A Systematic Review of PCSK9 Inhibitors Alirocumab and Evolocumab

. 2016 Jun;22(6):10.18553/jmcp.2016.22.6.641. doi: 10.18553/jmcp.2016.22.6.641

Strength of Evidence Grade	Study Design; No. Studies (N)	Study Limitations	Directness	Consistency	Precision	Reporting Bias	Other Issues	Finding
Key Question 1. Heterozygous Familial Hypercholesterolemia
Alirocumab vs. placebo x 6 weeks in patients taking atorvastatin 10 mg-40 mg⁷
LDL-C lowering ability
LDL-C: Insufficient	1 RCT, N = 21	Medium	Direct	Unknown	Imprecise	Undetected	None	No conclusion; range in difference in percent change from baseline vs. placebo (% points): -41.4% to -55.7%
HDL-C raising ability
HDL-C: Insufficient	1 RCT, N = 21	Medium	Direct	Unknown	Imprecise	Undetected	None	No conclusion; significant difference in % change from baseline for 50 mg or 100 mg dose, but greater increase for 150 mg vs. placebo = 23.0% (P = 0.033)
Overall adverse events
Overall AE: Insufficient	1 RCT, N = 21	Medium	Direct	Unknown	Imprecise	Undetected	None	Greater only for 150 mg dose: 80% vs. 0%; EPC-calculated P = 0.015
Withdrawals due to adverse events
AE withdrawal: Insufficient	1 RCT, N = 21	Medium	Direct	Unknown	Imprecise	Undetected	None	No difference; no events
Serious adverse events
Serious AE: Insufficient	1 RCT, N = 21	Medium	Direct	Unknown	Imprecise	Undetected	None	No difference; no events
Specific adverse events: neurocognitive events
Neurocognitive dysfunction: Insufficient	1 RCT, N = 21	Medium	Direct	Unknown	Imprecise	Undetected	None	No difference; no events
Specific adverse events: injection site
Injection site erythema: Insufficient	1 RCT, N = 21	Medium	Direct	Unknown	Imprecise	Undetected	None	No difference; no events
Alirocumab vs. placebo × 12 weeks in patients taking mixed max statin plus ezetimibe⁶
LDL-C lowering ability
LDL-C: Low	1 RCT, N = 77	Medium	Direct	Unknown	Imprecise	Undetected	None	Greater reduction; range in absolute difference in percent change from baseline vs. placebo (% points): -18% to -57%
HDL-C raising ability
HDL-C: Low	1 RCT, N = 77	Medium	Direct	Unknown	Imprecise	Undetected	None	No significant difference in % change from baseline except for 150 mg every 2 weeks: +12.34% vs. +2.20%; P=0.050
Overall adverse events
Overall AE: Insufficient	1 RCT, N = 77	Medium	Direct	Unknown	Imprecise	Undetected	None	No difference: 75% to 87% for alirocumab vs. 60% for placebo
Withdrawals due to adverse events
AE withdrawal: Insufficient	1 RCT, N = 77	Medium	Direct	Unknown	Imprecise	Undetected	None	No difference; only 1 patient taking alirocumab 300 mg every 4 weeks
Serious adverse events
Serious AE: Insufficient	1 RCT, N = 77	Medium	Direct	Unknown	Imprecise	Undetected	None	No difference; only 1 patient in the placebo group with GI disorder
Specific adverse events: neurocognitive events
Neurocognitive dysfunction: Insufficient	1 RCT, N = 77	Medium	Direct	Unknown	Imprecise	Undetected	None	No difference; no events
Specific adverse events: injection site
Injection site reactions: Insufficient	1 RCT, N = 77	Medium	Direct	Unknown	Imprecise	Undetected	None	No difference; 27% to 47% vs. 13%
Evolocumab vs. placebo × 12 weeks in patients taking high-intensity statins+ezetimibe (RUTHERFORD 1 and 2)^12,13
LDL-C lowering ability
LDL-C: High	2 RCTs, N = 499	Low	Direct	Consistent	Precise	Undetected	None	Greater reductions for evolocumab: absolute difference vs. placebo in change from baseline (% points): range, -44% to -61%
HDL-C raising ability
HDL-C: Moderate	2 RCTs, N = 499	Low	Direct	Consistent	Imprecise	Undetected	None	Greater increase for evolocumab: absolute difference vs. placebo in change from baseline (% points): range, 6.8% to 9.2%
