Cardiol Res

Cardiology Research, ISSN 1923-2829 print, 1923-2837 online, Open Access

Article copyright, the authors; Journal compilation copyright, Cardiol Res and Elmer Press Inc

Journal website https://www.cardiologyres.org

Original Article

Volume 12, Number 2, April 2021, pages 98-108

Effect of Ezetimibe Added to High-Intensity Statin Therapy on Low-Density Lipoprotein Cholesterol Levels: A Meta-Analysis

Figure 3. Forest plot of comparison: the mean difference in the reduction of LDL-C levels. LDL-C: low-density lipoprotein cholesterol.

**Table 1.** Study Characteristics
Studies	Design	Region	Patients eligibility	Treatment, patients number (n)	Baseline LDL-C (mmol/L (mg/dL))	LDL-C at the end of studies (mmol/L (mg/dL))
± indicates standard deviation. CHD: coronary heart disease; DB: double-blinded; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; MC: multicenter; NCEP ATP III: the third report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults; OL: open-label; PC: placebo-controlled; R: randomized; SC: single center; TG: triglyceride.
Azar et al, 2011 [15]	R, DB, PC, 8 weeks	Western countries	Adults with stable coronary artery disease or coronary artery disease equivalent	Atorvastatin 40 mg/day, n = 50	2.56 ± 0.54 (99 ± 21)	2.22 ± 0.36 (86 ± 14)
				Atorvastatin 40 mg/d + ezetimibe 10 mg/d, n = 50	2.64 ± 0.75 (102 ± 29)	1.99 ± 0.26 (77 ± 10)
Ballantyne et al, 2003_40 [16]	R, DB, PC, 12 weeks	Western countries	Adults with primary hypercholesterolemia, defined as calculated LDL-C of 145 - 250 mg/dL, inclusive, and TG levels ≤ 350 mg/dL.	Atorvastatin 40 mg/day, n = 57	N/A	N/A
				Atorvastatin 40 mg/day + ezetimibe 10 mg/day, n = 57
Ballantyne et al, 2003_80 [16]				Atorvastatin 80 mg/day, n = 57
				Atorvastatin 80 mg/day + ezetimibe 10 mg/day, n = 50
Ballantyne et al, 2007 [17]	R, OL, MC, 6 weeks	Western countries	Adults with hypercholesterolemia and a history of CHD or clinical evidence of atherosclerosis or a CHD risk equivalent (10-year CHD risk score > 20%); two most recent fasting LDL-C levels was ≥ 160 mg/dL and < 250 mg/dL and the two measurements were within 15% of each other; a fasting TG concentration of < 400 mg/dL	Rosuvastatin 40 mg/day, n = 230	4.94 (191)	2.12 (82)
				Rosuvastatin 40 mg/day + ezetimibe 10 mg/day, n = 235	4.88 (189)	1.47 (57)
Barbosa et al, 2013 [18]	R, OL, 4 weeks	Western countries	Adults with at high risk for CHD, characterized by at least one of the following conditions: established CHD or equivalent; diagnosis of type 2 diabetes; or those whose Framingham risk score was > 20%.	Atorvastatin 40 mg/day, n = 45	2.3 (89)	1.91 (74)
				Atorvastatin 40 mg/day + ezetimibe 10 mg/day, n = 37	2.30 (94)	1.60 (62)
Blom et al, 2014 [10]	R, DB, 52 weeks; atorvastatin and ezetimibe were not masked	Western countries	Adults with an LDL-C ≥ 75 mg/dL and a fasting TG level ≤ 400 mg/dL	Atorvastatin 80 mg/day, n = 73	2.49 ± 0.34 (96.2 ± 13.3)	2.70 ± 0.82 (104.6 ± 31.61)
				Atorvastatin 80 mg/day + ezetimibe 10 mg/day, n = 63	3.10 ± 0.84 (119.8 ± 32.4)	2.97 ± 1.15 (115.0 ± 44.44)
Hong et al, 2018 [19]	R, DB, MC, 8 weeks	South Korean	Adults with hypercholesterolemia requiring medical treatment according to NCEP ATP III.	Rosuvastatin 20 mg/day, n = 64	3.95 ± 0.81 (152.8 ± 31.4)	1.95 ± 0.88 (75.4 ± 34.0)
