Serious adverse events and deaths in PCSK9 inhibitor trials reported on ClinicalTrials.gov: a systematic review

Figures & data

Figure 1. Flow diagram of literature search and study selection.

Table 1. Characteristics of included placebo-controlled PCSK9 inhibitor trials.

Study	Acronym	Patient population	Background therapy	Duration, weeks	Patients randomized, n^
Alirocumab
McKenney 2012	DFI11565	HC	Statin	12	183
Roth 2012	DFI11566	HC	Statin*, diet	8	61
Stein 2012	CL-1003	HeFH	Diet	12	77
Kastelein 2015	ODYSSEY FH I	HeFH with/without CVD	Statin, diet	78	486
Kastelein 2015	ODYSSEY FH II	HeFH with/without CVD	Statin, diet	78	249
Kereiakes 2015	ODYSSEY COMBO I	HC with high CVD risk	Statin	52	316
Robinson 2015	ODYSSEY LONG TERM	HeFH with (high risk of) CVD	Statin, diet	78	2338
Ginsberg 2016	ODYSSEY HIGH FH	HeFH with very high LDL-D	Statin, diet	78	107
Roth 2016	ODYSSEY CHOICE I	HC	Statin, FF or diet	48	803
Stroes 2016	ODYSSEY CHOICE II	HC, statin intolerant, moderate to very high CVD risk	EZ, FF or diet	24	228
Teramoto 2016a	DFI12361	HC	Statin	12	100
Teramoto 2016b	ODYSSEY JAPAN	HeFH or HC with (high risk of) CVD	Statin	52	216
Teramoto 2017	ODYSSEY NIPPON	HeFH or HC with coronary heart disease	Statin, other lipid drug or diet	12	163
Schwartz 2014	ODYSSEY OUTCOMES	Prior ACS patients with HC	Statin	146#	19,924
Bococizumab
Ballantyne 2015	NCT01592240	HC	Statin	24	354
Ridker 2017a	SPIRE-AI	HC	Statin	12	299
Ridker 2017a	SPIRE-FH	Heterozygous Familial Hypercholesterolemia	Statin	52	370
Ridker 2017a	SPIRE-HR	Hyperlipidemia at high risk for CVD	Statin	52	711
Ridker 2017a	SPIRE-LDL	Hyperlipidemia patients with risk for CVD	Statin	52	2140
Ridker 2017a	SPIRE-LL	LDLC levels ≥100 mg/dL	Statin	52	750
Ridker 2017a	SPIRE-SI	Hyperlipidemia and statin intolerance	None	26	184
Ridker 2017b	SPIRE-1	HC with CVD, DM, or CKD, or PVD & CVD risk, or HeFH	Statin	30$	16,817
Ridker 2017b	SPIRE-2	See SPIRE-1, but statin intolerance allowed	Statin*	52$	10,621
Evolocumab
Giugliano 2012	LAPLACE-TIMI 57	HC	Statin	12	631
Koren 2012	MENDEL-1	HC and CVD risk up to 10% per 10 yrs	Statin use not required	12	365
Raal 2012	RUTHERFORD-1	HeFH	Statin	12	168
Sullivan 2012	GAUSS-1	HC and statin intolerant	Lipid drugs not allowed	12	64
Blom 2014	DESCARTES	Hyperlipidemia	Statin*, diet	52	905
Hirayama 2014	YUKAWA-1	HC, and high CVD risk	Statin	12	310
Koren 2014	MENDEL-2	HC and CVD risk up to 10% per 10 yrs	Lipid drugs not allowed	12	461
Robinson 2014	LAPLACE-2	HC or mixed dyslipidemia	Statin*	12	1678
Kiyosue 2015	YUKAWA-2	HC, mixed dyslipidemia or HeFH, high CVD risk	Statin	12	404
Raal 2015	RUTHERFORD-2	HeFH	Statin	12	331
Amgen 2016	FLOREY	HC and mixed dyslipidemia	Statin	10	45
Nicholls 2016	GLAGOV	HC and angiographic coronary disease	Statin	76	968
Sabatine 2017	FOURIER	HC, with CVD	Statin	114$#	27,564
Other PCSK9 inhibitors
Kastelein 2016	NCT01890967**	HC, or HeFH	Statin*, diet	16	527
Baruch 2017	EQUATOR^^	HC and (high risk for) CHD	Statin*	24	248

*Part of the study population used a statin; ^ only the groups included in our review; $ early terminated; # median follow-up; ** drug: LY3015014; ^^ drug: RG7652 ACS stands for acute coronary syndrome; CKD for chronic kidney disease; CVD for cardiovascular disease; DM for diabetes mellitus, EZ for ezetimibe; FF for fenofibrate; HC for hypercholesterolemia; HeFH for heterozygous familiar hypercholesterolemia; PVD for peripheral vascular disease.

Figure 2. Risk for individual SAE, all-cause SAE, and all-cause mortality for PCSK9 inhibitors versus placebo in (a) lipid-lowering trials and (b) clinical outcome studies.

Table 2. Effect of PCSK9 inhibitors on clinical outcomes in randomized placebo-controlled trials according to data reported on ClinicalTrials.gov.

*One trial (EQUATOR) did not report data on ClinicalTrials.gov; ^ For myocardial infarction and diabetes mellitus random effects models were used due to I² > 40%.

Table 3. Risk of clinical outcomes of evolocumab and alirocumab in randomized placebo-controlled trials according to data reported on ClinicalTrials.gov.

^For myocardial infarction and diabetes mellitus random effects models were used due to I² > 40%; # p < 0.05.

Figure 3. All-cause SAE and all-cause death as outcomes of PCSK9 inhibitors.