Overall adverse events
Overall AE: Moderate	2 RCTs, N = 499	Low	Direct	Consistent	Imprecise	Undetected	None	No difference; 58% vs. 52%; EPC-pooled RR 1.12 (95% CI, 0.94 to 1.33)
Withdrawals due to adverse events
AE withdrawal: Moderate	2 RCTs, N = 499	Low	Direct	Consistent	Imprecise	Undetected	None	No difference; 0.6% vs. 0.6%; pooled RR not possible because of no events in RUTHERFORD-2
Serious adverse events
Serious AE: Moderate	2 RCTs, N = 499	Low	Direct	Consistent	Imprecise	Undetected	None	No difference; 3% vs. 3%; EPC-pooled RR 0.81 (95% CI, 0.28 to 2.33)
Specific adverse events: neurocognitive events
Neurocognitive dysfunction: Moderate	2 RCTs, N = 499	Low	Direct	Consistent	Imprecise	Undetected	None	No events
Specific adverse events: injection site
Injection site: Moderate	2 RCTs, N = 499	Low	Direct	Consistent	Imprecise	Undetected	None	6% vs. 3%; EPC-pooled RR 0.76 (95% CI, 0.76 to 5.21)
Key Question 2. Homozygous Familiar Hypercholesterolemia
Evolocumab 420 mg Q4 weeks × 12 weeks in patients taking a statin with or without ezetimibe vs. placebo
LDL-C lowering ability
Evolocumab vs. Placebo: Low	RCT 1 (50)	Low	Direct	Unknown	Imprecise	Not detected	None	Evolocumab significantly reduced ultracentrifugation LDL-C at 12 weeks by 32.1% (95% CI, 45.1 to -19.2) compared to placebo
HDL-C raising ability
Evolocumab vs. Placebo: Low	RCT 1 (50)	Low	Direct	Unknown	Imprecise	Not detected	None	Evolocumab reduced HDL-C by 0.1% (95% CI, -9.4% to 9.2%) at week 12 compared to placebo (NS)
Overall adverse events
Evolocumab vs. Placebo: Low	RCT 1 (50)	Low	Direct	Unknown	Imprecise	Not detected	None	Any treatment emergent adverse events: Evolocumab vs. Placebo: 36% (12/33) vs. 63% (10/16)
Withdrawals due to adverse events
Evolocumab vs. Placebo: Low	RCT 1 (50)	Low	Direct	Unknown	Imprecise	Not detected	None	No difference in treatment emergent adverse events leading to discontinuation of study drug: Evolocumab vs. Placebo: 0% (0/33) vs. 0% (0/16)
Serious adverse events
Evolocumab vs. Placebo: Low	RCT 1 (50)	Low	Direct	Unknown	Imprecise	Not detected	None	No difference in serious treatment emergent adverse events: Evolocumab vs. Placebo: 0% (0/33) vs. 0% (0/16)
Specific adverse events: neurocognitive events^a
Evolocumab vs. Placebo: Low	RCT 1 (50)	Low	Direct	Unknown	Imprecise	Not detected	None	No difference between groups in neurocognitive events: Evolocumab vs. Placebo: 0% (0/33) vs. 0% (0/16)
Specific adverse events: potential injection-site reactions^b
Evolocumab vs. Placebo: Low	RCT 1 (50)	Low	Direct	Unknown	Imprecise	Not detected	None	Potential injection-site reactions: Evolocumab vs. Placebo: 0% (0/33) vs. 6% (1/16)
Specific adverse events: gastroenteritis
Evolocumab vs. Placebo: Low	RCT 1 (50)	Low	Direct	Unknown	Imprecise	Not detected	None	Gastroenteritis: Evolocumab vs. Placebo: 6% (2/33) vs. 0% (0/16)
Key Question 3. Not at Target
Alirocumab 150 mg Q2 weeks x 8-12 weeks vs. placebo
LDL-C lowering ability
*% at target (< 70 mg/dl)*
Alirocumab + low-dose statin vs. Placebo + high-dose statin Low	RCT 1 (61)	Medium	Direct	Unknown	Imprecise	Not detected	None	100% vs. 52%
Alirocumab vs. Placebo + low-moderate dose statin Low	RCT 1 (31)	Medium	Direct	Unknown	Imprecise	Not detected	None	100% vs. 16.1%
Alirocumab vs. Placebo + high-dose statin Low	RCT 1 (62)	Medium	Direct	Unknown	Imprecise	Not detected	None	100% vs. 52%
*% change in LDL*
Alirocumab + low-dose statin vs. Placebo + high-dose statin × 8 wks Low	RCT 1 (61)	Medium	Direct	Unknown	Imprecise	Not detected	None	Difference in LDL-C lowering: 48.9%, P < 0.001