				Rosuvastatin 20 mg/day + ezetimibe 10 mg/day, n = 64	3.97 ± 0.81 (153.5 ± 31.2)	1.37 ± 0.57 (53.1 ± 22.0)
Hougaard et al, 2017 [20]	R, DB, SC, 52 weeks	Western countries	Adults with ST-elevation myocardial infarction	Atorvastatin 80 mg/day, n = 41	4.10 ± 0.90 (158.55 ± 34.80)	2.00 ± 0.50 (77.34 ± 19.34)
				Atorvastatin 80 mg/day + ezetimibe 10 mg/day, n = 39	3.70 ± 0.71 (143.08 ± 27.67)	1.40 ± 0.80 (54.14 ± 30.94)
Kim et al, 2016 [21]	R, DB, MC, 8 weeks	South Korean	Adults with initial levels of LDL-C ≤ 250 mg/dL and TG < 400 mg/dL were selected for a lead-in period, then the patients who required lipid-lowering treatment according to the NCEP ATP III guidelines were finally enrolled in the study.	Rosuvastatin 20 mg/day, n = 68	N/A	N/A
				Rosuvastatin 20 mg/day + ezetimibe 10 mg/day, n = 68
Kim et al, 2018 [22]	R, DB, MC, 8 weeks	South Korean	Adults with primary hypercholesterolemia who had an LDL-C level < 250 mg/dL and TG level < 350 mg/dL requiring treatment according to NCEP ATPIII guidelines.	Rosuvastatin 20 mg/day, n = 63	4.16 ± 0.79 (160.90 ± 30.57)	N/A
				Rosuvastatin 20 mg/day + ezetimibe 10 mg/day, n = 64	4.12 ± 0.77 (159.56 ± 29.91)	N/A
Lins et al, 2014 [23]	R, OL, 4 weeks	Western countries	Adults at high-risk for CHD, characterized by at least one of the following conditions: stable CHD or CHD equivalent; diagnosis of type 2 diabetes; or those whose Framingham risk score was > 20%.	Atorvastatin 40 mg/day, n = 22	2.30 (89)	1.94 (75)
				Atorvastatin 40 mg/day + ezetimibe 10 mg/day, n = 21	2.45 (95)	1.60 (62)
Malina et al, 2015 [24]	R, OL, 4 weeks	Western countries	Adults in primary or secondary prevention of CHD, who had an indication for lipid-lowering therapy in accordance with NCEP ATP III	Atorvastatin 40 mg/day, n = 35	2.58 ± 0.83 (100 ± 32)	2.01 ± 0.67 (78 ± 26)
				Atorvastatin 40 mg/day + ezetimibe 10 mg/day, n = 22	2.30 ± 0.72 (89 ± 28)	1.42 ± 0.49 (5 5± 19)
Nicholls et al, 2017 [12]	R, DB, PC, 90 days	Western countries	Adults with either atherosclerotic cardiovascular disease or type 1 or 2 diabetes mellitus, treated with atorvastatin 40 mg daily for at least 30 days prior to screening and compliant with study drug for the 28-day lead-in phase, had an LDL-C > 70 mg/dL or non-HDL-C > 100 mg/dL at screening and prior to randomization and a TG ≤ 400 mg/dL.	Atorvastatin 40 mg/day, n = 40	N/A	N/A
				Atorvastatin 40 mg/day + ezetimibe 10 mg/day, n = 91
Robinson et al, 2014 [13]	R, DB, 12 weeks; atorvastatin was not masked	Western countries	Adults with a screening LDL-C level ≥ 150 mg/dL with no statin, or ≥ 100 mg/dL with non-intensive statin, or ≥ 80 mg/dL with intensive statin, and fasting TG ≤ 400 mg/dL.	Atorvastatin 80 mg/day, n = 110	2.52 ± 0.88 (97.5 ± 34.08)	2.71 ± 1.08 (104.8 ± 41.66)
				Atorvastatin 80 mg/day + ezetimibe 10 mg/day, n = 110	2.47 ± 0.72 (95.5 ± 27.70)	2.04 ± 1.31 (78.85 ± 50.89)
Yang et al, 2017 [25]	R, DB, 12 weeks	South Korean	Adults with high or moderately high cardiovascular disease as classified by NCEP ATP III	Rosuvastatin 20 mg/day, n = 39	3.88 ± 0.98 (150 ± 38)	1.68 ± 0.72 (65 ± 28)
				Rosuvastatin 20 mg/day + ezetimibe 10 mg/day, n = 42	3.82 ± 0.78 (148 ± 30)	1.34 ± 0.62 (52 ± 24)

