mg
+ Ezetimibe 10 mg
Rosuvastatin
40 mg
P
Value
LDL cholesterol -69.8 -57.1 < .001
Total cholesterol -51.3 -41.5 < .001
HDL cholesterol +10.8 +8.5 .151
Non-HDL cholesterol -64.6 -52.1 < .001
Triglycerides -35.4 -25.1 < .001
LDL/HDL cholesterol -72.2 -59.6 < .001
Total/HDL cholesterol -55.5 -45.1 < .001
non-HDL/HDL cholesterol -67.4 -54.8 < .001
Apo B -56.4 -44.7 < .001
Apo A-I +1.6 +3.2 .202
Apo B/A-I -56.7 -45.6 < .001
Apo = apolipoprotein; HDL = high-density lipoprotein; LDL = low-density lipoprotein

After 6 weeks of treatment, a significantly greater proportion of patients on rosuvastatin plus ezetimibe vs rosuvastatin monotherapy (94.0% vs 79.1%, P < .001) achieved the original NCEP ATP III LDL-cholesterol goal of < 100 mg/dL (2.59 mmol/L),[2] the primary endpoint of the study. However, during the course of the study the NCEP ATP III recommendations were updated,[3] including an optional goal for LDL cholesterol of < 70 mg/dL (1.81 mmol/L), and this more stringent goal was achieved by 79.6% of patients on combination therapy compared with 35.0% of patients on rosuvastatin monotherapy (P < .001).

Among the secondary endpoints of the study, more patients on combination therapy than monotherapy achieved European LDL-cholesterol goals of < 2.5 mmol/L or 3.0 mmol/L (97 mg/dL or 115 mg/dL)[4] -- 93.6% vs 74.3%, respectively.

Of note, the incidence of adverse events was low in both treatment groups (Table 3). The most frequently reported adverse event was myalgia (2.9% in the combination therapy group and 3.0% in the monotherapy group), which led to treatment withdrawal for 1 patient in each group. There were no cases of myopathy, myositis, or rhabdomyolysis.

Table 3. Adverse Events
  Rosuvastatin 40 mg
+ Ezetimibe 10 mg
Rosuvastatin
40 mg
Adverse events (%) 31.5 33.5
Serious adverse events (%) 2.1 1.7
Discontinuations due
to adverse events (%)
2.5 1.3

Commenting on these results, lead investigator Christie Ballantyne, MD (Methodist DeBakey Heart Center, Houston, Texas), concluded that "The EXPLORER trial [showed that] the use of rosuvastatin and ezetimibe together can help even the most difficult-to-treat patients achieve optimal cholesterol targets."

Ezetimibe-Simvastatin Fixed-Dose Combination vs Rosuvastatin Monotherapy

In a second study, funded by Merck/Schering-Plough Pharmaceuticals (Whitehouse Station and Kenilworth, New Jersey), 2955 patients with hypercholesterolemia (LDL cholesterol 145-250 mg/dL [3.75-6.47 mmol/L]) were randomized in a double-blind, 6-week, parallel-group design to treatment with 1 of 3 fixed-dose combinations of ezetimibe-simvastatin (10/20 mg, 10/40 mg, or 10/80 mg) or 1 of 3 doses of rosuvastatin monotherapy (10 mg, 20 mg, or 40 mg).

Across all doses, the ezetimibe-simvastatin combination was significantly more effective than rosuvastatin monotherapy in reducing LDL cholesterol, the primary endpoint of the study (-57.7% vs -52.5%, P < .001).[5] In addition, a greater proportion of patients on ezetimibe-simvastatin reached LDL-cholesterol goals of < 100 mg/dL (88.2% vs 81.9%, P < .001) or < 70 mg/dL (43.5% vs 20.5%, P < .001) than those on rosuvastatin.