Alirocumab vs. Placebo + moderate dose statin × 12 wks Low	RCT 1 (31)	Medium	Direct	Unknown	Imprecise	Not detected	None	Difference in LDL-C lowering: 67.3%, P < 0.001
*% change in LDL*
Alirocumab vs. Placebo + high-dose statin × 8 wks Low	RCT 1 (62)	Medium	Direct	Unknown	Imprecise	Not detected	None	Difference in LDL-C lowering: 55.9%, P < 0.001
*% change in HDL*
Alirocumab + low-dose statin vs. Placebo + high-dose statin × 8 wks Low	RCT 1 (61)	Medium	Direct	Unknown	Imprecise	Not detected	None	Difference in HDL-C lowering: 6 mg/dl; P = 0.06
Alirocumab vs. Placebo + moderate dose statin × 12 wks Low	RCT 1 (31)	Medium	Direct	Unknown	Imprecise	Not detected	None	Difference in HDL-C lowering: 6.5 mg/dl; P = 0.057
Alirocumab vs. Placebo + high-dose statin × 8 wks Low	RCT 1 (62)	Medium	Direct	Unknown	Imprecise	Not detected	None	Difference in HDL-C lowering: 9.4 mg/dL; P = 0.05
Overall adverse events
Alirocumab + low-dose statin vs. Placebo + high-dose statin Insufficient	RCT 1 (61)	Medium	Direct	Unknown	Imprecise	Not detected	None	61% vs. 45%
Alirocumab vs. Placebo + low/moderate-dose statin Insufficient	RCT 1 (31)	Medium	Direct	Unknown	Imprecise	Not detected	None	61.3% vs. 45.2%
Alirocumab vs. Placebo + high-dose statin Insufficient	RCT 1 (62)	Medium	Direct	Unknown	Imprecise	Not detected	None	61% vs. 60%
Withdrawals due to adverse events
Alirocumab + low-dose statin vs. Placebo + high-dose statin Insufficient	RCT 1 (61)	Medium	Direct	Unknown	Imprecise	Not detected	None	0% vs. 13%
Alirocumab vs. Placebo + low/moderate-dose statin Insufficient	RCT 1 (31)	Medium	Direct	Unknown	Imprecise	Not detected	None	3.2% vs. 0%
Alirocumab vs. Placebo + highdose statin Insufficient	RCT 1 (62)	Medium	Direct	Unknown	Imprecise	Not detected	None	3% vs. 13%
Serious adverse events
Alirocumab + low-dose statin vs. Placebo + high-dose statin	RCT 1 (61)	Medium	Direct	Unknown	Imprecise	Not detected	None	0 vs. 0
Alirocumab vs. Placebo + low/moderate-dose statin	RCT 1 (31)	Medium	Direct	Unknown	Imprecise	Not detected	None	0% vs. 3.2%
Alirocumab vs. Placebo + highdose statin Insufficient	RCT 1 (62)	Medium	Direct	Unknown	Imprecise	Not detected	None	0% vs. 3%
Specific adverse events: potential injection-site reactions^b
Alirocumab + low-dose statin vs. Placebo + high-dose statin	RCT 1 (61)	Medium	Direct	Unknown	Imprecise	Not detected	None	0% vs. 6.5%
Alirocumab vs. Placebo + low/moderate-dose statin Insufficient	RCT 1 (31)	Medium	Direct	Unknown	Imprecise	Not detected	None	3.2 to 32% vs. 0%
Alirocumab vs. Placebo + highdose statin Insufficient	RCT 1 (62)	Medium	Direct	Unknown	Imprecise	Not detected	None	3.3% vs. 6.5%
Alirocumab 75 mg to 150 mg Q 2 weeks vs. placebo at 24 weeks in high-risk patients
LDL-C lowering ability
*% at target (< 70 mg/dl)*
Alirocumab +	RCT	Low	Direct	Consistent	Precise	Not detected	None	Pooled RR 9.65 (95%
max-dose	2 (2,656)							CI, 7.7 to 12.0)
statin vs.								(75-79% vs. 8-9%)
Placebo +
max-dose
statin
High
Alirocumab +	RCT	Low	Direct	Unknown	Precise	Not detected	None	77% vs. 45.6%
max-dose	1 (720)							RR 1.70 (95% CI,
statin vs.								1.46 to 1.95)
ezetimibe
10 mg +
max-dose
statin
Moderate
*% change in LDL*
Alirocumab +	RCT	Low	Direct	Consistent	Precise	Not detected	None	Differenc = -45.9%,
max-dose	2 (2,656)							P < 0.001 (primarily
statin vs.								75 mg Q2 wks)
Placebo +								-61.9%, P < 0.001
max-dose								(150 mg Q2 wks)
statin
High
Alirocumab	RCT	Low	Direct	Unknown	Precise	Not detected	None	Difference = -29.8%,
+ max-dose	1 (720)							P < 0.001
statin vs.