Table 1. Study Characteristics

Studies

Design

Region

Patients eligibility

Treatment, patients number (n)

Baseline LDL-C (mmol/L (mg/dL))

LDL-C at the end of studies (mmol/L (mg/dL))

± indicates standard deviation. CHD: coronary heart disease; DB: double-blinded; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; MC: multicenter; NCEP ATP III: the third report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults; OL: open-label; PC: placebo-controlled; R: randomized; SC: single center; TG: triglyceride.

Azar et al, 2011 [15]

R, DB, PC, 8 weeks

Western countries

Adults with stable coronary artery disease or coronary artery disease equivalent

Atorvastatin 40 mg/day, n = 50

2.56 ± 0.54 (99 ± 21)

2.22 ± 0.36 (86 ± 14)

Atorvastatin 40 mg/d + ezetimibe 10 mg/d, n = 50

2.64 ± 0.75 (102 ± 29)

1.99 ± 0.26 (77 ± 10)

Ballantyne et al, 2003_40 [16]

R, DB, PC, 12 weeks

Western countries

Adults with primary hypercholesterolemia, defined as calculated LDL-C of 145 - 250 mg/dL, inclusive, and TG levels ≤ 350 mg/dL.

Atorvastatin 40 mg/day, n = 57

N/A

Atorvastatin 40 mg/day + ezetimibe 10 mg/day, n = 57

Ballantyne et al, 2003_80 [16]

Atorvastatin 80 mg/day, n = 57

Atorvastatin 80 mg/day + ezetimibe 10 mg/day, n = 50

Ballantyne et al, 2007 [17]

R, OL, MC, 6 weeks

Western countries

Adults with hypercholesterolemia and a history of CHD or clinical evidence of atherosclerosis or a CHD risk equivalent (10-year CHD risk score > 20%); two most recent fasting LDL-C levels was ≥ 160 mg/dL and < 250 mg/dL and the two measurements were within 15% of each other; a fasting TG concentration of < 400 mg/dL

Rosuvastatin 40 mg/day, n = 230

4.94 (191)

2.12 (82)

Rosuvastatin 40 mg/day + ezetimibe 10 mg/day, n = 235

4.88 (189)

1.47 (57)

Barbosa et al, 2013 [18]

R, OL, 4 weeks

Western countries

Adults with at high risk for CHD, characterized by at least one of the following conditions: established CHD or equivalent; diagnosis of type 2 diabetes; or those whose Framingham risk score was > 20%.

Atorvastatin 40 mg/day, n = 45

2.3 (89)

1.91 (74)

Atorvastatin 40 mg/day + ezetimibe 10 mg/day, n = 37

2.30 (94)

1.60 (62)

Blom et al, 2014 [10]

R, DB, 52 weeks; atorvastatin and ezetimibe were not masked

Western countries

Adults with an LDL-C ≥ 75 mg/dL and a fasting TG level ≤ 400 mg/dL

Atorvastatin 80 mg/day, n = 73

2.49 ± 0.34 (96.2 ± 13.3)

2.70 ± 0.82 (104.6 ± 31.61)

Atorvastatin 80 mg/day + ezetimibe 10 mg/day, n = 63

3.10 ± 0.84 (119.8 ± 32.4)

2.97 ± 1.15 (115.0 ± 44.44)

Hong et al, 2018 [19]

R, DB, MC, 8 weeks

South Korean

Adults with hypercholesterolemia requiring medical treatment according to NCEP ATP III.