A post hoc subgroup analysis was carried out on the results from 715 patients in the study who were classified as high risk on the basis of having proven CHD or a CHD risk equivalent.[6] Although the analysis was underpowered to show differences between subgroups, the investigators insisted that the results were generally consistent with those of the primary study. The LDL-cholesterol reduction was significantly greater with ezetimibe-simvastatin compared with rosuvastatin across all doses and at all dose comparisons, reaching a reduction of 62.7% with ezetimibe-simvastatin 10/80 mg (Table 4).

Table 4. Mean LDL-Cholesterol Levels
LDL Cholesterol R
10 mg
E-S
10/20 mg
R
20 mg
E-S
10/40 mg
R
40 mg
E-S
10/80 mg
Baseline -- mg/dL (mmol/L) 174.1
(4.50)
172.5
(4.46)
172.9
(4.47)
173.2
(4.48)
177.1
(4.58)
174.4
(4.51)
6 weeks -- mg/dL (mmol/L) 93.7
(2.42)
82.1
(2.12)
80.2
(2.07)
73.4
(1.90)
74.3
(1.92)
65.2
(1.69)
Change from baseline (%) -45.7 -52.6 -53.6 -57.7 -58.3 -62.7
Treatment difference (%)   -6.9*   -4.1   -4.5**
E-S = ezetimibe-simvastatin; LDL = low-density lipoprotein; R = rosuvastatin

*P < .001

P < .01

Averaged across all doses, significantly more of these high-risk patients reached LDL-cholesterol goals of < 100 mg/dL (90.1% vs 82.0%, P < .05) and < 70 mg/dL (50.1% vs 29.4%, P < .001) on ezetimibe-simvastatin vs rosuvastatin alone, respectively. The highest proportion of patients achieving these goals (96.3% vs 90.6%, P = NS and 68.5% vs 50.0%, P < .01, respectively) occurred in the group of patients who took ezetimibe-simvastatin 10/80 mg vs rosuvastatin 40 mg.

Both treatments were generally well tolerated with similar rates of adverse events in each group (Table 5).

Table 5. Adverse Events
  R
10 mg
E-S
10/20 mg
R
20 mg
E-S
10/40 mg
R
40 mg
E-S
10/80 mg
Adverse events (%) 22.3 27.9 32.8 25.2 32.7 29.0
Serious adverse events (%) 2.3 2.5 0.0 1.7 2.8 0.8
Discontinuations due
to adverse events (%)
3.1 1.6 0.8 2.5 2.8 2.3
E-S = ezetimibe-simvastatin; R = rosuvastatin

Lead investigator Michael Davidson, MD (Rush University Medical Center, Chicago, Illinois), commented: "These data provide further evidence that ezetimibe-simvastatin is an excellent option to help lower the LDL-cholesterol levels of patients with high cholesterol."

References
  1. Ballantyne CM, Sosef F, Duffield E; the EXPLORER study investigators. Efficacy and safety of rosuvastatin plus ezetimibe in high risk patients: results from the EXPLORER study. Atherosclerosis. 2006;7(suppl):552. Abstract Th-P16.270.

  2. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421. Abstract

  3. Grundy SM, Cleeman JI, Merz CNB, et al; for the Coordinating Committee of the National Cholesterol Education Program. Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227-239. Abstract

  4. De Backer G, Ambrosioni E, Borch-Johnsen K, et al; European Society of Cardiology Committee for Practice Guidelines. European guidelines on cardiovascular disease prevention in clinical practice: third joint task force of European and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of eight societies and by invited experts). Eur J Cardiovasc Prev Rehabil. 2003;10:S1-S10. Abstract

  5. Davidson MH, Catapano AL, Ballantyne CM, et al. Attainment of optimal NCEP ATP III treatment goals in high-risk patients: dose comparison of ezetimibe/simvastatin and rosuvastatin. Atherosclerosis. 2006;7(suppl):555. Abstract Th-P16.280.

  6. Davidson MH, Catapano AL, Ballantyne CM, et al. Lipid-altering efficacy and safety of ezetimibe/simvastatin versus rosuvastatin in patients with primary hypercholesterolemia. Atherosclerosis. 2006;7(suppl):555. Abstract Th-P16.282.

 

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