ezetimibe 10
mg + max-
dose statin
Moderate
*% change in HDL*
Alirocumab	RCT	Low	Direct	Consistent	Imprecise	Not detected	None	7.3, 95% Cl, 3.6 to
+ max-dose	2 (2,656)							11.0; P < 0.001
statin vs.								(primarily 75 mg Q2
Placebo +								wks)4.6 (0.7); 3.3 to
max-dose								5.9, P < 0.001 (150 mg
statin								Q2 wks)
Moderate
Alirocumab +	RCT	Low	Direct	Unknown	Imprecise	Not detected	None	Difference =
max-dose	1 (720)							8.1% (1.3), P < 0.001
statin vs.
ezetimibe
10 mg +
max-dose
statin
Low
Overall adverse events
Alirocumab +	RCT	Low	Direct	Consistent	Precise	Not detected	None	81.0% vs. 82.5%
max-dose statin	2 (2,656)							75.8% vs. 75.7%
vs. Placebo +
max-dose statin
High
Alirocumab +	RCT	Low	Direct	Unknown	Precise	Not detected	None	71.2% vs. 67.2%
max-dose	1 (720)
statin vs. ezeti-
mibe 10 mg +
max-dose
statin
Moderate
Withdrawals due to adverse events
Alirocumab + max-dose statin vs. Placebo + max-dose statin Moderate	RCT 2 (2,656)	Low	Direct	Consistent	Imprecise	Not detected	None	7.2% vs. 5.8% 6.3% vs. 7.5%
Alirocumab + max-dose statin vs. ezetimibe 10 mg + max-dose statin Low	RCT 1 (720)	Low	Direct	Unknown	Imprecise	Not detected	None	7.5% vs. 5.4%
Serious adverse events
Alirocumab + max-dose statin vs. Placebo + max-dose statin High	RCT 2 (2,656)	Low	Direct	Consistent	Precise	Not detected	None	18.7% vs. 19.5% 12.6% vs. 13.1%
Alirocumab + max-dose statin vs. ezetimibe 10 mg + max-dose statin Low	RCT 1 (720)	Low	Direct	Unknown	Imprecise	Not detected	None	18.8% vs. 17.8%
Specific adverse events: potential injection-site reactions^b
Alirocumab + max-dose statin vs. Placebo + max-dose statin Low	RCT 2 (2,656)	Low	Direct	Inconsistent	Imprecise	Not detected	None	Pooled RR 1.4 (95% CI, 0.98 to 2.1) Rates 5.9% vs. 4.2% and 5.3% vs. 2.8%
Alirocumab + max-dose statin vs. ezetimibe 10 mg + maxdose statin Low	RCT 1 (720)	Low	Direct	Unknown	Imprecise	Not detected	None	2.5% vs. 0.8%
Specific adverse events
Neurocognitive events
Alirocumab + ma x-dose statin vs. Placebo + max-dose statin Moderate	RCT 2 (2,656)	Low	Direct	Consistent	Imprecise	Not detected	None	1.2% vs. 0.5%; P = 0.17; 0 vs. 0.9%
Alirocumab + ma x-dose statin vs. ezetimibe 10 mg + max-dose statin Low	RCT 1 (720)	Low	Direct	Unknown	Imprecise	Not detected	None	0.8% vs. 1.2%
CV events (adjudicated)
Alirocumab + max-dose statin vs. Placebo + max-dose statin Moderate	RCT 2 (2,656)	Low	Direct	Consistent	Imprecise	Not detected	None	Pooled RR 0.91 (95% CI, 0.63 to 1.31)
Alirocumab + max-dose statin vs. ezetimibe 10 mg + max-dose statin Low	RCT 1 (720)	Low	Direct	Unknown	Imprecise	Not detected	None	RR 1.29 (95% CI, 0.60 to 2.74)
Evolocumab 420 mg Q4 weeks x 52 weeks vs. placebo
LDL-C lowering ability
*% at target (< 70 mg/dl)*
Evolocumab 420 mg Q 4 weeks × 48 weeks vs. Placebo Moderate	RCT 1 (901)	Low	Direct	Unknown	Precise	Not detected	None	82.3% evolocumab vs. 6.4% placebo; P < 0.001
*% change in LDL at 52 weeks*
Evolocumab 420 mg Q 4 weeks × 48 weeks vs. Placebo: Moderate	RCT 1 (901)	Low	Direct	Unknown	Precise	Not detected	None	Difference in ultracen-trifugation LDL-C at 52 weeks -57% (± 2.1 SD) compared to placebo
*% change in HDL at 52 weeks*
Evolocumab 420 mg Q 4 weeks × 48 weeks vs. Placebo: Low	RCT 1 (901)	Low	Direct	Unknown	Imprecise	Not detected	None	Difference vs. placebo in % change from baseline: 5.4%; P < 0.001