Rosuvastatin 20 mg/day, n = 64

3.95 ± 0.81 (152.8 ± 31.4)

1.95 ± 0.88 (75.4 ± 34.0)

Rosuvastatin 20 mg/day + ezetimibe 10 mg/day, n = 64

3.97 ± 0.81 (153.5 ± 31.2)

1.37 ± 0.57 (53.1 ± 22.0)

Hougaard et al, 2017 [20]

R, DB, SC, 52 weeks

Western countries

Adults with ST-elevation myocardial infarction

Atorvastatin 80 mg/day, n = 41

4.10 ± 0.90 (158.55 ± 34.80)

2.00 ± 0.50 (77.34 ± 19.34)

Atorvastatin 80 mg/day + ezetimibe 10 mg/day, n = 39

3.70 ± 0.71 (143.08 ± 27.67)

1.40 ± 0.80 (54.14 ± 30.94)

Kim et al, 2016 [21]

R, DB, MC, 8 weeks

South Korean

Adults with initial levels of LDL-C ≤ 250 mg/dL and TG < 400 mg/dL were selected for a lead-in period, then the patients who required lipid-lowering treatment according to the NCEP ATP III guidelines were finally enrolled in the study.

Rosuvastatin 20 mg/day, n = 68

N/A

Rosuvastatin 20 mg/day + ezetimibe 10 mg/day, n = 68

Kim et al, 2018 [22]

R, DB, MC, 8 weeks

South Korean

Adults with primary hypercholesterolemia who had an LDL-C level < 250 mg/dL and TG level < 350 mg/dL requiring treatment according to NCEP ATPIII guidelines.

Rosuvastatin 20 mg/day, n = 63

4.16 ± 0.79 (160.90 ± 30.57)

N/A

Rosuvastatin 20 mg/day + ezetimibe 10 mg/day, n = 64

4.12 ± 0.77 (159.56 ± 29.91)

N/A

Lins et al, 2014 [23]

R, OL, 4 weeks

Western countries

Adults at high-risk for CHD, characterized by at least one of the following conditions: stable CHD or CHD equivalent; diagnosis of type 2 diabetes; or those whose Framingham risk score was > 20%.

Atorvastatin 40 mg/day, n = 22

2.30 (89)

1.94 (75)

Atorvastatin 40 mg/day + ezetimibe 10 mg/day, n = 21

2.45 (95)

1.60 (62)

Malina et al, 2015 [24]

R, OL, 4 weeks

Western countries

Adults in primary or secondary prevention of CHD, who had an indication for lipid-lowering therapy in accordance with NCEP ATP III

Atorvastatin 40 mg/day, n = 35

2.58 ± 0.83 (100 ± 32)

2.01 ± 0.67 (78 ± 26)

Atorvastatin 40 mg/day + ezetimibe 10 mg/day, n = 22

2.30 ± 0.72 (89 ± 28)

1.42 ± 0.49 (5 5± 19)

Nicholls et al, 2017 [12]

R, DB, PC, 90 days

Western countries

Adults with either atherosclerotic cardiovascular disease or type 1 or 2 diabetes mellitus, treated with atorvastatin 40 mg daily for at least 30 days prior to screening and compliant with study drug for the 28-day lead-in phase, had an LDL-C > 70 mg/dL or non-HDL-C > 100 mg/dL at screening and prior to randomization and a TG ≤ 400 mg/dL.

Atorvastatin 40 mg/day, n = 40

N/A

Atorvastatin 40 mg/day + ezetimibe 10 mg/day, n = 91

Robinson et al, 2014 [13]

R, DB, 12 weeks; atorvastatin was not masked

Western countries

Adults with a screening LDL-C level ≥ 150 mg/dL with no statin, or ≥ 100 mg/dL with non-intensive statin, or ≥ 80 mg/dL with intensive statin, and fasting TG ≤ 400 mg/dL.