Overall adverse events
Evolocumab vs. Placebo: Moderate	RCT 1 (901)	Low	Direct	Unknown	Precise	Not detected	None	Evolocumab vs. Placebo: 75% vs. 74%
Withdrawals due to adverse events
Evolocumab vs. Placebo: Low	RCT 1 (901)	Low	Direct	Unknown	Imprecise	Not detected	None	Evolocumab vs. Placebo: 2% (13/599) vs. 1% (3/302)
Serious adverse events
Evolocumab vs. Placebo: Low	RCT 1 (901)	Low	Direct	Unknown	Imprecise	Not detected	None	Evolocumab vs. Placebo: 6% vs. 4%
Specific adverse events: potential injection-site reactions^b
Evolocumab vs. Placebo: Low	RCT 1 (901)	Low	Direct	Unknown	Imprecise	Not detected	None	Evolocumab vs. Placebo: 5.7% (34/599) vs. 5% (15/302)
Evolocumab 420 mg Q4 weeks x 12 weeks vs. placebo
LDL-C lowering ability
*% at target (< 70 mg/dl)*
Evolocumab 420 mg Q4 weeks × 12 weeks vs. Placebo High	RCT 2 (640 at 420 mg, 356 placebo)	Low	Direct	Consistent	Precise	Not detected	None	72% to 94% for evolocumab vs. 0% to 9% for placebo; P < 0.001
*% change in LDL at 12 weeks*
Evolocumab 420 mg Q 4 weeks × 12 weeks vs. Placebo: High	RCT 2 (640 at 420 mg, 356 placebo)	Low	Direct	Consistent	Precise	Not detected	None	Difference in ultra-centrifugation LDL-C -53% (95% CI, 56.0 to 44.6) to -70.5% (95% CI, -79.8 to -61.2) compared to placebo.
*% change in HDL at 12 weeks*
Evolocumab 420 mg Q4 weeks × 12 weeks vs. Placebo: Moderate	RCT 2 (640 at 420 mg, 356 placebo)	Low	Direct	Consistent	Imprecise	Not detected	None	Difference from placebo in % change from baseline: ranging from 4.5% (95% CI, 0.4 to 8.7) to 9.1% (95% CI, 4.4 to 13.7)
Overall adverse events
Evolocumab vs. Placebo: High	RCT 2 (640 at 420 mg, 356 placebo)	Low	Direct	Consistent	Precise	Not detected	None	Ranged from 31% to 60% with evolocumab 420 mg every 4 weeks and from 24% to 49% in the placebo group
Withdrawals due to adverse events
Evolocumab vs. Placebo: Moderate	RCT 2 (640 at 420 mg, 356 placebo)	Low	Direct	Consistent	Imprecise	Not detected	None	Evolocumab vs. Placebo: 1-2% vs. 2-4%
Serious adverse events
Evolocumab vs. Placebo: Moderate	RCT 2 (640 at 420 mg, 356 placebo)	Low	Direct	Consistent	Imprecise	Not detected	None	No difference, Evolocumab vs. Placebo: 0.9-2.7% vs. 1.8-3.6%
Specific adverse events: potential injection-site reactions^b
Evolocumab vs. Placebo: Moderate	RCT 2 (640 at 420 mg, 356 placebo)	Low	Direct	Consistent	Imprecise	Not detected	None	No difference, Evolocumab vs. Placebo: 0% vs. 1.3% in LAPLACE-TIMI-5 7; NR by group in LAPLACE-2
Evolocumab 420 mg Q4 weeks x 12 weeks vs. placebo, both added to primarily moderate-intensity statins in Japanese patients with high cardiovascular risk¹¹
LDL-C lowering ability
*% at target (< 70 mg/dl)*
Evolocumab 420 mg Q4 weeks × 12 weeks vs. placebo: Low	1 RCT; evolocumab 420 mg Q4 weeks N = 53, placebo every month N = 51	Medium	Direct	Unknown	Imprecise	Not detected	None	Greater for evo- locumab: < 100: 96% vs. 1%; P < 0.001 < 70: 82% vs. 0%; P < 0.001
*% change in LDL at 12 weeks*
Evolocumab 420 mg Q 4 weeks × 12 weeks vs. placebo: Low	1 RCT; evolocumab 420 mg Q4 weeks N = 53, placebo every month N = 51	Medium	Direct	Unknown	Imprecise	Not detected	None	Greater for evolocumab: Mean % change vs. placebo: -63.9%; P < 0.001
*% change in HDL at 12 weeks*
Evolocumab 420 mg Q 4 weeks × 12 weeks vs. placebo: Insufficient	1 RCT; evolocumab 420 mg Q4 weeks N = 53, placebo every month N = 51	Medium	Direct	Unknown	Imprecise	Not detected	None	No conclusion: Mean % change vs. placebo: 13.2%; P < 0.001
Overall adverse events
Evolocumab 420 mg Q4 weeks × 12 weeks vs. placebo: Insufficient	1 RCT; evolocumab 420 mg Q 4 weeks N = 53, placebo every month N = 51	Medium	Direct	Unknown	Imprecise	Not detected	None	No conclusion; 58.5% vs. 42.0%
Withdrawals due to adverse events
Evolocumab 420 mg Q4 weeks × 12 weeks vs. placebo: Insufficient	1 RCT; evolocumab 420 mg Q4 weeks N = 53, placebo every month N = 51	Medium	Direct	Unknown	Imprecise	Not detected	None	No conclusion; 3.8% vs. 0
Serious adverse events
Evolocumab 420 mg Q4 weeks × 12 weeks vs. placebo: Insufficient	1 RCT; evolocumab 420 mg Q4 weeks N = 53, placebo every month N = 51	Medium	Direct	Unknown	Imprecise	Not detected	None	No conclusion; 3.8% vs. 0
Specific adverse events: potential injection-site reactions^b
Evolocumab 420 mg Q 4 weeks × 12 weeks vs. placebo: Insufficient	1 RCT; evolocumab 420 mg Q 4 weeks N = 53, placebo every month N = 51	Medium	Direct	Unknown	Imprecise	Not detected	None	No conclusion; 1.9% vs. 0
Evolocumab 420 mg Q4 weeks x 12 weeks vs. ezetimibe 10 mg, both added to moderate-high intensity statins
LDL-C lowering ability
*% at target (< 70 mg/dl)*
Evolocumab 420 mg Q 4 weeks × 12 weeks vs. ezetimibe 10 mg: Low	1 RCT; Atorvastatin 10 mg group: evolocumab N = 110 vs. placebo N = 55 Atorvastatin 80 mg group: evolocumab N = 110 vs. ezetimibe N = 54	Medium	Direct	Unknown	Imprecise	Not detected	None	Higher for evolocumab: Atorvastatin 10 mg: 85.8% vs. 5.6%; EPC-calculated RR 5.22 (95% CI, 3.00 to 9.69) Atorvastatin 80 mg: 92.5% vs. 62.3%; EPC calculated RR 1.47 (95% CI, 1.23 to 1.88)
*% change in LDL at 12 weeks*
Evolocumab 420 mg Q 4 weeks × 12 weeks vs. ezetimibe 10 mg: Low	1 RCT; Atorvastatin 10 mg group: evolocumab N = 110 vs. placebo N = 55 Atorvastatin 80 mg group: evolocumab N = 110 vs. ezetimibe N = 54	Medium	Direct	Unknown	Imprecise	Not detected	None	Greater for evolocumab: % Change from baseline (95% CI): Atorvastatin 10 mg: -62.5% (95% CI, -66.1 to -58.9) vs. -19.0 (-24.0 to -13.9) Atorvastatin 80 mg: -65.1 (95% CI, -69.8 to -60.3) vs. -21.3 (95% CI, -28.0 to -14.5)
*% change in HDL at 12 weeks*
Evolocumab 420 mg Q4 weeks × 12 weeks vs. ezetimibe 10 mg: Insufficient	1 RCT; Atorvastatin 10 mg group: evolocumab N = 681110 vs. placebo N =55 Atorvastatin 80 mg group: evolocumab N = 110 vs. ezetimibe N = 54	Medium	Direct	Unknown	Imprecise	Not detected	None	Greater for evolocumab: % Change from baseline (95% CI): Atorvastatin \|10 mg: 7.7 (95% CI, 5.0 to 10.4) vs. -0.9 (95% CI, -4.7 to 2.9) Atorvastatin 80 mg: 7.8 (95% CI, 5.2 to 10.4) vs. -0.6 (95% CI, -4.3 to 3.1)
Overall adverse events
Evolocumab 420 mg Q 4 weeks × 12 weeks vs. ezetimibe 10 mg: Low	1 RCT; Atorvastatin 10 mg group: evolocumab N = 110 vs. placebo N = 55 Atorvastatin 80 mg group: evolocumab N = 110 vs. ezetimibe N = 54	Medium	Direct	Unknown	Imprecise	Not detected	None	No difference: Atorvastatin 10 mg: 30.9% vs. 40.0% Atorvastatin 80 mg: 39.1% vs. 35.2%
Withdrawals due to adverse events
Evolocumab 420 mg Q4 weeks × 12 weeks vs. ezetimibe 10 mg: Insufficient	1 RCT; Atorvastatin 10 mg group: evolocumab N = 110 vs. placebo N = 55 Atorvastatin 80 mg group: evolocumab N = 110 vs. ezetimibe N = 54	Medium	Direct	Unknown	Imprecise	Not detected	None	No difference: Atorvastatin 10 mg: 1.8% vs. 0 Atorvastatin 80 mg: 1.8% vs. 1.9%