Atorvastatin 80 mg/day, n = 110

2.52 ± 0.88 (97.5 ± 34.08)

2.71 ± 1.08 (104.8 ± 41.66)

Atorvastatin 80 mg/day + ezetimibe 10 mg/day, n = 110

2.47 ± 0.72 (95.5 ± 27.70)

2.04 ± 1.31 (78.85 ± 50.89)

Yang et al, 2017 [25]

R, DB, 12 weeks

South Korean

Adults with high or moderately high cardiovascular disease as classified by NCEP ATP III

Rosuvastatin 20 mg/day, n = 39

3.88 ± 0.98 (150 ± 38)

1.68 ± 0.72 (65 ± 28)

Rosuvastatin 20 mg/day + ezetimibe 10 mg/day, n = 42

3.82 ± 0.78 (148 ± 30)

1.34 ± 0.62 (52 ± 24)

**Table 2.** Exclusion Sensitivity Analysis
Study name	Mean difference	Standard error	Lower limit	Upper limit	z-value	P-value
Azar et al, 2011 [15]	-14.088	2.005	-18.018	-10.158	-7.026	< 0.001
Ballantyne et al, 2003_40 [16]	-14.250	2.071	-18.309	-10.191	-6.881	< 0.001
Ballantyne et al, 2003_80 [16]	-14.457	2.067	-18.508	-10.406	-6.995	< 0.001
Ballantyne et al, 2007 [17]	-14.099	2.090	-18.196	-10.002	-6.745	< 0.001
Barbosa et al, 2013 [18]	-13.895	1.998	-17.811	-9.979	-6.955	< 0.001
Blom et al, 2014 [10]	-14.323	2.015	-18.271	-10.374	-7.109	< 0.001
Hong et al, 2018 [19]	-13.924	2.098	-18.035	-9.812	-6.637	< 0.001
Hougaard et al, 2017 [20]	-14.400	2.076	-18.469	-10.330	-6.935	< 0.001
Kim et al, 2016 [21]	-14.562	2.060	-18.600	-10.524	-7.068	< 0.001
Kim et al, 2018 [22]	-14.047	2.144	-18.249	-9.844	-6.552	< 0.001
Lins et al, 2014 [23]	-13.784	1.999	-17.702	-9.866	-6.895	< 0.001
Malina et al, 2015 [24]	-14.101	2.014	-18.048	-10.154	-7.002	< 0.001
Nicholls et al, 2017 [12]	-13.091	1.850	-16.716	-9.465	-7.076	< 0.001
Robinson et al, 2014 [13]	-12.094	1.299	-14.641	-9.547	-9.307	< 0.001
Yang et al, 2017 [25]	-14.559	2.010	-18.499	-10.620	-7.244	< 0.001

Table 2. Exclusion Sensitivity Analysis

Study name

Mean difference

Standard error

Lower limit

Upper limit

z-value

P-value

Azar et al, 2011 [15]

-14.088

2.005

-18.018

-10.158

-7.026

< 0.001

Ballantyne et al, 2003_40 [16]

-14.250

2.071

-18.309

-10.191

-6.881

< 0.001

Ballantyne et al, 2003_80 [16]

-14.457

2.067

-18.508

-10.406

-6.995

< 0.001

Ballantyne et al, 2007 [17]

-14.099

2.090

-18.196

-10.002

-6.745

< 0.001

Barbosa et al, 2013 [18]

-13.895

1.998

-17.811

-9.979

-6.955

< 0.001

Blom et al, 2014 [10]

-14.323

2.015

-18.271

-10.374

-7.109

< 0.001

Hong et al, 2018 [19]

-13.924

2.098

-18.035

-9.812

-6.637

< 0.001

Hougaard et al, 2017 [20]

-14.400

2.076

-18.469

-10.330

-6.935

< 0.001

Kim et al, 2016 [21]

-14.562

2.060

-18.600

-10.524

-7.068

< 0.001

Kim et al, 2018 [22]

-14.047

2.144

-18.249

-9.844

-6.552

< 0.001

Lins et al, 2014 [23]

-13.784

1.999

-17.702

-9.866

-6.895

< 0.001

Malina et al, 2015 [24]

-14.101

2.014

-18.048

-10.154

-7.002

< 0.001

Nicholls et al, 2017 [12]

-13.091

1.850

-16.716

-9.465

-7.076

< 0.001

Robinson et al, 2014 [13]

-12.094

1.299

-14.641

-9.547

-9.307

< 0.001

Yang et al, 2017 [25]

-14.559

2.010

-18.499

-10.620

-7.244

< 0.001