Serious adverse events
Evolocumab 420 mg Q4 weeks × 12 weeks vs. ezetimibe 10 mg: Insufficient	1 RCT; Atorvastatin 10 mg group: evolocumab N = 110 vs. placebo N = 55 Atorvastatin 80 mg group: evolocumab N = 110 vs. ezetimibe N = 54	Medium	Direct	Unknown	Imprecise	Not detected	None	No difference; Atorvastatin 10 mg: 1.8% vs. 0 Atorvastatin 80 mg: 0.9% vs. 1.9%
Specific adverse events: potential injection-site reactions^b
Evolocumab 420 mg Q4 weeks × 12 weeks vs. ezetimibe 10 mg: Insufficient	1 RCT; Atorvastatin 10 mg group: evolocumab N = 110 vs. placebo N = 55 Atorvastatin 80 mg group: evolocumab N = 110 vs. ezetimibe N = 54	Medium	Direct	Unknown	Imprecise	Not detected	None	No difference; Any statin + any evolocumab = 1.3% vs. atorvastatin + ezetimibe = 0.9%; NR for individual ezetimibe or evolocumab groups
Key Question 4. Statin Intolerant
Evolocumab vs. ezetimibe over 12 weeks (GAUSS: evolocumab 280 mg, 350, or 420 mg given every 4 weeks vs. ezetimibe 10 mg; GAUSS-2: evolocumab 140 mg every two weeks or 420 mg once monthly to ezetimibe 10 mg)^17,18
LDL-C: Low	2 RCTs, N = 434	Medium	Direct	Consistent	Imprecise	Undetected	None	Higher reduction for evolocumab: -26% (95% CI, -34.1% to -17.9%) for 280 mg every 4 weeks in GAUSS to -38% (95% CI, -43.7 to -32.4) for 140 mg every 2 weeks in GAUSS-2
HDL-C: Low	2 RCTs, N = 434	Medium	Direct	Consistent	Imprecise	Undetected	None	Evolocumab has a similar or better % change from baseline: Range = 3.6% (95% CI, -1.5 to 8.6) to 8.5% (P = 0.020)
Overall AE: Low	2 RCTs, N = 434	Medium	Direct	Consistent	Imprecise	Undetected	None	63% vs. 69%; RR 0.92 (95% CI, 0.80 to 1.06)
AE withdrawal: Low	2 RCTs, N = 434	Medium	Direct	Consistent	Imprecise	Undetected	None	3% vs. 12%; RR 0.29 (95% CI, 0.14 to 0.63)
Serious AE: Low	2 RCTs, N = 434	Medium	Direct	Consistent	Imprecise	Undetected	None	3% vs. 3%; RR 1.04 (95% CI, 0.34 to 3.15)
Neurocognitive dysfunction: Low	2 RCTs, N = 434	Medium	Direct	Consistent	Imprecise	Undetected	None	No events
Injection site: Insufficient	1 RCT, N = 307	Medium	Direct	Unknown	Imprecise	Undetected	None	No difference; 3% vs. 8%
Evolocumab 420 mg every 4 weeks plus ezetimibe 10 mg versus ezetimibe 10 mg alone x 12 weeks
LDL-C: Low	1 RCT, N = 62	Medium	Direct	Unknown	Imprecise	Undetected	None	Greater reduction: (-47%; 95% CI, -53.7% to -40.8%)
HDL-C: Insufficient	1 RCT, N = 62	Medium	Direct	Unknown	Imprecise	Undetected	None	Greater increase: (12%; 95% CI, 3.9 to 20.1)
Overall AE: Insufficient	1 RCT, N = 62	Medium	Direct	Unknown	Imprecise	Undetected	None	67% vs. 59%
AE withdrawal: Insufficient	1 RCT, N = 62	Medium	Direct	Unknown	Imprecise	Undetected	None	3% vs. 6%
Serious AE: Insufficient	1 RCT, N = 62	Medium	Direct	Unknown	Imprecise	Undetected	None	No events
Neurocognitive dysfunction: Insufficient	1 RCT, N = 62	Medium	Direct	Unknown	Imprecise	Undetected	None	NR
Injection site: Insufficient	1 RCT, N = 62	Medium	Direct	Unknown	Imprecise	Undetected	None	NR
Long-term evidence in mixed populations (OSLER-1 and OSLER-2)¹⁶
Evolocumab 420 mg q 4w (OSLER-1) or 140 mg q 2w or 420 mg q 4w (OSLER-2) + standard therapy vs. standard therapy alone x 48w
LDL-C lowering ability
Evolocumab + standard therapy vs. standard therapy alone: Moderate	RCT: 2 (4,465)	Medium	Direct	Consistent	Precise	Undetected	None	Evolocumab reduced LDL-C by 61% (95% CI, 59 to 63, P < 0.001) at 12w and by 58.4% (95% CI NR, P < 0.001) at 48w as compared to standard therapy
LDL-C lowering ability: % patients with LDL < 100 or < 70 at 12 weeks
Evolocumab + standard therapy vs. standard therapy alone: Low	RCT: 2 (4,46S)	Medium	Direct	Unknown	Precise	Undetected	None	% patients with LDL reduced to 100 mg/dL or lower (90.2% vs. 26.0%) or 70 mg/dL (73.6% vs. 3.8%)
HDL-C raising ability
Evolocumab + standard therapy vs. standard therapy alone: Low	RCT: 2 (4,46S)	Medium	Direct	Unknown	Precise	Undetected	None	Change from baseline in HDL-C at 12w was 8.7% in evolocumab group vs. 1.7% in standard therapy alone group (P < 0.001)
Overall adverse events
Evolocumab + standard therapy vs. standard therapy alone: Low	RCT: 2 (4,46S)	Medium	Direct	Unknown	Precise	Undetected	None	Any AEs occurred in 69.2% of evolocumab group and 64.8% of standard therapy alone group
Withdrawals due to adverse events
Evolocumab + standard therapy vs. standard therapy alone: Insufficient	RCT: 2 (4,46S)	Medium	Direct	Unknown	Imprecise	Undetected	None	2.4% of patients in evolocumab group prematurely discontinued study drug due to AEs (NA for standard therapy group)
Serious adverse events
Evolocumab + standard therapy vs. standard therapy alone: Low	RCT: 2 (4,46S)	Medium	Direct	Unknown	Precise	Undetected	None	No difference in % of patients with SAEs (7.5% for both groups)
Specific adverse events: neurocognitive events
Evolocumab + standard therapy vs. standard therapy alone: Insufficient	RCT: 2 (4,46S)	Medium	Direct	Unknown	Imprecise	Undetected	None	0.9% in evolocumab group vs. 0.3% in standard therapy group
Specific adverse events: injection-site reactions
Evolocumab + standard therapy vs. standard therapy alone: Insufficient	RCT: 2 (4,46S)	Medium	Direct	Unknown	Imprecise	Undetected	None	4.3% of patients in evolocumab group (NA for standard therapy group)
Specific adverse events: gastroenteritis
Evolocumab + standard therapy vs. standard therapy alone: Insufficient	RCT: 2 (4,46S)	Medium	Direct	Unknown	Imprecise	Undetected	None	1.5% of patients in evolocumab group vs. 0.8% in standard therapy group
Specific adverse events: cardiovascular events
Evolocumab + standard therapy vs. standard therapy alone: Insufficient	RCT: 2 (4,46S)	Medium	Direct	Unknown	Imprecise	Undetected	None	CV events at 1 year reduced from 2.18% in standard therapy group vs. 0.95% in evolocumab group (HR evolocumab, 0.47; 95% CI, 0.28 to 0.78)

Note: Numbered footnotes refer to citations listed in References at the end of the appendices.

^aIncludes deliria (including confusion), cognitive and attention disorders and disturbances, dementia and amnestic disorders, disturbances in thinking and perception, and mental impairment disorders.

^bIncludes injection-site rash, inflammation, pruritus, reaction, or urticaria.

AE = adverse events; CI = confidence interval; CV = cardiovascular; EPC = Evidence-based Practice Center; GI = gastrointestinal; HDL-C = high-density lipoprotein cholesterol; HR = hazard ratio; LDL-C = low-density lipoprotein-cholesterol; NA = not available; NR = not reported; NS = not sufficient; RCT = randomized controlled trial; RR = relative risk.